The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation

Abstract

Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=C_dose/S_drug), cocrystal solubility advantage over drug (SA=S_cocrystal/S_drug), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and K_sp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pH_int) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σ_max=C_max/S_drug)and AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<<SA, cocrystal solubility is more than adequate to dissolve the dose. Low σ_max values (1.7 and 1.5) near the value of Do (2.3 and 2.4) were observed, where a large fraction of the cocrystal added is dissolved to reach σ_max. Two different cocrystal to drug conversion pathways were observed: (1) surface nucleation of the metastable MLX polymorph IV on the dissolving cocrystal preceeded formation of the stable MLX polymorph I in bulk solution (in all conditions without FeSSIF), and (2) bulk nucleation of the stable MLX polymorph (in FeSSIF). The interplay between cocrystal SA, Do_, and drug precipitation pathways provide a framework to interpret and understand the DSP behavior of cocrystals.

Keywords: Cocrystal; Disproportionation; Dose number; Interfacial pH; Precipitation; Supersaturation.