Analysis of relationships between solid-state properties, counterion, and developability of pharmaceutical salts

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.

Fig. 1

DSC trace of procaine besylate for measurement of T _g. Labeled are a T _g and b melting endotherm

Fig. 2

Correlations of salt solubility (ln K _sp) of procaine salts with a melting temperature T _m and b melting enthalpy. c The relationship between measured and ideal solubilities (mole fraction)

Fig. 3

PCA scatter plot for analysis of solubility of procaine salts showing the two PCs plotted against each other

Fig. 4

Observed vs. predicted values of solubility (M) for procaine salts from final PLS model

Fig. 5

Moisture sorption profiles for crystalline salts of procaine; data is normalized to surface area

Fig. 6

Plot of measured RH₀ vs. solubility for deliquescent procaine salts

Fig. 7

Glass transition temperature T _g of amorphous samples of procaine salts plotted with pK _a of the counterion. The line represents the T _g of procaine free base

Fig. 8

Observed vs. predicted values of T _g (°C) using PLS modeling

Fig. 9

Variable of importance in the projection (52) plot from the final PLS model of T _g of procaine salts