New formulas for successful drug deliveryHot-melt extrusion for enhanced solubility and bioavailability

Pharma Ingredients & Services. Welcome to more opportunities.

Custom Synthesis | Excipients | Active Ingredients

Andreas Gryczke,an enabler in excipients

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Pioneering drug delivery methods from BASF

“The key to success for our pharmaceutical customers is innovation, speed- to-market and cost-effectiveness. With our comprehensive product port-folio and expertise in hot-melt extrusion technology, we help our customers to successfully develop drug formulations, even for challenging APIs...”

… says Andreas Gryczke, Technical Marketing Manager. Our work in developing more effective excipients is designed to ensure the best pharmacological perfor-mance for active ingredients. Our excipients, in combination with hot-melt extrusion technology, help you to enhance and control the oral bioavailability of your active ingredient. Synthetic polymers are ideally suited for use in the hot-melt extrusion process, due to their easily controlled and adjustable characteristics.

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BASF leads the way in hot-meltextrusion polymers and technology

Hot-melt extrusion has been used in the plastics and food indus-tries since the 1930s. In the 1980s, BASF was the first company to introduce the hot-melt extrusion process to pharmaceutical production. Poorly soluble actives can often be enhanced in their solubility and thereby in their bioavailability, e. g. by molecularly dispersing them in a polymeric carrier. A hot-melt extrusion pro-cess always yields a solid dispersion. Since melt extrudates can have a high density and a low porosity, they can be used for controlled-release dosage forms as well, if a suitable polymer is used. The melt obtained from the extrusion process is a vis-cous fluid that can be directly shaped into any desired form.

As the extrusion and compounding process has been widely de-ployed and understood in the plastics industry for decades, it is our mission to help understand and implement the technology in the pharmaceutical industry. We help you to start using hot-melt extrusion technology and to discover its advantages, including the versatility it offers when developing drug formulations. The true potential of hot-melt extrusion technology in pharmaceuticals is only just beginning to be seen and BASF research is revealing just how exciting it could be.

From poor API solubility to final formulation

Crystalline drug Hot-melt extrusion

Solid solution extrudate

Tablets • Polymer acts as a protective matrix for the drug molecule to freeze the drug’s current condition

• Drug can be crystalline dispersed or molecularly dispersed in the polymer, depending on the desired application and given miscibility with the polymer

• Rate of dissolution will be controlled by the polymer and can be enhanced for the drug or can be delayed, depending on the chosen polymer

+ Temp.+ Polymer

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BASF polymers and the hot-melt extrusion process offer many advantages and opportunities when working on your formulation challenges

Free hot-melt extrusion compendium

The second edition of BASF’s Hot-Melt Extrusion Compendium delivers expert advice on creating solid dispersions using BASF pharmaceutical-grade polymers and is available for download and as a print version. The compendium now provides readers with an even better understanding of solid dispersions and the hot-melt extrusion process, and offers more real-world applica-tion data.

Download your free copy at:www.innovate-excipients.basf.com

Application

¢ Bioavailability enhancement

¢  Controlled release Sustained release

¢  Safer medication Abuse deterrent, reduced side effects

Dosage

¢ Direct shaping (calender)

¢  Powders, granules and spheres

¢  Films and patches

¢  Injection molding

Formulation

¢ Broad excipient range available

¢  Reduced number of ingredients for formulation

Process

¢  High throughput Flexible with respect to time and scale

¢  Continuous quality monitoring

¢  Continuous process, lower costs

¢  Small footprint

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BASF’s broad range of tried-and-trusted excipients

Function Product name Description

Solubilizer/matrix Soluplus®

Solubilizing agent, dispersant, crystallization inhibitor, immediate-release matrix Tg: 70°C

MatrixKollidon® VA 64 / VA 64 fine

Solubilizing agent, dispersant, crystallization inhibitor, immediate-release matrix Tg: 101°C

Kollidon® 12 PFSolubilizing agent, dispersant, crystallization inhibitor, immediate-release matrix Tg: 90°C

Kollidon® 17 PFSolubilizing agent, dispersant, crystallization inhibitor, immediate-release matrix Tg: 138°C

Kollidon® 25For immediate-release matrices Tg: 143°C

Kollidon® 30 LPFor immediate-release matrices Tg: 149°C

Kollidon® SRControlled-release matrix systems, also suitable for poorly soluble drugs Tg: 39°C / 152°C

Kollicoat® MAE 100 PFor enteric matrices, solid solutions for non-immediate-release drug delivery systems Tg: 114°C

Kollicoat® IR / ProtectFor immediate-release matrices Tg: 45°C, T melt: 205°C

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Function Product name Description

Solubilizer/plasticizer Kolliphor® TPGS

Antioxidant, solubilizer, stabilizer, plasticizer T melt: 40°C

Kolliphor® P 188 / P 188 microSolubilizer, emulsifier and plasticizer T melt: 55°C

Kolliphor® P 407 / P 407 microSolubilizer, emulsifier and plasticizer T melt: 55°C

