Expect More From Your Excipient

Expect More from Your Excipient

Overview of Presentation:
Evolving Role of Excipients Functionality
The Need for Better Understanding of Excipients
Not all Silicon Dioxides are the Same!

Syloid® FP Silicas’ Porosity Give Multi-functional Benefits:

• Advanced Adsorptive Capacity
A successful formulation depends on the careful selection of those
• Improved Glidant Properties
excipients that are added to promote the consistent release and
• Better Flow Characteristics
bioavailability of the drug and protect it from degradation.
• Greater Tablet Hardness with Less Compression Force
Handbook of Pharmaceutical Granulation Technology - Dilip Parihk from Synthon Pharmaceuticals USA

 New Applications
• Two-Step Mixing
• Oil Adsorption
• Film Coatings
• Liquisolids and Lipid-Based Systems

Expecting more from your excipient can improve formulation

Raising Expectations for Excipients
In the Past...
 Excipients were considered to be any compound other than the active ingredient.
 Excipients were used mainly as binders, fillers, or to improve stability.

Today:
 >70% of formulations contain excipients in higher concentrations than the drug.
 Increasing demand to improve formulations and bring drugs to market faster.
 Growing appreciation for excipients and a need to understand:
• Chemical interactions

• Physical interactions

• Physiological interactions

• Biopharmaceutical interactions

Today’s formulation challenges demand more from excipients

Raising Expectations for Excipients

The Need for a Better Understanding of Excipients

Exploit the benefits of existing approved excipients such as Syloid® FP
Silicas

More communication between user/researcher and manufacturer to:

•Ensure Excipients QUALITY
•Understand Interaction between ALL ingredients and API
•Determine what activity or functionality is needed to deliver to the API
Not all Silicon Dioxides are the Same

Silica Gel Spherical Silica Precipitated Silica Colloidal Silica Fumed Silica

3-Dimensional Spray drying of Growing of primary Growth of primary Pyrogenic process

network of primary silica slurry particles; due to the particles excluding formation of
particles; pH presence of electrolytes; pH aggregates and
dependent electrolytes, it dependent agglomerates
comes to an
agglomeration

Syloid® FP Tixosil ® Silica Aerosil® Silica

Silica Sipernat ® Silica Cab-o-sil ® Silica

Fumed (“colloidal”) silica is recognized as the industry

standard, but there is a great deal of confusion in terminology

June 29, 2013

Not all Silicon Dioxides are the Same
Syloid® FP Silica
• Low dust
• Easy to disperse/handle
• Porosity is developed intra-particle
• Porosity available after compression
improves release of API
• Higher available surface area
Colloidal (Fumed) Silica
• Very dusty
• Difficult to disperse/handle
• Porosity is developed inter-particle
• Porosity is not available
• Lower available surface area
Syloid® FP Silicas

Micronized, Multi-functional, and External

Surface
Highly Porous Area

 Multiple grades with different properties: 244FP,

72FP, and AL1-FP
Internal
 For over 40 years Syloid® FP silicas have been Surface
Area
used successfully in numerous pharmaceutical
formulations
 Formulation benefits beyond glidant and flow
improvement
 After more communication, understanding,
and research:
• Increased Stability
• Carrier in SEDDS
• Desiccant / Moisture control
• Wetting / Permeabilizing agent: ODT
• Anti-tacking agent in coatings
• Anti–static

This unique morphology defines Syloid® FP silica’s performance

Advanced Porosity - Adsorptive Capacity
For Moisture Control:
• Stabilizer / Protectant
• Dessicant / Drying Agent
For Advanced Adsorptive Capacity
• Tablet Wetting Properties
• Film Coatings
• Carrier
• Viscosity & Suspension

High
Adsorptive
Capacity

Greater
Moisture
Control
Syloid® FP Silicas as Glidants

A glidant improves the flow

characteristics of a powder mixture
• Typically used at 0.25% - 2.0% levels
• Optimum concentration coincides with amount
needed to build a layer around the bulk powder
• Allows for consistent feed from hopper
• Improves filling of die cavity

