Dr.

Verena Geiselhart
Technical Service Manager
Ludwigshafen am Rhein, Germany
Pharma Solutions Europe
Nutrition & Health Division

Soluplus – in wet extrusion

Introduction
The solubility and bioavailability challenge

The Venus de Milo is 10-times more soluble

in water than pharma actives like Itroconazol

Insoluble
Future actives
situation

Soluble
actives

What cannot be dissolved cannot be absorbed and cannot cure

Introduction
Biopharmaceutical Classification System (BCS)

Source: Adapted: J. M. Butler, J. B. Dressman, The developability classification system: application of biopharmaceutics concepts to formulation development
Journal of Pharmaceutical Sciences 99, 4940-4954 (2009).

Class II a: dissolution rate

limited Class I
Class II b: solubility limited
5%
70%
90%
Permeability

Class IV Class III

20% 5%

0.1 mg/mL
Solubility

About 95% of all new chemical entities (NCE) show

poor solubility and/or poor permeability
Introduction
Enhancement of “Biopharmaceutical Fitness”

Enhancement of solubility
• pH-adjustment
• co-solvents Class I
• surfactants
• formulation systems, e.g. SEDDS 5%
• complexation
• micronization / nanozization
90%
Permeability

• API modification (salts,…)

• … Enhancement of permeability
Enhancement of permeability • efflux inhibitors (P-gp)
• tight junction openers
&
• metabolic inhibitors
Enhancement of solubility
• motility modifier
• pro-drugs
• …
0.1 mg/mL
Solubility

Excipients with various functions are useful to increase

biopharmaceutical fitness of Class II-IV substances
Soluplus® - The Innovative Polymer For Solid Solutions
Spray Drying

Properties
HO
 PEG 6000 / vinylcaprolactam / vinyl acetate: 13 / 57 / 30
 Appearance: White to yellowish free flowing granules
O
 Glass transition temperature: ~ 70 °C O
N
 Molecular weight: ~ 118 000 g/mol
l
O
m
O
O

O
n

HO
Soluplus® - The Innovative Polymer For Solid Solutions
Fields of Application

Drug layering Hot melt extrusion Spray drying

Soluplus® Others…

Wet granulation Direct compression Melt granulation

Solubiliser Screening
Set-up for Pre-test of Solubilisation Capacity)

Active Polymer 72h stirring, UV detection

(excess) (10 w%) room of solubilized active
temperature
UV
H 2O Filtration

 Preparation of saturated solution of drug in 10 % polymer solution

 24 - 72 h stirring (room temperature) and filtration (0.45 µm filter)
 Determination of dissolved amount of drug by UV/Vis
 Soluplus® - The Innovative Polymer For Solid Solutions
Solubilisation Capacity

Saturation solubility in phosphate buffer pH 7.0 [g/100 ml]

0,35
0.35
Soluplus ® Pure API
0,30
0.30
0,25
0.25
0,20
0.20
0,15
0.15
0,10
0.10

~0.0001

~0.0001

~0.0001
~0.001

~0.001

~0.001

~0.001
0,05
0.05
0,00
0.00

10% solubilizer solution, saturation solubility detected after 72h stirring

Manifold increase in API solubility using Soluplus®! Solubilisation capability

of Soluplus® is not limited to certain chemical structures!
 Soluplus® - The Innovative Polymer For Solid Solutions
Solubiliser Comparison

Saturation solubility in phosphate buffer pH 7.0 [g/100 ml]

0,35
0.35
Soluplus ® Kolliphor® RH40 Tween® 80
0,30
0.30
Kolliphor® HS15 Kolliphor® P407
0,25
0.25
0,20
0.20
0,15
0.15
0,10
0.10
0,05
0.05
0,00
0.00

10% solubilizer solution, saturation solubility detected after 72h stirring

For 4 of 10 APIs
Soluplus® showed the highest solubilisation capacity!
 Soluplus® - The Innovative Polymer For Solid Solutions
Dependency of Solubility on pH

Saturation solubility [g/100 ml]

2,00
2.00
Soluplus® (pH 1.2)
1,60
1.60 Soluplus® (pH 7.0)
1,20
1.20 Soluplus® (pH 9)

0,80
0.80

0,40
0.40

0,00
0.00

10% solubilizer solution, saturation solubility detected after 72h stirring

Solubilization capacity comparable at different pH values!