Kolliphor® RH 40 Non-ionic solubilizer, emulsifier and plasticizer

Kollisolv® PEG 400Cosolvent and plasticizer T melt: 4 – 8°C

Kolliphor® PS 80Surfactant for drug solubilization T boiling: > 100°C

Kollisolv® GTAPlasticizer, solubilizer T melt: - 77°C, T boiling: approx. 258°C

SolubilizerKolliphor® SLS

Surfactant for solubilization T melt: approx. 205°C

PlasticizerKollisolv® PEG 300

Cosolvent and plasticizer T melt: -15 – -10°C

Kolliwax® GMS IPlasticizer T melt: 58 – 59°C, T boiling: 238 – 240°C

Kolliwax® SAPlasticizer T melt: 59°C, T boiling: 210°C

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The hot-melt extrusion process is ideally suited to deployment as part of the Quality by Design ap-proach. When used in design of experiments, this technology rapidly delivers detailed, comprehen-sive insights. BASF polymers can be extruded at a wider temperature range and are not sensitive to different shear stresses, allowing an optimum

processing range to be identified for your active pharmaceutical ingredient.

Depending on desired formulation characteris-tics, you can choose the right ingredients from our broad polymer and excipient portfolio.

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Matrix formers Solubilizers Plasticizers Dissolution enhancers

Kollidon® VA 64/FineKollidon® SRKollidon® 12/17PFKollidon® 25Kollidon® 30/90

Kolliphor® TPGSKolliphor® EL/ELPKolliphor® RH 40Kolliphor® HS 15

Kolliphor® P 188Kolliphor® P 188 microKolliphor® P 407Kolliphor® P 407 micro

Kollidon® CLKollidon® CL-FKollidon® CL-MKollidon® CL-SF

Kollicoat® IR/ProtectKollicoat® MAE

Kolliphor® P 188Kolliphor® P 188 microKolliphor® P 407 microKolliphor® P 407Kolliphor® SLSKolliphor® SLS Fine

Kollisolv® PEG 300Kollisolv® PEG 400

Soluplus®

Tech

nolo

gie

s Solid dispersions

Hot-melt extrusion Spray drying Other

BASF offers a complete range of excipients for solid dispersions

Award-winning Soluplus® provides a new dimensionin solubility and bioavailability

Our innovative Soluplus® product was the world’s first polymeric excipient designed especially for the hot-melt extrusion process. It shows outstanding solubilization proper-ties, high flowability and excellent extrudability, even at relatively low temperatures. The addition of a plasticizer is not required and the low extrusion temperature makes it pos-sible to extrude active ingredients that are thermally sensitive.

Soluplus® was developed to form glassy solid solutions with many drug molecules. Its chemical structure makes it possible to bind the drug via hydrogen bonding to immobi-lize the drug over its shelf-life. During dissolution, Soluplus® encapsulates the dissolved drug molecules in polymeric micelles, allowing for formulation of oversaturated drug solutions and avoiding drug precipitation. Because Soluplus® has been developed for high-content matrix systems, we have proven its toxicological safety in comprehensive studies, enabling you to quickly start developing stable and safe solid dispersions. As with other BASF excipients suitable for hot-melt extrusion, Soluplus® shows superior processing characteristics and yields for long-term stable solid dispersions.

Radically enhanced bioavailability

Poor solubility in drugs can lead to low or significantly reduced bioavailability. Two in-vivo studies with itraconazole and fenofibrate showed that Soluplus® delivered a major increase in bioavailability.

Soluplus® has already proved its worth in the industry. In 2010, it was awarded a silver medal in the CPhI Innovation Awards.

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Soluplus®: a winning solution

• Soluplus® acts as a solubilizer for poorly soluble active pharmaceutical ingredients• Soluplus® forms stable glassy solid solutions• Soluplus® shows superior extrudability and processability in subsequent process

steps compared to other pharmaceutical polymers

CPhIINNOVATION

AWARDS

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Disclaimer

The data contained in this publication are based on our current knowledge and experience. In view of the many factors that may affect processing and application of our product, these data do not relieve processors from carrying out their own investigations and tests; neither do these data imply any guarantee of certain properties, nor the suitability of the product for a specific purpose. Any descriptions, drawings, photographs, data, proportions, weights etc. given herein may change without prior information and do not constitute the agreed contractual quality of the product. It is the responsibility of the recipient of our products to ensure that any proprietary rights and existing laws and legislation are observed. (01/2013)

® = registered trademark of BASF SE, TM = trademark of BASF SE

Outstanding range. Uncompromising quality.

• Hot-melt extrusion allows innovative and cost-effective drug delivery formulation • Enhanced bioavailability and controlled release via hot-melt extrusion• BASF provides you with customer-specific solutions and global support

The hot-melt extrusion process is robust, consistent and can be used in any pharmaceutical manufacturing plant. Innovative products like Soluplus® demonstrate how active ingredients can be formulated within a reliable matrix and hence can show highly improved bioavailability.

Contact us to find out how Andreas Gryczke and his colleagues can use hot-melt extrusion technology to help you produce high-quality, high-performance pharma-ceutical products.

Contactsolid-dispersion@basf.comwww.innovate-excipients.basf.com