Benefits of improved flow

• Decreased tablet weight variation
• Increased content uniformity
• Reduced friability and improved tablet hardness
• Increased production rates
• Ability to use direction compression process in place
of granulation processes in some cases
Syloid® FP Silicas as Glidants

50
45 Paracetamol
40 Powder
35
30
Syloid® 244
Syloid 244 FP
FP
25 Silica
20 Aerosil 200
Fumed Silica
15
10
5
0
0 0.5 1 1.5 2

Angle of repose vs. % silicon dioxide

50
45
Mannitol
40
35
Syloid® 244 FP
30 Syloid 244 FP
Silica
25 Aerosil
Fumed 200
Silica
20 Neusilin US2
Magnesium
15 Aluminum Silicate
10
5
0
0 0.5 1 1.5 2
Superior Anti-static Behavior

The addition of Aerosil® as an anti-static agent to Flowlac® 100 showed a significant reduction of the
electrostatic charge whereas the flowability is only slightly influenced (Figure 4). The hydrophobic fumed
silica (Aerosil® R972) was superior to the hydrophilic type (Aerosil® 200). The porous silica Syloid® 244FP
was the best at reducing the charging to less than 0.1 kV in 1.0% concentration.

Aerosil® 200 Aerosil® R972 Syloid® 244 FP Aerosil® 200 Aerosil® R972 Syloid® 244 FP

Figure 4. Effect of addition of different anti-static agents on electrostatic charging resp. max. flowrate
FlowLac® 100, 25mm orifice diameter, mean +SD, n=5

Data Courtesy of K. Knop, S. Lindert, R. Meier. Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University,
Dusseldorf Germany
Better Tabletting with Less Force

Composition of Asagran® (Aspirin) Tablets Hardness vs. Compression Force

% Theoretical (g)
250
®
Asagran 50 75 200 Aerosil® 200
Syloid® Silica)
AL-1FP Silica

Hardness N
(Fumed
® Syloid® FP 244 (EU) Silica
Emcocel 7 10,5 150 Syloid® Al-1FP
Aerosil® 200 (Fumed
® 100 Silica)
Explotab 2 3 Syloid® 244 FP EU
50
®
Tablettose 41 61,5 0
1250 1500 1750 2000 2250
Silicon Dioxide 2 3 Compression Force N

100 150

Hardness vs. Friability Hardness vs. Disintegration Time

3 10

Desintegration Time (min)

9
2.5
8
7
Friability (%)

2 Aerosil®
® 200
Syloid Silica)
AL-1FP Silica
(Fumed
(Fumed Silica) Aerosil®
Syloid
(Fumed
200Silica
® AL-1FP
Silica)
Syloid® FP 244 (EU) Silica
6 (Fumed Silica)
®
Syloid FP 244 (EU) Silica
1.5 Syloid® Al-1FP 5
Aerosil® 200 (Fumed Syloid® Al-1FP
® 200
Aerosil (Fumed
Silica) 4 Silica)
1 Syloid® 244 FP-EU 3 Syloid® 244 FP-EU
0.5 2
1
0 0
50 70 90 110 130 150 170 190 50 70 90 110 130 150 170 190
Hardness (N) Hardness (N)

Data courtesy of Prof. Jacqueline Plaisier, Free Univ. of Brussels

Compression Force & Porosity

LOWER Compression Force MEDIUM Compression Force HIGHER Compression Force

MORE Pore Availability MEDIUM Pore Availability LESS Pore Availability

Porosity after compression IMPROVES release of API

Hardness vs. Compression Force
250
200 Aerosil®
Syloid 200
® AL-1FP Silica
Hardness N

(Fumed Silica)
Syloid® FP 244 (EU) Silica
150 Syloid®
Aerosil Al-1FPSilica)
® 200 (Fumed

100
Syloid® 244 FP EU
50
0
1250 1500 1750 2000 2250
Compression Force N
Improve Your Direct Compression

Porous Silica Can Improve Two-Step Glidant Mixing:

• Improves flow properties Syloid® Syloid®
AL1-FP 244 FP
for direct compression API Silica Filler Binder Disint. Lubricant Silica
• Improves stability of
physical properties
• Improves homogeneity,
uniformity Step 1 API Mixing Excipient Glidant Mixing