Exception: basic APIs show higher solubility at low pH values
Case study: Wet extrusion
Wet Extrusion with Soluplus
Experimental Set-Up
 Wet Granulation Set-Up Preblend
Crystalline Amorphous
API polymer

Granulation
Liquid
Wet Extrusion with Soluplus
Granules
 Granules

before dry sieving after dry sieving

The granules obtained from TSWG contain large agglomerates. A dry sieving step is
therefore required for getting material suitable for tableting.
Wet Extrusion with Soluplus
APIs

 Itraconazole  Danazole

 Ind: fungal infections, p.o.  Ind: endometriosis, benign breast disorders, p.o.
 Mw (g/mol): 705.63  Mw (g/mol): 337.46
 Melting point: 166.2 °C  Melting point: 224.2 °C
 Water solubility (mg/mL): 0.0096  Water solubility (mg/mL):0.0176
 LogP: 7.31  LogP: 3.62
 http://www.drugbank.ca/drugs/DB01167  http://www.drugbank.ca/drugs/DB01406

Itraconazole and Danazole were chosen as model APIs as both are poorly soluble
but behave differently in amorphous solid dispersions of Soluplus®.
Wet Extrusion with Soluplus
Formulations
 Formulation parameters

Granulac® 230 Soluplus® API water content (on granulation liquid

[%] [%] [%] wet mass) [%] (GL)

50 40 10 10 water
50 40 10 10 9.1% Soluplus®
solut. (*)
(*)1% of the total Soluplus® amount was added in liquid form

Granules API Avicel PH 102 Kollidon® CL-F Mg-stearate

357 mg [%] [%] [%] [%] [%]
70 7 19.5 10 0.5
(25 mg)
Wet Extrusion with Soluplus Drug
Release Itraconazole

 Itraconazole drug release

100

90

80  Itraconazole
70  Itraconazole/ Soluplus® phys. mix
released API [%]

60  Granules (Soluplus® solution)

50  Granules (water)

40
 Tablets (Soluplus® solution)
 Tablets (water)
30

20
Calibration with 0.1% SDS 0.08 M HCl
10
Dissolution profiles of itraconazole
0 containing samples using apparatus 2.
(Wave length: 260 nm; medium: 700 ml
0 20 40 60 80 100 120 140 0.08 M HCl; paddle: 100 rpm; tmp: 37°C;
time [s] filter: 45µm)

TSWG improves the solubilization of Itraconazole in comparison to the phys. mixture.

The highest Soluplus®.
16
Wet Extrusion with Soluplus Drug
Release Danazol

 Danazole drug release

100

90

80  Danazole
70  Danazole/ Soluplus® phys. mix
released API [%]

60  Granules (Soluplus® solution)

50  Granules (water)

40
 Tablets (Soluplus® solution)
 Tablets (water)
30

20
Calibration with 0.1% SDS 0.08 M HCl
10
Dissolution profiles of itraconazole
0 containing samples using apparatus 2.
(Wave length: 260 nm; medium: 700 ml
0 20 40 60 80 100 120 140 0.08 M HCl; paddle: 100 rpm; tmp: 37°C;
time [s] filter: 45µm)

TSWG improves the solubilization of Danazole. The highest drug release is provided
by the granules obtained from granulation with water.
BASF’s product portfolio - overview
Kolliphor® - solubilisers

Source: Global Product Management, BASF SE, Lampertheim, Germany

Name Solubiliser Monographs Former name

Kolliphor® EL / ELP Polyoxoyl 35 Castor Oil USP-NF, Ph.Eur. Cremophor® EL / ELP

Polyoxoyl 40
Kolliphor® RH 40 Hydrogenerated Castor USP-NF, Ph.Eur. Cremophor® RH 40
Oil
Macrogol 15
Kolliphor® HS 15 USP-NF, Ph.Eur. Solutol® HS 15
Hydroxystearate
Vitamin E Polyethylene
Kolliphor® TPGS USP-NF Speziol® TPGS Pharma
Glycol Succinate

