pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs

In amorphous solid dispersions (ASDs), the chemical potential of a drug can be reduced due to mixing with the polymer in the solid matrix, and this can lead to reduced drug release when the polymer is insoluble in the dissolution media. If both the drug and the polymer composing an ASD are ionizable, drug release from the ASD becomes pH-dependent. The goal of this study was to gain insights into the pH-dependent solubility suppression from ASD formulations.

The maximum release of clotrimazole, a weakly basic drug, from ASDs formulated with insoluble and pH-responsive polymers, was determined as a function of solution pH. Drug-polymer interactions in ASDs were probed using melting point depression, moisture sorption, and solid-state Nuclear Magnetic Resonance spectroscopy (SSNMR) measurements.

The extent of solubility suppression was dependent on polymer type and drug loading. The strength of drug-polymer interactions was found to correlate well with the degree of solubility suppression. For the same ASD, the degree of solubility suppression was nearly constant across the solution pH range studied, suggesting that polymer-drug interactions in residual ASD solids was independent of solution pH. The total drug release agrees with the Henderson-Hasselbalch relationship if the suppressed amorphous solubility of the free drug is independent of solution pH.

The mechanism of solubility suppression at different solution pHs appeared to be drug-polymer interactions in the solid-state, where the concentration of the free drug remains the same at variable pHs and the total drug concentration follows the Henderson-Hasselbalch relationship.