• Improves stability (helps

prevent moisture transfer) Step 2 Final DC Mixing Two-Step Glidant Mixing Process

High
Adsorptive
Capacity

Greater
Moisture
Control

Chem. Pharm. Bull. 57(7) 647—652 (2009)

Film Coatings
Syloid® FP Silica Benefits to Film Coatings
• Helps prevents valve blockage
• Increases permeability / Poreformer *
• Anti-tacking agent
Dissolution Profile Comparison
Ingredient: Parts by Weight:
EUDRAGIT® Acrylic Polymer 3,334 g
Triethyl Citrate 200 g
Syloid® 244 FP Silica 300 g
Water 3,361 g  = Syloid® 244FP Silica
 = Pyrogenic Silica

Ref : Kucera, et al.

Syloid® 244FP silica gives faster release then Syloid® AL1FP silica
Syloid® FP Silica
Fumed Silica

* Lower concentration will mainly help in better disperion and anti-tacking properties. Higher concentrations
will improve poreforming activity.
Permeabilizing Agent

ODT, ODMT, ODF, Effervescent:

LOWER Compression Force HIGHER Compression Force

MORE Pore Availability LESS Pore Availability

• Higher drug loading

• High porosity is needed: Aiding the disintegration
• Anti-static agent
• Thickening agent for stable suspensions
• Improve water adsorption
• Improve mechanical stability / improved tablet hardness
• In ODT’s compression forces are lower! Syloid® FP pores remain intact.
 Oil Adsorption

Oil Retention on Various Silica Gels

mg

500
Syloid® 244 FP Silica

Syloid® 72 FP Silica
400

300
Pyrogenic Silica

200
Natural Silica

100
Pure Peppermint Oil

1 Day 2 Days 3 Days 8 Days

Syloid® FP silica has greater adsorptive capacity for oils

Liquisolids and Lipid-Based Systems
Used with:
• Hydrolysis sensitive APIs
• Poorly soluble APIs
• SE pellets, SEDDS Conventional tablets (suspension)

The liquid system is added to MCC as the carrier and coated with Syloid®
244 FP silica and HPMC to form a free flow powder ready for compression
(extrusion and spheronisation)

100 Liquid
SEDDS
SE
NTD release (%) 80 Pellets

60
Conventional
Tablets
40

20

0
0 10 20 30 40 50 60
0 1mm
Time (min)

Microscopic SE pellets In vitro dissolution profiles

International Journal of Pharmaceutics 383 (2010) 1–6

Syloid® FP Silica Summary
Properties
• High internal porosity and surface area
• High adsorptive capacity
• Plastic behavior, pores stay available
• Tightly controlled particle size distribution
• Unique particle structure and morphology

Benefits
• High efficiency – low usage levels, lower cost
• Uniform blending – improved product uniformity
• Improved tablet hardness at lower compression forces
• High carrying level
• Protection against moisture pick up

Applications
• Glidant
• Carrier in SEDDS
• Desiccant / Moisture control
• Wetting agent / Permeabilizing agent: ODT
• Anti-tacking agent in coatings
• Anti–static

Syloid® FP silica is a versatile multi-functional excipient

Excipient Considerations for Formulation
API Property Impact on Tablet Formulation
Dose Low dose may have content uniformity
effects. High dose may result in direct
physical impact of the API on tablet
properties.
Particle Particle size of API will influence flow
Size properties, segregation, and uniformity. This
may also contribute to capping problems in
tablets.
Flow Poor flow of API may lead to decreased tablet
Properties hardness and weight inconsistencies.
Bulk density Density plays a significant role in the blend
uniformity of API along with other excipients.
Moisture High moisture content of API may result in
Content sticking issues during tablet compression.
Hygroscopicity Highly hygroscopic API’s may have tablet
punch issues. Choosing the right
manufacturing process under low humidity
conditions can become critical for such API’s.
Excipient Certain API’s may be incompatible with
Compatibility specific excipients and may limit their
selection.
Excipient Selection Considerations (QbD)
Choose excipients that improve uniformity and
those that improve the physical and chemical
stability of your API.
Choose glidants with controlled and narrow
particle size distribution that improve tabletting
properties and prevent segregation (mostly
micronised).
This may require granulation techniques or
micronised glidants. Choose glidants that do not
decrease dissolution and compaction.
In general, for a high density API, the diluent
selected should have a high density and vice
versa in order to avoid segregation issues in a
directly compressible formulation.Controlled
particle size should be considered.
Select glidants or hydrophilic lubricants with the
ability to adsorb excessive moisture without
diffusion to the surface.
Select excipients with dessicant properties (highly
hygroscopic) and the functionality to improve the
stability of your API under any relative humidity
preventing degradation.
Excipient/API and excipient/excipient compatibility
testing (QbD) help determine the best excipient
considering API and other excipients used. *
Choose the Grade for Your Needs

