AEROSIL® Colloidal Silicon Dioxide for Pharmaceuticals

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AEROSIL® colloidal silicon dioxide glidants help to improve tablet weight uniformity.

Evonik developed AEROSIL® colloidal silicon dioxide nearly 70 years ago and pharmaceuticals were an important application for this product right from the start. The first scientific literature on the use of AEROSIL® fumed silica as a pharmaceutical excipient was published in 1957. Since then, AEROSIL® 200 Pharma has gained acceptance and recognition as a pharmaceutical excipient.

All AEROSIL® products are characterized by their purity and chemical inertness, which are especially important characteristics for the pharmaceutical industry. AEROSIL® products are also very successful in other industries with high purity requirements such as cosmetics, foodstuffs, electronics, fiber optics and catalysis.

In addition to ISO 9001 certification, we manufacture our pharmaceutical grades according to IPEC GMP guidelines and supply all our customers with an extensive Certificate of Analysis according to the major pharmacopeias.

Our commitment to the pharmaceutical industry has remained strong throughout the years. Our highly specialized teams in research & development have continued to develop new pharmaceutical grades and products in response to our customers’ needs. These new products provide formulating alternatives and, in some cases, advantages over the traditional AEROSIL® 200 Pharma.

Our objective is to provide our customers with the optimum solution for their systems, to meet their high standards and to make their products even more successful.

AEROSIL® – More than just a powder

R & D,Applied

TechnologyCustomerProximity

ProductQuality

and ProductSafety

TechnicalLiterature

TechnicalService

LogisticsConcepts

SupplySecurity

HandlingTechnology

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AEROSIL® colloidal silicon dioxide has been used as a glidant to optimize the flow of powders since the earliest days of direct compression.

The small AEROSIL® fumed silica particles “coat” the larger excipient and active ingredient particles, thus reducing van der Waals attractive forces between them. It can also absorb moisture being present on the surface of hygroscopic powders, thereby minimizing powder caking and clumping. These two effects help to prevent the formation of powder bridges and rat holes, as well as improving the flow through hoppers. Production of solid dosage forms on high-speed tablet presses or capsule filling equipment requires optimal flow of the dry precursor mixture. Used as a glidant, AEROSIL® colloidal silicon dioxide improves dosage

uniformity and ultimately results in higher throughput.

The hydrophobic nature of AEROSIL® R 972 Pharma means it agglomerates less than hydrophilic colloidal silicon dioxide types and is especially suitable for short and/or low shear mixing processes.

In addition to their excellent glidant properties in dry precursor mixtures, AEROSIL® products can also improve the properties of the finished product. For example, the hydrophilic products can in some cases increase the hardness of tablets without increasing the compaction force. This effect helps to maintain tablet stability without the increased disintegration times of denser tablets pressed at higher compaction force. * Internal Evonik study.

Excipient content 99.5 - 100.0 wt%, silica content 0.5 - 0.0 wt%, respectively. Powders were mixed for ten minutes at 42 rpm in a gravity mixer. The angle of repose was measured according to DIN ISO 4324. The data are not legally Binding; results may vary according to equipment and formulation.

AEROSIL® – For Solid Dosage Forms

Flow behavior of microcrystalline cellulose with (left) and without (right) AEROSIL® colloidal silicon dioxide

angle of repose (degrees)

Pure exipient, no glidant AEROSIL® 200 Pharma AEROSIL® R 972 Pharma

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microcrystalline cellulose

pre-gelatinized starch

lactose monohydrate

Angle of repose of typical pharmaceutical excipients with and without AEROSIL® colloidal silicon dioxide as a glidant*

Could your tablet production ”flow” better?Advantages in solid dosage forms Better powder flow Reduced caking Improved tablet properties

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AEROPERL® 300 Pharma is a granulated form of colloidal silicon dioxide. Unlike highly disperse AEROSIL® products, AEROPERL® 300 Pharma consists of bead-like mesoporous granules with a particle size of on average 30 to 40 µm. The high specific surface area of 300 m2/g, coupled with the pore volume of approx. 1.6 ml/g mean that AEROPERL® 300 Pharma is a versatile and highly absorptive carrier that may be used to incorporate liquids into solid pharmaceutical dosage forms. Advantages of AEROPERL® 300 Pharma include:

High tapped density and nearly spherical shape. AEROPERL® 300 Pharma is easy to handle, even when loaded with more than its weight in liquid.

