Formulation Handbook MRK 02 2020

Formulation
Handbook
The life science business

of Merck operates as
MilliporeSigma in the
U.S. and Canada.
Contents
Introduction 3 Ibuprofen (200 mg) 58
Ibuprofen (200 mg), Colored Tablet NEW 59
Loratadine (10 mg) 61

Conventional Tablets 4 Paracetamol (100 mg) NEW 63
Paracetamol (250 mg) 64
Direct Compression 4 Rosuvastatin (5 mg) 65
Granulation 5 Sildenafil (50 mg) 67
Dry Granulation 5
Wet Granulation 6 Solubility Enhancement 69
Conventional Tablets Manufactured by Direct Compression 7
Acetylsalicylic Acid (250 mg) and Paracetamol (250 mg) 7 Hot-Melt Extrusion 69
Ascorbic Acid (500 mg) 8 Indomethacin Extrudate 75
Caffeine (100 mg) 9 Itraconazole Extrudate 77
Ibuprofen (200 mg) 10 Lamotrigine (25 mg) Tablet NEW 81
Magnesium Carbonate (280 mg) 12 Inorganic Carriers 84
Paracetamol (200 mg) NEW 13 Carvedilol Loading (without Final Formulation) 86
Paracetamol (300 mg) 14 Entacapone Loading (without Final Formulation) NEW 87
Prednisolone (20 mg) 15 Fenofibrate Loading (without Final Formulation) 89
Pyridoxine Hydrochloride (50 mg) 16 Fenofibrate (37.5 mg) Tablet 91
Pyridoxine Hydrochloride (300 mg) 17 Ibuprofen (37.5 mg) Tablet 93
Thiamine Hydrochloride (50 mg) 18
Water-Sensitive Low-Dose API Formulation (0.5 mg) 19 Sustained Release Tablets 95
Conventional Tablets Manufactured by Dry Granulation 19
Enalapril Maleate (2.5 mg) 20 Formulation Examples
Ibuprofen (400 mg) 21 Ascorbic Acid (125 mg) 96
Conventional Tablets Manufactured by Wet Granulation 22 Diclofenac (100 mg) NEW 98
Ascorbic Acid (100 mg) 22 Diltiazem Hydrochloride (90 mg) 100
Fenofibrate (100 mg) 23 Ibuprofen (200 mg) 102
Ibuprofen (400 mg) 25 Propranolol Hydrochloride (160 mg) Formulation A 104
Lisinopril (20 and 40 mg) 26 Propranolol Hydrochloride (160 mg) Formulation B 106
Telmisartan (40 mg) NEW 28 Theophylline (125 mg) 108
Chewable Tablets 30 Tablet Coatings NEW 110
Formulation Examples Formulation Examples

Acetylsalicylic Acid (500 mg) 31 Aqueous coatings: Ascorbic Acid (50 mg) NEW 111
Alginic Acid (350 mg) and Sodium Bicarbonate (140 mg) 32 Combination of Aqueous and Organic Solvents, Formulation A NEW 113
Calcium Carbonate (450 mg) 33 Combination of Aqueous and Organic Solvents, Formulation B:
Magnesium Carbonate (400 mg) 34 Ibuprofen (60 mg) NEW 115
Paracetamol (125 mg) 35
3D Printing NEW 117
Dry Syrups and Suspensions 36

Formulation Examples
Formulation Examples Ketoconazole (25 mg) NEW 119
Amoxicillin Trihydrate (50 mg/mL) 37

Ampicillin Trihydrate (50 mg/mL) 38 Technical Information on Excipients 122
Multivitamin Supplement 39
Product Overview – our Parteck® Excipient Range 122
Effervescent Tablets 40 Flexible Tableting 123
Parteck® CCS 123
Formulation Examples Parteck® COAT NEW 125
Magnesium Carbonate (1100 mg) 41 Parteck® Delta M 133
Multivitamin Supplement 42 Parteck® LUB 136
Parteck® M 100, M 200 NEW 137
Lozenges 43 Parteck® SI 150, SI 200, SI 400, SI 450 NEW 141
Optimized Drug Delivery 145
Formulation Examples Parteck® M DPI 145
Dextromethorphan Hydrobromide (5.5 mg) 44 Parteck® ODT NEW 147
Tyrothricin (2 mg) and Benzocaine (5 mg) 45 Parteck® SRP 80 NEW 151
Enhanced Solubility 157
Orally Disintegrating Tablets (ODTs) 46 Parteck® MXP NEW 157
Parteck® SLC 165
Formulation Examples Others 167
Ascorbic Acid (80 mg) 47 Sucralose NEW 167
Ascorbic Acid (80 mg), Coated NEW 48
Ascorbic Acid (200 mg) 50 List of APIs Used 171
Clozapine (25/50/100/200 mg) NEW 51
Fexofenadine Hydrochloride (30 mg) 53
Glimepiride (3 mg) 55 Abbreviation Index 173
Glycopyrrolate (1 mg/2 mg) NEW 56
Page 2 07/2020
Formulation Handbook
Introduction
Formulating pharmaceutical dosage forms is a complex An excipient's quality is just as critical as its
process. There are numerous available techniques to functionality. Even traces of impurities compliant with
choose from, and a successful formulation is strongly compendial specifications may have an effect – such
dependent on the choices made throughout the as on API stability. For this reason, we try to apply
formulation development process. strict specification limits and additional specification
parameters whenever possible. We also understand that
Of course, a thorough understanding of the active
often, compiling data needed to ensure the compliance
pharmaceutical ingredient (API) characteristics is
of your product may be holding you back. This is why
critical. This includes physicochemical properties of
we have developed our Emprove® Program, which
the API such as solubility, melting point, degradation
spans 400 pharmaceutical raw and starting materials
temperature, sensitivity to pH or oxidation, flowability
and a selection of filtration and single-use products. For
and compactibility, to name just a few. The necessary
each product, there are three different types of dossiers
API dose (high/low) is another important factor. The
to support you throughout the different stages of your
desired final formulation performance, which is very
operations: qualification, risk assessment and process
relevant both for the therapeutic effect and for patient
optimization.
compliance, must be considered at an early stage, as
it determines the choice of formulation technology and In this formulation handbook, we have compiled
excipients. Is the target an immediate release dosage formulation examples that can help you when
form, or are modified release kinetics needed? Do developing your formulation. We intend these
the excipients need to have specific functionalities to model formulations to serve as a guide on how to
facilitate successful formulation? manufacture a variety of different types of final
formulation. As such, we have used model APIs with
In the past, excipients were often neglected and, if we
specific properties and have focused on common
take solid formulation as an example, reduced to their
pharmaceutical techniques, as well as featuring a
role as mere fillers. Today, we know that excipients are
selection of our high-quality excipient products.
in fact the backbone of a successful formulation. Their
functionalities include facilitating the manufacturing For additional details on our products beyond the
process (such as by improving compressibility, flow formulation examples and results shown here, please
properties or lubrication) and defining the release refer to the appropriate product details sheet at
kinetics of the dosage form (such as by supporting the end of this handbook or contact your local sales
fast disintegration or, conversely, providing constant representative.
API release over a specific time frame). Functionalized
For more information on our Emprove® Program,
particle properties, as in our Parteck® product range,
please visit MerckMillipore.com/emprove
can be used to tailor excipients to specific needs. For
instance, API solubility can be enhanced via specific
particle surface properties that enable API adsorption
on the excipient's surface.
Page 3 07/2020
Conventional Tablets
Compressed tablets are one of the most widely used Our Formulation Ingredients for DC
oral solid dosage forms. Although they have been
a preferred dosage form for decades, they can still Category Products
present challenges for formulation scientists.
Filler Excellent flowability and compressibility
Typically, the ingredients consist of the API and required, often special DC grades
excipients, which may include fillers, binders,
disintegrants, lubricants, and perhaps coating DC mannitol: Parteck® M 100 (100494),
Parteck® M 200 (100419)
systems or taste modifiers. Choosing the right
excipients is a prerequisite for successful formulation, DC sorbitol: Parteck® SI 150 (103583),
and the excipients can support the therapeutic effect Parteck® SI 200 (115079), Parteck® SI 400
by optimizing the formulation’s release kinetics, (103140), Parteck® SI 450 (103557)
stability and API solubility.
Disintegrant Superdisintegrant: Parteck® CCS
Three different techniques can be used: direct (croscarmellose sodium, 102310)
compression, dry granulation, and wet granulation.
Disintegrant: Starch (101253)
Direct compression (DC) Lubricant Parteck® LUB MST (magnesium stearate,

100663), Parteck® LUB CST (calcium
DC is a popular choice as it provides a very effective stearate, 100664), Parteck® LUB STA
way to produce tablets. The process consists of (stearic acid, 100661)
blending the API with the excipients and the lubricant,
followed by compression. Unlike the other approaches, Glidant Silicon dioxide, highly dispersed (113126)
it requires no additional processing steps.
A DC process is highly suitable for moisture- or heat- Sweetener Sucralose (100894, 100895),
sensitive ingredients, which would be contraindicated glucose (108346), sucrose (107653),
in wet granulation. fructose (105321), maltose (105911)
Both high and low API doses may present a challenge.

Flavoring Vanillin (108510)
High API doses may cause difficulties during development,
as most APIs tend to have poor compressibility, which
affects the quality of the final form. With low API doses, Coloring agent Candurin® pigments such as Candurin®
it may be difficult to achieve the desired homogeneity Gold Lustre (120610), Candurin® NXT Ruby
Red (120624), Candurin® NXT
and content uniformity, and segregation or sedimentation
Silver Blossom (120625)
may occur.
To ensure good processability via DC, excipients with
good flowability and compressibility are needed. Special
DC grades of excipients that meet these requirements
are often available.
Page 4 07/2020
Granulation Our Formulation Ingredients for DG

Granulation is a process of particle enlargement by Category Products
agglomeration and serves to reduce undesirable powder
characteristics and achieve properties required for Filler Parteck® M (DC mannitol, 100419,
subsequent process steps, e.g. by improving content 100494), Parteck® Delta M (mannitol,
uniformity, flowability and compressibility. 112635), mannitol (105980, 105988),
Parteck® MXP (polyvinyl alcohol, 141464),
However, granulation is a more time-consuming Parteck® SRP 80 (polyvinyl alcohol,
technique than DC, and there is also a risk of product 141439), calcium phosphate dihydrate
cross-contamination and product loss during the (102146), calcium hydrogen phosphate
different processing steps (granulation, drying, anhydrous (102144, 102304)
sieving). All of these factors can increase costs
compared to DC processes. Disintegrant Superdisintegrant: Parteck® CCS
(croscarmellose sodium, 102310)
Dry Granulation (DG)
DG is used to form granules without the need for a Lubricant Parteck® LUB MST (magnesium stearate,
binder solution. Forming granules without moisture 100663), Parteck® LUB CST (calcium
involves compacting the mix followed by size reduction stearate, 100664), Parteck® LUB STA
of the compact to the desired particle size. (stearic acid, 100661)
DG is used to improve flow properties and prevent

Glidant Silicon dioxide, highly dispersed (113126)
segregation of components in cases where DC processes
reach their limits, and to avoid API degradation induced
by wet granulation. Compared to wet granulation, it has Sweetener Sucralose (100894, 100895),
a shorter, more cost-effective manufacturing process. glucose (108346), sucrose (107653),
fructose (105321), maltose (105911)
Because it does not entail moisture, dry granulation is
especially suitable for active ingredients that are sensitive
to solvents or moisture. Flavoring Vanillin (108510)
DG can be done in two ways: either a large tablet (slug)

Coloring agent Candurin® pigments such as Candurin®
is produced in a heavy-duty tablet press or a continuous
Gold Lustre (120610), Candurin® NXT
sheet of materials is produced by compaction of the Ruby Red (120624), Candurin® NXT Silver
materials between two rollers (roller compactor/ Blossom (120625)
chilsonator). The benefit of using a roller compactor
is that the auger-feed system delivers the powder
materials consistently between the two rollers, in
contrast to tablet press compaction, where poor flow
properties of the material may result in various degrees
of densification of the compacts produced.
Page 5 07/2020
Wet Granulation (WG) Our Formulation Ingredients for WG

In WG, a liquid binder is used to granulate the powder. Category Products
The process generally includes the following steps:
blending, wetting, wet mass stage, drying and sizing. Filler Parteck® Delta M (mannitol, 112635),
The technology is widely used in the pharmaceutical Parteck® M (DC mannitol, 100419,
sector, and various types of process equipment are 100494), mannitol (105980, 105988),
available: lactose monohydrate (107656, 108195),
calcium phosphate dihydrate (102146),
calcium hydrogen phosphate anhydrous
(102144, 102304)
1. Low-shear WG processes use very simple mixing
equipment, and can take a considerable time to
achieve a uniformly mixed state. Binder Starch (101253), gelatin (104072,
104078), polyvinyl alcohol 4-88 (141350),
2. High-shear WG processes use equipment that polyvinyl alcohol 5-88 (141354)
mixes the powder and liquid at a very fast rate
using high shear forces, and thus speed up
Disintegrant Superdisintegrant: Parteck® CCS
the manufacturing process. (croscarmellose sodium, 102310)
3. Twin-screw granulation is a new process of interest Disintegrant: Starch (101253)
to the pharmaceutical industry that can continuously
manufacture wet granulate powders at lower
Lubricant Parteck® LUB MST (magnesium stearate,
liquid concentrations and with improved product 100663), Parteck® LUB CST (calcium
consistency. stearate, 100664), Parteck® LUB STA
(stearic acid, 100661)
4. Fluid bed granulation is a multiple-step WG process
in which the powders are pre-heated, granulated and
dried in the same vessel. It is used because it allows Glidant Silicon dioxide, highly dispersed (113126)
close control of the granulation process.
Sweetener Sucralose (100894, 100895),
glucose (108346), sucrose (107653),
Coloring agent Candurin® pigments such as Candurin®

Gold Lustre (120610), Candurin® NXT
Ruby Red (120624), Candurin® NXT Silver
Blossom (120625)
Page 6 07/2020
Formulation Examples: Conventional Tablets Manufactured
by Direct Compression
Acetylsalicylic Acid (250 mg) and

Paracetamol (250 mg)
Amount [mg/tablet] Amount [% w/w]

API
Acetylsalicylic
Acetylsalicylic acid (fine powder) 250 35.71 acid
Paracetamol DC 96 % 260 37.14

Formula C9H8O4
Parteck® SI 400 (DC sorbitol, 103140) 80 11.43
Molar mass 180.16 g/mol
Microcrystalline cellulose (MCC)
50 7.14
DC 50 µm Melting point 143 °C
Parteck® CCS pKa 3.49

30 4.29
BCS class IV
Powdered triglyceride 30 4.29
Total 700 100 Solubility Slightly

in water soluble
Manufacturing:
The formulation constituents are passed through a 1 mm sieve and then
mixed for 5-10 minutes using a shaker-mixer. The homogeneous mixture is
compressed on a single-punch instrumented tablet press at 15 kN and at a rate
of 54 rpm.
API
Paracetamol
Tablet properties:
Formula C8H9NO2
Compression force [kN] 15

Tablet weight [mg] 700
Melting point 169 – 170.5 °C
Weight variation [%] 0.4
BCS class I
Tablet diameter [mm] 13
Tablet thickness [mm] 4.5 Solubility Sparingly

in water soluble
Tablet hardness [N] 60
Friability [%] 0.6
Disintegration time [min] 1
Page 7 07/2020
Ascorbic Acid (500 mg)
Ascorbic acid (fine powder) 500 50 API

Ascorbic acid
Parteck® SI 400 (DC sorbitol, 103140) 380 38

100 10
DC 50 µm
Formula C6H8O6
Silicon dioxide, highly dispersed

10 1 Molar mass 176.12 g/mol
(113126)
about 190 °C,
Parteck® LUB MST Melting point
10 1 with decomposition
(magnesium stearate, 100663)
pKa1 = 4.17;
pKa
Total 1000 100 pKa2 = 11.57
BCS class III
Manufacturing:
Solubility in Freely
Mix ascorbic acid, Parteck® SI and all other excipients with the exception of water soluble
Parteck® LUB MST. The lubricant Parteck® LUB MST is sieved through a 250 µm
sieve onto the mixture, followed by another mixing step. The homogeneous
mixture is then compressed at 26 kN.
Tablet properties:
Tablet thickness [mm] 4.0
Friability [%] 0.4
Page 8 07/2020
Caffeine (100 mg)
Caffeine 100 26.32 API

Caffeine

35 9.21
DC 50 µm
Formula C8H10N4O2
Parteck® CCS
35 9.21 Molar mass 194.19
Silicon dioxide, highly dispersed BCS class I

3.5 0.92
(113126)
Solubility in Sparingly
Parteck® LUB MST water soluble
3.5 0.92
Total 380 100
Manufacturing:
Mix caffeine, Parteck® SI and all other excipients with the exception of
Tablet properties:
Friability [%] 0.2
Page 9 07/2020
Ibuprofen (200 mg)

API
Ibuprofen, 38 micron 200 40 Ibuprofen
Parteck® M 200 (DC mannitol, 100419) 270 54

Formula C13H18O2
Parteck CCS
®
25 5
(croscarmellose sodium, 102310) Molar mass 206.29 g/mol
Parteck® LUB MST Melting point 75 – 77 °C

5 1
BCS class II
Total 500 100
Solubility Practically
in water insoluble
Manufacturing:
Parteck® M 200, ibuprofen and Parteck® CCS are blended for 5 minutes and
passed through a 1 mm sieve. Afterwards, Parteck® LUB MST is passed through
a 250 μm sieve onto the mixture, then all components are again blended for
5 minutes in a shaker-mixer. In the next step, the tableting mixture is
compressed on a single-punch instrumented tablet press at compression forces
of 5, 10 and 20 kN at a rate of 50 rpm. The resulting 11 mm tablets have a
total tablet weight of 500 mg each and are flat and faceted.
Tablet properties obtained at different compression forces:
Compression force [kN] 5 10 20
Tablet weight [mg] 500 500 500
Weight variation [%] 0.59 0.43 0.53
Tablet diameter [mm] 11 11 11
Tablet thickness [mm] 5.2 4.8 4.5
Tablet hardness [N] 81 160 222
Hardness variation [%] 7.74 3.02 2.80
Friability [%] 0.2 0.2 0.2
Disintegration time [s] 28 52 136
Page 10 07/2020
250 160 Figure 1:

Tablet hardness and disintegration
140 time of the ibuprofen formulation
with Parteck® M, manufactured
200 at compression forces of 5, 10
120 and 20 kN.
Disintegration time [s]

Tablet hardness [N]
100
150
80
100
60
40
50
20
0 0
5 10 20
Compression force [kN]
Tablet hardness Disintegration time
As the compression force increases, so do tablet hardness and disintegration time

(see Fig. 1). However, regardless of the compression force, all three assessed
batches are well within the desired range for tablet hardness and disintegration
time, allowing for a certain flexibility in the manufacturing process depending on
the desired final product properties and performance.
Page 11 07/2020
Magnesium Carbonate (280 mg)
Amount [mg/tablet] Amount [% w/w] API

Magnesium carbonate, heavy
Parteck® Mg DC (DC magnesium
280 80
hydroxide carbonate, 102440)
Formula acc. to
pharmacopoeial
Parteck® M 200 (DC mannitol, 100419) 59.8 17.1
Molar mass specification
Parteck® CCS
3.2 0.9
(croscarmellose sodium, 102310) Solubility Practically
in water insoluble
3.5 1
(113126)
Parteck® LUB MST

3.5 1
Total 350 100
Manufacturing:
Parteck® Mg DC, Parteck® M 200, Parteck® CCS and silicon dioxide are blended
for 10 minutes in a drum hoop mixer and passed through a 1 mm sieve. After
that, Parteck® LUB MST is sieved through a 250 μm sieve onto the mixture,
then all components are again blended for 10 minutes in a drum hoop mixer.
The tableting mixture is compressed on a high-speed rotary press at
compression forces of 10, 15, 20 and 25 kN. The resulting 11 mm tablets have
a total tablet weight of 500 mg each and are flat and faceted.
Compression force [kN] 10 15 20 25
Tablet weight [mg] 350 350 350 350
Weight variation [%] 1.62 1.49 1.54 2.00
Tablet diameter [mm] 11 11 11 11
Tablet thickness [mm] 3.03 2.77 2.62 2.51
Tablet hardness [N] 71 126 166 205
Friability [%] < 0.1 < 0.1 < 0.1 < 0.1
Disintegration time [s] 39 32 36 39
Page 12 07/2020
Paracetamol 200 58 API

Paracetamol
Parteck® LUB MST (magnesium

10 2
stearate, 10063)
Formula C8H9NO2
Total 500 100


Manufacturing:
BCS class I
Paracetamol and Parteck® SI are blended for 5 minutes. Next, Parteck® LUB
MST is sieved through a 250 μm sieve onto the mixture, then all components
are again blended for 5 minutes in a shaker-mixer. After that, the tableting water soluble
mixture is compressed using a single-punch instrumented tablet press at
different compression forces into 11 mm biconvex tablets with a total tablet
weight of 500 mg.
Tablet properties:
Compression force [kN] 10 20
Tablet weight [mg] 500 500
Weight variation [%] 0.48 0.48
Tablet thickness [mm] 4.5 4.3
Tablet hardness [N] 65 85
Hardness variation [%] 3.9 7.5
Friability [%] 0.67 0.61
Disintegration [s] 837 1140
Disintegration variation [s] 42 58
Page 13 07/2020
Paracetamol DC 96% 313 52.17 API

Paracetamol

50 8.33
DC 50 µm
Formula C8H9NO2
Sodium starch glycolate 33 5.5

9 1.5
(113126) Melting point 169 – 170.5 °C
Parteck® LUB MST BCS class I

15 2.5
Total 600 100 water soluble
Manufacturing:
Mix paracetamol, Parteck® SI and all other excipients with the exception of
Tablet properties:
Friability [%] 0.6
Page 14 07/2020
Prednisolone (20 mg)
Prednisolone 20 10 API
Prednisolone

10 5
DC 50 µm
Formula C21H28O5
Parteck® CCS
6 3 Molar mass 360.44
Parteck® LUB MST Melting point 169 – 170.5 °C

2 1
BCS class I
Total 200 100
Solubility in Very slightly
water soluble
Manufacturing:
Mix prednisolone, Parteck® SI and all other excipients with the exception of
Tablet properties:
Friability [%] 0.4
Page 15 07/2020
Pyridoxine Hydrochloride (50 mg)
Pyridoxine HCl 50 50 API

Pyridoxine
hydrochloride
Parteck® LUB MST

1 1
Formula C8H11NO3 · HCl
Total 100 100

Molar mass 205.64
BCS class I
Manufacturing:
Solubility in
Mix pyridoxine HCl and Parteck® SI. The lubricant Parteck® LUB MST is sieved water
Freely soluble
through a 250 µm sieve onto the mixture, followed by another mixing step.
The homogeneous mixture is then compressed at 30 kN.
Tablet properties:
Friability [%] 0.6
Page 16 07/2020
Pyridoxine Hydrochloride (300 mg)
Pyridoxine HCl 300 75.0 API

Pyridoxine
hydrochloride

45 11.25
DC 50 µm
Formula C8H11NO3 · HCl

3 0.75 Molar mass 205.64
(113126)
Parteck® LUB MST BCS class I

2 0.5
Solubility in
Freely soluble
Total 400 100 water
Manufacturing:
Mix pyridoxine HCl, Parteck® SI and all other excipients with the exception of
Tablet properties:
Friability [%] 0.3
Page 17 07/2020
Thiamine Hydrochloride (50 mg)
Thiamine HCl 50 25 API

Thiamine
hydrochloride
Sodium starch glycolate 10 5

Formula C12H17ClN4OS · HCl
2 1
(113126)
Molar mass 337.27
Parteck® LUB MST
2 1
(magnesium stearate, 100663) BCS class I
Total 200 100 Solubility in

Freely soluble
water
Manufacturing:
Mix thiamine HCl, Parteck® SI and all other excipients with the exception of
Tablet properties:
Friability [%] 0.3
Page 18 07/2020
Water-Sensitive Low-Dose API

Formulation (0.5 mg)
EMD 122xyz (water-sensitive API) 0.5 0.4

23.0 19.2
DC 50 µm
Glyceryl behenate 4.8 4
Crospovidone 2.4 2
Total 120 100
Manufacturing:
The API is premixed with 15% of Parteck® M 200, then diluted with the rest
of the formulation. The homogeneous blend is then tableted on a high-speed
rotary tablet press (7 mm punch, 9.1 kN) at speeds of 40,000 tablets/h and
80,000 tablets/h.
Effect of production speed on tablet properties:
Production speed [tablets/h] 40,000 80,000
Compression force [kN] 9.1 9.1
Disintegration time [s] 205 202
Content uniformity [%] ± 1.8 ± 1.8
Changing the speed of the tableting process from 40,000 tablets per hour to
80,000 does not result in significant deviations in tablet weight and hardness.
This is due to the good flow and compressibility of Parteck® M, which make it
ideal for high-throughput production on fast rotary presses.
Page 19 07/2020
by Dry Granulation
Enalapril Maleate (2.5 mg)

API
Enalapril
Granulation maleate
Enalapril maleate 1.263

Formula C24H32N2O9
Parteck® M 200 (DC mannitol, 100419) 98.737
Tableting
Enalapril maleate-Parteck® M 200
198 99
granules
pKa1 3.0;
pKa
pKa2 5.4
Parteck LUB MST
®
2 1
Solubility Sparingly
in water soluble
Total 200 100
Manufacturing:
Parteck® M 200 and enalapril maleate are blended for 20 minutes in a shaker-
mixer. The blend is granulated using an instrumented roller compactor with a
set compression force of 8 kN/cm, a gap width of 2 mm and a roller speed of
3 rpm. Granulation of the ribbons is performed at a speed of 40 rpm clockwise
and 60 rpm counterclockwise using a 1.25 mm sieve. Afterwards, Parteck® LUB
MST is added to the granules, followed by blending for 2 minutes in a shaker-
mixer. In the next step, the mixture is compressed on an instrumented rotary
tablet press at compression pressures of 60, 119, 179, 239, 298 and 358 MPa.
The resulting 8 mm biplanar tablets have a total tablet weight of 200 mg each.
Properties of granules:
Amount of fines [%] 9.1 ± 0.2
Flow function coefficient ffc 10.8 ± 1.7
Tablet properties obtained at different compression pressures:
Compression pressure [MPa] 60 119 179 239 298 358
Tablet weight [mg] 200 200 200 200 200 200
23.8 18.8 15.0 12.0 9.5 7.9

Tablet porosity [%] ± 0.2 ± 0.8 ± 0.2 ± 0.3 ± 0.2 ± 0.3
Tensile strength [MPa] 0.9 2.2 4 5.3 5.7 5.9
Friability [%] 0.7 0.5 0.5 0.5 0.6 0.7
Disintegration time [s] 64 205 234 264 334 375
Page 20 07/2020
by Dry Granulation
Ibuprofen (400 mg)

API
Granulation Ibuprofen
Ibuprofen 70.759
Formula C13H18O2
Crospovidone 3.000
Melting point 75 – 77°C
Tableting
Ibuprofen-Parteck® M 200 granules 565.3 99 BCS class II
Parteck® LUB MST

