Salt Disproportionation in the Solid State: Role of Solubility and Counterion Volatility

Molecular Pharmaceutics
Naveen K ThakralGregory A Stephenson

Abstract

Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and cocrystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, "prototype" formulations of salts and cocrystal in tablet form were stored at 40 °C and several water vapor pressures. Disproportionation kinetics were studied in these prototype tablet formulations using two-dimensional X-ray diffractometry. Formulations containing the adipic acid cocrystal or heminapadisylate salt did not show disproportionation of API when stored at 40 °C/75% RH for 300 days. On the other hand, formulations containing HCl or HBr salt disproportionated. Though isostructural, the disproportionation propensity of HBr and HCl salts was quite different. The HCl salt highlighted the important role that volatility of the counterion plays in the physical stability of the f...Continue Reading

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Citations

Oct 2, 2019·Pharmaceutics·Sawittree SahakijpijarnRobert O Williams
Sep 25, 2018·Journal of Pharmaceutical Sciences·Naveen K ThakralRaj Suryanarayanan
Feb 14, 2021·International Journal of Pharmaceutics·Anthony LaiChristopher J H Porter
Nov 4, 2017·Journal of Pharmaceutical Sciences·Katie L CavanaghNaír Rodríguez-Hornedo
Aug 14, 2021·Journal of Pharmaceutical Sciences·Navpreet Kaur, Raj Suryanarayanan
Dec 5, 2017·Molecular Pharmaceutics·Mitulkumar A PatelLynne S Taylor
Jul 18, 2018·Molecular Pharmaceutics·David A HirshRobert W Schurko

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