Analysis of Relationships Between Solid-State Properties, Counterion, and Developability of Pharmaceutical Salts

Abstract

Abstract. The solid-state properties of pharmaceutical salts, which are dependent on the counterion used to form the salt, are critical for successful development of a stable dosage form. In order to better understand the relationship between counterion and salt properties, 11 salts of procaine, which is a base, were synthesized and characterized using a variety of experimental and computational methods. Correlations between the various experimental and calculated physicochemical properties of the salts and counterions were probed. In addition to investigating the key factors affecting solubility, the hygroscopicity of the crystalline salts was studied to determine which solid-state and counterion properties might be responsible for enhancements in moisture uptake, thus providing the potential for adverse chemical stability. Multivariate principal components and partial least squares projection to latent structures analyses were performed in an attempt to establish predictive models capable of describing the relationships between these characteristics and both measured and calculated properties of the counterion and salt. Some success was achieved with respect to modeling crystalline salt solubility and the glass transition temperature of the amorphous salts. Through the modeling, insight into the relative importance of various descriptors on salt properties was achieved. The solid-state properties of crystalline and amorphous salts of procaine are highly dependent on the nature of the counterion. Important properties including aqueous solubility, melting point, hygroscopicity, and glass transition temperature were found to vary considerably between the different salts.

The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

“…Much research has been devoted to understanding the dependence of pharmaceutical salt physical stability on counterion during formulation development, manufacturing, and storage. [32][33][34] Many studies have also been performed to elucidate the correlation between solubility of a pharmaceutical salt and the properties of counterion such as hydrophilicity, number of hydroxyl groups, chain length, and hydrogen bonding. 1,[34][35][36] However, to the best of our knowledge, the dependence of biopharmaceutical performance on the acid strengths of counterions is not well understood.…”

Effect of Counterions on Physicochemical Properties of Prazosin Salts

“…This is in agreement with a previously reported study, wherein sulfonic acid salts with a moderate number of hydrocarbons, namely, bisulfate, mesylate, and besylate had favorable interaction with water. In contrast, counterions with larger, more hydrophobic structure, e.g., besylate and tosylate, had limited interaction with water (31).…”

Prediction of the solubility in lipidic solvent mixture: Investigation of the modeling approach and thermodynamic analysis of solubility

“…Also, activity = a i = Çi [C] where C is the concentration of the species. This means that as the concentration increases activity coefficient decreases (Guerrieri et al, 2010;Serajuddin, 2007;Wang et al, 2012).…”