High Bulk-Density Amorphous Dispersions to Enable Direct Compression of Reduced Tablet Size Amorphous Dosage Units |
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| Affiliation: | 1. Process Research & Development, Merck & Co., Inc., Rahway, NJ, USA;2. Formulation Sciences, Merck & Co., Inc., Rahway, NJ, USA;3. Pharmaceutical Commercialization Technologies, Merck & Co., Inc., Rahway, NJ, USA;4. Analytical Research & Development, Merck & Co., Inc., Rahway, NJ, USA;5. Biopharmaceutics, Merck & Co., Inc., Rahway, NJ, USA;1. Department of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece;2. Janssen Pharmaceutica NV, Beerse, Belgium;3. Chemical & Pharmaceutical Development, Merck Healthcare KGaA, The healthcare business of Merck KGaA, Darmstadt, Germany;4. Dissolution & Biopharmaceutics, Analytical Research and Development, Technical Research and Development, Novartis AG, CH-4056, Basel, Switzerland;5. Pharmaceutical Development, Technical Research and Development, Novartis AG, CH-4056, Basel, Switzerland;6. Pharmaceutical Development, Technical Research and Development, Novartis Pharmaceuticals Corporation, Fort Worth TX 76134, United States of America;1. State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana;3. Department of Pharmaceutical Chemistry, School of Pharmacy and Pharmaceutical Sciences, University for Development Studies, Tamale, Ghana;1. Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455;2. Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA 94080;3. Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455;1. Bristol Myers Squibb, USA;2. University College Dublin, Ireland;3. Pfizer R&D, UK;4. JPharmSci, USA |
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| Abstract: | Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets. |
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