Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity
We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address th...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | International Journal of Pharmaceutics: X |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590156721000219 |
| _version_ | 1818701438463770624 |
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| author | Daniel A. Davis, Jr Dave A. Miller Supawan Santitewagun J. Axel Zeitler Yongchao Su Robert O. Williams, III |
| author_facet | Daniel A. Davis, Jr Dave A. Miller Supawan Santitewagun J. Axel Zeitler Yongchao Su Robert O. Williams, III |
| author_sort | Daniel A. Davis, Jr |
| collection | DOAJ |
| description | We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time. |
| first_indexed | 2024-12-17T15:20:51Z |
| format | Article |
| id | doaj.art-99a533e6ece349858e1b1e00f0811dc7 |
| institution | Directory Open Access Journal |
| issn | 2590-1567 |
| language | English |
| last_indexed | 2024-12-17T15:20:51Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal of Pharmaceutics: X |
| spelling | doaj.art-99a533e6ece349858e1b1e00f0811dc72022-12-21T21:43:25ZengElsevierInternational Journal of Pharmaceutics: X2590-15672021-12-013100092Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinityDaniel A. Davis, Jr0Dave A. Miller1Supawan Santitewagun2J. Axel Zeitler3Yongchao Su4Robert O. Williams, III5College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; Corresponding author at: Department of Molecular Pharmaceutics and Drug Delivery, The Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.DisperSol Technologies, LLC, 111 W. Cooperative Way, Building 3, Suite 300, Georgetown, TX 78626, USADepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB3 0AS, UKDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB3 0AS, UKCollege of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; Pharmaceutical Sciences, Merck & Co., Inc., Rahway, NJ 07065, USACollege of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USAWe seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.http://www.sciencedirect.com/science/article/pii/S2590156721000219Residual crystallinitySeed crystallinityAmorphous solid dispersionDegradationBioavailability enhancementKinetiSol processing |
| spellingShingle | Daniel A. Davis, Jr Dave A. Miller Supawan Santitewagun J. Axel Zeitler Yongchao Su Robert O. Williams, III Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity International Journal of Pharmaceutics: X Residual crystallinity Seed crystallinity Amorphous solid dispersion Degradation Bioavailability enhancement KinetiSol processing |
| title | Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity |
| title_full | Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity |
| title_fullStr | Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity |
| title_full_unstemmed | Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity |
| title_short | Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity |
| title_sort | formulating a heat and shear labile drug in an amorphous solid dispersion balancing drug degradation and crystallinity |
| topic | Residual crystallinity Seed crystallinity Amorphous solid dispersion Degradation Bioavailability enhancement KinetiSol processing |
| url | http://www.sciencedirect.com/science/article/pii/S2590156721000219 |
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