5.7 1 Solubility Practically
(magnesium stearate, 100663) in water insoluble
Total 571 100
Manufacturing:
Parteck® M 200, ibuprofen and crospovidone are blended for 10 minutes in a
shaker-mixer. The blend is granulated using an instrumented roller compactor
with a set compression force of 8 kN/cm, a gap width of 2 mm and a roller
speed of 3 rpm. Granulation of the ribbons is performed at a speed of 40 rpm
clockwise and 60 rpm counterclockwise using a 1.25 mm sieve. Afterwards,
Parteck® LUB MST is added to the granules, followed by blending for 2 minutes
in a shaker-mixer. In the next step, the tableting mixture is compressed on an
instrumented rotary tablet press at compression pressures of 43 and 51 MPa. The
resulting 12 mm biconvex tablets have a total tablet weight of 571 mg each.
Properties of granules:
Amount of fines [%] 10.1 ± 1.1
Flow function coefficient ffc 9.5 ± 0.6
Tablet properties obtained at different compression pressures:
Compression pressure [MPa] 43 51
Tensile strength [MPa] 0.8 1.1
Page 21 07/2020
by Wet Granulation
Granulation API
Ascorbic acid
Ascorbic acid 20.3
Parteck® Delta M
79.7
(delta mannitol, 112635)
Formula C6H8O6
Water 15*
Tableting
about 190 °C,
Melting point
with decomposition
Ascorbic acid-Parteck Delta M granules
®
495 99
pKa1 = 4.17;
Parteck® LUB MST pKa
5 1 pKa2 = 11.57
BCS class III

Total 500 100
*Amount of water is calculated relative to the total amount of ascorbic acid and Parteck® Delta M Solubility in Freely
water soluble
Manufacturing:
Ascorbic acid is dissolved in water. Parteck® Delta M is granulated in a high-
shear mixer using the ascorbic acid solution. The granules are dried at 50 °C
and, following the drying step, passed through a 1 mm sieve. The residual water
content should not exceed 0.4%.
Parteck® LUB MST is sieved through a 250 µm sieve onto the granules, followed
by mixing in a shaker-mixer for 5 minutes. The blend is then compressed on a
single-punch instrumented tablet press at compression forces of 5, 10, 20 and
30 kN. The resulting 11 mm tablets have a total tablet weight of 500 mg each
and are flat and faceted.
Friability [%] 0.67 0.29 0.22 0.33
Page 22 07/2020
by Wet Granulation
Fenofibrate (100 mg)

API
Fenofibrate 100.0 20 Fenofibrate
Parteck® Delta M
387.5 77.5 Formula C20H21ClO4
Silicon dioxide, highly dispersed 5.0 1 Molar mass 360.83 g/mol
Parteck® LUB MST BCS class II

7.5 1.5
Melting point 80 – 81 °C

Total 500 100
in water insoluble
Manufacturing:
Parteck® Delta M and fenofibrate are wetted in a universal mixer. The wet mass
is then granulated using a wet granulator with oscillating rotor (mesh size 0.8
mm), tray-dried at 50 °C to a water content < 0.5%, and finally sieved over a
1 mm sieve.
For comparison purposes, Parteck® Delta M is also granulated separately, with
the API being added to the dried granules.
Parteck® LUB MST and silicone dioxide are added to the dried granules and
mixed. Afterwards, the blends are tableted on a single-punch instrumented
tablet press equipped with 12 mm biplanar, beveled punches. The aim is to
produce tablets of comparable hardness (75 ± 5 N), so an appropriate
compression force is chosen.
100 Figure 2:
Dissolution of fenofibrate tablets
90
based on either a physical mixture
of fenofibrate with wet-granulated
80
Parteck® Delta M or a co-processed
mixture of fenofibrate with Parteck®
70
Delta M.
Drug release [%]
60
50
40
30
20
10
0
0 1 2 3 4 5 6
Time [h]
Co-granulation Mixture
Page 23 07/2020
by Wet Granulation
A Figure 3:
1.6
Comparison of BET surface area (A)
and disintegration time (B) of the
1.4
physical and co-processed mixtures
of fenofibrate with Parteck® Delta M.
1.2
BET surface area [m2/g]
1.0
0.8
0.6
0.4
0.2
0
B
16
14
12
Disintegration time [min]
10
0
The initial dissolution rates are higher for the co-processed mixture of
fenofibrate and Parteck® Delta M than for the physical mixture of the API with
wet-granulated Parteck® Delta M (see Fig. 2). Co-processing results in an
increased BET surface area (see Fig. 3 A) and pore volume (data not shown),
which shortens the disintegration time of the final tablets (see Fig. 3 B).
Page 24 07/2020
by Wet Granulation
Ibuprofen (400 mg)
Granulation API
Ibuprofen
Ibuprofen 50
Parteck® Delta M
50
Formula C13H18O2
Water 27.5*
Tableting
Ibuprofen-Parteck® Delta M granules 800 98.5
BCS class II
Parteck® CCS
4 0.5
Solubility in
Practically insoluble
water
Parteck LUB MST
®
8 1
Total 812 100
*Amount of water is calculated relative to the total amount of ibuprofen and Parteck® Delta M
Manufacturing:
Parteck® Delta M is mixed with ibuprofen in a high-shear mixer for 2 minutes at
a speed of 50 rpm. Water is added at a flow rate of 23 mL/min. The granules
are dried at 50 °C and, following the drying step, passed through a 1 mm sieve.
Parteck® CCS and the granules are premixed in a shaker-mixer for 5 min.
Parteck® LUB MST is sieved through a 250 µm sieve onto the premixture, followed
by mixing in a shaker-mixer for 5 minutes. The blend is then compressed on a
single-punch instrumented tablet press at compression forces of 5, 10 and 20 kN.
The resulting 13 mm tablets have a total tablet weight of 812 mg each and are
round and convex.
Friability [%] 0.85 0.43 0.41
Page 25 07/2020
by Wet Granulation
Lisinopril (20 and 40 mg)
20 mg 40 mg API
Lisinopril
Lisinopril USP 20.00 40.00 10.00
Parteck® Delta M
93.25 186.50 46.62
Formula C21H31N3O5 ∙ 2 H2O
Calcium hydrogen phosphate dihydrate

44.00 88.00 22.00 Molar mass 441.52 g/mol
(102146)
Maize starch 33.25 66.50 16.63 BCS class III
Water q.s.* q.s.* * Solubility

Soluble
in water
Parteck CCS
®
7.50 15.00 3.75
Parteck® LUB MST

2.00 4.00 1.00
Total 200 400 100
*Water is removed during the drying step of the process.
Manufacturing:
Lisinopril, Parteck® Delta M and calcium hydrogen phosphate are weighed
and sieved through a 425 μm sieve. The powder blend is then mixed until
homogeneous. Starch paste is prepared from maize starch and water and
added to the powder blend, followed by kneading until the desired granulation
end point is reached. The granules are dried at 55 ± 5 °C, then passed through
an appropriate sieve. The coarser granules are milled using a mill with an
appropriate screen size. The dried granules are then mixed with Parteck® CCS
and Parteck® LUB MST using a double cone blender. Using a rotary tablet press
equipped with round flat face beveled edge punches, the blend is compressed
into tablets with a total tablet weight of 200 mg (API content 20 mg) and 400
mg (API content 40 mg) each at compression forces of 6.0 and 6.6 kN
respectively.
Page 26 07/2020
by Wet Granulation
Tablet properties:
API content [mg] 20 40
Weight variation [%] 5 5
Figure 4:
100 Dissolution profile of wet-granulated
lisinopril tablets based on Parteck®
Delta M.
80
Drug release [%]
60
40
20
0
0 5 10 15 20 25 30 35
Time [min]
Lisinopril tablets 20 mg
Lisinopril tablets 40 mg
Page 27 07/2020
by Wet Granulation
Telmisartan (40 mg)
In the present example, an ethanolic granulation medium is used in a high-

shear granulation process. In such a case and for other organic solvents, the
application of Parteck® M 200 excipient provides the benefit of very hard
API
tablets with a fast disintegration behavior. For high-shear processes which use
Telmisartan
water as granulation medium, Parteck® Delta M delta-polymorphic mannitol is
recommended as its conversion into the beta-polymorph during the process
leads to excellent binding and tableting properties.
Formula C33H30N4O2
Amount [mg/tablet] Amount [% w/w] Molar mass 514.63 g/mol
Granulation Melting point 261 – 263 °C
Telmisartan 40.0 16.67 BCS class II
Sodium hydroxide (106482) 3.5 1.46

Solubility in Practically
Povidone 0.5 0.21 water insoluble
Water 8.0* *
Ethanol absolute (100986) 120.0* *
Parteck® M 200
162.1 67.54
(DC mannitol, 100419)
Meglumine (106187) 12.0 5.0
Tableting
Parteck® M 200
11.4 4.75
Parteck® CCS
7.5 3.13
Parteck® LUB MST

3.0 1.25
Total 240 100
*Solvents are evaporated off during the process.
Page 28 07/2020
by Wet Granulation
Manufacturing:
Sodium hydroxide is dissolved in water while stirring. The solution is then
added to ethanol while stirring. Telmisartan and povidone are weighed and
added slowly to the ethanolic sodium hydroxide solution with continuous
stirring until completely dissolved. It must be ensured that the solution is clear
before advancing to the granulation step. Parteck® M 200 and meglumine are
sieved through an 600 μm sieve and transferred into a rapid mixer granulator.
The blend is mixed for 5 minutes at a slow impeller speed. The telmisartan
solution is added slowly. Once the telmisartan solution has been fully added,
the solution vessel is rinsed with additional ethanol, which is then added to the
blend. After granulation, the wet mass is passed through a 2 mm sieve. Next,
the granules are dried in a fluidized bed dryer at a temperature of 55 ± 5 °C.
The dried granules are sieved through a 600 μm sieve and transferred into a
double cone blender. Parteck® M 200 and Parteck® CCS are sieved through a
600 μm sieve and added to the granules. The components are then mixed for
10 minutes at 20 rpm. Finally, Parteck® LUB MST is sieved through a 250 μm
sieve and added to the blend, which is then mixed for another 5 minutes.
The mixture is then compressed on a rotary tablet press at 9 kN using an 8 mm
round D tooling punch.
Tablet properties:
Friability [%] 0.16
Disintegration time [s] 530
100 Figure 5:
Dissolution profile of wet-granulated
80 telmisartan tablets based on
Drug released [%]
Parteck® M.
60
40
20
0
0 5 10 15 20 25 30
Time [min]
Page 29 07/2020
Chewable Tablets
Chewable tablets are an oral dosage form formulated Our Formulation Ingredients
and manufactured so that they may be chewed,
producing a pleasant-tasting residue in the oral cavity Category Products
that is easily swallowed and does not leave a bitter or
unpleasant aftertaste. Chewable tablets are available Filler/Diluent Parteck® SI (DC sorbitol, 103583, 103557,
for many over-the-counter (OTC) and prescription 103140, 115079), Parteck® M (DC mannitol
drug products. 100419, 100494), Parteck® Delta M
(mannitol, 112635), mannitol (105980,
Patients judge a formulation based on its palatability: 105988), sucrose (107653), lactose
its physical appearance in the mouth and dissolution monohydrate (107656, 108195), starch
properties are just as important as its taste. A cooling (101253)
effect adds more appeal, while insoluble particles
will lead to rejection. As such, taste and mouthfeel Binder Gelatin (104072, 104078), sucrose
must be given special consideration when choosing (107653), polyvinyl alcohol 4-88 (141350),
excipients for a chewable tablet formulation. polyvinyl alcohol 5-88 (141354), starch
(101253)
Manufacturing process: Chewable tablets may be Lubricant Parteck® LUB MST (magnesium stearate,
manufactured by direct compression, dry granulation 100663), Parteck® LUB CST (calcium
or wet granulation. stearate, 100664), Parteck® LUB STA
Formulation requirements: Low moisture content,
rapid disintegration, chewability, pleasant taste and Glidant Silicon dioxide, highly dispersed (113126)
good mouthfeel.
Formulation challenges: Taste optimization or taste Sweetener Sucralose (100894, 1.00895),
masking, sweetness, chewability, mouthfeel. glucose (108346), sucrose (107653),
Formulation benefits: Increased bioavailability, faster
onset of action, pre-gastric absorption to avoid first
pass metabolism, overcomes swallowing difficulties,
no need to take with water.
Raw material recommendation: Low moisture
content, good compressibility, excipients that give
good chewability.
Packaging: Individual jars/jars in a folding box, tubes,
blisters, side-sealed bags, wallet packs etc. Care should
be taken to protect from moisture.
Recommended for: antacids, dietary supplements,
OTC drugs, antibiotics.
Page 30 07/2020
Formulation Examples: Chewable Tablets
Acetylsalicylic Acid (500 mg)
Acetylsalicylic acid (fine crystalline) 500 33.4 API

Acetylsalicylic
acid
DC dextrose 400 26.8

Formula C9H8O4
120 8.0
DC 50 µm
Talc 70 4.7
Melting point 143 °C
Sucralose powder (100894) 5 0.3
pKa 3.49
Total 1495 100
BCS class IV
Manufacturing: Solubility in Slightly

water soluble
All components are blended in a shaker-mixer until a homogeneous mixture is
achieved. The mixture is then compressed at 15 kN.
Tablet properties:
Friability [%] 1.4
Page 31 07/2020
Alginic Acid (350 mg) and

Sodium Bicarbonate (140 mg)
Alginic acid 350 35 API

Alginic acid
Sodium bicarbonate (106323) 140 14

Formula (C6H8O6)n
50 5
DC 50 µm
20,000 – 240,000
Molar mass
g/mol
Calcium gluconate (102094) 30 3
Silicon dioxide, highly dispersed Acidity (pH of

10 1 3% w/v aqueous 1.5–3.5
(113126)
dispersion)
Flavoring 8 0.8
Solubility in Swells, but does
water not dissolve
Parteck® LUB MST

10 1
Total 1000 100
API
Sodium
Manufacturing: bicarbonate
Parteck® SI 450, alginic acid, sodium bicarbonate and all other ingredients with
the exception of Parteck® LUB MST are mixed. Next, Parteck® LUB MST is added,
followed by another mixing step. The blend is then compressed at 30 kN. Formula NaHCO3
Tablet properties:
Solubility in
Soluble
water
Friability [%] 0.8
Page 32 07/2020
Calcium Carbonate (450 mg)
Calcium carbonate API

450 45.0 Calcium
(fine powder, 102069)
carbonate

Formula CaCO3
Parteck® LUB MST

30 3.0 Molar mass 100.09 g/mol

water
Manufacturing:
Calcium carbonate, Parteck® SI and sucralose are mixed for 5-10 minutes using
a shaker-mixer. Next, magnesium stearate is added, followed by another
mixing step. The homogeneous mixture is then compressed on a single-punch
instrumented tablet press at 20 kN at a rate of 54 rpm.
Tablet properties:
Friability [%] 0.6
Page 33 07/2020
Parteck® Mg DC (DC magnesium API

400 40
hydroxide carbonate, 102440) Magnesium carbonate, heavy
Sucralose powder (100894) 2.5 0.25

Formula acc. to
pharmacopoeial
Orange flavoring 5.0 0.5
Lemon flavoring 7.5 0.75

Solubility in 0.0139 g/100 ml
Hydroxypropyl methylcellulose (HPMC) 25.0 2.5 water (25 °C)

10 1
(113126)
Parteck® LUB MST

10 1
Total 1000 100
Manufacturing:
All components with the exception of Parteck® LUB MST are blended for 10
minutes in a drum hoop mixer and passed through a 1 mm sieve. Next,
Parteck® LUB MST is sieved through a 250 μm sieve onto the blend, followed by
another mixing step for 10 minutes in a drum hoop mixer. The tableting
mixture is compressed on a high-speed rotary press at compression forces of
10 and 12.6 kN. The resulting 15 mm tablets have a total tablet weight of 1000
mg each and are flat and faceted.
Compression force [kN] 10 12.6
Page 34 07/2020
Paracetamol (96%) 130 26 API

Paracetamol

50 10
DC 50 µm
Formula C8H9NO2
Flavoring 4 0.8
Parteck® LUB MST
10 2
Total 500 100

water soluble
Manufacturing:
Paracetamol, Parteck® SI 200, MCC, flavoring and sweetener (sucralose)
are blended in a shaker-mixer until a homogeneous mixture is achieved.
Parteck® LUB MST is added, followed by another mixing step. The blend is
then compressed at 15 kN.
Tablet properties:
Friability [%] 0.7
Page 35 07/2020
Dry Syrups and

Suspensions
A dry syrup or dry suspension is reconstituted prior to Raw material recommendation: Palatable and
use and thus combines advantages of both liquid and pleasant taste, taste-masking ability, high aqueous
solid formulations: while it is manufactured, transported solubility and fast dissolution, prevention of API
and stored as a solid formulation, it is applied as a segregation under physical stress, chemical inertness.
liquid formulation after reconstitution with water.
Packaging: Typically, tightly sealed and moisture-proof
Benefits include a reduced susceptibility to stability
containers.
issues (e.g. resulting from outer temperature conditions
or limited stability of the API in an aqueous phase), Recommended for: antibiotics, often for pediatric
a reduced weight of the product to be shipped, and application.
an easy-to-swallow liquid formulation well-suited to
pediatric use, for instance.
Dry syrups and dry suspensions are typically formulated Our Formulation Ingredients
as a powder blend or granulated. Several characteristics Category Products
must be taken into consideration when choosing the
excipients: mixture uniformity, fast and complete Carrier Parteck® SI (DC sorbitol, 103583, 103557,
dissolution or dispersion upon the addition of water, 103140, 115079)
stability of the suspension or quick redispersion to
ensure dosing uniformity, and taste. For the powder in
particular, blend homogeneity and content uniformity Possible alternative carriers with a potential
may present a challenge, especially in the case of low for API adsorption on the particle surface:
dose formulations. Parteck® M (DC mannitol, 100419,
100494), Parteck® Mg DC (DC magnesium
Particle-engineered products featuring a particle hydroxide carbonate, 102440)
structure that allows for the formation of ordered
mixtures through binding of the API onto the carrier Suspending Gum arabic (104228), silicon dioxide highly
particle surface support the creation of dry powder and viscosity dispersed (113126)
formulations with good content uniformity throughout increasing agent
processing and filling. The particle structure of Parteck® SI
excipient consists of very loosely packed, interwoven Preservative Sucrose at higher concentrations (107653),
filamentary crystals with a large surface area for the sodium benzoate (106290), sorbic acid
adsorption of micronized API particles. Due to this (100662), potassium sorbate (105118)
ability to form stable ordered mixtures with APIs, as
well as its sweet taste, good solubility and the rapid pH modifier Trisodium citrate anhydrous (111037),
disintegration of particles, particle-engineered citric acid anhydrous (100241)
Parteck® SI excipient is very well-suited for the
formulation of sugar-free dry syrups. Sweetener Sucralose (100894, 100895), glucose
(108346), sucrose (107653), fructose
Manufacturing process: In the case of a powder (105321), maltose (105911)
formulation, by mixing. Wet granulation techniques
may also be employed to formulate dry syrups or dry
suspensions.
Formulation requirements: Content uniformity, rapid
dissolution, quick redispersion, pleasant taste and good
mouthfeel, physical and chemical stability.
Formulation challenges: Rapid dissolution or
disintegration, taste optimization or taste masking,
content uniformity (especially in the case of high and
low API doses).
Formulation benefits: Physically and chemically
stable during transport and storage, overcomes
swallowing difficulties.
Page 36 07/2020
Formulation examples: Dry Syrups and Suspensions
Amoxicillin Trihydrate (50 mg/mL)
Amount [g] Amount [% w/w]
Amoxicillin trihydrate 5.74 15.645 API

Amoxicillin
trihydrate
Parteck® SI 400 (DC sorbitol, 103140) 30.00 81.766
Potassium sorbate (105118) 0.30 0.818

Formula C16H19N3O5S ∙ 3H2O
Aspartame 0.20 0.545
Flavoring, dry powder 0.25 0.681 Molar mass 419.45 g/mol
Xanthan gum 0.20 0.545 BCS III
Total 36.69 100

Solubility in
Slightly soluble
water
Manufacturing:
Micronized amoxicillin trihydrate (particle size 5 – 30 µm) and about 25% of
the total amount of Parteck® SI are pre-mixed. The remaining Parteck® SI is
then added and the blend mixed again. Next, all other ingredients are added,
and the blend is mixed until homogeneous.
Reconstitution with water ad 100 mL. One 5 mL measuring spoon corresponds
to 250 mg of amoxicillin.
Page 37 07/2020
Ampicillin Trihydrate (50 mg/mL)
Ampicillin trihydrate 5.77 13.954 API

Ampicillin
trihydrate
Sodium benzoate (106290) 0.25 0.605

Formula C16H19N3O4S ∙ 3H2O
Saccharin sodium dihydrate 0.10 0.242
Flavoring, liquid 0.03 0.073 Molar mass 403.46 g/mol
Xanthan gum 0.20 0.484 BCS III
Total 41.35 100

Solubility in
Slightly soluble
water
Manufacturing:
Micronized ampicillin trihydrate (particle size 5 – 30 µm) and about 25% of the
total amount of Parteck® SI are pre-mixed. The remaining Parteck® SI is then
added and the blend mixed again. Next, all other ingredients are added, and
the blend is mixed until homogeneous.
Reconstitution with water ad 100 mL. One 5 mL measuring spoon corresponds
to 250 mg of ampicillin.
Page 38 07/2020
Multivitamin Supplement
Due to the unique particle properties of Parteck® SI excipient, it is possible to

manufacture a simplified sachet formulation. A stable, ordered mixture with the
vitamins is formed, showing rapid dissolution properties and a pleasant, sweet
taste.
Thiamine mononitrate 0.192 0.192
Riboflavine-5-phosphate 0.254 0.254
Pyridoxine hydrochloride 0.074 0.074
Vitamin B12 (0.1% on lactose) 0.250 0.250
Calcium panthothenate 0.232 0.232
Nicotinamide 1.833 1.833
Total 100 100
Manufacturing:
The micronized active ingredients (particle size 5 – 30 µm) and about 25% of
the total amount of Parteck® SI are pre-mixed. The remaining Parteck® SI is
then added and the blend mixed again until homogeneous.
If desired, additional excipients such as thickeners, preservatives or pH
modifiers may be added to the formulation.
Page 39 07/2020
Effervescent Tablets
Effervescent tablets are intended to be dissolved Our Formulation Ingredients

or dispersed in water before administration and are
well-suited for fast-acting formulations. They are Category Products
prepared by compression and contain, in addition
to the API, a mixture of acids and carbon dioxide Acid source Citric acid (100241, 100247, 100243)
tartaric acid (100802, 100803), fumaric
sources that results in a release of carbon dioxide and
acid (817073), malic acid (100383)
disintegration upon contact with water.
Carbon dioxide Carbonates: Sodium carbonate (106383,

source 106386, 106398), potassium carbonate
Manufacturing process: Soluble effervescent tablets (104924), calcium carbonate (12422,
are prepared by direct compression, wet granulation 102064, 102069, 102074).
or dry granulation. Tablet presses must be adapted
Bicarbonates: Sodium hydrogen carbonate
to handle effervescent products. A relative humidity
(106323), potassium hydrogen carbonate
of ≤20% at a temperature of approximately 21 °C is (104852)
desirable, but a maximum of 25% rH at a controlled
room temperature of 25 °C or less is usually sufficient
to avoid problems caused by atmospheric moisture. Lubricant Parteck® LUB MST (magnesium stearate,
Formulation requirements: Rapid disintegration, stearate, 100664), Parteck® LUB STA
low moisture content, compression without binder or (stearic acid, 100661)
with use of water-soluble binder.
Filler/Diluent Generally not required as effervescent
Formulation challenges: Premature effervescent
ingredients are in higher concentration. If
reaction, stability of the effervescent system. required, preferably water-soluble fillers
Formulation benefits: Faster onset of action, such as Parteck® SI (DC sorbitol, 103583,
103557, 103140, 115079), Parteck® M
overcomes swallowing difficulties.
(DC mannitol, 100419, 100494), Parteck®
Raw material recommendation: Low moisture Delta M (mannitol, 112635), mannitol
content, aqueous solubility, poor compactability of (105980, 105988)
the excipient cannot be compensated for by using
high amounts of binder, so excipients with good Disintegrant Not required, since the combination of
compressibility are needed. acids and (bi)carbonates also serves as a
disintegrant
Packaging: Tightly sealed, moisture-proof containers
or packs. Packed in individual aluminum foil pouches. Sweetener Sucralose (100894, 100895),
Often packed in metal tubes. glucose (108346), sucrose (107653),
Recommended for: analgesics such as acetylsalicylic
acid, paracetamol, ibuprofen or diclofenac, and
Flavoring, Water-soluble or water-dispersible dry
antacid formulations; also for OTC formulations, such
coloring agent flavorings, water-soluble colors
as those containing vitamins, minerals and trace
minerals.
Page 40 07/2020
Formulation examples: Effervescent Tablets
Parteck® Mg DC (DC magnesium API

1100* 50
hydroxide carbonate, 102440) Magnesium carbonate, heavy
Citric acid anhydrous (100241) 748 34
Sodium hydrogen carbonate (106323) 154 7

Formula acc. to
pharmacopoeial
Orange flavoring 22 1
Lemon flavoring 33 1.5

Sucralose powder (100894) 11 0.5 water insoluble
Polyethylene glycol (PEG) 6000,

132 6
fine powder
Total 2200 100
*The magnesium carbonate content of the final tablet corresponds to a magnesium content of
approximately 275 mg.
Manufacturing:
All components are blended for 10 minutes in a drum hoop mixer and passed
through a 1 mm sieve. Next, the mixture is blended again for 10 minutes in a
drum hoop mixer. The tableting mixture is then compressed on a high speed
rotary press at a compression force of 30 kN. The resulting 18 mm tablets have
a total tablet weight of 2200 mg and are flat and faceted.
Tablet properties:
Page 41 07/2020
Formulation examples: Effervescent Tablets
Multivitamin Supplement
Ascorbic acid 35 1.75
Vitamin E (50%, spray-dried) 11 0.55
Folic acid 0.3 0.015
Thiamine mononitrate 1.7 0.085
Riboflavine 5-phosphate sodium 1.3 0.065
Vitamin B12 (0.1%) 2.7 0.135
Pyridoxine hydrochloride 0.8 0.04
Nicotinamide (500299) 7 0.35
Biotin 1% 0.2 0.01
Calcium pantothenate 5 0.25
Sodium bicarbonate 600 30.0
Citric acid anhydrous fine-granular

500 25.0
(100247)
Fumaric acid (817073) 160 8
Flavoring 56 2.8
Total 2000 100
Manufacturing:
All components are blended. The mixture is then compressed at 25 kN into 18 mm
tablets with a total tablet weight of 2000 mg.
Tablet properties:
Friability [%] 0.7
Disintegration time (150 ml, 20 °C) [s] 70
Page 42 07/2020
Lozenges
Lozenges are solid preparations which are intended Our Formulation Ingredients
to dissolve or disintegrate slowly in the mouth. They
contain one or more APIs, usually in a flavored, Category Products
sweetened base. There are different types of lozenges,
such as compressed, soft and hard candy. Any of Filler/Diluent Parteck® SI (DC sorbitol, 103583, 103557,
the common tablet-processing methods such as wet 103140, 115079), Parteck® M (DC
granulation, dry granulation or direct compression may mannitol, 100419, 100494), Parteck® Delta
M (mannitol, 112635), mannitol (105980,
be utilized in the production of lozenge tablets, and the
105988), sucrose (107653)
suitability of the manufacturing process and excipients
depends on the lozenge type.
Binder Acacia (104228), gelatin (104072,
As with chewable tablets and ODT formulations, the 104078), polyethylene glycol 6000
palatability of a lozenge formulation is crucial for patient (817007), polyvinyl alcohol 4-88 (141350),
compliance. The lozenge's mouthfeel - its physical polyvinyl alcohol 5-88 (141354)
appearance and dissolution properties in the mouth -
and taste are important characteristics that must be Lubricant Parteck® LUB MST (magnesium stearate,
taken into account when choosing the excipients. 100663), Parteck® LUB CST (calcium
stearate, 100664), Parteck® LUB STA (stearic
Manufacturing process: acid, 100661)
Compressed tablet: General tablet-processing methods
such as wet granulation, dry granulation and direct Glidant Silicon dioxide, highly dispersed (113126)
compression can be used. However, because the tablets
should dissolve very slowly without disintegration, wet Humectant Parteck® SI (DC sorbitol, 103583, 103557,
granulation with a suitable binder is often preferred. 103140, 115079), glycerol (104091,
104093)
Hard candy: Molding method or ribbon method
Soft lozenges: Molding method Sweetener Sucralose (100894, 100895),
glucose (108346), sucrose (107653),
Formulation requirements: Pleasant taste and good fructose (105321), maltose (105911)
mouth-feel.
Formulation challenges: Taste optimization or taste Flavoring Menthol (105995), vanillin (108510)
masking, sweetness, chewability, mouthfeel. Citric acid (100241, 100247), tartaric acid
Formulation benefits: Overcomes swallowing (100802, 100803), malic acid (100383),
fumaric acid (817073)
difficulties, no need to take with water, local effect of
API, possibility to increase bioavailability via pre-gastric
absorption to avoid first pass metabolism for faster Coloring agent Complementing the flavor, typically water-
onset of action of the API. soluble
Raw material recommendation: Good compressibility

for compressed tablet, low melting point for soft
lozenges.
Packaging: Lozenges, especially hard candies,
are hygroscopic and may tend to absorb moisture
throughout storage. Complex moisture-protective
packaging may therefore be necessary, depending on
the formulation.
Recommended for: formulations targeting local
irritations or infections of the mouth or throat as
well as for systemic absorption after swallowing.
Other applications may include smoking deterrents,
nonsteroidal anti-inflammatory drugs, anti-infectives,
mineral supplements and antiulcer agents.
Page 43 07/2020
Formulation Examples: Lozenges
Dextromethorphan
Hydrobromide (5.5 mg)

API
Dextromethorphan HBr 5.5 0.4 Dextro-
methorphan
Parteck® SI 150 (DC sorbitol, 103583) 1368 97.7 HBr
Flavoring 4 0.3
C18H25NO · HBr ·
Formula
Sucralose powder (100894) 2.5 0.2 H2O
Parteck® LUB MST Molar mass 370.32 g/mol

20 1.4
Total 1400 100
BCS class II
Manufacturing: water soluble
Dextromethorphan HBr, Parteck® SI 150, flavoring and sucralose are mixed for
several minutes in a shaker-mixer. Next, Parteck® LUB MST is added, followed
by another mixing step. The homogeneous mixture is tableted using a single-
punch instrumented tablet press at a compression force of 25 kN.
Tablet properties:
Friability [%] 0.05
Page 44 07/2020
Formulation Examples: Lozenges
Tyrothricin (2 mg) and

Benzocaine (5 mg)
Amount [mg/tablet] Amount [% w/w] API

Tyrothricin
Tyrothricin 2 0.4
acc. to
Formula pharmacopoeial
Benzocaine 5 1.1
specification,
mixture of
Parteck® SI 200 (DC sorbitol, 115079) 425 94.5 antimicrobial
Molar mass linear and cyclic
Flavoring 5 1.1 polypeptides
Solubility in Practically insoluble

water in water
Parteck® LUB MST

10 2.2
Total 450 100
Manufacturing: API
Benzocaine
Tyrothricin, benzocaine, Parteck SI 200, flavoring and sucralose are mixed for
®
several minutes in a shaker-mixer. Next, Parteck® LUB MST is added, followed

by another mixing step. The homogeneous mixture is tableted using a single-
punch instrumented tablet press at a compression force of as low as 5 kN, Formula C9H11NO2
which is possible due to the very good compressibility of Parteck® SI 200.

