Journal
MOLECULAR PHARMACEUTICS
Volume 15, Issue 4, Pages 1700-1713Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.8b00104
Keywords
amorphous solid dispersion; dissolution; mass flow rate; telaprevir; surfactant
Funding
- American Association of Pharmaceutical Scientists (AAPS)
- McKeehan Graduate Fellowship in Pharmacy
- Migliaccio/Pfizer Graduate Fellowship in Pharmaceutical Sciences
- National Science Foundation [DMR-1308276]
- Direct For Mathematical & Physical Scien
- Division Of Materials Research [1309218] Funding Source: National Science Foundation
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During the dissolution of amorphous solid dispersions (ASDs), various phase transformations can occur, which will ultimately impact the degree of supersaturation. This study employed dissolution and diffusion measurements to compare the performance of various ASD formulations based on the maximum amount of free drug in the solution that was able to permeate through a cellulose-based membrane. Telaprevir (TPV) was used as the model drug compound, and ASDs were prepared with different drug loadings and with four different polymers. Four possible scenarios that can influence TPV mass flow rates upon ASD dissolution were described and supported with experimental data: (1) a system dissolves readily and completely undergoes phase separation via glass liquid phase separation (GLPS), forming drug-rich aggregates, and reaches the maximum anticipated mass flow rate; (2) where the maximum mass flow rate decreases due to substantial mixing of the polymer into the drug-rich phase, and/or due to the formation of soluble polymer drug complexes; (3) a system does not undergo GLPS due to slow drug release and/or matrix crystallization; and (4) a system does not undergo GLPS due to rapid crystallization from the supersaturated solution generated during dissolution. The results described herein support the importance of the combined use of the dissolution diffusion measurements to determine the maximum level of supersaturation achievable for diverse drug formulations.
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