Formulation and Processing Strategies which Underpin Susceptibility to Matrix Crystallization in Amorphous Solid Dispersions

• Published in: Journal of pharmaceutical sciences Vol. 112; no. 1; pp. 108 - 122
• Main Authors: Moseson, Dana E., Hiew, Tze Ning, Su, Yongchao, Taylor, Lynne S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023
• Subjects: Amorphous solid dispersion; Congruent release; Crystallization; Dissolution; Drug Liberation; Matrix crystallization; Polymers - chemistry; Sodium Dodecyl Sulfate - chemistry; Solubility; Supersaturation; Surface-Active Agents; Amorphous solid dispersion; Supersaturation; Congruent release; Matrix crystallization; Dissolution
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2022.03.020

Through matrix crystallization, an amorphous solid may transform directly into its more stable crystalline state, reducing the driving force for dissolution. Herein, the mechanism of matrix crystallization in an amorphous solid dispersion (ASD) was probed. ASDs of bicalutamide/copovidone were prepared by solvent evaporation and hot melt extrusion, and sized by mortar and pestle or cryomilling techniques, modulating the level of mechanical activation experienced by the sample. Drug loading (DL) of the binary ASD was varied from 5-50%, and ternary systems were formulated at 30% DL with two surfactants (sodium dodecyl sulfate, Vitamin E TPGS). Imaging of partially dissolved or crystallized compacts by scanning electron microscopy with energy-dispersive X-ray analysis and confocal fluorescence microscopy was performed to investigate pathways of hydration, phase separation, and crystallization. Monitoring drug and polymer release of ASD powder under non-sink conditions provided insight into supersaturation and desupersaturation profiles. Systems at the greatest risk of matrix crystallization had high DLs, underwent mechanical activation, and/or contained surfactant. Systems having greatest resistance to matrix crystallization had rapid and congruent drug and polymer release. This study has implications for formulation and process design of ASDs and risk assessment of matrix crystallization. [Display omitted]