Tablet properties:
Compression force [kN] 5 pKa 2.5
Tablet weight [mg] 450 Solubility in Very slightly

water soluble
Friability [%] 0.1
Page 45 07/2020
Orally Disintegrating
Tablets (ODTs)
An orally disintegrating tablet (ODT) is a dosage Recommended for: formulations requiring a fast
form that helps improve patient convenience and release of the active, such as analgesics, antiallergics,
compliance. It dissolves quickly in the mouth without and drugs for the pediatric and geriatric population as
water before being swallowed, and ideally has a well as institutionalized patients, psychiatric patients,
pleasant mouthfeel and taste without an adverse and patients with nausea, vomiting, and motion sickness
aftertaste. A disintegration time of < 30 s is typically complications.
aimed for by formulators, a value which is based on a
Our Formulation Ingredients
recommendation by the FDA. However, it is important
to note that the Ph. Eur. specifies a disintegration time Category Products
of < 180 s for ODTs, while the USP specifies different
disintegration times depending on the API. As a dosage Diluent Sugar alcohol-based diluents with high
form that provides fast-acting medication, ODTs allow aqueous solubility and sweetness are
you to add value to existing compounds and extend commonly used. Parteck® ODT (mannitol-
your product life cycles. based ODT excipient system, 100490),
Parteck® M (DC mannitol 100419, 100494),
Several technologies are available to manufacture ODTs, Parteck® Delta M (mannitol, 112635),
such as molding, lyophilization and direct compression. mannitol (105980, 105988)
The method undoubtedly of greatest interest to ODT
formulators is direct compression, as it is a cost-effective Disintegrant Superdisintegrant: Parteck® CCS
production technology with a wide range of applications (croscarmellose sodium, 102310)
that has the fewest limitations with regard to the API.
Manufacturing process: Conventional tableting
methods (direct compression, wet granulation, dry Sweetener Sucralose (100894, 100895),
granulation), lyophilization, heat processing (cotton glucose (108346), sucrose (107653),
candy, molding, solid dispersion). fructose (105321), maltose (105911)
Formulation requirements: Rapid disintegration,

pleasant taste and good mouthfeel, low moisture
sensitivity, good hardness. stearate, 100664), Parteck® LUB STA
Formulation challenges: Rapid disintegration (stearic acid, 100661)
(specifications vary between pharmacopoeias), taste
optimization or taste masking, high-dose product Glidant Silicon dioxide, highly dispersed (113126)
manufacturing, moisture-protective packaging, stability
issues related to product performance, product Flavoring Vanillin (108510)
degradation and tablet handling.
Formulation benefits: Increased bioavailability, faster
onset of action, pre-gastric absorption to avoid first
pass metabolism, overcomes swallowing difficulties, no In general, coatings are considered not to be suitable
need to take with water. for ODT formulations. This is because they are
designed to disintegrate very fast upon the contact
Raw material recommendation: Palatable and with very little moisture and, for this reason, many
pleasant taste, taste-masking ability, high aqueous ODT formulations are compressed to rather weak
solubility, good compressibility and excellent binding units. However, tablets based on orally disintegrating
properties, ready-to-use ODT excipients. excipient system Parteck® ODT were successfully
Packaging: Typically, tightly sealed and moisture-proof processed using a drum coater and commercially
containers or packs or individual aluminum foil pouches available aqueous coating systems based on polyvinyl
are needed. For formulations based on the Parteck® ODT alcohol (PVA) and HPMC. Our PVA-based coating
excipient system, conventional packaging may be used; excipient Parteck® COAT is also very well suitable for
the directly compressed formulation with Parteck® ODT coatings of Parteck® ODT tablet formulations.
excipient in particular shows improved physical For more information on Parteck® ODT excipient in
properties. general and on coatings of ODT formulations, please
refer to the respective formulation example or the
Parteck® ODT product page.
Page 46 07/2020
Formulation Examples: ODTs
Ascorbic acid 80 20 API

Ascorbic acid
Parteck® ODT (mannitol-based ODT
193.2 48.3
excipient system, 100490)

Formula C6H8O6
Parteck® LUB MST

about 190 °C,
Blackcurrant flavor 2 0.5 Melting point
with decomposition
Sucralose powder (100894) 0.8 0.2 pKa1 = 4.17;

pKa
pKa2 = 11.57
Total 400 100
BCS class III
Manufacturing: water soluble
Parteck® M 100 is sieved through a 1 mm sieve. Sucralose is sieved through

a 250 µm sieve onto Parteck® M 100. Parteck® ODT, blackcurrant flavoring
and ascorbic acid are added and the components are blended for 10 minutes
in a drum mixer. The pre-mixture is then passed through a 1 mm sieve.
Parteck® LUB MST is sieved through a 250 µm sieve onto this pre-mixture.
The components are then blended again for 10 minutes in the drum mixer.
After that, the tableting mixture is compressed on an instrumented rotary
press (50 rpm, 42,000 tablets/h, 11 mm punch diameter, biconvex) with the
compression force set so as to produce tablets with a hardness of 50 N (9 kN).
Tablet properties:
Hardness variation [%] 6.68
Friability [%] 0.45
Disintegration variation [s] 2
Page 47 07/2020
Ascorbic Acid (80 mg), Coated
Tablet core API

Ascorbic acid
Ascorbic acid 80 20

316 79
Formula C6H8O6
Parteck® LUB MST

about 190 °C,
Total 400 100 Melting point
with decomposition
Coating A pKa1 = 4.17;

pKa
pKa2 = 11.57
Commercially available, ready-to-use/
one-step polyvinyl alcohol (PVA)–based 8.8 88* BCS class III
film coating system (aqueous)
Colorant/pigment, e.g. Candurin® Brown water soluble
1.2 12*
Amber (120617)
Water q.s.** q.s.**
Coating B
Commercially available, ready-to-use/

one-step cellulose ether–based film 8.8 88*
coating system (aqueous)
Colorant/pigment, e.g. Candurin® Brown

1.2 12*
Amber (120617)
Water q.s.** q.s.**
*Amounts related to the solid content of the spraying liquid.

**Water is removed during the drying step of the coating process.
Manufacturing:
Ascorbic acid and Parteck® ODT are blended for 10 minutes in a drum hoop
mixer and passed through a 1 mm sieve. After that, Parteck® LUB MST is
sieved through a 250 μm sieve onto the mixture, then all components are
again blended for 10 minutes in a drum hoop mixer. The tableting mixture is
compressed on a high-speed rotary press at compression forces of
8.8-8.9 kN, resulting in 11 mm biconvex tablets with a total tablet weight of
500 mg each and a tablet hardness of 50 kN.
The specified amount of PVA–based film coating (coating A) or cellulose
ether-based film coating (coating B) is added in portions to 90% of the
indicated quantity of water and stirred until homogeneous (approximately
30 – 45 minutes). Next, colorants are added while continuously stirring, until
a uniform dispersion is obtained.
Page 48 07/2020
Coating process parameters:
Parameter
Drum 15
Nozzle Two-substance nozzle
Nozzle diameter [mm] 0.7
Distance between nozzle and product [cm] approx. 15
Batch size [g] 2.000
Quantity of coating suspension applied [g] 595
Atomizing pressure [MPa] 0.1
Flat jet pressure [MPa] 0.5
Spray rate [g/min] 11-14
Spray time [min] 50
Drum speed (spraying) [rpm] 19-20
Drum speed (drying) [rpm] 3-5
Iniet temperature [°C] 54-63
Outlet temperature [°C] 46-51
Iniet air flow [m3/h] 580-600
Final drying time [min] 10
Figure 6 shows that coating the tablets using the PVA-based coating system
approximately doubles their hardness, while the disintegration time increases
slightly. The formulation coated with the cellulose-based coating system
shows a less pronounced increase in tablet hardness but a higher increase in
tablet disintegration time. To meet specific requirements, the tablet
disintegration time may be adjusted, such as by adding a superdisintegrant to
the formulation.
160 160 Figure 6:
140 140 Comparison of tablet hardness and

disintegration time of tablets before
120 120 and after coating using PVA-based

Tablet hardness [N]
(coating A) and cellulose-based

100 100
(coating B) coating systems.
80 80
60 60
40 40
20 20
0 0
Tablet core Coating A Coating B

Page 49 07/2020
Ascorbic acid 200 40 API

Ascorbic acid
295 59
Parteck® LUB MST Formula C6H8O6

5 1

Total 500 100
about 190 °C,
Melting point
with decomposition
Manufacturing: pKa
pKa1 = 4.17;
pKa2 = 11.57
Parteck® ODT and ascorbic acid are blended for 5 minutes and passed through
a 1 mm sieve. Next, Parteck® LUB MST is sieved through a 250 µm sieve onto BCS class III
the pre-mixture, followed by mixing of all components for 2 minutes in a shaker-
mixer. In the next step, the tableting mixture is compressed on a single-punch Solubility in Freely
instrumented tablet press (50 rpm, 11 mm punch diameter, flat, faceted) at water soluble
11 and 16 kN.
Page 50 07/2020
Clozapine (25/50/100/200 mg)
Amount [mg/tablet]
25 mg 50 mg 100 mg 200 mg API

Clozapine
Granulation
Clozapine 25 50 100 200

Formula C18H19ClN4
Parteck® ODT (mannitol-based
10 20 40 80
ODT excipient system, 100490)
Water q.s.* q.s.* q.s.* q.s.*
Solubility in
Tableting water
Parteck® M 200 (DC mannitol,

72.12 37.125 34.25 68.50
100419)

5 5 10 20
DC 100 µm
Parteck® CCS (croscarmellose

7.5 7.5 15 30
sodium, 102310)
Crospovidone 5 5 10 20
Saccharin sodium dihydrate 2.5 2.5 5 10
Iron oxide yellow 0.125 0.125 0.25 0.5
Orange flavoring 1.75 1.75 3.5 7

1 1 2 4
stearate, 100663)
Total 130 130 220 440
Page 51 07/2020
Manufacturing:
Clozapine and Parteck® ODT are weighed, sieved with a mesh size of 850 µm
and mixed. Water is added, and the blend is kneaded until the desired
granulation end point is reached. The wet mass is sieved using a mesh size of
2.00 mm. The granules are dried at 55° ± 5 °C until loss on drying is ≤ 0.5%
w/w, and then sieved using a sieve with a mesh size of 1.00 mm. The coarser
granules are milled using a mill with the desired screen size.
Parteck® M 200, Parteck® CCS, crospovidone and MCC are weighed and sieved
with a mesh size of 600 µm. The flavoring and coloring ingredients are
weighed and sieved using a mesh size of 180 µm and transferred into an
octagonal blender. The dried granules are added and mixed with the
extragranular materials for 10 min at 20 rpm.
Magnesium stearate is sieved through a mesh size of 250 µm and added to

the blend, followed by another mixing step. The blend is then compressed
using suitable tooling to the desired tablet weight and hardness.
Tablet properties:
API content [mg] 25 50 100 200
Compression force [kN] 3 3.3 4.2 3.5
Friability [%] 0.29 0.36 0.33 0.31
Page 52 07/2020
Fexofenadine Hydrochloride (30 mg)
The challenge with a fexofenadine HCl ODT formulation is the API's bitter taste.
To overcome this and facilitate patient compliance, its taste was masked by wet
granulation with polyvinyl alcohol (PVA) and sucralose. API
Fexofenadine
HCl
Granulation Formula C32H39NO4 ∙ HCl
Fexofenadine HCl 30.0 12.50 Molar mass 501.67 g/mol
Parteck® ODT (mannitol-based ODT Melting point 195 – 197 °C

110.0 45.83
BCS class III

Parteck® CCS
5.0 2.08
Solubility in Slightly
water soluble
Polyvinyl alcohol 4-88

3.0 1.25
(polyvinyl alcohol, 141350)
Water q.s.* q.s.*
Tableting
Parteck® ODT (100490) 53.0 22.09
Parteck® CCS
20.0 8.33
Parteck® LUB MST

4.0 1.67
Total 240 100
Manufacturing:
Fexofenadine HCl, Parteck® ODT and Parteck® CCS are weighed, sieved and
mixed in a rapid mixer granulator for 5-10 minutes. To make the granulation
solution, PVA is dissolved in warm water and cooled to room temperature.
Sucralose is dissolved separately in water. Both solutions are then mixed
together for 10 minutes. The powder mixture is then granulated using the
prepared granulation solution, dried, and sieved through appropriate sieves.
Next, the granules are blended with Parteck® ODT, sucralose, and Parteck® CCS
for 10 minutes in a cone mixer. Finally, Parteck® LUB MST is added to the blend,
followed by mixing for 5 minutes. The mixture is then compressed on a rotary
tablet press using a 9 mm round D tooling punch.
Page 53 07/2020
Even at a compression force of just 3.9 kN, good tablet hardnesses and low
tablet friabilities are observed. The tablets disintegrate quickly; those produced
at a compression force of 3.9 kN disintegrate within 30 seconds.
Page 54 07/2020
Glimepiride (3 mg)
Glimepiride 3.0 2.50 API

Glimepiride
93.0 77.50
Sodium dodecyl sulfate (817034) 5.0 4.17

Formula C24H34N4O5S
D(-)-Mannitol (105980) 10.0 8.33

Sucralose granular (100895) 2.0 1.67
Melting point 207 °C
Parteck® CCS
6.0 5.00
(croscarmellose sodium, 102310) pKa 4.99

1.0 0.83
Solubility in
Total 120 100 Practically insoluble
water
Manufacturing:
Glimepiride is mixed with sodium dodecyl sulfate. Parteck® ODT, Parteck® CCS,
sucralose and D(-)-mannitol are sieved and mixed separately. The two
mixtures are combined and mixed for 10 minutes in a double cone blender.
Parteck® LUB MST is added to the blend, which is then mixed for another
5 minutes. The mixture is then compressed on a rotary tablet press using a
7 mm round flat punch.
Even at a compression force of just 4 kN, good tablet hardnesses and low
tablet friabilities are observed. The tablets disintegrate quickly; those produced
at a compression force of 4 kN disintegrate within 30 seconds.
Page 55 07/2020
Glycopyrrolate (1 mg/2 mg)
Amount Amount Amount Amount

[mg/tablet] [% w/w] [mg/tablet] [% w/w]
API
1 mg 2 mg Glycopyrrolate
Glycopyrrolate 1 0.83 2 1.67
Parteck® M 200 (DC mannitol, Formula C19H28BrNO3

103.75 86.46 102.75 85.62
100419)
Citric acid anhydrous (100241) 3 2.5 3 2.5
Crospovidone 7 5.83 7 5.83 Solubility in

Freely soluble
water
Saccharin sodium dihydrate 1.5 1.25 1.5 1.25
Orange flavoring 1.5 1.25 1.5 1.25
Quinolin yellow lake 0.25 0.21 0.25 0.21
Parteck® LUB MST

2 1.67 2 1.67
Total 120 100 120 100
Manufacturing:
Glycopyrrolate is weighed and sieved with a mesh size of 250 µm.The
flavoring and coloring agents and saccharin sodium are weighed and sieved
through a mesh size of 425 µm. All ingredients are mixed using an octagonal
blender. Citric acid and crospovidone are sieved with a mesh size of 425 µm,
and added to the blend, followed by another mixing step. Parteck® M 200 is
weighed and sieved with a mesh size of 600 µm. Half of the sieved Parteck® M
200 material is added to the powder blend and mixed. This blend is
transferred into a blender with the remaining amount of Parteck® M 200, and
mixed for 10 min at 20 rpm. Parteck® LUB MST is sieved using a mesh size of
250 µm and added to the blend, followed by another mixing step for 3 min at
20 rpm. The mixture is compressed using a compression force of 2 – 3 kN
into tablets of 120 mg total tablet weight.
Page 56 07/2020
120 Figure 7:
110 Content uniformity test for low dose
glycopyrrolate ODT formulation
Drug content [%]
100 (target API content 1 mg) with direct

compression; content uniformity
90
according to the pharmacopoeial
80 specifications (acceptance value
AV = 13.8)
70
60
50
0 1 2 3 4 5 6 7 8 9 10
Tablet number
Page 57 07/2020
Ibuprofen (200 mg)
Ibuprofen 200 40 API

Ibuprofen
290 58
Silicon dioxide, highly dispersed Formula C13H18O2

5 1
(113126)

Parteck® LUB MST
5 1
Total 500 100
BCS class II
Solubility in
Manufacturing: water
Parteck® ODT, silicon dioxide and ibuprofen are blended for 5 minutes and
passed through a 1 mm sieve. Parteck® LUB MST is then sieved through a 250
µm sieve onto the pre-mixture, and all components are mixed for 2 minutes in
a shaker-mixer. In the next step, the tableting mixture is compressed on a
single-punch instrumented tablet press (50 rpm, 11 mm punch diameter, flat,
faceted) at 6, 12, 17 and 20 kN.
Hardness variation [%] 11.47 7.19 5.87 6.31
Friability [%] 0.20 0.16 0.28 0.23
Disintegration variation [s] 2 6 16 8
Page 58 07/2020
Ibuprofen (200 mg), Colored Tablet
The coloration of solid drug forms is a generally accepted and effective way to
prevent medication errors and to increase the safety of drug use. As coating
requires an additional process step, this formulation example describes how
API
tablets may be given an unmistakable appearance by dry blending only. In
Ibuprofen
addition to Parteck® ODT excipient, Parteck® SI and Parteck® M excipients are
also well-suited for direct compression of tablets containing Candurin®
pigments. Candurin® pearl effect colors are a unique range of mineral food and
pharmaceutical colors based on a natural silicate (mica) combined with
Formula C13H18O2
titanium dioxide and/or iron oxide. These colorants are widely used in tablet
coatings and capsules. Candurin® mineral, non-artificial pearl effect colors are
compatible with other colors and are exceedingly stable. They are also ideal for
pediatric nutritional formulations for which some synthetic colors have to be
labeled with a warning in the EU (Regulation (EC) No 1333/2008, Annex V, Melting point 75 – 77 °C
Official Journal of the European Union, L 354/16-L354/33).
BCS class II
Solubility in
water
Ibuprofen 200 40

278.75 55.75

5 1
stearate, 100663)
Candurin® Gold Sheen (120608) 15 3
Iron oxide yellow 1.25 0.25
Total 500 100
Manufacturing:
Ibuprofen, Parteck® ODT and the coloring agents are blended for 5 minutes in a
shaker-mixer. Next, magnesium stearate is added, then all components are
again blended for 5 minutes.
In the next step, the tableting mixture is compressed on a single-punch
instrumented tablet press into 11 mm tablets with a total tablet weight of 500 mg.
Page 59 07/2020
Hardness variation [%] 6.8
Friability [%] 0.35
Figure 8:
A B
A) SEM of Parteck® ODT and
Candurin® particles B) Pearlescent
Parteck® and Candurin® tablets
exhibiting a shiny surface with a
homogeneous, uniform golden color.
30 μm
The SEM picture shows the microstructure and the distribution of the flat
Candurin® platelets on the excipient particles (Figure 8 A).
The platelets are fixed by adsorption onto the rough surface structure of the
polyol excipient particles, facilitating good content uniformity throughout the
tableting process. The resulting tablets have a shiny surface with a
homogeneous, uniform golden color (Figure 8 B).
To assess possible effects of Candurin® and iron oxide yellow on the dissolution
behavior of the formulation, tablets without coloring agents were also
manufactured. No effect of Candurin® on the in vitro dissolution profile was
observed (data not shown).
The study results show that Parteck® ODT excipient and Candurin® pearl effect
colors are perfectly compatible with other formulation ingredients and boast
excellent direct compressibility, making them suitable for cost-effective
production of rapidly disintegrating oral tablets. Using Candurin® pearl effect
colors during direct compression eliminates the need for additional film coating,
and gives tablets an unmistakable luster that helps prevent medication errors
while making it harder for counterfeiters to copy drug products.
Page 60 07/2020
Loratadine (10 mg)
Loratadine 10 5.4 API

Loratadine
166.67 90.1
Sucralose powder (100894) 1.85 1

Formula C22H23ClN2O2
Parteck® LUB MST

2.78 1.5 Molar mass 382.89 g/mol
Parteck® LUB STA 50 Melting point 134 – 136 °C

3.7 2
pKa 5.25
Total 185 100
BCS class II
Manufacturing: water insoluble
Parteck® ODT, sucralose and loratadine are blended for 5 minutes and passed
through a 1 mm sieve. Parteck® LUB MST and Parteck® LUB STA 50 are then
sieved through a 250 µm sieve onto the pre-mixture, and all components are
mixed for 2 minutes in a shaker-mixer. In the next step, the tableting mixture
is compressed on a single-punch instrumented tablet press (50 rpm,
9 mm punch diameter, biconvex) at 3, 6, 8 and 10 kN.
Friability [%] 0.49 0.34 0.26 0.29
Disintegration variation [s] 4 3 8 6
Page 61 07/2020
140 60 Figure 9:
Influence of compression force
120 on disintegration time and tablet
50
hardness.
100

40
Tablet hardness [N]
80
30
60
20
40
10
20
0 0
3 6 8 10
Tablet hardness
Disintegration time
The loratadine formulation based on Parteck® ODT excipient shows very good
tablet disintegration times over a broad range of compression forces. Even at
high tablet hardnesses, the disintegration time is short. Tablet friability remains
low for all disintegration times.
Page 62 07/2020
Paracetamol 100 25 API

Paracetamol
239.6 59.9
Microcrystalline cellulose (MCC) DC Formula C8H9NO2

40 10
100 µm

Sodium stearyl fumarate 12 3
Silicon dioxide, highly dispersed Melting point 169 – 170.5 °C

4 1
(113126)
BCS class I
Dry cherry flavoring 2 0.5 water soluble
Total 400 100
Manufacturing:
Paracetamol, Parteck® ODT, MCC, silicon dioxide, sucralose powder and the
flavoring are blended for 5 minutes and passed through a 1.0 mm sieve. Next,
sodium stearyl fumarate is sieved through a 250 μm sieve onto the mixture,
then all components are again blended for 5 minutes in a shaker-mixer. After
that, the tableting mixture is compressed at 50 rpm using a single-punch
instrumented tablet press at different compression forces into 11 mm biconvex
Page 63 07/2020
Paracetamol 97% 257.7 51.5 API

Paracetamol
222.3 44.5
Silicon dioxide, highly dispersed Formula C8H9NO2

15 3
(113126)

Total 500 100 Melting point 169 – 170.5 °C
BCS class I
Manufacturing: Solubility in Sparingly

water soluble
Parteck ODT, paracetamol and silicon dioxide are blended for 5 minutes and
®
passed through a 1 mm sieve. Sodium stearyl fumarate is then sieved through

a 250 µm sieve onto the pre-mixture, and all components are again blended for
5 minutes in a shaker-mixer. In the next step, the tableting mixture is compressed
on a single-punch instrumented tablet press (50 rpm, 11 mm punch diameter,
flat, facetted) at 6, 10 and 20 kN.
Friability [%] 0.26 0.25 0.21
Disintegration variation [s] 16 7 4
Page 64 07/2020
Rosuvastatin (5 mg)
Since rosuvastatin is a moisture- and light-sensitive API susceptible to oxidation

and hydrolysis, a direct compression process was chosen. Special consideration
was given to the selection of excipients due to a possible effect on API stability. API
Rosuvastatin
calcium

Formula (C22H27FN3O6S)2 Ca
Rosuvastatin calcium 5.21* 2.605
Parteck® ODT (mannitol-based ODT Molar mass 1001.14 g/mol

149.79 74.895
pKa 4.6
Meglumine (106187) 3.00 1.50
BCS class II
Parteck® CCS
15.00 7.50
(crosscarmellose sodium, 102310) Solubility in Slightly
water soluble
16.50 8.25
100 µm

2.00 1.00
(113126)
Talc 5.00 2.50
Parteck® LUB MST

2.50 1.25
Total 200 100
*5.21 mg rosuvastatin calcium is equivalent to 5 mg of rosuvastatin.
Manufacturing:
Rosuvastatin calcium is mixed with meglumine, subsequently adding MCC,
Parteck® CCS, silicon dioxide, sucralose and talc. Parteck® ODT is sieved
separately and blended with the previous mixture for 15 minutes in a double
cone blender. Parteck® LUB MST is added to the blend, which is then mixed for
another 5 minutes. The mixture is then compressed on a rotary tablet press
using an 8 mm round flat punch.
Page 65 07/2020
120 Figure 10:

