Cocrystals Mitigate the Effect of pH on Solubility and Dissolution of Basic Drugs

Abstract

Pharmaceutical cocrystals are emerging as a useful strategy for enhancing solubility, dissolution, and bioavailability for poorly water-soluble drugs. One of the most important properties of cocrystals is their fine-tunable solubility. This property enables cocrystals to increase or decrease solubility. Cocrystal solubility is the result of intricate chemical interactions between cocrystal solution components and conditions such as additives and pH. Without the critical knowledge of cocrystal solution behavior and the underlying solution interactions, studying cocrystals is a trial and error exercise that can be time consuming. This dissertation determines the mechanisms by which the cocrystal solubility is influenced by pH and solubilizing agents and investigates the relationship between cocrystal supersaturation index and conversion kinetics. The objectives of this work are to (1) determine the effect of pH and solubilizing agents on cocrystal solubility, supersaturation index, and dissolution, (2) derive mathematical equations that describe cocrystal solubility and supersaturation index behavior based on solution equilibria of cocrystal dissociation, component ionization, and component solubilization, (3) investigate the relationship between cocrystal supersaturation index and risk of solution-mediated conversion, and (4) assess the ability of cocrystals to generate and maintain supersaturation. Three cocrystals (1:1 stochiometric ratio) composed of a basic drug, ketoconazole (KTZ), and acidic coformers, adipic acid (ADP), fumaric acid (FUM), and succinic acid (SUC), were used as model compounds. While KTZ has shown orders of magnitude decreases in solubility and dissolution as pH increases from 1 to 7, the cocrystal solubility increases with respect to drug at pH above pHmax (pHmax range 3.6 to 3.8). Cocrystal solubility advantage (SA), also referred to as the supersaturation index, increased from 1 at pHmax to between 900 and 6000 at pH 6.5. This range of SA translated into cocrystals that sustain supersaturation levels to different extents or not at all. SA values ranged from 5 to 13 (FeSSIF), 13 to 36 (blank FeSSIF), 221 to 1418 (FaSSIF), and 440 to 3118 (blank FaSSIF). Maximum supersaturation with respect to drug and AUC ratio of cocrystal to drug during dissolution showed that cocrystals exhibited superior dissolution behavior over drug in all media except for the cocrystal with the highest SA (3118, KTZ-FUM in blank FaSSIF). Cocrystals showed the highest supersaturation (22 to 30) and AUC ratio (10 to 16) values in FaSSIF. Supersaturation and AUC ratio increased with SA in FaSSIF, and they leveled off at SA between 460 and 1400. The lowest supersaturation (1.5) and AUC ratio (1.6) values were observed in FeSSIF, where cocrystals were fully dissolved and no drug precipitation occurred. pH-shift dissolution studies also showed that the cocrystal Cmax and AUC values exhibited less sensitivity to gastric pH than the drug. KTZ was also observed to undergo liquid-liquid phase separation when high levels of supersaturation (about 150) were generated by rapid pH-shift from 2 to 6.5. These metastable forms exhibited higher solubility compared to the crystalline form, and their formation appeared to delay crystallization. Formation of such metastable phases may increase oral absorption.