Hydrophilic nature. AEROPERL® 300 Pharma is an efficient desiccant. For example, AEROPERL® 300 Pharma may be used in moisture assisted dry granulation (MADG) processes thus avoiding the need for large amounts of water to be evaporated.

High absorption capacity and high surface area. AEROPERL® 300 Pharma may help to avoid costly and time consuming API crystallization. AEROPERL® may also assist to increase the bioavailability of low-solubility APIs.

AEROPERL® 300 Pharma fulfils requirements of Ph. Eur. as well as USP/NF. Due to its high bulk density, AEROPERL® 300 Pharma does not fulfil the “volume test” of the JP, however it complies with all other JP parameters.

Flow behavior of AEROPERL® 300 Pharma before and after loading with typical liquids.

Internal Evonik study. The AEROPERL® granulated colloidal silicon dioxide was loaded with liquid using an addition funnel while stirring at 100 rpm. The angle of repose was measured after 24 hours. The data are not legally binding; results may vary according to equipment and formulation.

AEROPERL® 300 Pharma – a versatile carrier for liquid or low-solubility APIs

Scanning electron micrograph image of AEROPERL® 300 Pharma shows the spherical bead form.

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Pore Volume by N2-Desorption

Angle of respose of AEROPERL® 300 Pharma absorbates

unloaded AEROPERL® 300 Pharma loaded 1 : 1 loaded 1 : 1,5

Pore Diameter in nm

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The graph shows the differential (grey) and cumulative (purple) pore volume of AEROPERL® 300 Pharma as measured using N2-desorption.

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Dimethicone (type 350) Vitamin E acetate

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While not quite as common as solid dosage forms, semi-solid and liquid dosage forms have important functions in the pharmaceutical industry, particularly with regard to topical preparations (creams, gels, etc.) and products that do not pass through the digestive tract (suppositories, transdermal delivery systems). In these AEROSIL® fumed silica can help to achieve the desired product properties by acting as a rheology controlling and suspending agent or by improving thermal and storage stability.

AEROSIL® colloidal silicon dioxide may be used as an efficient thickener of pharmaceutical media to create soft creams or more viscous gels. Clear gels can be obtained if the refractive index of the media is similar to that of the silica. The pseudo-plastic flow behavior of the resulting gels is advantageous for both packaging and application – the viscosity

decreases during filling and spreading, then increases upon storage. In addition, AEROSIL® colloidal silicon dioxide is a completely inorganic thickener and is therefore not a source of microbial nutrition. In suppositories, AEROSIL® colloidal silicon dioxide may be used to thicken the suppository base to the desired viscosity, but even more importantly, it keeps the active ingredient evenly suspended until the product has cooled and set.

AEROSIL® products also improve the thermal stability of the suppositories by increasing the softening temperature of the mass (e.g. during storage in warm climates), while not changing the melting temperature (e.g. during production). The thickening and stabilizing properties of AEROSIL® colloidal silicon dioxide are also the reason it is used in formulating transdermal delivery systems.

AEROSIL® – Ideal for Semi-Solid and Liquid Dosage Forms

Internal Evonik study. The AEROSIL® colloidal silicon dioxide was dispersed in the liquid using a dissolver (speed 21 m/sec) for seven minutes. The viscosity was measured after 24 hours using a Brookfield viscometer (5 rpm). The data are not legally binding; results may vary according to equipment and formulation.

AEROSIL® colloidal silicon dioxide helps to ensure the uniform distribution of active ingredients in suppositories (left)…

… and transdermal therapy systems AEROSIL® colloidal silicon dioxide can be used to thicken oils into clear gels for topical applications

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pure oil, no AEROSIL® colloidal silica oil containing 3 % AEROSIL® 300 Pharma oil containing 3 % AEROSIL® R 972 Pharma

Do you want to improve efficacy?Advantages in liquid and semi-solid dosage forms Viscosity controlling agent Inorganic composition Forms clear gels Stabilizes suspensions

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Evonik has a portfolio of colloidal silicon dioxide products that offers formulators options for improving their products and/or their production processes.

