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Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation.
Mohan, Shikhar; Li, Yi; Chu, Kevin; De La Paz, Liliana; Sperger, Diana; Shi, Bing; Foti, Chris; Rucker, Victor; Lai, Chiajen.
Afiliación
  • Mohan S; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Li Y; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Chu K; Velexi Corporation, Burlingame, California 94010, United States.
  • De La Paz L; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Sperger D; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Shi B; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Foti C; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Rucker V; Gilead Sciences, Inc., Foster City, California 94404, United States.
  • Lai C; Gilead Sciences, Inc., Foster City, California 94404, United States.
Mol Pharm ; 21(5): 2590-2605, 2024 May 06.
Article en En | MEDLINE | ID: mdl-38656981
ABSTRACT
We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Solubilidad / Química Farmacéutica / Composición de Medicamentos / Fumaratos Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Solubilidad / Química Farmacéutica / Composición de Medicamentos / Fumaratos Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos