AEROSIL Colloidal Silicon Dioxide for Pharmaceuticals

AEROSIL Colloidal Silicon Dioxide for Pharmaceuticals

Product Quality and Product Safety Customer Proximity R & D, Applied Technology Technical Literature Technical Service Logistics Concepts Supply Security Handling Technology 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. AEROSIL More than just a powder 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, has gained acceptance and recognition as a pharmaceutical excipient. 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. 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. 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. 2 3

Could your tablet production flow better? Advantages in solid dosage forms Better powder flow Reduced caking Improved tablet properties Flow behavior of microcrystalline cellulose with (left) and without (right) AEROSIL colloidal silicon dioxide Angle of repose of typical pharmaceutical excipients with and without AEROSIL colloidal silicon dioxide as a glidant* AEROSIL For Solid Dosage Forms angle of repose (degrees) microcrystalline cellulose pre-gelatinized starch lactose monohydrate 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. 50 48 46 44 42 40 38 36 34 32 30 * 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. Pure exipient, no glidant 4 5

Pore Volume by N 2 -Desorption 8,0 2,0 Differntial Pore Volume in ml/g*dl 6,0 4,0 1,5 1,0 Cumulative Pore Volume in n 2,0 0,5 1 0,0 10 100 1000 0,0 Pore Diameter in nm Scanning electron micrograph image of AEROPERL 300 Pharma shows the spherical bead form. The graph shows the differential (grey) and cumulative (purple) pore volume of AEROPERL 300 Pharma as measured using N 2 -desorption. AEROPERL 300 Pharma a versatile carrier for liquid or low-solubility APIs Angle of respose of AEROPERL 300 Pharma absorbates 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. Angle of response ( ) 35 30 25 20 15 10 5 0 unloaded AEROPERL 300 Pharma loaded 1 : 1 loaded 1 : 1,5 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. Dimethicone (type 350) Vitamin E acetate 6 7

Do you want to improve efficacy? Advantages in liquid and semi-solid dosage forms Viscosity controlling agent Inorganic composition Forms clear gels Stabilizes suspensions 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 AEROSIL Ideal for Semi-Solid and Liquid Dosage Forms Simethicone Glycerin 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. Pa s η 10 5 10 4 10 3 10 2 10 1 10 0 10-1 10-2 10-3 10-2 10-1 10 0 10 1 10 2 10 3 10 4 Shear Rate γ 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. 1/s Pa s 10 5 10 4 10 3 10 η 2 10 1 10 0 10-1 10-2 10-3 10-2 10-1 10 0 10 1 10 2 10 3 10 4 Shear Rate γ 1/s pure oil, no AEROSIL colloidal silica oil containing 3 % oil containing 3 % 8 9

Hydrophilic is fully dispersible in water (left); hydrophobic is not, and floats on top (right) AEROSIL Pharmaceutical Products an Overview Evonik has a portfolio of colloidal silicon dioxide products that offers formulators options for improving their products and/ or their production processes. is highly dispersed, with a tapped density of only 50 g/l. From our product portfolio, is the traditional choice for glidant applications. is a highly disperse hydrophilic colloidal silica with an exceptionally high specific surface area of 300 m 2 /g. It may be used in applications that benefit from higher surface area such as viscosity control of liquids and filtration of blood plasma. is a colloidal silicon dioxide that has been chemically treated to render its surface hydrophobic. is less agglomerated than other AEROSIL types, and is an excellent glidant with extremely low moisture absorption. 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. Product Recommendations 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 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 Products AEROPERL 300 Pharma AEROPERL 300 Pharma Stabilization Keeps particles in suspension Prevents hard sediments from forming 10 11

Excipient Pharma grades mean Manufactured according to appropiate GMPs Tested according to compendial methods Every lot certified with complete documentation The extensive testing of AEROSL pharmaceutical grades done at our plant means that your analytical labs can focus on other things AEROSIL Pharma quality AEROSIL Regulatory Information 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 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 colloidal silicon dioxide has been safely used as a pharmaceutical excipient for decades. Compendial compliance of AEROSIL products Product USP/NF Ph. Eur. JP DMF* Colloidal Silicon Dioxide Silica, Colloidal Anhydrous Light Anhydrous Silicic Acid 1115 Colloidal Silicon Dioxide Silica, Colloidal Anhydrous Light Anhydrous Silicic Acid 1115 AEROPERL 300 Pharma Colloidal Silicon Dioxide Silica, Colloidal Anhydrous ** 1115 Hydrophobic Colloidal Silica Silica, hydrophobic colloidal no monograph 1115 * 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 12 13

For more information on other Evonik products for the pharmaceutical industry, visit: www.evonik.com/pharma 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. Internet and Literature Service The Advantage of a Global Company: Local Proximity 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, technical service 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. 14 15

Europe, Middle-East, Africa, Latin America Evonik Resource Efficiency GmbH Business Line Silica Rodenbacher Chaussee 4 63457 Hanau-Wolfgang Germany Phone +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 609927 Phone +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. 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 RE-14-1-OKT15Tools