Carrier of Actives/Delivery (Syloid® FP 244 silica)

• To effectively convert liquids/API’s to free-flowing powders by mixing
with Syloid® silica (1:1 wt. ratio)
• To improve or aid disintegration
• Better storage of aroma
• To facilitate dry liquid blending/mixing with other constitutes
• To assist active ingredients’ release when exposed to moisture
vapor and water

Processing Aid (Syloid® FP 244 silica)

• Helps keep powders dry in a free flowing state
• Enables more uniform blending, more consistent fill weight, and
consistent distribution of the API
• Improves resistance to sticking
• Eliminates or reduces the need for sieving - low dust

Glidant (Syloid® FP 244 silica, Syloid® AL1-FP silica)

• Anti-caking agent
• Improves flow properties and homogeneity
• All at any relative humidity
Choose the Grade for Your Needs

Coating (Syloid® FP 244 silica, Syloid® AL1-FP silica)

• Anti-static agent + better dispersion and spray properties
• Wetting agent: capillary wetting, aqueous and gastric wetting

Tabletting Aid (Syloid® FP 244 silica, Syloid® AL1-FP silica)

• Improves tablet hardness, tensile strength, structural stability and reduces
friability
• Helps ensure uniform tablet weight

Thickening/Gellation/Suspension Aid (Syloid® FP 72 silica, Syloid® FP 244 silica)

• Turn liquids into clear gels, creams or pastes
• Acts as a suspension agent for actives in aerosols and provides uniform
dispersion

Wetting Agent/Disintegrant Aid (Syloid® FP 244 silica, Syloid® AL1-FP silica)

• Helps tablet break up faster
•Wetting agent: : aqeuous and gastric wetting, ODT’s
•Permeabilising agent / pore former

Desiccant/Moisture control (Syloid® AL1-FP silica = lowest LOD)

• Helps ensure long term product storage stability
• Adsorbs moisture and oils keeping powders dry to prevent degradation
Conclusions
Expect more from your excipient
• Quality
• Functionality
• Performance

Work with the manufacturer to maximize understanding of:

• Interaction between ALL ingredients and API
• What activity or functionality excipients can bring to the API

Consider partnerships to discover new solutions and drug

delivery technologies
• Customized solutions
• Novel technologies to improve solubility and bioavailability

“The joint goal for industry, regulators, practioners and patients is to

encourage drug development in order to create a situation where substantially
more people have access to safe and effective medication”
European Federation of Pharmaceutical Industries and Associations (EFPIA®)

Excipients are emerging as strategic drug development tools

All you need is ….
Syloid® FP Silica
High
Adsorptive
Capacity

Greater
Moisture
Control

And, a Better Understanding

of Excipients!
Grace – A Global Company
Well positioned to support global
manufacturing needs
• Advanced Silica Manufacturing
• Security & Compliance
• World-Leanding Quality

Global Manufacturing
Sites:
• Baltimore, MD USA
• Albany, OR USA
• Worms, Germany
• Sorocaba, Brazil

Global presence - Local service and expertise

Synthesis
solutions
The information presented herein is derived from our testing and experience. It is offered for your consideration and verification. Since operating conditions vary significantly, and are not under our control, we disclaim all
warranties on the results that may be obtained from the use of our products. W. R. Grace & Co.-Conn. and its subsidiaries can not be held responsible for any damage or injury occurring as a result of improper
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