Dissolution profile of rosuvastatin
100
calcium ODT tablets based on
Parteck® ODT compressed at 4.1 kN.
Drug release [%]
80
60
40
20
0
0 10 20 30 40 50
Time [min]
The tablets disintegrate within 30 seconds. Even at a compression force of just

4 kN, good tablet hardnesses and low tablet friabilities are observed.
Page 66 07/2020
Sildenafil (50 mg)
Sildenafil citrate 71.14* 35.57 API

Sildenafil
citrate
107.86 53.93
Silicon dioxide, highly dispersed Formula C28H38N6O11S

1 0.5
(113126)

15 7.5
100 µm
BCS class I
Parteck® LUB MST
2 1
(magnesium stearate, 100663) Solubility in
Slightly soluble
water
Total 200 100
*71.14 mg sildenafil citrate is equivalent to 50 mg of sildenafil.
Manufacturing:
Parteck® ODT, MCC, sucralose, sildenafil citrate and silicon dioxide are
blended for 5 minutes and passed through a 1 mm sieve. Parteck® LUB MST
is then sieved through a 250 µm sieve onto the pre-mixture, and all
components are mixed for 2 minutes in a shaker-mixer. In the next step, the
tableting mixture is compressed on a single-punch instrumented tablet press
(50 rpm, 9 mm punch diameter, biconvex) at 6, 8 and 12 kN.
Friability [%] 0.56 0.24 0.23
Disintegration variation [s] 5 2 4
Page 67 07/2020
200 60 Figure 11:

180 Influence of compression force
50 on disintegration time and tablet
160
hardness.

Tablet hardness [N]
140
40
120
100 30
80
20
60
40
10
20
0 0
6 8 12
Page 68 07/2020
Solubility Enhancement
Hot-melt extrusion
Hot-Melt Extrusion
Sufficient aqueous solubility is one prerequisite for Our Formulation Ingredients

absorption of the API into the body and the needed
functionality in vivo. There are different methods to Category Products
increase solubility, such as by using an inorganic drug
carrier or creating a solid dispersion or solution via a Hot-melt extrusion
variety of techniques, including hot-melt extrusion.
As there is no one-size-fits-all solution, an appropriate Matrix polymer Parteck® MXP (polyvinyl alcohol, 141464)
approach must be chosen depending on the properties suitable for
of the API, the desired final dosage form and the HME
required formulation performance.
Plasticizer Parteck® SI 150 (sorbitol, 103583),
meglumine (106187), triethyl citrate
Hot-melt extrusion (817059), polyethylene glycol (e.g. PEG
6000, 817007)
Hot-melt extrusion (HME) is a solvent-free process
Plasticizers can be used to reduce processing
which, through heating and mixing, disperses the API
temperature without influencing torque or
within a matrix polymer, often at a molecular level. die pressure.
The resulting solid dispersion or solid solution shows
an increased dissolution rate and improved apparent
solubility for otherwise extremely poorly soluble
Downstream processing into final formulation
APIs. The extrudate intermediate can be processed (e.g. tablet)
further for final drug formulation. HME is also highly
suitable for continuous manufacturing processes, the
benefits of which include real-time quality control Diluent Parteck® M (DC mannitol, 100419,
100494), Parteck® Delta M (mannitol,
based on process analytical technology (PAT), less
112635), Parteck® SI (DC sorbitol, 103583,
complex scale-up, and a reduction in raw material 115079, 103140, 103557), lactose
and intermediate inventories. monohydrate (107656, 108195), calcium
hydrogen phosphate dihydrate (102146),
calcium hydrogen phosphate anhydrous
= API (102144, 102304), calcium phosphate
= MATRIX POLYMER (102143)
COOLING
stearate, 100664), Parteck® LUB STA
MELTING MIXING HOMOGENEOUS
DISPERSION Glidant Silicon dioxide, highly dispersed (113126)
Schematic overview of the HME process
Page 69 07/2020
Manufacturing process: Following the extrusion Screw and barrel design:

process, the extrudate may be directly shaped into
Typically, the screw design of a lab- or production-
tablets or processed downstream into a variety
scale extruder can be set according to the individual
of final formulations such as capsules or tablets
formulation needs. An example screw design is shown
(typically using pelletized or milled extrudate).
below. Three different kneading zones ensure good
Formulation requirements: Stable final dosage form mixing of the polymer melt. Optional vent ports can be
with defined release kinetics of APIs. used for degassing in order to remove residual moisture
during the process.
Formulation challenges: Solubility enhancement
of APIs (e.g. in the case of amorphous solid
dispersions), achievable drug load, stability of the
API (heat/shear stress), storage stability of the
formulation (recrystallization possible in the case of
supersaturated solutions). There is a large potential
pool of insoluble (BCS II and IV) APIs for which
HME can be used. However, this API range can be
limited due to factors such as the thermostability of Schematic view of the screw configuration used for the extrusion of
the API and/or polymer, the compatibility of the API the sample formulation of itraconazole with Parteck® MXP excipient
and polymer (and plasticizer, where necessary), and presented in this chapter.
undesired chemical interactions with the polymer

which can lead to degradation of the API. Screening methods
Formulation benefits: Different release kinetics In early development stages, there is usually only a
are possible depending on the matrix polymer used, very limited amount of API available for initial solid
pellet size or final formulation. dispersion testing. At the same time, it is crucial to
select the right polymer-API combination. Screening
Raw material recommendation: Excellent methods can serve this purpose and help to quickly
flowability, homogeneity with APIs, solubilization assess the compatibility of API and polymer (polymer
capacity with APIs, thermostability. screening), API load, and stability.
Packaging: Tightly sealed, moisture-proof containers Solvent film casting
or packs. Packaging dependent on final formulation
type. There are a number of suitable solvents and/or
solvent mixtures available that enable pre-experiment
Recommended for: APIs with poor aqueous film casting for insoluble drugs prior to extrusion
solubility; mainly BCS class II compounds, also BCS (see Table 1 for suitable solvents for Parteck® MXP
class IV; APIs not sensitive to heat (high degradation excipient). Please be advised that there are potential
temperatures). Plasticizers such as sorbitol can be limitations to this method, including possible
added to reduce processing temperatures as well as deviations from the predicted results and actual
enable the formulation of APIs with low or medium HME results, resulting in a limited predictability of
melting temperatures. performance. Also, the method is typically not well-
suited to water-soluble polymers.
Page 70 07/2020
Formulation Examples: Solubility Enhancement –
Hot-Melt Extrusion
Table 1:
Solubility at room Solubility when organic
Solvent Boiling point Solubility of Parteck® MXP excipient
temperature 25 °C solvent heated in different organic solvents at 25 °C,
as well as with initial heating of the
MeOH 65 °C 0.07 mg/mL 1.07 mg/mL at 50 °C polymer in the solvent, which was
then cooled to room temperature
before measurement of the solubility.
EtOH 78 °C 0.04 mg/mL 1.17 mg/mL at 50 °C
This heating and cooling process is
recommended to increase the kinetic
Acetone 56 °C 0.03 mg/mL No data available solubility of Parteck® MXP excipient
in the organic solvent if the solubility
Acetonitrile 82 °C 0.06 mg/mL 0.87 mg/mL at 50 °C at 25 °C proves insufficient for the
concentrations required by the pre-
extrusion assessment.
MTBE 55 °C 0.05 mg/mL No data available
DMF 153 °C 0.06 mg/mL 15.9 mg/mL at 90 °C
DMSO 189 °C 17.1 mg/mL 20.2 mg/mL at 50 °C
DCM 40 °C 0.06 mg/mL No data available
NMF 203 °C 0.06 mg/mL 19.2 mg/mL at 90 °C
THF 66 °C 0.09 mg/mL 0.98 mg/mL at 50 °C
Differential scanning calorimetry (DSC)

To overcome the limitations of solvent film casting and enable reliable
screening prior to extrusion, a simplified DSC heating program was developed.
It involves heating the closed DSC pan from 25 to 230 °C at a rate of 30 °C/
min, followed by a heating isotherm for 3 min at 230 °C, then a cooling step
from 230 back down to 25 °C at a rate of 30 °C/min.
Figure 12:
Fill physical mixture of API and polymer directly into DSC Schematic overview of DSC screening
pan. Target weight: 25 mg (100 µL pan) method
Close the DSC pan
Initiate dedicated heating program
Remove cover of DSC pan -> further analysis
Page 71 07/2020
Hot-Melt Extrusion
900 Figure 13:

A
800 Direct comparison of the dissolution
profile of hot-melt-extruded
700 formulation (A) vs. DSC screening
method (B) using ketoconazole as the
Concentration [µg/ml]
600 model API (DL 20%) and 4 different

commercially available polymers,
500
including Parteck® MXP excipient.
400
300
200
100
0 20 40 60 80 100 120
Time [min]
900
B
800
700
600
500
400
300
200
100
0 20 40 60 80 100 120
Time [min]
Crystalline API Polymer 2
Parteck® MXP excipient Polymer 3
Polymer 1
While Figure 13 shows that the screening results cannot be transferred 1:1 to
the final extrudate (results A vs. B), a good correlation of the solubility
enhancement properties exists (onset of dissolution data) and allows for the
selection of suitable polymers. The DSC screening method can be easily
implemented using existing equipment.
Page 72 07/2020
Hot-Melt Extrusion
Vacuum compression molding (VCM)

This is an alternative screening method that allows for a deeper understanding
of your formulation and makes it possible to perform an extended analytical
evaluation including DSC, PXRD and/or advanced dissolution testing. After the
application of vacuum and compression, the blend is heated using a simplified
heating program. As with the DSC screening, this comprises a heating step
from 25 to 230 °C at a rate of 30 °C/min, followed by a heating isotherm for
3 min at 230 °C, then a cooling step from 230 back down to 25 °C at a rate of
30 °C/min.
Figure 14:
Schematic overview of VCM screening
method
Insert physical Apply vacuum Initiate the Cool to room

mixture (polymer and compress heating program, temperature as
+ API) the mixture including defined above
isothermal step
The VCM screening method provides reliable insights in the polymer

performance. The capability of the polymers to enhance the supersaturation of
poorly water-soluble soluble drug substances after release is an important
aspect during screening which can be successfully assessed. When compared to
the performance of the final extrudate (Fig. 15 A), the screening results
(Fig 15 B) show a clear correlation, making it possible to select the ideal matrix
polymer for the API in question. In the presented examples, PVA provides an
extended prolongation of the supersaturated state after release. The difference
between PVP/VA copolymer and PVP which is demonstrated in the screening
tool can also observed in the extruded formulations. The generally observed
earlier precipitation of the samples created via VCM screening is potentially a
result of remaining crystalline residuals.
Page 73 07/2020
Hot-Melt Extrusion
900 Figure 15:

A
800 Direct comparison of the dissolution
profile of hot-melt-extruded
700 formulation (A) vs. VCM screening
method (B) using ketoconazole as the
600 model API (DL 20%) and 4 different

commercially available polymers,
500
including Parteck® MXP excipient.
400
300
200
100
0 20 40 60 80 100 120
Time [min]
900
800
700
B
600
500
400
300
200
100
0 20 40 60 80 100 120
Time [min]
Crystalline API Polymer 2
Parteck® MXP excipient Polymer 3
Polymer 1
Page 74 07/2020
Hot-Melt Extrusion
Indomethacin Extrudate
Process conditions:
Parameter
API
Indomethacin
API load 50%
Temperature 20 °C 80 °C 180 °C 180 °C 180 °C 180 °C
RPM 200 rpm Formula C19H16ClNO4
Dosing rate 200 g/h Molar mass 357.79 g/mol
Pressure ~8 bar Melting point 151°C
Torque 7 - 8%
LogP 4.27
Nozzle diameter 2.0 mm
pKa 4.5
SME [kW/h∙kg] 0.291
H-acceptors 4
H-donors 1
Manufacturing:
Depending on the process setup, a drying step may or may not be necessary BCS class II
for Parteck® MXP excipient prior to the extrusion. In the present case and at
this scale, the Parteck® MXP material is dried at 85 °C (under vacuum) for Solubility in Practically
water insoluble
1 hour or at 105 °C for 3 hours.
Indomethacin is mixed with Parteck® MXP in a shaker-mixer for 5 minutes at
46 rpm. The mixture is then filled into a feeder and extruded using the given
process parameters. The extrudate is cut using a pelletizer into pellets of 1 mm
length and milled into powder using an ultra centrifugal mill at 18,000 rpm with
a 0.35 ring sieve insert under the application of liquid nitrogen cooling. The
milled extrudate powder is used for analytical assessment and is suitable
for further downstream processing methods such as tableting.
Page 75 07/2020
Hot-Melt Extrusion
Solid state analysis:

DSC thermograms confirm the amorphous state of the API after extrusion.
A glass transition is seen at about 51 °C, and no crystalline melting peak of
the API is observed in the targeted temperature range (see Fig. 16).
0 Figure 16:
DSC thermogram of indomethacin-
Parteck® MXP extrudate (DL 50%
-1 w/w) compared to pure crystalline
Heat flow [W/g]
API.
-2
-3
-4
20 40 60 80 100 120 140 160 180 200

Temperature [°C]
Crystalline indomethacin
Extruded Parteck MXP (50% indomethacin)
Dissolution behavior:
Figure 17 shows that the initial dissolution rate and maximum amount of API
dissolved in the medium was improved for the extrudate formulation in
comparison to the crystalline, unprocessed API.
350 Figure 17:

Dissolution of milled indomethacin-
300
Parteck® MXP extrudate
250
Dissolution [mg/L]
Dissolution procedure:
FDA-recommended conditions for
200 indomethacin 500 mL, FeSSIF, 37 °C,
75 rpm, 150 mg indomethacin,
150 30% drug load; n=3
100
50
0 100 200 300 400 500 600 700 800

Time [min]
Crystalline indomethacin Indomethacin: Parteck® MXP Extrudate
Storage stability:
The stability of the hot-melt-extruded formulation was assessed under three
different sets of conditions: cold (2 – 4 °C), room temperature (25 °C / 60% rH),
and accelerated (40 °C / 75% rH). At each time point, the extrudates were
measured using DSC (to assess the amorphous state), HPLC (to assess API
degradation), and repeat dissolution. In all three cases, no instability was found
throughout the testing period of 6 months.
Page 76 07/2020
Hot-Melt Extrusion
Itraconazole Extrudate
Process conditions:
Parameter
API
Itraconazole
API load 30%
Temperature 20 °C 80 °C 190 °C 190 °C 190 °C 190 °C
RPM 200 rpm Formula C35H38Cl2N8O4
Dosing rate 200 g/h Molar mass 705.64 g/mol
Pressure ~ 2-3 bar Melting point 166.2 °C
Torque 10 – 21%
logP 5.90
Nozzle diameter 2.0 mm
pKa 3.7
SME [kW/h∙kg] 0.601
H-acceptors 9
H-donors 0
Manufacturing:
Depending on the process setup, a drying step may or may not be necessary BCS class II
for Parteck® MXP excipient prior to the extrusion. In the present case and at
this scale, the Parteck® MXP material is dried at 85 °C (under vacuum) for 1 Solubility in Practically
water insoluble
hour or at 105 °C for 3 hours.
Because of its poor flowability, itraconazole is granulated with Parteck® MXP
excipient and water (50% relative to the total amount of itraconazole and
Parteck® MXP) in a low-shear mixer first. The granules are then filled into a
feeder and extruded using the given process parameters. The extrudate is cut
using a pelletizer into pellets of 1 mm length and milled into powder using an
ultra centrifugal mill at 18,000 rpm with a 0.35 ring sieve insert under the
application of liquid nitrogen cooling. The milled extrudate powder is used for
analytical assessment and is suitable for further downstream processing
methods such as tableting.
Solid state analysis:

DSC thermograms of the API and itraconazole-loaded extrudate are shown in
Fig. 18. The distinct melting point of the crystalline API at about 166 °C cannot
be seen in the extruded product, indicating the amorphous state of the API. A
prominent glass transition can be detected at about 60 °C, followed by slight
indications of mesophase transitions between 70 °C and 90 °C.
The solid state analysis by XRD confirms these results, clearly indicating that
no crystalline API is present in the extrudate.
Page 77 07/2020
Hot-Melt Extrusion
Figure 18:
0.0 DSC thermogram of itraconazole-
Parteck® MXP extrudate (DL 30%)
compared to the pure crystalline API.
-0.5
Heat flow [W/g]
-1.0
-1.5
-2.0
-2.5
20 40 60 80 100 120 140 160 180 200

Temperature [°C]
— Crystalline itraconazole
— Extruded Parteck® MXP (30% itraconazole)
Dissolution behavior and storage stability:

Since possible degradation and recrystallization of the API is a frequently
described challenge in HME formulations, special emphasis was placed on the
storage stability analysis. Samples were stored under three different sets of
conditions: cold (2 – 4 °C), room temperature (25 °C/60% rH), and accelerated
(40 °C/75% rH). Repeat dissolution, DSC (to assess the amorphous state of
the API; data not shown) and HPLC (to detect API degradation; data not shown)
were used to analyze the extrudates. No instability was found throughout the
testing period of 12 months regardless of the conditions.
120 Figure 19:

Dissolution profile of itraconazole-
100 Parteck® MXP extrudates (DL 30%)
directly after manufacture and after
12 months of storage under cold
Dissolution [mg/L]
80 (2 – 4 °C), room temperature (25 °C /

60% rH), and accelerated conditions
(40 °C /75% rH) compared to the
60
pure crystalline API.
40
20
0
0 20 40 60 80 100 120
Time [min]
Crystalline itraconazole Extrudate after 12 months at 25 °C / 60% rH
Extrudate at t=0 Extrudate after 12 months at 40 °C / 75% rH
Extrudate after 12 months at 2 - 4 °C
Page 78 07/2020
Hot-Melt Extrusion
Improving the supersaturation of poorly soluble drug substances:

Parteck® MXP excipient is able to not only increase the dissolved amount of API
to above saturation level, but also to delay the precipitation of poorly soluble
APIs and maintain supersaturation levels for a prolonged amount of time, which
can enhance the bioavailability of the API in vivo.
60 Figure 20:
Dissolution profile of itraconazole-
50 Parteck® MXP extrudate (DL 30%)
with a pH shift after 120 min
compared to the API’s saturation
Drug release [mg/L]
40 solubility concentration.
30
20
10
0
0 30 60 90 120 150 180 210 240
Time [min]
30% itraconazole-loaded Parteck® MXP matrix
Saturation solubility of pure itraconazole
Biphasic dissolution:
In-vitro biphasic dissolution studies were performed to assess a possible effect
of hot-melt extrusion with Parteck® MXP excipient on dissolution and
subsequent absorption in comparison to the crystalline form of the API. A
significant increase in API concentration in the receiver compartment for the
hot-melt-extruded formulation was shown, with the crystalline API reaching
concentrations of 2-10 ng/ml after 180 min and the extrudate reaching
concentrations as high as 180-780 ng/ml.
Final formulation:
Depending on the formulation, it is possible to apply Parteck® MXP excipient for
both sustained and immediate release formulations, which makes it a very
versatile excipient in HME. In the present example, the itraconazole-Parteck®
MXP extrudate was formulated into oral tablet formulations with different
release kinetics (see Figure 21). For further final formulation examples,
including capsules and directly-shaped tablets, please refer to the publication
Kasselkus, A., E. Weiskircher-Hildebrandt, et al. (2018) Polyvinyl alcohol -
Revival of a long lost polymer. BioProcess Online, 2018 or contact your sales
representative.
Page 79 07/2020
Hot-Melt Extrusion
100 Figure 21:

Dissolution profile of compressed
80 tablets: Sustained release and
immediate release, depending on the
Dissolution [%]
tablet composition
60
40 Dissolution procedure:
itraconazole, 900 mL SGF, 37 °C, 100 rpm,
20 30% drug load; n = 3
0 20 40 60 80 100 120 140
Time [min]
Tablet 1 Tablet 2
Tablet 3 Tablet 4
crystalline itraconazole
Formulation composition of compressed tablets

based on a itraconazole-Parteck® MXP extrudate
Tablet 1 Tablet 2 Tablet 3 Tablet 4
Extrudate [%] 50 50 50 60
Microcrystalline cellulose [%] 10 10 10 10
K2CO3 [%] - - 14.75 10
NaCl [%] 14.75 14.75 - -
Magnesium stearate [%] 0.5 0.5 0.5 0.5
Lactose [%] 16.25 16.25 16.25 11
Silicon dioxide, highly dispersed [%] 1 1 1 1
Crospovidone [%] 7.5 7.5 7.5 7.5
Tmax [min] 15 30 60 120
Page 80 07/2020
Hot-Melt Extrusion
Lamotrigine (25 mg) Tablet
Process conditions:
Parameter API
Lamotrigine
API load 30%
Polymer 65%
Formula C9H7Cl2N5
Plasticizer 5%
Operating temperature range 160 - 180 Molar mass 256.1 g/mol
Screw speed [rpm] 25 Solubility in

Very slightly soluble
water
Feeder speed [rpm] 80
Torque [Ncm] 55 - 20
Manufacturing of extrudates:
API lamotrigine, matrix polymer Parteck® MXP and plasticizer Parteck® SI 150
are sieved separately using a mesh size of 425 µm, followed by a mixing step
at slow speed for 5 minutes. The mixture is then filled into a feeder and
extruded using the given process parameters.
Figure 22:
DSC thermograph of lamotrigine-
Parteck® MXP extrudate (DL 30%)
compared to the pure crystalline API
20 mW
230 240 250 260 270
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220
Temperature [°C]
— Pure lamotrigine — Lamotrigine-Parteck® MXP extrudate
Page 81 07/2020
Hot-Melt Extrusion
Tableting:
Lamotrigine extrudate* 83.33 33.33
Microcrystalline cellulose
50 20
(MCC) DC 100 µm
Parteck® CCS (croscarmellose sodium,

10 4
102310)

3 1.2
stearate, 100663)
Total 250 100
*amount is equivalent to an API content of 25 mg in the final tablet.
Manufacturing of tablets:
Milled lamotrigine extrudate, MCC and Parteck® CCS are weighed and sieved
with a mesh size of 425 µm. Parteck® M 200 is sieved separately using a mesh
size of 600 µm. All ingredients are mixed using a suitable mixer for 10 minutes.
Parteck® LUB MST is sieved through a mesh size of 250 µm onto the mixture,
followed by another mixing step. The blend is then compressed using suitable
tooling to a target tablet weight of 250 mg at a compression force of 9 kN.
Tablet properties: Amount [mg/tablet]
Friability [%] 0.32
Page 82 07/2020
Hot-Melt Extrusion
100 Figure 23:

Dissolution profile of lamotrigine
tablet 25 mg based on extrudate
80 with Parteck® MXP excipient (DL
30% w/w) compared to the pure
Drug release [%]
crystalline API.
60
Dissolution procedure: USP Apparatus
2 (Paddle), 900 mL, pH 1.2 HCl
40 buffer, 50 rpm, 37 °C; n=3
20
0 10 20 30 40 50 60 70
Time [min]
Crystalline API Lamotrigine tablet
Page 83 07/2020
Sufficient aqueous solubility is one prerequisite for Our Formulation Ingredients
absorption of the API into the body and the needed
functionality in vivo. There are different methods to
increase solubility, such
Formulation as by using an inorganic drug
Handbook
carrier or creating a solid dispersion or solution via a
variety of techniques, including hot-melt extrusion.
As there is no one-size-fits-all solution available, an
appropriate approach must be chosen depending on
the properties of the API, the desired final dosage
form and the required formulation performance.
Inorganic Carriers
Inorganic carriers
As such, silica is widely used in solid oral dosage
Sufficient
forms for aqueous solubility
flow enhancement or as an is antiadhesive.
one prerequisite for Our Formulation Ingredients
The useabsorption of theParteck
of mesoporous API into ® the body and the needed
SLC to enhance the Category Products
functionality
solubility in vivo. Theresmall
of poorly water-soluble are different
moleculemethods
APIs to
increase solubility, such as by using
is novel and is only possible with specially designed an inorganic drug
carrier or creating a solid dispersion or solution via a Loading procedure
silica particles that have mesopores and a large
surfacevariety of techniques,
area. For including
this application, the APIhot-melt
needs extrusion.
to
As there
be loaded is no
onto the one-size-fits-all
surface of the silica solution available, an
particles, Inorganic Parteck® SLC 500 (mesoporous silica,
such asappropriate
by dissolving approach
the API must be selected
in organic solventdepending
and carrier 120091)
removingon the
the solvent
properties of the
during theAPI, the desired
loading process.final
Thedosage
form andpresent
API is typically the required formulation
in its more soluble performance.
amorphous Solvent Organic solvents with a low boiling point
form, embedded in the porous surface structure of and high vapor pressure to ensure easy
the Parteck® SLC carrier particles, which may then be and comprehensive removal after the
loading process and for compliance with
Inorganic
formulated carriers
into solid oral dosage forms.
limits for residual solvent content.
As such, silica is widely used in solid oral dosage Examples of suitable solvents include:
forms for flow enhancement or as an antiadhesive.
Acetone (100013), ethanol (100967),
The use of mesoporous Parteck® SLC excipient methanol (106008), dichloromethane
to enhance the solubility of poorly water-soluble (106049)
small molecule APIs is novel and is only possible
with specially designed silica particles that have
Downstream processing into final formulation
mesopores and a large surface area. For this (e.g. tablet)
application, the API needs to be loaded onto the
surface of the silica particles, such as by dissolving
Diluent Parteck® M (DC mannitol, 100419,
the API in organic solvent and removing the solvent
100494), Parteck® Delta M (mannitol,
during the loading process. The API is typically 112635), Parteck® SI (DC sorbitol, 103583,
present in its more soluble amorphous form, 115079, 103140, 103557), lactose
embedded in the porous surface structure of the monohydrate (107656, 108195), calcium
Parteck® SLC carrier particles, which may then be hydrogen phosphate dihydrate (102146),
formulated into solid oral dosage forms. calcium hydrogen phosphate anhydrous
(102144, 102304), calcium phosphate
(102143)

stearate, 100664), Parteck® LUB STA
Crystalline API API dissolved in Amorphous API loaded Improved API

organic solvent on Parteck® SLC excipient dissolution
Schematic overview of the functionality of inorganic (meso-)porous drug carriers
Page 84 07/2020
Manufacturing process: Loading of the API onto •T

he API is dissolved in the organic solvent
the carrier, typically via adsorption within the porous (recommendation: ≥10% below saturation solubility).
structure in the amorphous phase. Further processing of
tirring of Parteck® SLC excipient in a sealed beaker
•S
the loaded carrier after a drying step, e.g. into tablets
in a water bath set to the boiling temperature of the
via direct compression (see “General description of the
solvent. Gentle mixing settings are preferred,
loading process” for more details).
e.g. 15 rpm, to avoid powder turbulences.
Formulation requirements: Stabilization of the API in
ropwise addition of API solution to Parteck® SLC
•D
its better soluble amorphous form throughout storage.
excipient. The delivery rate depends on the scale
Formulation challenges: Finding a suitable solvent used; the droplet size should not be too small so as to
(loading process); high API dose, as silica load factor avoid solvent evaporation before API reaches the pore
is approx. 30% and maximum silica content in tablet structure of the Parteck® SLC particle, which would
is also approx. 30%; smaller API dosages are most induce a risk of crystallization.
likely better suited to ensure feasible tablet size; tablet
• I f the Parteck® SLC powder begins to form lumps or
hardness in case of very high silica content (a lot higher
granules, this is an indication that it is oversaturated
than 30%).
with solvent. In this case, the addition of API should
Formulation benefits: Good organic solubility is only be paused to allow the Parteck® SLC material to dry
required for the API. This offers benefits compared to (with continuous stirring).
polymeric amorphous solid dispersion where finding a
•A
fter complete addition of the API solution, the loaded
solvent for both API and polymer can be challenging.
Parteck® SLC material is dried for several hours (or
Raw material recommendation: Dry rather than overnight) in an oven set to the boiling point of the
overly humid, as silica is somewhat hygroscopic. solvent and at reduced pressure.
Packaging: Tightly sealed, moisture-proof containers •F
ollowing the loading process, analytical tests
or packs. assessing the residual solvent content should be
performed.
Recommended for: APIs with poor aqueous solubility;
mainly BCS class II compounds, also BCS class IV; This technique has been developed to allow the use
ideally suited to compounds with both poor solubility of commonly available laboratory equipment instead
and amorphous stability due to enhanced stabilization of specialized equipment. In this document, only
in the nano-sized pores. a simplified description of the loading process is
given. More information on lab-scale loading and the
General description of the loading process
equipment needed for the process can be provided on
Prior to loading the API onto the silica carrier, a suitable request. Please contact your local sales representative.
organic solvent from which the API will be loaded must
be determined. It is important to choose a solvent with
an appropriate boiling point, as this is critical for the
easy removal of the solvent after the loading process.
The loading process itself needs to be performed in
a well-ventilated environment suitable for handling
organic solvents. Nitrogen and gas removal is applied
to prevent solvent condensation. The application of
vacuum and sweep gas (nitrogen) also ensures the
comprehensive removal of the organic solvent.
Page 85 07/2020
Inorganic Carriers
Carvedilol Loading (without Final Formulation)
Loading procedure (lab-scale loading)