AEROSIL® 200 Pharma is highly dispersed, with a tapped density of only 50 g/L. From our product portfolio, AEROSIL® 200 Pharma is the traditional choice for glidant applications.

AEROSIL® 300 Pharma is a highly disperse hydrophilic colloidal silica with an exceptionally high specific surface area of 300 m2/g. It may be used in applications that benefit from higher surface area such as viscosity control of liquids and filtration of blood plasma.

AEROSIL® R 972 Pharma is a colloidal silicon dioxide that has been chemically

treated to render its surface hydrophobic. AEROSIL® R 972 Pharma is less agglomerated than other AEROSIL® types, and is an excellent glidant with extremely low moisture absorption. AEROSIL® R 972 Pharma is especially suitable for short and/or low shear mixing processes.

AEROPERL® 300 Pharma is a spherical granulated colloidal silicon dioxide with a mean particle size of 30-40 µm and a pore volume of approx. 1.6 ml/g. It can be used as a carrier to convert liquids into powders for better processing in solid dosage forms or to increase the accessible surface area of absorbed APIs. It is also an effective desiccant, for example in moisture assisted granulation processes.

AEROSIL® Pharmaceutical Products – an Overview

Hydrophilic AEROSIL® 200 Pharma is fully dispersible in water (left); hydrophobic AEROSIL® R 972 Pharma is not, and floats on top (right)

Dosage Form

Solid(tablets, capsules)

Semi-solid (suppositories, transdermal patches)

Liquid(gels, suspensions, creams)

Effect

Improved powder flow

Improved compact properties

Carrier

Viscosity control

Stabilization

Viscosity control

Stabilization

Benefits

•   Improves unit weight uniformity  (i.e. uniform drug content)

•  Higher throughput

•  Reduces caking through moisture scavenging

•   Optimizes the flow of very hygroscopic  and/or cohesive powders

•   Reduced mixing shear and/or time is possible

•   Increases tensile strength•   Improves friability•   Counteracts negative effects of lubricants

•   Converts liquids to powders

•   Adsorbs moisture to protect hydroscopic or moisture-sensitive APIs

•   For moisture-assisted dry granulation processes

•   Increases viscosity•   Inorganic thickener, not metabolized by microbes

•   Keeps active ingredient uniformly distributed

•   Thickens pharmaceutical media•   Makes clear gels possible•   Inorganic thickener•   Pseudoplastic flow behavior

•   Keeps particles in suspension•   Prevents hard sediments from forming

Products

AEROSIL® 200 PharmaAEROSIL® R 972 Pharma

AEROSIL® 200 Pharma

AEROSIL® R 972 Pharma

AEROSIL® 200 PharmaAEROSIL® 300 Pharma

AEROPERL® 300 Pharma

AEROPERL® 300 Pharma

AEROSIL® 200 PharmaAEROSIL® 300 Pharma

AEROSIL® 200 PharmaAEROSIL® 300 Pharma

AEROSIL® 200 PharmaAEROSIL® 300 PharmaAEROSIL® R 972 Pharma

AEROSIL® 200 PharmaAEROSIL® 300 PharmaAEROSIL® R 972 Pharma

Product Recommendations

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As is appropriate for pharmaceutical excipients, AEROSIL® pharmaceutical grades are manufactured according to Good Manufacturing Practices established by the International Pharmaceutical Excipients Council (IPEC) for bulk Pharmaceutical excipients.

Products with the suffix ”Pharma“ are supplied with a certificate of analysis stating that the product has been tested according to and meets the standards of the most recent pharmacopoeia. This means that your regulatory affairs department can use the documentation supplied by Evonik to show compliance the next time an audit comes your way.

AEROSIL® colloidal silicon dioxide has been safely used as a pharmaceutical excipient for decades.

AEROSIL® fumed silica is a high purity synthetic silica, with a silicon dioxide content of over 99.8 %. Over the last 50 years, many studies have been undertaken and all have shown that, unlike crystalline silica, the amorphous structure of colloidal silicon dioxide does not induce pulmonary fibrosis.

AEROSIL® Pharma quality

AEROSIL® Regulatory Information

The extensive testing of AEROSL® pharmaceutical grades done at our plant means that your analytical labs can focus on other things

Product

AEROSIL® 200 Pharma

AEROSIL® 300 Pharma

AEROPERL® 300 Pharma

AEROSIL® R 972 Pharma

USP/NF

“Colloidal Silicon Dioxide”

“Colloidal Silicon Dioxide”

“Colloidal Silicon Dioxide”

“Hydrophobic Colloidal Silica”

Ph. Eur.