Kolliphor® PS 20 Polysorbate 20 USP-NF, Ph.Eur. Polysorbate 20 PH

Kolliphor® PS 80 Polysorbate 80 USP-NF, Ph.Eur. Polysorbate 80 PH

PEG-PVAc-polyvinyl
Soluplus® - Soluplus®
caprolactam
Texapon® K 12 G PH
Kolliphor® SLS
Sodium Lauryl Sulphate USP-NF, Ph.Eur., JP Texapon® K 12 P PH
Kolliphor® SLS Fine
Speziol® V 95 G
BASF’s product portfolio - overview
Kolliphor® P- solubilisers
Kollidon® – complexing agents
Source: Global Product Management, BASF SE, Lampertheim, Germany

Name Solubiliser Monographs Former name

Kolliphor® P 188 Poloxamer 188 USP-NF, Ph.Eur., JPE Lutrol® F 68

Kolliphor® P 188 micro Poloxamer 188 USP-NF, Ph.Eur., JPE Lutrol® 68 micro

Kolliphor® P 338 Poloxamer 338 USP-NF, Ph.Eur., JPE Lutrol® F 108

Kolliphor® P 407 Poloxamer 407 USP-NF, Ph.Eur., JPE Lutrol® F 127

Kolliphor® P 407 micro Poloxamer 407 USP-NF, Ph.Eur., JPE Lutrol® F micro

Kollidon® 12 PF, 17 PF, Kollidon® 12 PF, 17 PF,

Povidone USP, Ph.Eur., JPE
25, 30, 90 F 25, 30, 90 F

Kollidon® CL, CL-F, CL- Kollidon® CL, CL-F, CL-

Crospovidone USP-NF, Ph.Eur., JPE
SF, CL-M SF, CL-M

Kollidon VA 64 USP-NF, Ph.Eur., JPE Kollidon VA 64

Copovidone
& VA 64 fine & VA 64 fine
BASF’s product portfolio - overview
Kollisolv® - solvents and co-solvents

Source: Global Product Management, BASF SE, Lampertheim, Germany

Name Solubiliser Monographs Former name

Triglycerides
Kollisolv® MCT 70 USP-NF, Ph.Eur. Myritol® 318 PH
medium chain

Kollisolv® PEG 300 Macrogol 300 USP-NF, Ph.Eur., JPE Lutrol® E 300

Kollisolv® PEG 400 Macrogol 400 USP-NF, Ph.Eur., JPE Lutrol® E 400

Kollisolv® P 124 Poloxamer 124 USP-NF, Ph.Eur., JPE Lutrol® L44

Kollisolv® PG Propylene glycol USP-NF, Ph.Eur., JPE Propylene glycol

Kollisolv® PYR Pyrrolidone Ph.Eur. Soluphor® P

Kollisolv® GTA Triacetin USP-NF, Ph.Eur. Speziol® GTA

Thank you for your attention!

Questions?

Dr. Verena Geiselhart

Technical Service Manager

BASF SE
G-ENP/ET – Nutrition & Health
Pharma Ingredients & Services
Europe, Africa, West Asia

Phone: + 49 (0) 621 / 60 – 76 907

Mobile: + 49 (0) 174 / 349 555 0
Fax: + 49 (0) 621 / 60 – 66 76 907
Mail: verena.geiselhart@basf.com
Internet: www.pharma-ingredients.basf.com
Back-up

29
Kolliphor®
Application Chart

Source: Reintjes T., Solubility Enhancement with BASF Pharma Polymers – BASF Solubilizer Compendium (2011)

Topical formulation

Parenteral solution

soft gel capsules

Mode of action

Matrix for HME

(ointment/gel)

Plasticiser for
Oral solution

spray drying
State (RT)

Matrix for
Matrix in
Mode of action

HME
Substance M micellisation
Soluplus® MC S O O O O ++ O ++ C complex formation

Kolliphor® TPGS M S + + O ++ O + O
Kolliphor® HS 15 M P + + ++ + O O O State at room
temperature
Kolliphor® RH 40 M P + ++ O ++ O + O
S solid
Kolliphor® EL M L ++ + + O O O P pasty
Kolliphor® ELP M P + + ++ + O O O L liquid
Kollisolv® P 124 M L + + O ++ O O O
Kolliphor® P 188 M S + + O O O + O
Suitability for specific
Kolliphor® P 188 micro M S + + O O O ++ O applications
Kolliphor® P 237 M S + + O O O O O
++ excellent
Kolliphor® P 338 M S ++ + O O O O O + works, but others
may be better
Kolliphor® P 407 M S ++ + O O O + O O no data supporting
Kolliphor® P 407 micro M S + + O O O ++ O suitability