• Dissolution of carvedilol in acetone
API
•D
ropwise addition of the API solution to the silica powder via solvent Carvedilol
impregnation method
• Removal of residual solvent by drying overnight at 50 °C
• A target drug load of 25% (w/w) Formula C24H26N2O4

2 Wg-1
BCS class II
water insoluble
30 40 50 60 70 80 90 100 110 120 130 140 °C

Figure 24:
Pure carvedilol Parteck SLC, API load 25%

® DSC thermogram of carvedilol-loaded
Parteck® SLC excipient (DL 25% w/w)
60
DSC method: Temperature range

50 30 – 150 °C, scan rate 5 K/min,
nitrogen gas flow 50 mL/min.
Drug release [µg/mL]
Weighted samples corresponding to

40 an amount of 2 mg API were used.
30
20
Figure 25:
Dissolution profile of carvedilol-loaded
10 Parteck® SLC excipient (DL 25% w/w)
0
0 20 40 60 80 100 120
Time [min] Dissolution procedure:
USP Apparatus 2 (Paddle Apparatus),
Parteck SLC, API load 25%
®
API solubility (24h shake-flask method) 1000 mL phosphate buffer pH 6.8,
Crystalline API 75 rpm, 37 °C, n=3
Tests performed under sink conditions
Differential scanning calorimetry (DSC) thermograms confirm that carvedilol is

present in its amorphous state after loading onto Parteck® SLC excipient (see
Fig. 24). The dissolution rate is increased compared to the pure crystalline API.
After 120 minutes of dissolution, the amount of dissolved API is 2.2 times the
saturation solubility (see Fig. 25).
Page 86 07/2020
Inorganic Carriers
Entacapone Loading (without Final Formulation)

• Dissolution of entacapone in acetone
API
•D
ropwise addition of the API solution to the silica powder via solvent Entacapone
impregnation method
• A target drug load of 33% (w/w) Formula C14H15N3O5
Amount [g] Amount [%]

Melting point Practically insoluble
Entacapone 5 33.33
Parteck® SLC (mesoporous silica,

10 66.67
120091)
Acetone (127021) 150* *
*Solvent evaporated during the drying step of the process.
Figure 26 shows that the dissolution rate and maximum amount of dissolved
API are significantly enhanced compared to the pure, crystalline API.
80 Figure 26:
Dissolution profile of entacapone-
70
loaded Parteck® SLC excipient (DL
33% w/w) compared to the pure
60
crystalline API.
Drug release [%]
50
40
2 (Paddle), 900 mL, water, 50 rpm,
detection wavelength 313 nm, 37 °C;
30
n=3
20
10
0
0 20 40 60 80 100
Time [min]
Crystalline API Entacapone-loaded Parteck® SLC
Page 87 07/2020
Inorganic Carriers
4.5 Figure 27:

A
4
Particle size distribution of A) pure
API, B) pure Parteck® SLC excipient
3.5 and C) API-loaded Parteck® SLC
excipient
3
Volume [%]
2.5
1.5
0.5
0.1 1 10 100 1000 3000

Particle size [μm]
API entacapone
14
B
12
10
Volume [%]
0
0.1 1 10 100 1000 3000
Particle size [μm]
Parteck® SLC
4.5 C
3.5
3
Volume [%]
2.5
1.5
0.5
0.1 1 10 100 1000 3000

Particle size [μm]
Loaded Parteck® SLC
Page 88 07/2020
Inorganic Carriers
Fenofibrate Loading (without Final Formulation)

• Dissolution of fenofibrate in acetone
API
•D
ropwise addition of the API solution to the silica powder via solvent Fenofibrate
impregnation method
• A target drug load of 30% (w/w) Formula C20H21ClO4
BCS class II
10 mW
water insoluble
Figure 28:
70 75 80 85 90 95 °C Solid state analysis of fenofibrate-

Pure fenofibrate Parteck® SLC, API load 30% loaded Parteck® SLC excipient (DL
30% w/w) in comparison to pure
crystalline API: A) XRD graph and B)
DSC thermogram.
50
45
40
35 Figure 29:
30
Dissolution profile of fenofibrate-
loaded Parteck® SLC excipient (DL
25 30% w/w) compared to the pure
crystalline API.
20
15
5 1000 mL SGFsp + 0.1 % SDS, 75
0 rpm, 37 °C, n=3
0 20 40 60 80 100 120
Time [min]
Parteck® SLC, API load 30% API solubility (24h shake-flask method)
Crystalline API
Both XRD and DSC confirm that fenofibrate is present in its amorphous state
after loading onto Parteck® SLC excipient (XRD data not shown). The
dissolution rate is significantly increased compared to the pure crystalline API.
Dissolution reaches cmax after 15 minutes. At that time point, the dissolved
amount of API is 2.2 times the saturation solubility (see Fig. 29).
Page 89 07/2020
Inorganic Carriers
The observed recrystallization may be reduced by the addition of other excipients,

such as inorganic salts (see Fig. 30) or polymers (see Fig. 31). This makes it
possible to stabilize the supersaturation of the API and control the release
profile.
50 Figure 30:
45 Inhibition of the recrystallization
of fenofibrate via the addition of
40 inorganic salts to the API-loaded
35 Parteck® SLC powder, compared

to fenofibrate-loaded Parteck® SLC
30 powder without additives and to the
pure crystalline API.
25
20
10
1000 mL SGFsp + 0.1 % SDS, 75
5 rpm, 37 °C, n=3
0
0 50 100
Time [min]
Parteck® SLC, API load 30% Physical mixture FF-Parteck® SLC:
Al2O3 (2:1)
Physical mixture FF-Parteck® SLC:
MgO (4:1) Physical mixture FF-Parteck® SLC:
Al2O3 : MgO (4:0.5:0.5)
Physical mixture FF-Parteck® SLC:
Al2O3 (4:1) Crystalline API
100
90
80 Figure 31:
70 Inhibition of the recrystallization

of fenofibrate via the addition of a
60 polymer to the API-loaded Parteck®
50 SLC powder, compared to fenofibrate-
loaded Parteck® SLC powder without
40 additives, fenofibrate-loaded Parteck®
SLC powder with an inorganic salt as
30
a recrystallization inhibitor, and the
20 physical mixture of the crystalline API
and the polymer.
10
0
0 30 60 90 120 Dissolution procedure:
Time [min] USP Apparatus 2 (Paddle Apparatus),
500 mL FaSSIF 75 rpm, 37 °C, n=3
API solubility (24 h shake-flask method) Parteck® SLC, API load 30% Tests performed under sink conditions
Physical mixture FF-Parteck® SLC : Physical mixture FF-Parteck® SLC : Al2O3 (4:1)
HPMC-AS (4:1)
Physical mixture FF : HPMC-AS (4:1)
Page 90 07/2020
Inorganic Carriers
Fenofibrate (37.5 mg) Tablet
Fenofibrate-loaded Parteck® SLC 125 25 API

Fenofibrate
Parteck® M 200
100 20
Microcrystalline cellulose (MCC) Formula C20H21ClO4

255 51
100 µm

Sodium carboxymethyl cellulose (Na-CMC) 10 2
Silicon dioxide, highly dispersed Melting point 80 – 81 °C

5 1
(113126)
BCS class II
Parteck® LUB MST
5 1
(magnesium stearate, 100663) Solubility in Practically
water insoluble
Total 500 100
Manufacturing:
The API-loaded Parteck® SLC powder (DL 30%) is blended with the other
components. The tableting mixture is compressed on a bench top tablet press
at a compression force of 45 kN. The resulting 11 mm tablets have a total
tablet weight of 500 mg.
Tablet properties:
Weight variation [%] 5
Hardness variation [N] 6.4
Friability [%] 0.01
Page 91 07/2020
Inorganic Carriers
50 Figure 32:
Dissolution profile of a fenofibrate
tablet formulation based on API-
40 loaded Parteck® SLC excipient after
storage for 0, 1, 4, 12, and 52 weeks

at 25 °C/60% rH compared to the
30 pure crystalline API.
20
38 mg API, USP Apparatus 2 (Paddle
Apparatus), 750 mL SGFsp + 0.1 %
10
SDS, 75 rpm, 37 °C, n=3
0
0 30 60 90 120
Time [min]
Start 52 weeks
1 week Crystalline fenofibrate
4 weeks Saturation solubility of fenofibrate
26 weeks
After 5 minutes of dissolution, the dissolved amount of API is at saturation

solubility level, reaching cmax values of approx. 2.1 times saturation solubility
after 45 minutes. The improved dissolution performance of the tablet
formulation using fenofibrate loaded onto Parteck® SLC excipient is maintained
throughout storage for 52 weeks at 25 °C/60% rH conditions (see Fig. 32) and
40 °C/75% rH (data not shown).
Page 92 07/2020
Inorganic Carriers
Ibuprofen (37.5 mg) Tablet
Ibuprofen-loaded Parteck® SLC 125 25 API

Ibuprofen

255 51
100 µm
Formula C13H18O2
Sodium carboxymethyl cellulose (Na-CMC) 10 2

5 1
(113126) Melting point 75 – 77 °C

5 1
Total 500 100 water insoluble
Manufacturing:
The API-loaded Parteck® SLC powder (DL 30%) is blended with the other
components. The blend is then processed into tablets or capsules. The tableting
mixture is compressed on a rotary tablet press at a compression force of 30 kN.
The resulting 11 mm tablets have a total tablet weight of 500 mg. The same
amount of material is filled into capsules of different sizes (00, 0 and 1).
Tablet properties:
Hardness variation [N] 13.6
Friability [%] 0.02
Disintegration variation [s] 3.7
Page 93 07/2020
Inorganic Carriers
100 Figure 33:

Dissolution profile of ibuprofen tablet
and capsule formulations based on
80 API-loaded Parteck® SLC excipient
compared to the pure crystalline API
Drug release [%]
and API-loaded Parteck® SLC powder.

60
40 USP Apparatus 2 (Paddle Apparatus),
500/1000 mL SGFsp, 75 rpm, 37 °C, n=3
20
0
0 30 60 90 120
Time [min]
Tablet Capsule size 00 Capsule size 0
Capsule size 1 Powder Crystalline ibuprofen
All formulations with the API loaded onto the Parteck® SLC carrier show an
increased dissolution rate and improved maximum amounts of API dissolved in
comparison to crystalline ibuprofen. The capsule dissolution profiles show an
initial lag time which can be attributed to the dissolution of the capsule shell.
Page 94 07/2020
Sustained Release
Tablets
Sustained-release (SR) formulations are designed to Packaging: Tightly sealed, moisture-proof containers
release one or more drugs over a prolonged period or packs. Packed in individual aluminum foil pouches.
of time. With SR formulations, the release rate is
Recommended for: APIs with targeted release
lower than for an immediate release formulation
over several hours, APIs intended for long-term
administered via the same route. SR delivery systems
treatment and multiple daily doses necessary with the
make it possible to reduce dosing frequency and drug
conventional, immediate release dosage form.
fluctuation in steady-state level, lessen adverse effects,
increase therapeutic efficacy and improve patient
compliance. There are several techniques to achieve
SR, such as by using a release-rate-controlling coating Our Formulation Ingredients
or dispersing the API in a release-rate-controlling Category Products
matrix. Monolithic matrix systems are especially
widely used due to their simplicity, flexibility and cost- Polymer/ Directly compressible SR excipient:
effectiveness. Compared to coated systems, there is matrix former Parteck® SRP 80 (polyvinyl alcohol,
generally a reduced risk of dose dumping: in the case of 141439)
a single-unit dosage form where the only release-rate-
controlling material is the film coating on the surface, Diluent Parteck® M (DC mannitol, 100419,
defects in the coating layer or division of the tablet by 100494), Parteck® Delta M (mannitol,
the patient may compromise the intended modified 112635), Parteck® SI (DC sorbitol, 103583,
release profile and result in an immediate release of the 115079, 103140, 103557), lactose
full amount of API. monohydrate (107656, 108195), calcium
hydrogen phosphate dihydrate (102146),
Manufacturing process: Matrix systems using direct calcium hydrogen phosphate anhydrous
compression, wet granulation or dry granulation. (102144, 102304), calcium phosphate
Reservoir systems typically using functional coatings. (102143)
Reservoir systems and other technologies that The type and amount of diluent used may
enable sustained release, such as the ion exchange impact the release profile.
mechanism, microencapsulation and osmotic systems,
are not addressed in this publication. Lubricant Parteck® LUB MST (magnesium stearate,
Formulation requirements: Consistent release stearate, 100664), Parteck® LUB STA
performance regardless of process parameter variations (stearic acid, 100661)
and outer conditions (such as alcohol content or pH), to
prevent API level variations or dose-dumping.
Formulation challenges: Release behavior
consistency, stability, processability.
Formulation benefits: Increased patient compliance
through reduced number of daily doses, improved
therapeutic effect and fewer adverse effects due to
reduced API level fluctuations.
Raw material recommendation: High batch-to-batch
consistency (variations may be observed, especially
with naturally derived materials), consistent release
performance regardless of process parameter variations
and outer conditions (such as alcohol content or pH),
excellent compressibility.
Page 95 07/2020
Formulation Examples: Sustained Release
Ascorbic acid powder (D50 217 μm) 125.00 25.00 API

Ascorbic acid
Parteck® SRP 80
186.25 37.25
Microcrystalline cellulose (MCC) 100 μm 186.25 37.25

Formula C6H8O6

1.25 0.25 Molar mass 176.12 g/mol
(113126)
about 190 °C,
Parteck® LUB MST Melting point
1.25 0.25 with decomposition
pKa1 = 4.17;
pKa
Total 500 100 pKa2 = 11.57
BCS class III
Manufacturing:
Parteck® SRP 80 and MCC are mixed in a 1:1 ratio. Next, ascorbic acid, silicon water soluble
dioxide and Parteck® LUB MST are added, followed by another mixing step.
The mixture is then compressed at 10, 20 and 30 kN into 11 mm flat faceted
Figure 34:
400 600 Tablet hardness of ascorbic
acid-Parteck® SRP 80 excipient
350 tablets compressed at different
500
350 compression forces.
300
Tablet hardness [N]
Ejection force [N]
400
250
259
200 300
150
200
100
119
100
50
0 0
10 20 30
Ejection force
Tablet hardness
The sample formulation with Parteck® SRP 80 excipient shows high

compressibility and low ejection forces over a vast range of compression forces.
Page 96 07/2020
120 Figure 35:

Dissolution profile of ascorbic
100 acid-Parteck® SRP 80 excipient
tablets compressed at different
Drug release [%]
compression forces.
80
60
2 (Paddle Apparatus), 900 mL special
40 release medium ensuring the stability
of ascorbic acid over 12-hour release
20 time, 100 rpm, 37 °C, detection
wavelength 244 nm
0
0 2 4 6 8 10 12
Time [h]
Ascorbic acid-Parteck® SRP 80 (10 kN) Ascorbic acid-Parteck® SRP 80 (20 kN)
Ascorbic acid-Parteck® SRP 80 (30 kN)
The sample formulation shows a robust release profile over a broad range of
compression forces and tablet hardnesses.
Page 97 07/2020
Diclofenac (100 mg)
Diclofenac sodium 100 28.17 API

Diclofenac
sodium
Parteck® SRP 80
148.95 41.97
Microcrystalline cellulose (MCC) Formula C14H10Cl2NNaO2

35.62 10.03
DC 50 µm Type 802

53.43 15.05
DC 50 µm Type 1000
Solubility in
sparingly soluble
Silicon dioxide, highly dispersed (113126) 7 1.97 water
Talc 5 1.41
Parteck® LUB MST (magnesium stearate,

5 1.41
100663)
Total 355 100
Manufacturing:
Diclofenac sodium and Parteck® SRP 80 are weighed and sieved with a mesh
size of 425 µm and mixed geometrically. MCC, talc and silicon dioxide are
weighed and sieved together with a mesh size of 425 µm. Afterwards, the
powder blend is mixed using a suitable mixer for 10 minutes. The prelubricated
blend is then mixed with pre-sieved Parteck® LUB MST through a mesh size of
250 µm using a suitable blender. Lastly, the blend is compressed using suitable
tooling into tablets with a target weight of 355 mg at compression forces of
6, 9 and 12 kN.
Friability [%] 0.25 0.22 0.19
Page 98 07/2020
250 10 Figure 36:

Effect of compression force on tablet
200 8
hardness and ejection force during
the tableting process for diclofenac
Tablet hardness [N]
matrix formulation based on Parteck®
Ejection force [N]

185
150 6 SRP 80 excipient (n = 20)
150
100 4
100
50 2
0 0
6 9 12
Ejection force
Tablet hardness
120
Figure 37:
Dissolution profile of diclofenac
100 Parteck® SRP 80 tablets
80
Drug release [%]
USP Apparatus 2 (Paddle), 900 mL,
60 pH 7.5 phosphate buffer, 50 rpm,
detection wavelength 276 nm, 37 °C;
40 n=6
20
0
0 5 10 15 20
Time [h]
Compression force 6 kN Tablet hardness 100 N Compression force 12 kN Tablet hardness 185 N
Compression force 9 kN Tablet hardness 150 N
The diclofenac formulation with Parteck® SRP 80 excipient shows high

Dissolution testing confirms prolonged release kinetics over several hours.
Page 99 07/2020
Diltiazem Hydrochloride (90 mg)
Diltiazem HCl 90 23 API

Diltiazem HCl
Parteck® SRP 80
153 38
Microcrystalline cellulose (MCC) Formula C22H26N2O4S · HCl

153 38
100 µm

2 0.5
(113126) about 213 °C, with
Melting point
decomposition
Parteck® LUB MST
2 0.5
Total 400 100

water soluble
Manufacturing:
Parteck® SRP 80 and MCC are pre-mixed for 10 minutes in a shaker-mixer.
Diltiazem HCl and silicon dioxide are added, and the blend is mixed again for
10 minutes then passed through an 800 μm sieve to destroy agglomerates.
Parteck® LUB MST is sieved through a 250 μm sieve onto the mixture. All
components are blended again for 5 minutes. The mixture is then compressed
at 10, 20 and 30 kN into 11 mm flat faceted tablets with a total tablet weight
of 400 mg.
Friability was measured according to the Ph. Eur./USP test method, and was
found to be 0.0% for compression forces ≥ 10 kN.
Friability [%] 0.6 0 0 0
Page 100 07/2020

Figure 38:
600
Ejection force [N]

300 hardness and ejection force during
Tablet hardness [N]
the tableting process for diltiazem HCl

269
400 matrix formulation based on Parteck®
200 211 SRP 80 excipient (n=20).
200
100
108
0 0
10 20 30
Tablet hardness [N]
Ejection force [N]
The sample formulation with Parteck® SRP 80 excipient shows high

100 Figure 39:

Dissolution profile of diltiazem HCl
matrix formulation based on Parteck®
80 SRP 80 excipient, prepared at
different compression forces.
Drug release [%]
60
900 mL phosphate buffer pH 7.2, 50
rpm, 37 °C, detection wavelength
237 nm; n=3
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time [h]
Compression force 10 kN Compression force 20 kN Compression force 30 kN
Tablet hardness 108 N Tablet hardness 211 N Tablet hardness 269 N
The sample formulation with Parteck® SRP 80 excipient shows a robust release
profile over a broad range of compression forces and tablet hardnesses.
The dissolution of the API from the Parteck® SRP 80-based tablet was observed
not to be dependent on the pH or ethanolic content of the outer medium, both
very relevant for sustained release formulations. Please refer to the detailed
product information at the end of this document for additional details.
Page 101 07/2020

Ibuprofen (200 mg)

API
Ibuprofen DC 85 235 47 Ibuprofen
Parteck® SRP 80
190 38 Formula C13H18O2
Microcrystalline cellulose (MCC) Molar mass 206.29 g/mol

65 13
100 µm
5 1
(113126) BCS class II
Parteck® LUB MST

5 1 Solubility Practically
(magnesium stearate, 100663) in water insoluble
Total 500 100
Manufacturing:
Parteck® SRP 80 and MCC are blended for 10 minutes. Next, ibuprofen and
silicon dioxide are added and all components are again mixed for 10 minutes.
The blend is then sieved over an 800 μm sieve and Parteck® LUB MST is passed
through a 250 μm sieve onto the mixture. After further blending of all
components for 5 minutes, the tableting mixture is compressed on a single-punch
instrumented tablet press at compression forces of 10, 20 and 30 kN. The
resulting 11 mm tablets have a total tablet weight of 500 mg each and are flat
and faceted.
Ejection force [N] 202 228 234
Friability [%] 0.14 0.07 0.04
Page 102 07/2020

Figure 40:
100
Dissolution profiles of ibuprofen-
Parteck® SRP 80 excipient tablets
80 manufactured at compression forces
of 10, 20 and 30 kN.
Drug release [%]
60

40
2 (Paddle Apparatus), 900 mL
phosphate buffer pH 7.2, 50 rpm,
20 37 °C, detection wavelength 221 nm
0
0 2 4 6 8 10 12
Time [h]
Ibuprofen-Parteck® SRP 80 (10 kN) Ibuprofen-Parteck® SRP 80 (20 kN)

Ibuprofen-Parteck® SRP 80 (30 kN)
The sample formulation shows a robust release profile over a broad range of
compression forces and tablet hardnesses.
Page 103 07/2020

Propranolol Hydrochloride (160 mg)

Formulation A
Propranolol HCl 160.0 32.0 API

Propranolol
HCl
Parteck® SRP 80
167.5 33.5
Microcrystalline cellulose (MCC) Formula C16H21NO2 · HCl

167.5 33.5
100 µm

2.5 0.5
(113126)
Parteck® LUB MST
2.5 0.5

Soluble
water
Manufacturing:
Parteck® SRP 80 and MCC are pre-mixed for 10 minutes in a shaker-mixer.
Propranolol HCl and silicon dioxide are added, and the blend is mixed again
for 10 minutes then passed through an 800 μm sieve to destroy agglomerates.
Parteck® LUB MST is sieved through a 250 μm sieve onto the mixture.
All components are blended again for 5 minutes.
The mixture is then compressed at 10, 20 and 30 kN into 11 mm flat faceted
Hardness variation [%] 6 4.9 4.4
Friability [%] 0 0 0
Page 104 07/2020

Figure 41:
300 318 600 hardness and ejection force during
the tableting process for propranolol
Tablet hardness [N]
278 HCl matrix formulation A based on
Ejection force [N]

Parteck® SRP 80 excipient (n=20).
200 400
150
100 200
0 0
10 20 30
Tablet hardness [N]
Ejection force [N]
The formulation demonstrates very good compressibility. Tablet hardness is

shown to increase with higher compression forces while the ejection force
remains virtually constant (see Fig. 41).
100 Figure 42:

90
Dissolution profile of propranolol
80 HCl matrix formulation A based on
Drug release [%]
70 Parteck® SRP 80 excipient prepared

60 at different compression forces.
50
40
10 900 mL phosphate buffer pH 6.8, 50
0 rpm, 37 °C, detection wavelength
214 nm; n=3
0 2 4 6 8 10 12
Time [h]
The in-vitro dissolution of tablets manufactured at different compression forces

is very consistent (see Fig. 42) irrespective of tablet hardness, which is shown
to increase with higher compression forces (see Fig. 41).
Page 105 07/2020

Propranolol Hydrochloride (160 mg)

Formulation B
Propranolol HCl 160 32 API

Propranolol
HCl
Parteck® SRP 80
335 67
Silicon dioxide, highly dispersed Formula C16H21NO2 · HCl

2.5 0.5
(113126)

2.5 0.5
100663)
Total 500 100
BCS class I
Solubility in
Soluble
Manufacturing: water
Parteck® SRP 80, propranolol HCl and silicon dioxide are passed through a 1 mm
sieve to destroy agglomerates. The three components are then mixed for
5 minutes in a shaker-mixer. Parteck® LUB MST is sieved through a 250 μm
sieve onto the mixture. All components are again blended for 5 minutes.
The mixture is then compressed at 20 and 30 kN into 11 mm flat faceted
Page 106 07/2020

200 600 Figure 43:

Tablet hardness [N]
162 hardness and ejection force during
Ejection force [N]

400 the tableting process for propranolol
124 HCl matrix formulation B based on
100
Parteck® SRP 80 excipient (n=20).
200
0 0
20 30
Tablet hardness [N]

Ejection force [N]
Tablet hardness is shown to increase with increasing compression force.

Compression forces of 20 and 30 kN result in tablets with very good tablet
hardness at virtually constant ejection forces (see Fig. 43).
100 Figure 44:

Dissolution profile of propranolol
HCl matrix formulation B based on
80 Parteck® SRP 80 excipient prepared
at different compression forces.
Drug release [%]
60
40
20
0
0 2 4 6 8 10 12
Time [h]
Compression force 20 kN Compression force 30 kN
Tablet hardness 124 N Tablet hardness 162 N
The sample formulation shows a very robust release profile over a broad range
of tablet hardnesses.
Page 107 07/2020

Theophylline (125 mg)

API
Theophylline anhydrous 125 25 Theophylline
Parteck® SRP 80
185 37 Formula C7H8N4O2
Microcrystalline cellulose (MCC) Molar mass 180.17

185 37
100 µm
BCS class I
2.5 0.5
(113126) Solubility Slightly
in water soluble
Parteck® LUB MST
2.5 0.5
Total 500 100
Manufacturing:
Parteck® SRP 80 and MCC are blended for 10 minutes. Next, theophylline and
silicon dioxide are added and all components are again mixed for 10 minutes.
The blend is then sieved over an 800 μm sieve, and Parteck® LUB MST is
passed through a 250 μm sieve onto the mixture. All components are blended
for 5 minutes. The tableting mixture is compressed on an instrumented rotary
tablet press at compression forces of 10, 20 and 30 kN. The resulting 11 mm
tablets have a total tablet weight of 500 mg each and are flat and faceted.
Ejection force [N] 80 92 84
Friability [%] 0.1 0.0 0.0
Page 108 07/2020

100 Figure 45:

90 Dissolution profiles of theophylline-
Parteck® SRP 80 excipient tablets
80
manufactured at compression forces
Drug release [%]
70 of 10, 20 and 30 kN.

