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

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 formulations. Solution state stability (i.e., in dissolution medium) of salts and cocrystal was also assessed and compared with solid state stability, by determining their solubility at different pH's, and intrinsic dissolution rate.

Understanding the Differences Between Cocrystal and Salt Aqueous Solubilities

“…The range of values is similar to those reported for pharmaceutical salts. 28–30 pK sp values for CBZ cocrystals are in the range of 2 to 9, indicating increases in K sp by orders of magnitude. When solubility is determined by solvation and not by solid-state lattice energy, 17,31 cocrystal solubility is dependent on the solubility of its components.…”

Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies

“…One added advantage of the design is that the API will not come in contact with MgSt and can therefore be used for drugs incompatible with MgSt, such as hydrochloride salts. 45 These tablets were compressed using MCC as coating material and CPM-C as core, and the extent of transformation of the API was evaluated (Fig. 7a).…”

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

“…Salt formation is a well-known strategy to increase the solubility of either lipophilic weak acids or bases in order to improve oral absorption. Nevertheless, the expected benefits of forming a salt may not work if the level of supersaturation leads to drug precipitation to the free acid or base, thereby reducing the drug exposure levels for absorption [14,15,16]. The “supersaturation/precipitation interactive process” depends on the characteristics of the weak acid or base and, not unimportant, on the dissolution study design with respect to media composition and hydrodynamics that will determine the bulk and interfacial pH around the dissolving particles.…”