“Silica, Colloidal Anhydrous”

“Silica, Colloidal Anhydrous”

“Silica, Colloidal Anhydrous”

“Silica, hydrophobic colloidal”

DMF*

1115

1115

1115

1115

JP

“Light Anhydrous Silicic Acid”

“Light Anhydrous Silicic Acid”

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no monograph

Compendial compliance of AEROSIL® products

* US Food and Drug Administration (FDA) Drug Master File Type IV (excipient)** Granulated AEROPERL® 300 Pharma does not fulfill the JP “Volume Test” due to its high bulk density

Excipient ”Pharma” grades mean Manufactured according to appropiate GMPs

Tested according to compendial methods

Every lot certified with complete documentation

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For more information on other Evonik products for the pharmaceutical industry, visit: www.evonik.com/pharma

For further information on our products visit our website

www.aerosil.com

There you can download our Technical Information Number 1281 with more detailed references to the varied uses of AEROSIL® colloidal silicon dioxide in pharmacy.

As a registered user you can download Product Information sheets and Safety Data Sheets (SDS).Customers with special registration status may also find certificates of analysis, order confirmation, etc.

As one of the world’s leading manufacturers of specialty chemicals, Evonik bases its management philosophy on being as decentralized as possible, and as centralized as necessary. This decentralized organization is evident at all levels and divisions, which are divided into operating units able to respond to market needs quickly, flexibly, and with the customer in mind.

Business Line Silica – one of the most important manufacturers of colloidal

silicon dioxide – takes advantage of the global presence of Evonik.

AEROSIL® production plants, technicalservice centers, and research centers are located in all regions of the world. With distributors located worldwide, we guarantee that you will enjoy the best possible service.

Internet and Literature ServiceThe Advantage of a Global Company: Local Proximity

AEROSIL® silica around the world: More than 100 distributors in 95 countries, production sites on three continents and applied technology service centers in Asia, America and Europe.

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Evonik Resource Efficiency GmbH Business Line Silica P.O. Box 1345 63403 Hanau Germany Phone +49 6181 59-12532 Fax +49 6181 59-712532 aerosil@evonik.com www.evonik.com

Europe, Middle-East, Africa, Latin America Evonik Resource Efficiency GmbH Business Line Silica Rodenbacher Chaussee 4 63457 Hanau-Wolfgang GermanyPhone +49 6181 59-12532 Fax +49 6181 59-712532 aerosil@evonik.com

North America Evonik Corporation Business Line Silica 299 Jefferson Road Parsippany, NJ 07054-0677 USA Phone +1 800-233-8052 Fax +1 973-929-8502 aerosil@evonik.com

Asia, Pacific Evonik (SEA) Pte. Ltd. Business Line Silica 3 International Business Park #07-18 Nordic European Centre Singapore 609927Phone +65 6809-6877 Fax +65 6809-6677 aerosil@evonik.com

This information and any recommendations, technical or otherwise, are presented in good faith and believed to be correct as of the date prepared. Recipients of this information and recommendations must make their own determination as to its suitability for their purposes. In no event shall Evonik assume liability for damages or losses of any kind or nature that result from the use of or reliance upon this information and recommendations.EVONIK EXPRESSLY DISCLAIMS ANY REPRESENTATIONS AND WARRANTIES OF ANY KIND, WHETHER EXPRESS OR IMPLIED, AS TO THE ACCURACY, COMPLETENESS, NON-INFRINGEMENT, MERCHANTABILITY AND/OR FITNESS FOR A PARTICULAR PURPOSE (EVEN IF EVONIK IS AWARE OF SUCH  PURPOSE) WITH RESPECT TO ANY INFORMATION AND RECOMMENDATIONS PROVIDED.Reference to any trade names used by other companies is neither a recommendation nor an endorsement of the corresponding product, and does not imply that similar products could not be used. Evonik reserves the right to make any changes to the information and/or recommendations at any time, without prior or subsequent notice.

AEROSIL® and AEROPERL® are registered trademarks of Evonik Industries or its subsidiaries.