60
50
40
30 phosphate buffer pH 6.8, 50 rpm,
37 °C, detection wavelength 293 nm
20
10
0
0 2 4 6 8 10 12
Time [h]
Theophyline-Parteck® SRP 80 (10 kN) Theophyline-Parteck® SRP 80 (20 kN)

Theophyline-Parteck® SRP 80 (30 kN)
The Parteck® SRP 80-based theophylline matrix tablets show a constant

prolonged release effect over a very broad range of compression forces
and tablet hardnesses.
Page 109 07/2020

Tablet Coatings
Coating of tablets is beneficial in many ways. It may Our Formulation Ingredients

be used to improve the appearance of the final drug
product, mask unpleasant colors and taste or be applied Category Products
for anti-counterfeiting reasons. An additional benefit is
improved patient safety, as coatings can make tablets
Polymer Parteck® COAT (polyvinyl alcohol, 141517)
easier for patients to identify. Functional reasons
for coatings include protection of the API from light,
moisture or oxidation, and modification of the dosage Plasticizer Parteck® SI 150 (sorbitol, 103583),
form’s release behavior. Generally speaking, a coated Parteck® M 100 (mannitol, 100494),
tablet is easier to swallow – which is especially relevant glycerol (104091), triethyl citrate (817059),
triacetin (103000), polyethylene glycol (e.g.
for patients with dysphagia, a swallowing difficulty often
PEG 200, 817001; PEG 600 817004; PEG
experienced in the elderly population. 1000, 817009; PEG 1500, 817005; PEG
3000, 817019; PEG 4000, 817006; PEG
6000, 817007)
Manufacturing process: Conventional tableting
processes followed by aqueous film coating process Anti-tacking Parteck® LUB MST (magnesium stearate,
using pan coating or fluid bed coating equipment. agent 100663), Parteck® LUB CST (calcium
stearate, 100664), Parteck® LUB STA 50
Formulation requirements: Smooth surface finishing, (stearic acid, 100661), silicon dioxide,
consistent coating film thickness, moisture and oxidation highly dispersed (113126)
barrier.
Formulation challenges: Coating defects; low process Viscosity Gum arabic (104228)
efficiency due to rapid increase in viscosity of certain modifier
polymers, resulting in higher drying times and increased
process temperatures. Flavoring Vanillin (108510)
Formulation benefits: Protection from light, moisture

and oxidation; improved tablet appearance; taste Coloring agent Water soluble colors e.g. Candurin® pigments
masking; easier to swallow thanks to smooth surface. such as Candurin® Gold Lustre (120610),
Candurin® NXT Ruby Red (120624),
Raw material recommendation: High solubility or Candurin® NXT Silver Blossom (120625),
dispersibility in coating solvent, low viscosity at required Candurin® Silver (120600 - 120603),
concentrations. Candurin® Interference (120604 - 120607),
Candurin® Gold (120608 - 120610),
Packaging: Tightly sealed, moisture-proof containers Candurin® Iron oxide (120613 - 120619)
or packs. Water dispersible colors e.g. calcium
Recommended for: tablets containing moisture- or carbonate (102069), titanium(IV) oxide
(100805)
light-sensitive APIs; large tablets, to improve ease of
swallowing; enhancement of tablets’ visual appearance
(e.g. to mask intrinsic color or give the tablet a unique
look), taste masking.
Page 110 07/2020

Formulation Examples: Tablet Coatings
Aqueous Coatings:
Tablet core API

Ascorbic acid
Ascorbic acid 50 10
Formula C6H8O6
5 1
(113126)
about 190 °C,
Melting point
with decomposition
Total 500 100
pKa1 = 4.17;
Coating pKa
pKa2 = 11.57
Parteck® COAT
10.5 70* BCS class III
Triethyl citrate 3 20* Solubility in Freely

water soluble
Talc 1.5 10*
Water q.s.** q.s.**
Total 515 100
*Amounts related to the solid content of the spraying liquid. Targeted coating gain weight of 3%.
**A 9% (w/w) solution was used for spraying. Water is removed during the drying step of the
coating process.
Manufacturing:
Ascorbic acid, Parteck® M 200 and silicon dioxide are blended for 10 minutes in a
drum hoop mixer and passed through a 1 mm sieve. After that, sodium stearyl
fumarate is sieved through a 250 μm sieve onto the mixture, then all
components are again blended for 10 minutes in a drum hoop mixer. The
tableting mixture is compressed on a high-speed rotary press at a compression
force of 20 kN. The resulting 11 mm tablets have a total tablet weight of 500 mg
and a tablet hardness of 300 N each and are flat and faceted.
To prepare the coating solution, Parteck® COAT is added to cold water while
stirring, and dissolved while applying elevated temperatures of about 60 °C. The
tablets are then coated using standard lab-scale pan coating equipment.
Page 111 07/2020

As an immediate release polymer, Parteck® COAT excipient shows less influence

on the release kinetics of the active ingredients compared to the HPMC-based
coating. An overview of the dissolution kinetics is presented in Figure 46:
Figure 46:
50
Dissolution data of ascorbic acid
tablets with different coatings.
40
Dissolution [mg/mL]
Dissolution conditions: 50 rpm at

30 37 °C; 900 mL KH2PO4 buffer at pH
2.7; UV-VIS detection at 244 nm.
20
10
0 5 10 15 20 25
Time [min]
Uncoated tablets
Parteck® COAT
HPMC based coating
For details and results for water and oxygen transmission rates, please refer to
the Parteck® COAT product page.
Page 112 07/2020

Combination of Aqueous and Organic Solvents,

Formulation A
Binary solvents systems based on water and alcohol can be used for
Parteck® COAT polyvinyl alcohol-based coatings. With increasing concentrations
of an organic solvent, the coating spray rate can be increased while maintaining
same low process temperatures and film coating properties.
Amount Amount
[mg/tablet] [% w/w]
Tablet Core

7.5 1.5
stearate, 100663)
Total 500 100
Water:Alcohol ratio 95:5/90:10/80:20 50:50
Amount Amount Amount Amount

[mg/tablet] [% w/w] [mg/tablet] [% w/w]
Coating
Parteck® COAT
13 65* 13 65*
(PVA, 141517)
Talc 3.6 18* 3.6 18*
Polyethylene glycol
3.4 17* 3.36 16.8*
6000 (PEG, 817007)
Coloring 0 0* 0.04 0.2*
Water q.s.*** q.s.*** q.s.*** q.s.***
Alcohol** q.s.*** q.s.*** q.s.*** q.s.***
Total 520 100 520 100
*Amounts related to the solid content of the coating weight gain. Targeted weight gain 4% (w/w).
**Ethanol absolute (100986) or 2-propanol (100995)
***A 10% (w/w) solution was used for spraying with varying ratios of water:alcohol (95:5; 90:10;
80:20; 50:50 as stated in table). Solvents are removed during the drying step of the coating process.
Manufacturing:
Parteck® M 200 is sieved through a 600 µm sieve. After that, Parteck® LUB MST
is sieved through a 250 μm sieve, then both components are blended for 10
minutes in a double cone blender. The tableting mixture is compressed on a
high-speed rotary press at a compression force of 8 - 10 kN. The resulting 11
mm tablets have a total tablet weight of 500 mg and a tablet hardness of 100 N
each and are round and concave.
Page 113 07/2020

To prepare the coating solution, water is heated to 40 - 50 °C. Parteck® COAT is

added while stirring and dissolved while stirring for 45 minutes. The solution is
cooled to room temperature and the alcohol is slowly added under gentle
stirring. PEG is dissolved separately in a small amount of water. Talc and the
coloring agent are dispersed in the remaining amount of water (in case of high
organic solvent concentrations use organic solvent) using a homogenizer.
The PEG solution is added to the polymer solution while stirring. In the next step,
the talc and coloring agent dispersion is added. After stirring for another 20
minutes, the coating solution is filtered using a 150 µm sieve. The tablets are
then coated using standard lab-scale pan coating equipment with parameters set
as follows.
Water:Alcohol ratio 95:5 90:10 80:20 50:50
Pan load [%] 60 60 60 60
Pan size [L] 0.8 0.8 0.8 0.8
Inlet air flow [CFM] 60 60 60 45
Gun to bed distance [mm] 13 - 14 13 - 14 13 - 14 13 - 14
Gun aperture size [mm] 0.5 0.5 0.5 0.5
Tube diameter [mm] 3 3 3 3
Inlet air temperature [°C] 45 ± 2 45 ± 2 45 ± 2 45 ± 2
Outlet air temperature [°C] 40 ± 2 40 ± 2 40 ± 2 40 ± 2
Spraying rate [g/min] 4-5 4-5 6-7 10 - 12
Pan speed [rpm] 20 20 20 20
Pattern air pressure [bar] 0.8 0.8 0.8 0.8
Atomizing air pressure [bar] 0.8 0.8 0.8 0.8
Tablet properties:
Water:Alcohol ratio 95:5 90:10 80:20 50:50
Tablet weight (uncoated tablets) [mg] 500 500 500 500
Disintegration time (uncoated tablets) [min] 3.5
Tablet weight (coated tablets) [mg] 519.05 519.8 521.8 520.5
5.9 ± 5.9 ± 5.9 ± 5.9 ±

Tablet thickness (coated tablets) [mm]
0.15 0.15 0.15 0.15
Disintegration time (coated tablets) [min] 4.6 4.7 4.9 4.6
Page 114 07/2020

Combination of Aqueous and Organic Solvents,

Formulation B: Ibuprofen (400 mg)
Amount Amount
[mg/tablet] [% w/w] API
Ibuprofen
Tablet core
Formula C13H18O2
Ibuprofen 400 61.5
Parteck® ODT (mannitol-based ODT Molar mass 206.29 g/mol

167 25.7
Microcrystalline cellulose 70 10.8
BCS class II
Silicon dioxide, highly dispersed (113126) 6.5 1
6.5 1 in water insoluble
100663)
Total 650 100
Coating
Parteck® COAT (polyvinyl alcohol, 141517) 17 65.4*
Polyethylene glycol 6000 (PEG, 817007) 5 19.2*
Talc 3.95 15.2*
Coloring 0.05 0.2*
Water q.s.** q.s.**
2-Propanol (100995) q.s.** q.s.**
Total 676 100
*Amounts related to the solid content of the spraying liquid. Targeted coating weight gain of 4% (w/w).
**A 10% (w/w) solution was used for spraying with a water: 2-propanol ratio of 90:10. The solvents
are removed during the drying step of the coating process.
Manufacturing:
Ibuprofen, Parteck® ODT, microcrystalline cellulose, silicon dioxide are passed
through a 600 µm sieve and blended for 10 minutes in double cone blender.
After that, Parteck® LUB MST is sieved through a 250 μm sieve, then all
components are blended for 5 minutes in a double cone blender. The tableting
mixture is compressed on a high-speed rotary press at a compression force of
12 - 15 kN. The resulting 12 mm tablets have a total tablet weight of 650 mg
and a tablet hardness of 120 N each and are round and concave.
Page 115 07/2020

To prepare the coating solution, water is heated to 40 – 50 °C. Parteck® COAT is

added while stirring and dissolved while stirring for 45 minutes. The solution is
cooled to room temperature and the alcohol is slowly added under gentle
stirring. PEG is dissolved separately in a small amount of water. Talc and the
coloring agent are dispersed in the remaining amount of water using a
homogenizer.
The PEG solution is added to the polymer solution while stirring. In the next
step, the talc and coloring agent dispersion is added. After stirring for another
20 minutes, the coating solution is filtered using a 150 µm sieve. The tablets are
then coated using standard lab-scale pan coating equipment with parameters
set as follows.
Parameter
Pan load [%] 60
Pan size [L] 0.8
Inlet air flow [CFM] 50
Gun to bed distance [mm] 13 - 14
Gun aperture size [mm] 0.5
Tube diameter [mm] 3
Inlet air temperature [°C] 45±2
Outlet air temperature [°C] 40±2
Spraying rate [g/min] 4-5
Pan speed [rpm] 20
Pattern air pressure [bar] 0.8
Atomizing air pressure [bar] 0.8
Figure 47:
Ibuprofen tablets coated with
Parteck® COAT using hydroalcoholic
solvents
Page 116 07/2020

3D Printing
In recent years, the use of three-dimensional (3D) Manufacturing process: A variety of 3D printing
printing as a novel manufacturing technology for techniques may be used, such as fused deposition
pharmaceuticals has drawn a great deal of attention. modeling (FDM; sometimes also referred to as fused
Since a drug manufactured using 3D printing received filament fabrication, FFF), binder jet printing, selective
approval for the first time in 2015, interest in this laser sintering (SLS), semi-solid extrusion (SSE)
technology has gained further momentum. and stereolithography (SLA). In FDM, HME is used
to produce API-polymer filaments which are then
Often also referred to as additive manufacturing, 3D
used in the FDM 3D-printing process to produce the
printing is a technology in which the API is embedded
final dosage form. One benefit is that HME is now a
within a polymer, both of which are then deposited
well-established technology in the pharmaceutical
layer-by-layer to create a 3D object – such as a tablet
sector. Drawbacks include the limited availability of
– based on a computer-modeled design. Depending
suitable polymers, and the high thermostability of
on the polymer used, final drug products with various
the API needed for the HME process. The diameter
release profiles can be manufactured. In literature, 3D
of the manufactured filament is critical when using
printing is often referred to as a disruptive technology
FDM for 3D-printing processes. With polyvinyl alcohol
with the potential to revolutionize the pharmaceutical
(PVA)-based Parteck® MXP excipient, it is possible to
landscape and conventional manufacturing techniques.
manufacture filaments with specific diameters to high
Even if this should not entirely prove true, 3D printing
precision thanks to the excipient’s excellent film-
clearly offers great possibilities, and the technique’s
forming capability.
potential suitability for personalized medicine
approaches and on-demand manufacture makes Formulation requirements: Homogeneous filament
it highly relevant for the future of pharmaceutical diameter to ensure dose consistency during production,
formulation development and manufacture. optimized mechanical properties adapted to the
individual requirements of the 3D printer, mechanical and
One of the potential applications of 3D printing is
physicochemical stability of filament during storage.
personalized medicine. There is an increasing trend in
the pharmaceutical industry to step away from mass Formulation challenges: Stability of the API and
manufacturing in favor of providing a more personalized polymer to the heat, shear stress and mechanical stress
approach* . Pediatric and geriatric patients are an employed during the process. A constant filament
interesting target group for this new technology, as diameter and a uniform composition must be ensured
they have a high demand for individualized dosing and for the final product to have consistent quality.
for the combination of multiple APIs within a single
Formulation benefits: Continuous process, well
dosage form.
suited for personalized medicine approaches due to
* Trenfield SJ, Awad A, Goyanes A, Gaisford S, Basit AW. 3D Printing individualized dose adaptation, potential to embed
Pharmaceuticals: Drug Development to Frontline Care. Trends in
Pharmacological Sciences. 2018;39(5):440-51.
poorly water-soluble APIs and create modified release
formulations with tailored release kinetics.
Raw material recommendation: Excellent flowability,
Our Formulation Ingredients homogeneity with APIs, high thermostability.
Packaging: Tightly sealed, moisture-proof containers
Category Products or packs.
Recommended for: personalized medicine, APIs not
Matrix polymer Parteck® MXP (polyvinyl alcohol, 141464)
sensitive to heat (high degradation temperatures).
Plasticizers such as sorbitol can be added to reduce
Plasticizer Parteck® SI 150 (sorbitol, 103583), processing temperatures and enable the formulation of
Parteck® M 100 (mannitol, 100494), APIs with low or medium melting temperatures.
triethyl citrate (817059), polyethylene
glycol (e.g. PEG 4000, 817006; PEG 6000,
817007)
Plasticizers can be used to reduce
processing temperature.
Page 117 07/2020

General description of FDM 3D printing using

Parteck® MXP excipient:
• Filament formulation
• Filaments with Parteck® MXP excipient can
be easily produced using HME followed by a
downstream step via a pulling line or a standard
cooling belt setup
•A
gear pump can be integrated into the process
to further improve filament homogeneity, but is
not mandatory for successful filament production.
Since the consistency of the filament diameter is
critical to ensuring that the final formulation has
homogeneous properties and performs effectively,
the use of a gear pump may prove beneficial if
variations are observed.
•M
echanical behavior can be individually tailored by
adding plasticizers like sorbitol (Parteck® SI 150 Figure 48:
excipient) Parteck® MXP filament undergoing three-point bending test
• Filaments can be characterized using the three-
point bending test (see Figure 48).
•3
D printing process
• The desired shape of the 3D printed formulation is
designed using appropriate software.
• The filament is fed into the 3D printer, typically
from a coil. The filament material softens when
passing through the heated nozzle. It is then
deposited layer by layer so as to form the defined Figure 49:
shape.
Parteck® MXP filament A) extrusion B) ready for further processing or
storage
Recommended process parameters: For further information, please refer to the formulation
examples or the following sources:
Pre-testing speed [mm/s] 1.0
-K
allakunta, V. R., S. Sarabu, et al. (2019). "An update
on the contribution of hot-melt extrusion technology to
Test speed [mm/s] 0.1 novel drug delivery in the twenty-first century: part I."
Expert Opinion on Drug Delivery 16(5): 539-550.
Support span of the rig [mm] 15 -P
alekar, S., P. K. Nukala, et al. (2019). "Application
of 3D printing technology and quality by design
approach for development of age-appropriate pediatric
formulation of baclofen." International Journal of
Pharmaceutics 556: 106-116.
Page 118 07/2020

Formulation Examples: 3D Printing
Ketoconazole (250 mg)
Ketoconazole 20 20 API
Ketoconazole
Parteck® MXP (polyvinyl alcohol,
200 80
141464)
Total 250 100

Formula C26H28Cl2N4O4
Molar mass 531.4

Manufacturing:
Solubility in
Filament production water
Ketoconazole and Parteck® MXP were pre-mixed for 10 minutes using a drum
hoop mixer, then fed into a Pharma 11 twin-screw extruder from Thermo
Scientific (Karlsruhe, Germany) equipped with an extrex® PFS 20GP melt pump
from Maag Automatik GmbH (Groß-Ostheim, Germany) to produce filaments for
3D printing with a target diameter of 1.75 mm. The diameter of the filaments
was measured with a 3-axis laser micrometer (see Fig. 50).
3D printing
3D printing was performed using an Ultimaker 3 (Ultimaker, Geldermalsen,
Netherlands) modified to enable the printing of filaments with a diameter of
1.75 mm. The nozzle diameter was 0.4 mm. The tablets were designed in Fusion
360 (Autodesk®, Farnborough, United Kingdom), and a cylindrical shape was
chosen (diameter: 10 mm, height: 2.4 mm). Simplify 3D (Simplify3D, Cincinnati,
USA) was used for slicing. Tablets were printed at 10 mm/s with an infill density
of 100% at 210 °C. For comparison purposes, placebo trials with Parteck® MXP
excipient were also conducted, using the same process parameters but a printing
temperature of 230 °C.
Figure 50:
Schematic view of the 3-axis laser
measurement device.
Y Z
Page 119 07/2020

Figures 51 A and 51 B show sample data sets for the 3-axis laser measurement
of the placebo filaments. It is observed that the use of a melt pump can increase
the consistency and stability of the process. The effect of using a melt pump on
tablet weight, height and diameter is shown for both the ketoconazole and a
placebo formulation in Figure 52.
2 2 Figure 51:
A B
Example of how diameter varies
1.95 1.95
over time for Parteck® MXP placebo
extrudates without (A) and with (B) a
1.9 1.9
melt pump.
1.85 1.85
Diameter [mm]
Diameter [mm]
1.8 1.8
1.75 1.75
1.7 1.7
1.65 1.65
1.6 1.6
1.55 1.55
1.5 1.5
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time [min] Time [min]
X axis X axis
Y axis Y axis
Z axis Z axis
Page 120 07/2020

0.35 A 14 B Figure 52:

Variation of the 3D-printed tablets in
0.30 12 A) tablet weight, B) tablet diameter
and C) tablet height (n=5).
0.25 10
Diameter [mm]
0.20 8
Mass [g]
0.15 6
0.10 4
0.05 2
0 0
4 C
3.5
2.5
Height [mm]
2
Placebo - no melt pump
1.5
Ketoconazole - no melt pump
Placebo - with melt pump
1
Ketoconazole - with melt pump
0.5
Identifying the right downstream equipment can be an important factor in

creating a homogeneous filament. The use of a melt pump can improve the
consistency, and also ensures the safety of the process.
For the evaluated samples, both technologies resulted in reliable material
properties for 3D printing. It can be expected that the benefits of using a melt
pump are even greater on a larger production scale.
Page 121 07/2020

Technical Information
on Excipients
Our portfolio of formulation products includes excipients Optimized drug delivery

for solid, semi-solid and liquid dosage forms for small
Functional excipients that modify the release kinetics of
and large molecules, allowing you to formulate APIs
your formulation and for different routes of administration
to your exact specifications and requirements. We
offer both customized manufacturing and a standard arteck® M DPI: mannitol-based versatile alternative
•P
portfolio of synthetic lipids and functionalized PEGs, carrier for dry powder inhalation applications
biodegradable polymers for injectable sustained
release formulations of small and large molecules • Parteck® ODT: rapid disintegration and exceptional
and functional excipients for excellent performance strength for orally disintegrating tablets
in tableting processes, solubility enhancement and • Parteck® SRP 80: polyvinyl alcohol-based excipient
controlled release. for consistent, sustained drug release of solid oral
On the following pages, you will find detailed formulations
information on selected products for solid application.
Enhanced solubility
Product Overview – Functional excipients that boost the efficacy of your

final drug product by enhancing API solubility
our Parteck® Excipient Range
• Parteck® MXP: polyvinyl alcohol for hot-melt
With formulation challenges in mind, we have used
extrusion, allowing for stable and high drug loads
particle engineering technologies to develop functional
and with a high thermostability
excipients specifically for solid oral dosage forms.
The products in our Parteck® portfolio feature unique • Parteck® SLC: silica drug carrier with a unique surface
particle properties tailored for excellent performance structure
in tableting processes, for specific drug delivery
technologies, or for solubility enhancement.
For a full overview of our formulation excipients offering
and to find the right product in our portfolio for your
Flexible tableting specific application, please refer to
MerckMillipore.com/formulationapp or contact your local
Functional excipients for different tableting technologies
sales representative.
that achieve high tablet hardness at a low compression
force, as well as short disintegration time, and tailored
API dosages thanks to the unique particle surface
• Parteck® CCS: superdisintegrant for solid formulations
• Parteck® COAT: rapid preparation times and full
flexibility in film coatings
• Parteck® Delta M: convertible mannitol specifically
designed for wet granulation
• Parteck® LUB: range of vegetable-origin stearates for
reliable lubrication
• Parteck® M: directly compressible mannitol, combining
stability and rapid disintegration
• Parteck® SI: directly compressible sorbitol, combining
excellent flowability and great mouthfeel
Page 122 07/2020

Product Overview – our Parteck® Excipient Range
for Flexible Tableting
Parteck® CCS
Parteck® CCS excipient is a superdisintegrant for oral pharmaceutical

formulations. Its unique swelling properties shorten tablet disintegration time,
thereby increasing disintegration efficiency. Parteck® CCS is highly flexible and
suitable for use in capsule formulation, wet granulation, roller compaction and
direct compression.
PARTECK® CCS EXCIPIENT PROVIDES:

•F
ast disintegration over a broad range of compression forces and tablet
hardnesses due to unique particle size distribution
• I ncreased API stability compared to other types of superdisintegrant,
as no peroxides
• Fast water absorption, ensuring fast disintegration
• Emprove® documentation
• Compliance with Ph. Eur., JP, NF
Figure 53:
Scanning electron microscopy (SEM)
image of Parteck® CCS excipient.
300 μm
Because of the coarser particle size of Parteck® CCS excipient compared to

other commercially available superdisintegrants of the same kind, formulations
with Parteck® CCS excipient show faster disintegration.
Page 123 07/2020

Physicochemical properties
Composition Crosslinked carboxymethylcellulose sodium
CAS registry 74811-65-7
Bulk density [g/mL] 0.50 – 0.53
Tapped density [g/mL] 0.70 – 0.74
Angle of repose [°] 35 – 39
Particle size (laser diffraction D50) [μm] 54 – 61
Surface area (nitrogen adsorpt. BET)

0.210 – 0.247
[m2/g]
Loss on drying [%] 2.9 – 5.8
Water activity, aw value 0.141 – 0.158
Peroxide number (acc. to DAB 7 method) ≤ 0.1
Typical technical data for general characterization. Specification available at MerckMillipore.com
General formulation
Active ingredient 1 – 50%
Filler/binder1 30 – 80%
Parteck® CCS (102310)
Tablet applications 0.5 – 5%

Capsule applications 10 – 25%
Silicon dioxide, highly dispersed (113126) 0.2 – 1.0%
Parteck® LUB MST (magnesium stearate, 100663) 0.25 – 1.0%
Alternative lubricants
Parteck® LUB CST (calcium stearate, 100664) 0.5 – 1.0%
Parteck® LUB STA (stearic acid, 100661) 1.0 – 3.0%
1
e.g. Parteck® M 200 (100419), Parteck® Mg DC (102440), Parteck® ODT (100490),
Parteck® SI 150 (103583), Parteck® SI 400 (103140).
For wet granulation processes, it is recommended to apply Parteck® CCS

excipient as part of the extra-granular phase as it usually does not regain its
original performance after being wetted and dried. However, depending on
disintegration and drug release behavior, it is possible to use it in the intra-
granular phase. In this case, a higher amount of Parteck® CCS excipient –
in the range of 3 - 5% w/w – may be necessary.
For additional information on the product, material specification, safety data
sheet or packaging and storage information, please refer to
MerckMillipore.com or contact your local sales representative.
Page 124 07/2020

Parteck® COAT
Parteck® COAT is a particle-engineered polyvinyl alcohol (PVA) with a unique

structure specifically designed for immediate-release film coating applications.
Due to its optimized particle size, it helps to reduce dissolving times when
preparing the coating solution, thus increasing process efficiency. Its low
viscosity and high stability against moisture and oxidation makes it very
well-suited for use as a film-forming polymer in coatings. Parteck® COAT
excipient can be combined with a variety of supporting excipients such as
plasticizers, anti-tacking agents and pigments – all available in our portfolio –
to give you full flexibility in designing just the right coating for your need, and
in the right timeframe. It is also very well-suited for coating ODT formulations
using the Parteck® ODT orally disintegrating excipient system.
PVA has a long safety record related to its usage in drugs and is generally
recognized as safe (GRAS) by the U.S. Food and Drug Administration.
PARTECK® COAT EXCIPIENT PROVIDES:

• Flexibility in coatings, enabling you to adapt the coating to your needs
•R
apid preparation of coating liquids, as the water-soluble PVA particles
dissolve very quickly even at room temperature
•H
igh concentration of spraying liquid, shortening process times and
increasing coating efficiency
• Stable moisture barrier, protecting your moisture-sensitive APIs
• Stable oxygen barrier, enhancing API stability
• Excellent surface finishing, increasing the value of your formulation
•R
eliable product performance, due to its fully synthetic origin and high
batch-to-batch consistency
•M
ulti-compendial material, a GRAS polymer and compliant with Ph Eur, ChP,
JPE and USP
Figure 54:
SEM image of Parteck® COAT
particles.
100 μm
Page 125 07/2020

Composition Polyvinyl alcohol 5-88
Bulk density [g/mL] 0.6 - 0.7
Tapped density [g/mL] 0.8 - 0.9
Angle of repose [°] 30 - 35
Particle size (laser diffraction D10) [μm] 30 - 120
pH value of 4% solution 5.0 - 6.5
Hydrolysis degree [%] 85 - 89
Mass average molar mass (Mw) [g/mol] approx. 40,000
5000 Figure 55:

Direct comparison of concentration-
viscosity relationships of Parteck®
4000 COAT excipient and HPMC-based
polymers.
Apparent viscosity [mPas]
3000
2000
1000
0 5 10 15 20
Concentration [%]
Parteck® COAT
Low-viscosity HPMC-based polymer 1
Low-viscosity HPMC-based polymer 2
Page 126 07/2020

Dissolving time
The optimized particle size of Parteck® COAT excipient not only results in a
reduction of dissolving time, but also allows for the coating solution to be
prepared at room temperature. Standard, non-particle-engineered PVA grades
and other polymers commonly used in coatings were observed not to dissolve
below 60 °C (Table 2).
Table 2:
Parteck® Standard PVA HPMC-based HPMC-based Overview of dissolving parameters for
COAT grade (flakes) polymer 1 polymer 2 different polymer samples commonly
used for coating applications.
20 °C 60 not dissolved* not dissolved* not dissolved*

Time to dissolve [min]
40 °C 35 not dissolved* not dissolved* not dissolved*
60 °C 20 30 not dissolved* not dissolved*
*after 4 h.
Hygroscopicity
Parteck® COAT excipient was shown to exhibit a lower moisture uptake and
lower hysteresis compared to a cellulose-based polymer frequently used for
coating applications (Fig. 56).
45 Figure 56:
Moisture sorption and desorption
isotherms of PVA-based Parteck®
40 Parteck® COAT sorption COAT excipient compared to a
Parteck® COAT desorption cellulose-based polymer at 25 °C.
HPMC-based polymer sorption
35
HPMC-based polymer desorption
30
25
Mass [%]
20
15
10
0
0 10 20 30 40 50 60 70 80 90 100
Target rH [%]
Page 127 07/2020

General formulation
Parteck® COAT (polyvinyl alcohol, 141517) 30-70%*
Plasticizer, e.g. triethyl citrate (817059),

triacetin (103000) or Parteck® M (mannitol, 10-30%*
100494 or 100419)
Anti-tacking agent, e.g. talc 5-30%*
Coloring agent, e.g. calcium carbonate (102069),

0 - 30%*,**
titanium dioxide (100805) or Candurin® pigments
Water q.s.***
*The amounts specified refer to the solid content of the liquid. The concentration of solids in the
spraying liquid can vary from 5% up to 20%. The final amount of spraying liquid then needs to be
adapted to the desired coating weight gain.
**Calcium carbonate can be used to replace titanium dioxide in coating formulations with a
recommended amount of up to 30%; for Candurin® pearl effect colors, amounts of 5-10% are
typically sufficient.
***Water is removed during the drying step of the coating process.
Coating processes require a tablet core of sufficient stability with a

recommended breaking strength of > 100 N, minimum 80 N (at a standard
tablet diameter of around 10 mm).
Manufacturing of the coating liquid:

The best way to prepare solutions for coating with Parteck® COAT excipient is
by gently introducing the polymer to the cold medium while creating a defined
vortex. As soon as all particles are distributed within the liquid, additional heat
can be applied in order to speed up the dissolving process. A schematic view of
the preparation process is given in Figure 57.
Compared to PVA in flake form or other coating polymers such as HPMC, the
dissolving time and required temperatures are greatly reduced for particle-
engineered Parteck® COAT excipient. For additional details, please see the
Parteck® COAT product page in the second part of this document.
Figure 57:
Schematic overview of how to
prepare Parteck® COAT solutions
Fill the beaker with cold In order to achieve fast Heat the beaker slightly
water and create a vortex dispersion in order to dissolve the
polymer while reducing
the stirring speed
Page 128 07/2020

Table 3:
Parameter Optimal ranges Recommended process conditions
for coatings using Parteck® COAT
Pan load [kg] 1-2 excipient
Pan size [L] 2.5
Inlet air flow [m3/h] 75
Gun to bed distance [mm] 10 - 15
Inlet air temperature [°C] 70 – 80
Outlet air temperature [°C] 35 – 45
Spraying rate [g/min] 5 – 10
Pan speed [rpm] 15 – 20
Pattern air pressure [bar] 0.3 – 0.7
Atomizing air pressure [bar] 0.1 – 0.3
Drying temperature [°C] 40 – 50
Final finishing: Plasticizers’ effect on surface structure

The impact of different plasticizers on the homogeneity of the coated tablet
surfaces was successfully evaluated for Parteck® COAT-based coatings. A
simplified placebo tablet core formulation was used to assess the performance
of the coating compositions (see Table 3). The concentrations of different
plasticizers were varied (10% and 30%) to evaluate the effect on the tablet
coating process and on the characteristics of the final coated tablets. Water
was used to dissolve the coating materials but was removed in the drying step
of the coating process.
Page 129 07/2020

Table 4:
Tablet core Amount [%]*
Different compositions of coating
formulations using Parteck® COAT
excipient and various plasticizers.
(Percentages refer to solid content.)

