Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization

Abstract

The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick’s law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid–liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine–saccharin (CBZ-SAC) and carbamazepine–salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

“…Interest in pharmaceutical cocrystals emerged rapidly in the last decade [30,[87][88][89][90][91][92][93][94][95][96]. Quite often cocrystals can be formed in the physical mixtures of the two components even without any action, merely due to moisture sorption by components themselves [97], or by a polymer excipient [96,98].…”

“…Quite often cocrystals can be formed in the physical mixtures of the two components even without any action, merely due to moisture sorption by components themselves [97], or by a polymer excipient [96,98]. Presence of cocrystals in the drug formulation is thus possible even when not anticipated.…”

“…Presence of cocrystals in the drug formulation is thus possible even when not anticipated. Cocrystals are often designed and produced on purpose, to increase the solubility, or the stability, or the tabletability of an active pharmaceutical ingredient (API) [30,92,96,[99][100][101][102][103][104]. However, when a cocrystal is dissolved, the initially high concentration of the API in solution can drop down with time, and sometimes this happens very fast.…”

“…Whereas the micellar solubilization of single-component crystals has been thoroughly studied, micellar solubilization of cocrystals is not well understood. A key question is: how do surfactants that solubilize the drug, influence cocrystal solubility and dissolution [33,96]? The solubility of a hydrophobic drug in aqueous solution depends on the total surfactant concentration [33].…”

Cocrystal solubility-pH and drug solubilization capacity of sodium dodecyl sulfate – mass action model for data analysis and simulation to improve design of experiments

“…For solid dosage forms, recent approaches have included the use of CC formulations [2][3][4][5]. Cocrystal suspensions can be stabilized using surfactants [6][7][8][9]. For liquid dosage forms (e.g., soft gel capsules), surfactants are used to solubilize the active pharmaceutical ingredient (API) [10][11][12].…”