1.5
100663)
Coating
Parteck® COAT
70 50 70 50 70 50 70 50 70 50
(PVA, 141517)
Talc 20 20 20 20 20 20 20 20 20 20
Triethyl citrate
10 30
(817059)
Glycerol (104091) 10 30
Triacetin (103000) 10 30
Parteck® SI 150
10 30
(sorbitol, 103583)
Parteck® M 200
10 30
(mannitol, 100419)
Total 100 100 100 100 100 100 100 100 100 100
*The amounts specified refer to the solid content of the liquid. The concentration of solids in the
spraying liquid can vary from 5% up to 20%. The final amount of spraying liquid then needs to be
adapted to the desired coating weight gain. For the above results, a solid content of 9% was used.
Table 4 shows that in addition to common plasticizers like triethyl citrate and
triacetin, the use of polyols such as mannitol and sorbitol can deliver very good
results when it comes to improving the surface finishing of PVA-based coatings.
Page 130 07/2020

10% 30% Figure 58:

Effect of different plasticizer types
and concentrations on the surface
roughness, using topographic maps
Triethyl citrate created by laser scanning microscopy
(LSM) at center-point images (C).
The defined raster pattern ensures a
representative dataset.
Glycerol
Triacetin
Parteck® Sl 150
Parteck® M 200
Dissolution data
Compared to tablets using an HPMC-based coating, Parteck® COAT excipient
was observed to have less influence on dissolution behavior (see Fig. 59). This
characteristic is especially important for immediate release formulations and in
the evaluation of BCS-based biowaivers, where 85% of the labeled content
needs to be dissolved within 15 minutes.
Figure 59:
100
Release of a model compound
(ascorbic acid) from tablets coated
80 with different polymers.
Dissolution [%]
60
40
20
0
0 5 10 15 20 25
Time [min]
Uncoated tablets
Parteck® COAT
HPMC based coating
Page 131 07/2020

Barrier function
Parteck® COAT excipient provides an excellent barrier function to protect
sensitive APIs from water and oxygen. Polymer films were prepared via film
casting and assessed for their water (Fig. 60) and oxygen permeation
(Fig. 61).
35 HPMC 1 for coating Figure 60:

30 HPMC 2 for coating Water transmission rate measured in
PEG-PVA graft copolymer* relation to DIN 53380-1, gravimetric
Water permeation rate [g* mm/(m2* day)]
25
Parteck® COAT method (evaluated film thickness: ~
20 200 µm)
15 *PEG-PVA graft copolymer: Single data
point only due to low physical stability of
10 the films.
5
0.8
0.6
0.4
0.2
0.0
200 HPMC 1 for coating Figure 61:

180 HPMC 2 for coating Oxygen transmission rate using an
160 PEG-PVA graft copolymer Oxtran 2/21 oxygen permeability
Oxygen permeation rate [cm3/(m2* day)]
Parteck® COAT instrument; samples masked to

140 20 cm2 (evaluated film thickness:
120 ~ 200 µm)
100
80
60
40
20
0.0

sheet or packaging and storage information, please refer to MerckMillipore.com
or contact your local sales representative.
Page 132 07/2020

Parteck® Delta M
Parteck® Delta M excipient is a convertible mannitol specifically designed to

handle wet granulation. Its delta-polymorphic crystals make it extremely
adaptable. While it is monographed as a standard mannitol, this exceptional
excipient changes its structure and converts into a beta-polymorph when it
comes into contact with water. This creates a porous structure, thereby
increasing the surface area, which leads to the ability to produce exceptionally
hard tablets with fast disintegration.
Figure 62:
SEM of Parteck® Delta M excipient A)
A B before and B) after wet granulation,
showing that the excipient’s delta-
polymorphic crystals have been
transformed into beta-polymorphic
crystals with a unique morphology
during the process.
PARTECK® DELTA M EXCIPIENT PROVIDES:

• Large surface area after granulation
• Excellent binding properties
• Accelerated disintegration
• Non-hygroscopicity
• Exceptionally low content of reducing sugars
• Compliance with Ph. Eur., BP, USP, JP, E 421
Page 133 07/2020

Composition Delta-polymorphic mannitol
Angle of repose [°] >40
Particle size (laser diffraction D10) [µm] 16
General formulation
Parteck® Delta M (112635) 50 – 98%
Water* 15 – 20 % low-shear granulation

20 – 25 % high-shear granulation
25 – 30 % fluid bed granulation
Glyceryl behenate 1.0 – 3.0%
Sodium stearyl fumarate 0.5 – 2.0%
*Wet granulation of Parteck® Delta M excipient separately or in combination with the API (if possible).
In consequence, the amount of water is calculated relative to the amount of Parteck® Delta M
excipient only or relative to the total amount of API and Parteck® Delta M.
Page 134 07/2020

Figure 63:
Compression profiles of granulated
Parteck® Delta M excipient (delta-
mannitol) and granulated beta-
140 mannitol (placebo tablets).
120
After granulation with 15% water,

100
the dried material was mixed for
Tablet hardness [N]
5 minutes with 1.5% magnesium

80
stearate and compressed into
400 mg tablets at different
60
compression forces using a single-
punch press with an 11 mm flat
40 facetted punch.
20
0
0 5 10 15 20 25
Parteck® Delta M excipient Beta-mannitol
Continuous manufacturing
Parteck® Delta M excipient has been successfully tested in continuous
manufacturing processes. More information can be provided on request.
Please contact your local sales representative.
For additional information on the product, material specification,

safety data sheet or packaging and storage information, please refer to
Page 135 07/2020

Parteck® LUB
Parteck® LUB, a product line of our most effective excipients for lubrication,
demonstrates excellent batch-to-batch consistency and helps you to achieve a
reliable workflow in your tablet manufacture.
Parteck® LUB products are available in three vegetable-origin variants:
• Parteck® LUB MST (magnesium stearate)
• Parteck® LUB CST (calcium stearate)
• Parteck® LUB STA (stearic acid)
PARTECK® LUB EXCIPIENTS PROVIDE:

• High batch-to-batch consistency
• Reliable performance thanks to specified particle size and surface area
•V
egetable origin and regulatory documentation for minimal qualification and
registration efforts
•C
ompliance with Ph. Eur./BP/JP/NF/FCC depending on the particular lubricant
(different lubricants meet different pharmacopoeia requirements)
•G
ood tablet dissolution over a broad range of compression forces and tablet
hardnesses, allowing for a wide variety of applications
Particle size and surface area of Parteck® LUB excipients
Parteck® LUB MST Parteck® LUB CST Parteck® LUB STA
D10 [μm] ≥1 ≥ 0.8 ≥5
D50 [μm] ~5 ~4 ~ 35
D90 [μm] ≤ 20 ≤ 20 ≤ 200
BET [m2/g] 5 – 12 4 – 8 0.90 – 1.40
Figure 64:
A B SEM of A) Parteck® LUB MST and B)
Parteck® LUB CST excipients.

Page 136 07/2020

Parteck® M 100, M 200
Parteck® M excipient achieves excellent compressibility while keeping the API

stable throughout your manufacturing process and beyond. Based on directly
compressible mannitol, it does not require further processing or high
compression forces. The unique and large surface area of Parteck® M excipient
enables rapid disintegration and quick release regardless of the dosage.
Adsorption of the API on the particles' surface area supports a good content
uniformity of low dose API formulations. This and the excellent compressibility
of Parteck® M excipient allows to reduce the tablet size by using less or no
binder, or to reduce the compression force at a given hardness while
maintaining high API content.
PARTECK® M EXCIPIENT PROVIDES:
• High compactibility thanks to unique particle properties

• Uniform doses with homogenous distribution
• High dilution potential
• Rapid disintegration
•E
xcellent API stability thanks to low hygroscopicity, water content
and exceptionally low reducing sugar content, and only low compression
forces required. Also non-reactive and compatible with amines. Figure 65:
Compression profile of Parteck® M
• Emprove® documentation excipient compared to other types
of mannitol.
• Compliance with Ph. Eur., BP, JP, USP, E 421
350
300
250
Tablet hardness [N]
200
150
100
50
0
0 5 10 15 20 25 30 35
Parteck® M 200 excipient Spray-dried mannitol Granulated mannitol
Page 137 07/2020

Parteck® M 100 Parteck® M 200
Composition Beta-polymorphic mannitol
Bulk density [g/mL] 0.50 – 0.60 0.52 – 0.53
Tapped density [g/mL] 0.65 – 0.75 0.62 – 0.67
Particle size (laser diffraction D10) [μm] 26 35
Angle of repose [°] 27 – 34 29 – 35
Pore volume (nitrogen adsorption BET) [cm3/g] 0.02 – 0.07 0.01 – 0.02
Surface area (nitrogen adsorption BET) [m2/g] 2.6 – 3.9 2.8 – 3.0
General formulation
Parteck® M 100 (100494) or Parteck® M 200 (100419) 40 – 99%
Page 138 07/2020

Figure 66:
SEM images of Parteck® M 200
particles.
The open and filamentary particle structure of Parteck® M excipient provides a

large surface area and excellent compression behavior. This allows for very low
compression forces during the tableting process, minimizing wear and tear to
tableting equipment.
Figure 67:
100
Sample dissolution profiles for
formulations manufactured using
80 Parteck® M and other mannitol-based
filler excipients.
Drug release [%]
60
40
20
0
0 1 2 3 4 5 6
Time [h]
Parteck® M 200 excipient Granulated mannitol 1

Spray-dried mannitol Granulated mannitol 2
Granulated mannitol 3
Hygroscopicity
Parteck® M excipients exhibit only very slight hygroscopicity, a typical and
well-known characteristic of D-mannitol, which means they can be handled
without precautions at ambient humidity of 80% or less. Due to this relatively
non-hygroscopic behavior, Parteck® M excipient is eminently suitable for
moisture-sensitive active ingredients.
Page 139 07/2020

10 Figure 68:
9 Dynamic vapor sorption (DVS)
8 isotherm of Parteck® M excipient at
25°C, average from 3 batches
Change in mass [%]
7
6
5
4
3
2
1
0
0 10 20 30 40 50 60 70 80 90 100
Target rH [%]
Purity
Pure mannitol may contain reducing sugars as impurities due to the
manufacturing process. This is limited to 0.1% by USP and Ph. Eur. However, for
Parteck® M excipients, the level of reducing sugars is limited to 0.05%. This
exceptionally low content of reducing sugars is important for the stability of the
formulation, as reducing sugars are subject to the Maillard reaction, which
causes API instability and browning.
Compatibility with lubricants

Parteck® M excipient has been tested with several different lubricants commonly
used in pharmaceutical formulation (magnesium stearate, stearic acid, glyceryl
behenate, sodium stearyl fumarate) with very constant results. It was shown
that the choice of lubricant has very little influence on the compressibility of
Parteck® M excipient and on tablet hardness.
Parteck® M excipient has been successfully tested in continuous manufacturing
processes. More information can be provided on request. Please contact your
local sales representative.

Page 140 07/2020

Parteck® SI 150, SI 200, SI 400, SI 450
Parteck® SI excipient is a directly compressible sorbitol which combines

excellent tableting behavior, resulting in very robust and shiny tablets, with a
pleasant mouthfeel and taste. It comes in a variety of particle sizes and
qualities to meet the needs of a very wide range of applications. The particle
structure consists of very loosely packed, interwoven filamentary crystals
pointing in all directions. These needle-like crystals are unique to Parteck® SI
excipient and are the basis of its distinctive physical properties, allowing you to
combine many ingredients into a robust tablet formulation. The unique and
large surface area allows for a fast disintegration and dissolution, even at high
tablet hardnesses. Adsorption of the API on the particles' surface supports a
good content uniformity of low dose API formulations. This and the excellent
compressibility of Parteck® SI excipient allows to reduce the tablet size by
using less or no binder, or to reduce the compression force at a given hardness
while maintaining high API content.
PARTECK® SI EXCIPIENT PROVIDES:

• Excellent compressibility
• Exceptionally low specified level of reducing sugars
• High dilution and adsorption capacity
• Pleasant mouthfeel
• Good flowability
•C
ompliance with Ph. Eur./BP/JSFA/NF/E 420 depending on the grade
(different grades meet different compendial requirements)
Figure 69:
SEM of Parteck® SI 400 excipient.
The particle structure of Parteck® SI excipient provides a large surface area and
excellent compression behavior. This allows for very low compression forces
during the tableting process, minimizing wear and tear to tableting equipment.
Page 141 07/2020

Lactose Figure 70:

Sweetness
MCC
7 Multivariate data analysis of
Mannitol palatability parameters for five
6
Sorbitol Onset of typical tablet fillers.
Mouth-filling
5 bitterness
Maltodextrin A professional sensory panel
4 evaluated the properties of
commonly used fillers in a
3
randomized, blind study. Test
2 Grittiness persons (n=8) were given 500 mg
Bitter aftertaste of granulate of a mixture of filler and model
1
bitter API quinine (DL 0.06%).
0 Low value = positive evaluation
High value = negative evaluation
Dissolution
Cooling effect
of granulate
Stickiness Clumping
Overall bitterness
600 Figure 71:

Compression profiles of
500 Parteck® SI 150 and 400 excipients
compared to crystallized sorbitol.
Tablet hardness [N]
400
300
100
100
0
0 5 10 15 20 25 30 35
Parteck® SI 150 excipient Parteck® SI 400 excipient Crystallized sorbitol
Page 142 07/2020

Parteck® Parteck® Parteck® Parteck®

SI 150 SI 200 SI 400 SI 450
Composition D-sorbitol
Bulk density [g/mL] 0.44 – 0.53 0.40 – 0.51 0.40 – 0.51 0.36 – 0.47
Tapped density [g/mL] 0.57 – 0.65 0.58 – 0.65 0.52 – 0.60 0.50 – 0.59
Angle of repose [°] 30 – 35 28 – 33 30 – 39 32 – 39
Particle size (laser diffraction D10)

68 92 228 292
[μm]

149 190 469 495
[μm]

337 357 857 833
[μm]
Pore volume (nitrogen adsorption

0.0155 0.0165 0.0088 0.0056
BET) [cm3/g]
Surface area (nitrogen adsorption

1.94 2.15 0.88 0.7
BET) [m2/g]
General formulation
Parteck® SI (103583; 103140; 103557 or 115079) 25 – 99%
Page 143 07/2020

Hygroscopicity
Parteck® SI excipients exhibit low hygroscopicity at a humidity of up to 60%,
meaning they can be handled without precautions at an ambient humidity of
60% or less. Tablets made with Parteck® SI excipient show slower water uptake
than those made with other sorbitol types which helps to minimize the effect of
sorbitol's intrinsic hygroscopicity.
120 Figure 72:

DVS isotherm of Parteck® SI excipient
100 at 25°C, average from 3 batches
Change in mass [%]
80
60
40
20
0 10 20 30 40 50 60 70 80 90 100
Target rH [%]
Purity
Pure sorbitol may contain reducing sugars as impurities due to the
manufacturing process. This is limited to 0.3% by USP and to 0.2% by Ph. Eur.
However, for Parteck® SI excipients, the level of reducing sugars is limited to
0.11%. This exceptionally low content of reducing sugars is important for the
stability of the formulation, as reducing sugars are subject to the Maillard
reaction, which causes API instability and browning.
Parteck® SI excipient is suitable for continuous manufacturing processes. More
information can be provided on request. Please contact your local sales
representative.

Page 144 07/2020

for Optimized Drug Delivery
Parteck® M DPI
Engineered from mannitol, Parteck® M DPI particles are designed to improve

the flow and release characteristics of APIs in drugs delivered via dry inhaled
powders. The carrier particles exhibit a remarkable structured surface area of
greater than 2.5 m2/g, providing exceptional homogeneity with micronized
APIs.
Parteck® M DPI excipient is engineered to limit impurities such as reducing
sugars to levels below compendial specifications. This allows it to be used for a
wide range of APIs and also supports good API stability, even with APIs with
primary or secondary amine groups that are known to interact with reducing
sugars.
PARTECK® M DPI EXCIPIENT PROVIDES:

• Superior chemical, physical and biological stability
•F
low properties well-suited for optimal blend homogeneity,
API delivery to the lungs and constant dose uniformity
• Compatibility with a wide range of APIs
• A viable alternative for patients with lactose intolerance
• Low hygroscopicity
• Compliance with Ph. Eur., BP, JP, USP, E 421
• Emprove® Expert product with specified low endotoxin and microbial limits
addressing high risk applications
Composition Mannitol
Particle size (laser diffraction D10) [µm] 75 – 115
Hausner index 1.17 – 1.23
Page 145 07/2020

General formulation with Parteck® M DPI excipient –

important considerations
• I t is essential that the final formulation be homogeneous and have good flow
properties to ensure dosing quality (such as in a multiple unit dosing system)
and facilitate filling (e.g. into capsules)
•L
oading capacity: Typically low dose formulations, but higher doses of up
to 50 % possible
•M
agnesium stearate may be added to improve the fine particle fraction
of the API
Figure 73:
Micronized model API budesonide on
Parteck® M DPI particle.
60
Figure 74:
Fine particle fraction with two
Fine particle fraction [%]
commercial devices compared to

40 two different commercial carriers
based on lactose, measured using
Next Generation Impactor.
20
0
Novolizer® Cyclohaler®
Parteck® M DPI excipient Lactose A Lactose B
For additional information on formulation with Parteck® M DPI excipient, please

refer to Rhein N, Birk G and Scherließ R. (2018). Spray-granulated mannitol as
a viable alternative for lactose in DPI formulations: Preparation of ordered
mixtures and storage stability. Inhalation Magazine, October 2018. 17-23 or
contact your local sales representative.

Page 146 07/2020

Parteck® ODT
Our Parteck® ODT excipient is directly compressible and contains two

ingredients: spray-granulated D-mannitol and croscarmellose sodium, both
compliant with with the main pharmacopoeias. This excipient facilitates the
production of robust, pleasant-tasting tablets that rapidly disintegrate and
dissolve across a broad range of tablet hardnesses and compression forces.
PARTECK® ODT EXCIPIENT PROVIDES:

• Rapid disintegration with pleasant taste and mouthfeel for patient compliance
• Fast dissolution for rapid relief
• Direct compressibility, for cost-effective development and production
• Exceptionally hard tablets, for simplified formulation work and handling
• High dilution potential – allows up to 50% active ingredients in DC formulations
ll components of Parteck® ODT excipient conform to the requirements of the
•A
relevant pharmacopeias.
Figure 75:
80 Tablet hardness and disintegration
time of Parteck® ODT tablets
compared to other marketed

60 ODT excipient systems. Different
compression forces (5, 10, 20 and
30 kN) were applied with the aim of
40 achieving a tablet hardness > 100 N.
At 5 kN compression force, products
C and E show no measurable tablet
20 hardness (friability 100%).
0
0 20 40 60 80 100 120 140 160 180 Tablets compressed with 1% Parteck®
LUB MST into 300 mg tablets using
Tablet hardness [N] a single-punch press fitted with an
Parteck® ODT Product B Product D 11 mm flat faceted punch
Product A Product C Product E
Due to its unique properties, Parteck® ODT excipient is very well suited for rapidly
disintegrating solid oral formulations. Typically, it is applied in ODT formulations
that are intended for a disintegration in the patient’s mouth. However, it can also
be used to formulate chewable tablets or for fast release tablets intended to be
swallowed.
Page 147 07/2020

Figure 76:
A B
SEM of A) Parteck® ODT excipient
before and B) Parteck® ODT tablet
breaking edge after compression
(compression force: 10.5 kN, tablet
hardness: 151 N).
5 μm 5 μm
The open, filamentous particle structure of Parteck® ODT excipient (Fig 76 A)

results in high tablet hardness even at low compression forces, minimizing
wear and tear to tableting equipment. Figure 76 B shows that the filamentous
particle structure of Parteck® ODT excipient is still present after the
compression procedure. The unique particle structure and large surface area of
Parteck® ODT excipient facilitate extremely fast disintegration, even for very
hard tablets.
Specifically spray-granulated
Composition
D-mannitol and croscarmellose sodium
CAS registry 69-65-8 and 74811-65-7
Surface area (nitrogen adsorption BET) [m2/g] 2.4 – 3.5
Page 148 07/2020

General formulation
Parteck® ODT (100490) 30 – 80%
Alternative lubricant
Hygroscopicity
14 Figure 77:
DVS isotherm for Parteck® ODT
excipient at 25°C.
12
10
Change in mass [%]
0
0 10 20 30 40 50 60 70 80 90 100
Target rH[%]
Parteck® ODT excipient exhibits low hygroscopicity, a typical and well-known

characteristic of mannitol. Below 80% relative humidity at 25°C, the moisture
sorption of Parteck® ODT excipient is below 2%. Due to its low hygroscopic
behavior, it is eminently suitable for moisture-sensitive active ingredients.

Parteck® ODT excipient has been tested with several different lubricants
commonly used in pharmaceutical formulation (magnesium stearate, sodium
stearyl fumarate, trimyristin, polyethylene glycol 6000) with very constant
results. It was shown that the choice of lubricant has very little influence on the
tablet hardness and dissolution of Parteck® ODT-based formulations.
Page 149 07/2020

Coating of ODT formulations

Unlike some other commercially available ODT excipient systems, Parteck® ODT
tablets are suitable for use with aqueous coating systems. This was shown using
two different commercially available coating systems and both placebo and model
API formulations. Both the polyvinyl alcohol-based and cellulose-based coating
systems resulted in tablets with a smooth surface for Parteck® ODT formulations.
It was observed that coating the tablets approximately doubles their hardness,
while the disintegration time remains constant or increases only slightly,
depending on the properties of the coating system. If needed, the tablet
disintegration time may be adjusted to meet specific requirements, e.g. by adding
a superdisintegrant to the formulation. For additional details, please refer to the
respective formulation example in the chapter “Orally Disintegrating Tablets
(ODTs)” or contact your local sales representative.
Figure 78:
Sample Parteck® ODT tablet coated
using a commercially available,
cellulose-based aqueous coating
system
Parteck® ODT excipient has been successfully tested in continuous manufacturing
processes. More information can be provided on request. Please contact your local
For additional information on the product, material specification, safety data sheet
or packaging and storage information, please refer to MerckMillipore.com or
Page 150 07/2020

Parteck® SRP 80
Parteck® SRP 80, a functional, fully synthetic excipient based on polyvinyl

alcohol (PVA), provides consistent, sustained drug delivery over long release
periods. Due to its optimized particle properties, Parteck® SRP 80 excipient has
a high compressibility and high dilution potential as well as reliable in-vitro
drug dissolution. It is of fully synthetic origin, therefore there are no problems
with raw material variations. Compared with natural or semi-natural polymers,
QbD and validation processes in particular are greatly simplified with
Parteck® SRP 80 excipient.
PARTECK® SRP 80 EXCIPIENT PROVIDES:

• Consistent API release over several hours
•R
eliable product performance due to its fully synthetic origin and
high batch-to-batch consistency
• Convenient, cost-efficient manufacturing
• No pH or alcohol induced dose dumping (in vitro)
• Low hygroscopicity
• Compliance with Ph. Eur., USP, JPE
Figure 79:
SEM images of Parteck® SRP 80

excipient showing a smooth surface
structure of the particles.
30 μm 1 μm
Figure 80:
A B
Appearance of sample Parteck® SRP
80 formulation before (A) and after
(B) contact with the dissolution
medium for 1 hour in a disintegration
tester at 37 °C.
Page 151 07/2020

Figure 81:
300 318 600
Correlation of compression force and
Tablet hardness [N]
Ejection force [N]

278 tablet hardness with ejection force
based on a sample Parteck® SRP 80
200 400 formulation (n=20).
150
100 200
63
0 0
5 10 20 30
Tablet hardness [N] Ejection force [N]
Composition Polyvinyl alcohol PVA 40-88
Pore volume (nitrogen adsorption BET) [cm3/g] Not detectable
Surface area (nitrogen adsorption BET) [m2/g] 0.3 – 0.5
Loss on drying (3h, 105 °C) [%] ≤ 5.0
Page 152 07/2020

Hygroscopicity
35 Figure 82:
DVS isotherm for Parteck® SRP 80
excipient at 25 °C.
30
25
Change in mass [%]
20
15
10
0
0 10 20 30 40 50 60 70 80 90 100
Target rH [%]
Parteck® SRP 80 exhibits only slight hygroscopicity. Normally this allows

handling without special precautions. Storage containers should nevertheless
always be tightly closed and stored under dry conditions.
Page 153 07/2020

General formulation
Parteck® SRP 80 (141439) 20 – 70%1
Microcrystalline cellulose (MCC) 0 – 60%2
1
The content of Parteck® SRP 80 excipient in the formulation should not be less than 20%, otherwise
gel forming will be inhomogeneous.
2
Depending on formulation composition, API dose, compactability and other parameters, an additional
binder such as MCC may be either beneficial or unnecessary.
Dissolution
Parteck® SRP 80 forms a swellable and erodible matrix (visualized in Fig. 80)
and is used in the formulation of pharmaceutical oral dosage forms showing a
sustained API release. The release profiles of Parteck® SRP 80 formulations
were investigated over a broad range of compression forces and tablet
hardnesses (see Fig. 81). In addition, the effect of media of different pH and
ethanol content was assessed (see Fig. 84 A and 84 B). The dissolution of the
API from the Parteck® SRP 80-based tablet was observed to be very robust
over a broad range of compression forces and tablet hardnesses and not to be
dependent on the pH or ethanolic content of the outer medium, all very
relevant for sustained release formulations.
Figure 83:
100
Release profile of sample Parteck®
90
SRP 80 formulation manufactured at
80 different compression forces, showing
robust dissolution behavior regardless
Drug release [%]
70
60
of tablet hardness.
50
40
30 2, 900 mL phosphate buffer pH 6.8,
20 50 rpm, 37 °C, n=3.
10
0
0 2 4 6 8 10 12
Time [h]
Page 154 07/2020

A Figure 84:
Dissolution of sample Parteck®
100 SRP 80 formulation A) in media of
90 different pH and B) in media with
different ethanol contents.
80
Drug release [%]
70
60
50
40 medium for A without pH switch,
30 1000 mL medium for A with pH
20 switch and 900 mL HCl/ethanol
medium for B, 50 rpm, 37 °C, n=3.
10
Samples used: tablets compressed
0 at 20kN
0 2 4 6 8 10 12
Time [h]
HCl 0.1 M HCl buffer pH 1.2
HCl phosphate buffer pH 6.8 HCl 0.1 M (2h)  Phosphate buffer pH 6.8
100
80
Drug release [%]
60
40
20
0
0 2 4 6 8 10 12
Time [h]
HCl 0.1 M HCl 0.1 M / Ethanol 95 / 5% (v/v)
HCl 0.1 M / Ethanol 80 / 20% (v/v) HCl 0.1 M / Ethanol 60 / 40% (v/v)
Page 155 07/2020


Parteck® SRP 80 excipient has been tested with several different lubricants
commonly used in pharmaceutical formulation (magnesium stearate, stearic
acid, sodium stearyl fumarate, trimyristin). It was shown that the choice of
lubricant has very little influence on the sustained release behavior of Parteck®
SRP 80-based formulations. An extraordinarily high tablet hardness was
achieved with magnesium stearate (Parteck® LUB MST excipient; see Fig. 41),
with alternative lubricants still resulting in very hard tablets. Ejection forces
were lowest for the formulations using magnesium stearate and stearic acid
(Parteck® LUB MST and Parteck® LUB STA 50 excipients).
Parteck® SRP 80 excipient is suitable for continuous manufacturing processes.
More information can be provided on request. Please contact your local sales
representative.
For additional information on the product, material specification, safety data sheet
or packaging and storage information, please refer to MerckMillipore.com or
Page 156 07/2020

for Enhanced Solubility
Parteck® MXP
Parteck® MXP excipient is a new polyvinyl alcohol (PVA)-based excipient

specifically designed for hot-melt extrusion to increase the solubility of poorly
water-soluble APIs. It allows for stable and high drug loads and can be used for
a broad range of poorly water-soluble APIs. The Parteck® MXP-based extrudate
can be easily formulated into a variety of final oral dosage forms with immediate
or sustained release kinetics.
PARTECK® MXP EXCIPIENT PROVIDES:

• Enhanced solubility
• Stable high drug load
• High thermostability and suitability with a broad range of APIs
• Flexible release kinetics
• Ease of use
• Prolonged supersaturated state after release
• Stable excipient for hot melt extrusion with little to no chemical
instability for all assessed APIs
• Reliable product performance due to its fully synthetic origin and
high batch-to-batch consistency
• Compliance with Ph. Eur., JPE, USP
120 Figure 85:

Dissolution performance of sample
100 Parteck® MXP formulation compared
to extrudates based on other
Drug release [mg/L]
80 polymers and the corresponding

marketed formulation.
60
itraconazole, 900 mL SGF, 37 °C, 100
20
rpm, 100 mg itraconazole, 30% drug
load, n=3
0
0 20 40 60 80 100 120 140 160 180 200
Time [min]
Crystalline API
API: Parteck® MXP extrudate
API: Marketed polymer 1 extrudate
Page 157 07/2020

Figure 86:
SEM image of Parteck® MXP particles
30 μm
Composition Polyvinyl alcohol PVA 4-88
Loss on drying [%] ≤ 5.0
Solubility (max. in water) [%] 33
Page 158 07/2020

Application range
APIs from different chemical families and with varying physicochemical
properties were selected (Table 5) to investigate the suitability of Parteck® MXP
excipient for a broad API range. Extrudates were assessed for their
homogeneity (using NMR analysis; data not shown) and stability over time.
Dissolution studies were performed using FDA-recommended conditions.
Table 5:
Aqueous
Physicochemical properties of
MW Tm solubility
API (BCS II) pKa LogP Charge selected APIs
[g/mol] [°C] [mg/mL,
25 °C]
Ibuprofen 206.28 4.9 78 4.0 -1 0.021
Cinnarizine 368.51 8.4 118-122 5.2 1 0.00172
Ketoconazole 531.43 6.8 146 4.3 0 0.00931
Indomethacin 357.79 4.5 151 4.3 -1 0.000937
Naproxen 230.26 4.2 152 3.3 -1 0.0511
Atorvastatin 558.64 4.3 159-160 4.4 -1 0.000495
Itraconazole 705.63 3.7 167 5.9 0 0.00964
16 [SA]
Carbamazepine 236.27 204-206 2.1 0 0.152
-3.8 [SB]
3.7 [SA]
Telmisartan 514.62 260 7.7 -1 0.0035
6.1 [SB]
Page 159 07/2020

Table 6:
Solubility
API Load
API Tm of API [°C] Enhancement Solubility enhancement and drug
Achieved* [%] loads of selected APIs after extrusion
(max.)
with Parteck® MXP excipient
Ibuprofen** 78 30 2×
Cinnarizine 118 – 122 < 20 10 ×
Indomethacin 151 50 3×
Ketoconazole 146 35 17 ×
Naproxen 152 30 4×
Atorvastatin 159 – 160 55 154 ×
Itraconazole 166.5 30 80 ×
Carbamazepine 204 30 2×
Telmisartan** 260 15 35 ×
*Maximum API load is defined as the maximum amount of API present in an amorphous state in the
extrudate observed for experimental data.
**Plasticizer is required to make the extrusion feasible or easier.
For the APIs assessed, solubility was enhanced in all cases with no detectable
degradation of the API. Seven of nine extrudates demonstrated a minimum API
load of 30% (w/w), some going up as high as 55% (w/w). Solubility showed a
significant increase – from doubling to an over 150-fold increase compared to
the solubility of the crystalline drug (see Table 6).
In summary, dissolution was rapid, and in many cases, maximum solubility was
reached in under 15 minutes. This rapid dissolution can likely be attributed to
the fact that Parteck® MXP excipient is a water-soluble polymer and thus does
not limit the dissolution rate, a phenomenon which often occurs when a poorly
water-soluble polymer is used in HME. Please see the respective formulation
example for dissolution results.
Page 160 07/2020

Stability of the extrudate

After extrusion and milling, the stability of three different API:Parteck® MXP
extrudates was assessed under three different sets of conditions: cold
(2 – 4 °C), room temperature (25 °C, 60% rH), and accelerated (40 °C, 75%
rH). At each time point, the extrudates were measured using DSC (to assess
the amorphous state), HPLC (to assess API degradation), and repeat
dissolution. For all three examples, no instability was found throughout the
testing period of 6 or 12 months. (see summary of results in Table 7). For
detailed dissolution results, please refer to the respective formulation example.
Table 7:
API Storage conditions Time Results* Stability results for extruded
Parteck® MXP formulations with three
different model APIs stored for 6 or
Stable under all 12 months under three different sets
Itraconazole Low: 2-4 °C 12 M of conditions.
conditions
Room: 25 °C, Stable under all

Ibuprofen 6M
60% humidity conditions
Accelerated: 40 °C, Stable under all

Indomethacin 6M
75% humidity conditions
Thermal properties
Tg (by DSC) [°C] 40-45
Tm (by DSC) [°C] 170
Td (by DSC) [°C] >250
Melt viscosity at D=200 s-1, 210 °C [Pa·s] 702
Page 161 07/2020

Parteck® MXP excipient is a semi-crystalline polymer and thus possesses both a

glass transition temperature (Tg) and a melting temperature (Tm). The semi-
crystalline nature of Parteck® MXP excipient has not proven to be a limiting
factor in HME. For 75 % of the model APIs assessed, no plasticizer was
necessary to achieve an amorphous solid dispersion (see “Solubility
enhancement and drug loads of selected APIs after extrusion with Parteck®
MXP excipient”). For plasticizer recommendations, see the section “General
recommendations for formulation with Parteck® MXP excipient”. Once extruded,
the API and polymer form an amorphous extrudate which has been
demonstrated to be remarkably stable, even under accelerated conditions (see
Table 7).
Parteck® MXP excipient has been found to have an appropriate melt viscosity
for HME applications, which is highly relevant, as the melt viscosity of the
polymer can impact melting and mixing in the extruder. If the melt viscosity is
too high, the required mechanical energy may also be too high, resulting in
equipment breakage and/or breakdown. If the melt viscosity is too low, the
mixing process may be less effective in creating an amorphous solid dispersion.
Viscosity behavior
Parteck® MXP polyvinyl alcohol is a thermoplastic polymer with pseudo-plastic
viscosity behavior. Figure 87 shows how the material’s viscosity is reduced with
increasing shear force. This characteristic of the material enables high
throughput rates, an optimized flow of the molten material through the die
channels, and extended process ranges, and supports an easier process and
reduced torque, even at high shear rates.
10000 Figure 87:

Viscosity of Parteck® MXP excipient
as a function of shear rate at process
temperatures of 210 and 230 °C.
Viscosity [Pa* s]
Viscosity was measured using a

1000 capillary rheometer with the melting
time set to 300 s and a capillary
geometry of 30 mm in length and 1
mm in diameter.
100
10 100 1000 10000

Shear rate [s-1]
Parteck® MXP melt at 210 °C Parteck® MXP melt at 230 °C
Page 162 07/2020

Hygroscopicity
Parteck® MXP excipient is slightly hygroscopic and should be stored in tightly
sealed packaging under dry conditions. Before extrusion, it is recommended to
dry the material at 105 °C for 3 hours. After this, losses during drying will be
less than 0.1 %.
40 Figure 88:
DVS isotherm for Parteck® MXP
excipient at 25 °C.
35
30
Change in mass [%]
25
20
15
10
0
0 10 20 30 40 50 60 70 80 90 100
Target rH [%]
General recommendations for formulation with Parteck® MXP excipient:

• Drying: Before the hot melt extrusion process, the Parteck® MXP material can
be dried at 105 °C for 3 hours. After this, losses during drying will be less
than 0.1%.
xtrusion: Parteck® MXP excipient can be used on standard extruders with 3
•E
– 5 heat zones for thermoplastic processing. The process temperatures are
subject to change based on the formulation (plasticizer, API characteristics
etc.; see Table 8). The extrusion temperature should not be above 250 °C, as
higher temperatures may cause the material to degrade. Residence time
should not exceed 10 minutes. If the flowability of the drug:excipient mixture
is not ideal for feeding the extruder, add 1-2 % highly disperse silicon dioxide
(113126) to improve it.
Figure 89:
Exemplary temperature
profile. Recommended feed
rate: approximately 0.4 kg/h;
recommended rotation speed:
80 150 200 200 200 200 200 200 300 rpm.
Page 163 07/2020

Table 8:
HME processing
Composition Extrudate Effect of recommended plasticizer
temperature [°C] Parteck® SI on extrusion conditions.
It was found that spray-dried
Parteck® MXP without sorbitol 190 Transparent Parteck® SI 150 sorbitol (103583)
had better plasticizing properties and
performance in HME than crystallized
Parteck® MXP/ Parteck® SI [5:1] 160 Transparent
sorbitol. For additional information on
Parteck® SI excipients, please refer
Parteck® MXP/ Parteck® SI [4:1] 150-160 Transparent to the respective product page in this
document.
Parteck® MXP/ Parteck® SI [2:1] 140-150 Transparent
•F
inal formulation: Parteck® MXP excipient is suitable for a variety of
downstream options. The different final formulations evaluated to date are:
1. immediate-release capsules
2. immediate-release compressed tablets
3. sustained-release compressed tablets
4. sustained-release directly-shaped tablets
5. extruded films for transdermal application
6. orally dissolving films (ODF)
7. filament-based 3D-printed formulations
The above immediate and sustained release solid oral dosage forms 1-4 were
prepared using the same extrudate, which demonstrates the versatility of
Parteck® MXP excipient. For detailed dissolution results, please refer to the
formulation example “Itraconazole Extrudate”.
Inorganic salts may be used to fine-tune the release profile of the final dosage
form to one’s needs. For further information on this, please contact your local
Parteck® MXP excipient is suitable for continuous manufacturing processes.
More information can be provided on request.

Page 164 07/2020

Parteck® SLC
Parteck® SLC excipient is an innovative silica drug carrier that enhances drug
solubility thanks to its unique surface structure. This allows for significantly
increased dissolution of your API. Parteck® SLC’s disordered mesopores
(~ 6 nm) create a large and easily accessible surface area of approx.
500 m²/g, enabling high API load. The API is deposited within the particle
structures in its amorphous form, leading to increased dissolution rate and
solubility through supersaturation.
PARTECK® SLC EXCIPIENT PROVIDES:

• Superior dissolution performance
• Good compressibility, making it suitable for direct compression processes
• User-friendly particle size
• High-end application support
50
Figure 90:
Dissolution performance of sample
40 tablet formulation with API loaded
onto Parteck® SLC particles, showing
Drug release [mg/mL]
the formulation’s stability throughout

30 storage for 52 weeks at 25 °C /
60% rH.
20
Dissolution procedure: 38 mg
10 fenofibrate, 750 mL SGFsp + 1.0%
SDS, 75 rpm, n=3
0
0 30 60 90 120
Time [min]
Saturation solubility of API 1 week

Start 4 weeks
Crystalline API 26 weeks
52 weeks
Figure 91:
SEM images of Parteck® SLC particles
30 μm 500 nm
Page 165 07/2020

Composition Silicon dioxide
Pore size [nm] ca. 6 (disordered)
Surface area (nitrogen adsorption BET)

ca. 500
[m2/g]
General formulation with Parteck® SLC excipient –

important considerations
Solubility
• Drug must be soluble in an acceptable solvent
• Solvent properties: Low boiling point, high vapor pressure
•A
PI concentrations of 50-60 mg/mL ideal; lower concentrations possible
Loading procedure
• Loading should be carried out so as not to oversaturate the silica
• Good experience with approx. 30% w/w for fully amorphous state
• Drying is needed to remove residual solvents
•D
rying temperature should be selected based on solvent boiling point and
drug melting point
Formulation
• Type of final solid dosage form (tablet, capsule)
• Loading capacity: approx. 30% API
• Tableting capacity: up to 30% loaded silica

Page 166 07/2020

Product Overview – Sucralose
Sucralose
Sucralose is an innovative, highly intense sweetener which is readily soluble,

easy to use and non-cariogenic. It masks both bitterness and medicinal off-
notes with equal ease and is suitable for diabetics and people with impaired
glucose tolerance. For these reasons, sucralose is exceptionally well-suited for
pharmaceutical applications. Our sucralose is part of our Emprove® product
range, which combines outstanding quality with comprehensive documentation
and excellent service tailored to the pharmaceutical industry. It is available in
micronized or granular form, both pharmaceutical-grade.
OUR SUCRALOSE PROVIDES:

•C
lean, sugar-like taste that is on average 600 times sweeter than sugar, but
with zero calories
• Masking of bitterness and medicinal off-notes, improving patient compliance
•R
eadily soluble, for easy handling
•B
atch-to-batch consistency, for reliable results
•A
queous heat and pH-stability, enabling stable formulations
•C
ompliant with Ph. Eur., JPE and USP-NF
Safety considerations
Studies have demonstrated that sucralose has a good safety profile. It was
therefore approved by the US Food and Drug Administration (FDA) as a
general-purpose sweetener in 1999 and by the European Food Safety Authority
(EFSA) in 2004. A sucralose monograph was adopted by the European
Directorate for the Quality of Medicines & HealthCare (EDQM) for its use as a
pharmaceutical excipient in 2010, followed by excipient monographs in the
major pharmacopoeias.
Figure 92:
SEM images of sucralose
30 μm 300 µm
Page 167 07/2020

Sucralose Sucralose
powder granular
Sucralose (1,6-Dichloro-1,6-dideoxy-
Composition β-D-fructofuranosyl-4-chloro-4-deoxy-
α-D-galactopyranoside)
Bulk density [g/mL] 0.30-0.40 0.70-0.85
Tapped density [g/mL] 0.45–0.65 0.80–0.95
Particle size (laser diffraction D10) [μm] 0.5 119
BET surface area [m2/g] 1.4–2.2 < 0.01
Angle of repose [°] Not measurable 27–33
pH value of 10% aqueous solution 5–8 5–8
130 130
Melting point [°C] (decomposition)
(decomposition)
Sensory aspects: Potency of sucralose

On average, sucralose is approximately 600 times sweeter than sugar (see Fig.
93). The potency will vary, however, depending on a number of factors, including:
• concentration – this has the largest impact
• pH value and acid content
• temperature of product
• presence of ingredients such as other sweeteners and fillers.
Page 168 07/2020

14 Figure 93:
Potency of sucralose compared to
12
sugar, depending on its concentration
Sugar equivalence [%]
(in pH 3 citric acid medium)

10
Potency ca. 480 x
8
6
Potency ca. 600 x
4
2
Potency ca. 750 x
0
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300
Sucralose concentration [ppm]
Citric acid pH 3
For a detailed investigation of sucralose’s sweetening profile compared to other

commonly used sweeteners, please refer to our publication Taste Optimization
in Solid Dose: A Human Sensory Panel Study (2018).
Hygroscopicity
0.6 Figure 94:

DVS isotherm for the two forms of
0.5 sucralose at 25°C.
Change in mass [%]
0.4
0.3
0.2
0.1
0 10 20 30 40 50 60 70 80 90 100
Target rH [%]
Sucralose powder
Sucralose granular
100894 Sucralose powder and 100895 Sucralose granular show no

hygroscopicity. The moisture sorption values for the two sucralose types are
below 0.2% at all target relative humidity points at 25 °C (see Fig. 94). Due to
their non-hygroscopic nature, the two forms of sucralose are eminently suitable
for moisture-sensitive active ingredients and do not require special storage
conditions to prevent moisture pick-up.
Page 169 07/2020

General formulation
Table 9:
100894 Sucralose 100895 Sucralose
Application/ Dosage form Recommended pharmaceutical
powder granular applications for the two available
types of sucralose: powder and
Cough and cold syrup + ++ granular
Lozenges + ++
Tablets ++ +
Tablet coating ++ +
Sachets ++ +
Medicated chewing gum ++ +
Sucralose powder and sucralose granular may be used in solid and liquid oral
dosage form drug products in doses of 0.05 to 1.0%, even up to 2.0%. These
low amounts should give good results for a variety of drugs. Due to its optimal
dispersion behavior, sucralose powder is typically recommended for solid dose
formulations, while the fast dissolution behavior of sucralose granular makes it
very well-suited for liquid formulations.
Use in tablets
•S
ucralose may be used in directly compressed, roller-compacted and wet-
granulated tablets.
• It provides sweetness without adding significant bulk.
•A
dding sweetness to the tablet may eliminate the need for a pan-coating
step.
• I f a coating is used, sucralose may be incorporated into the coating for
intense sweetness.
•W
hen dry-blending, sucralose powder's small particle size allows for an even
distribution.

sheet, storage conditions or packaging and ordering information, please refer
to MerckMillipore.com or contact your local sales representative.
Page 170 07/2020

List of APIs used
API name page Fexofenadine HCl

ODT 53
Acetaminophen Glimepiride
See paracetamol ODT 55
Acetylsalicylic acid Glycopyrrolate
DC 7 ODT NEW
56
Chewable 31 Glycopyrronium bromide
Alginic acid See Glycopyrrolate
Chewable 32 Ibuprofen
Amoxicillin trihydrate Coated NEW
115
Dry syrups and suspensions 37 DC 10
Ampicillin trihydrate DG 21
Dry syrups and suspensions 38 Inorganic carriers 93
Ascorbic acid ODT 58, NEW
59, NEW 115
Coated NEW
48, NEW 111 SR 102
DC 8, NEW 111 WG 25
ODT 47, 48, 50 Indomethacin
SR 96 HME 75
WG 22 Itraconazole
Benzocaine HME 77
Lozenge 45 Ketoconazole
Caffeine 3DP NEW
119
DC 9 Lamotrigine
Calcium carbonate HME NEW
81
Chewable 33 Lisinopril
Carvedilol WG 26
Inorganic carriers 86 Loratadine
Clozapine ODT 61
ODT NEW
51 Magnesium carbonate
Dextromethorphan HBr Chewable 34
Lozenge 44 DC 12
Diclofenac Effervescent 41
SR NEW
98 Multivitamin supplement
Diltiazem HCl Dry syrups and suspensions 42
SR 100 Effervescent 39
Enalapril maleate Paracetamol
DG 20 DC 7, NEW
13, 14
Entacapone Chewable 35
Inorganic carriers NEW
87 ODT NEW
63, 64
Fenofibrate Prednisolone
Inorganic carriers 89, 91 DC 15
WG 23
Page 171 07/2020

List of APIs used
API name page
Propranolol HCl
SR 104, 106
Rosuvastatin
ODT 65
Pyridoxine hydrochloride
DC 16, 17
Sildenafil
ODT 67
Sodium bicarbonate
Chewable 32
Sodium hydrogen carbonate
See sodium bicarbonate
Telmisartan
WG NEW
28
Thiamine hydrochloride
DC 18
Tyrothricin
Lozenge 45
Theophylline
SR 108
Vitamin C
See ascorbic acid
Water-sensitive low-dose API
DC 19
Page 172 07/2020

Abbreviation index
ADI - Allowed daily intake
API - Active pharmaceutical ingredient
BCS - Biopharmaceutical classification system
BET - Brunauer, Emmett, Teller
BSA - Bovine serum albumine
DC - Direct compression
DG - Dry granulation
DL - Drug load
DSC - Differential scanning calorimetry
DVS - Dynamic vapor sorption
FDM - Fused deposition modeling
GRAS - Generally recognized as safe
HBSSg - Hank's Balanced Salt Solution containing 15 mM glucose
HME - Hot-melt extrusion
IR - Immediate release
MCC - Microcrystalline cellulose
ODT - Orally disintegrating tablet
PEG - Polyethylene glycol
PVA - Polyvinyl alcohol
PVP - Polyvinylpyrrolidone
PVP/VA - Polyvinylpyrrolidone/vinyl acetate copolymer
rH - Relative humidity
SEM - Scanning electron microscopy
SGF - Simulated gastric fluid
SME - Specific mechanical energy
SR - Sustained release
TGA - Thermogravimetric analysis
VCM - Vacuum compression molding
WG - Wet granulation
XRD - X-ray diffraction
3DP - 3D printing, also referred to as additive manufacturing
Page 173 07/2020

The typical technical data above serve to generally characterize the excipient. These values are not meant as specifications and they do not have
binding character. The product specification is available separately at: MerckMillipore.com
We provide information and advice to our customers on application technologies and regulatory matters to the best of our knowledge and ability, but
without obligation or liability. Existing laws and regulations are to be observed in all cases by our customers. This also applies in respect to any rights
of third parties. Our information and advice do not relieve our customers of their own responsibility for checking the suitability of our products for the
envisaged purpose.
For additional information, please visit MerckMillipore.com
To place an order or receive technical assistance, please visit MerckMillipore.com/contactPS
Merck, the Vibrant M, SAFC, Candurin, and Parteck are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the
property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2020 Merck KGaA, Darmstadt,
Germany and/or its affiliates. All Rights Reserved.
07/2020 Lit. No.: MK_AG3737EN

Formulation Handbook MRK 02 2020

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Formulation

The life science business

Loratadine (10 mg) 61

Chewable Tablets 30 Tablet Coatings NEW 110

Formulation Examples Formulation Examples

Dry Syrups and Suspensions 36

Amoxicillin Trihydrate (50 mg/mL) 37

Direct compression (DC) Lubricant Parteck® LUB MST (magnesium stearate,

Both high and low API doses may present a challenge.

Granulation Our Formulation Ingredients for DG

DG is used to improve flow properties and prevent

DG can be done in two ways: either a large tablet (slug)

Wet Granulation (WG) Our Formulation Ingredients for WG

Flavoring Vanillin (108510)

Coloring agent Candurin® pigments such as Candurin®

Acetylsalicylic Acid (250 mg) and

Amount [mg/tablet] Amount [% w/w]

Paracetamol DC 96 % 260 37.14

Parteck® CCS pKa 3.49

Total 700 100 Solubility Slightly

Compression force [kN] 15

Tablet thickness [mm] 4.5 Solubility Sparingly

Friability [%] 0.6

Disintegration time [min] 1

Ascorbic Acid (500 mg)

Amount [mg/tablet] Amount [% w/w]

Ascorbic acid (fine powder) 500 50 API

Microcrystalline cellulose (MCC)

Silicon dioxide, highly dispersed

BCS class III

Compression force [kN] 26

Tablet weight [mg] 1000

Weight variation [%] 0.7

Tablet diameter [mm] 15

Tablet thickness [mm] 4.0

Tablet hardness [N] 112

Friability [%] 0.4

Disintegration time [min] 5

Caffeine (100 mg)

Amount [mg/tablet] Amount [% w/w]

Caffeine 100 26.32 API

Microcrystalline cellulose (MCC)

Silicon dioxide, highly dispersed BCS class I

Total 380 100

Compression force [kN] 7

Tablet weight [mg] 380

Weight variation [%] 0.3

Tablet diameter [mm] 11

Tablet thickness [mm] 3.4

Tablet hardness [N] 79

Friability [%] 0.2

Disintegration time [min] 3

Ibuprofen (200 mg)

Amount [mg/tablet] Amount [% w/w]

Parteck® M 200 (DC mannitol, 100419) 270 54

Parteck® LUB MST Melting point 75 – 77 °C

Tablet properties obtained at different compression forces:

Compression force [kN] 5 10 20

Tablet weight [mg] 500 500 500

Weight variation [%] 0.59 0.43 0.53

Tablet diameter [mm] 11 11 11

Tablet thickness [mm] 5.2 4.8 4.5

Tablet hardness [N] 81 160 222

Hardness variation [%] 7.74 3.02 2.80