Release performance and crystallization of racemic and enantiopure praziquantel amorphous solid dispersion in various media†

Abstract

Praziquantel (PZQ) is the first-line treatment for schistosomiasis, but its low aqueous solubility and extensive first-pass metabolism limit PZQ's bioavailability. Furthermore, the commercial formulation of PZQ includes the inactive (S)-PZQ enantiomer, which causes unwanted side effects and a bitter taste. This work aimed to evaluate the impact of chirality on PZQ's performance in amorphous solid dispersion (ASD) formulations prepared from both racemic and the active (R)-PZQ enantiomer, with additional studies on polymer type and processing method. ASDs of (R,S)-PZQ and (R)-PZQ at 30% drug loading were prepared with HPMCAS MF and HPMC E5 via solvent evaporation (SE) and hot-melt extrusion (HME). Release testing was conducted in aqueous media with different pH values and in biorelevant media simulating fasted- and fed-state conditions. Results demonstrated that ASDs significantly enhanced PZQ concentrations, with the amorphous solubility being up to 8-fold higher than that of the corresponding crystalline form. HPMCAS-based ASDs showed pH-dependent release, with poor release at gastric pH but achieving near-complete release with crystallization inhibition at intestinal pH conditions, while HPMC-based ASDs exhibited faster gastric release but reduced stability due to crystallization, which was confirmed by polarized light microscopy (PLM) and powder X-ray diffraction (PXRD). (R)-PZQ-HPMCAS ASDs outperformed (R,S)-PZQ-HPMCAS ASDs in simple media at pH 6.5 at high target concentration, which was attributed to a slightly higher amorphous solubility. However, both ASDs exhibited comparable release in fasted-state media due to bile salt-enhanced solubility. PZQ-ASDs showed crystallization when evaluated in FeSSIF-V2 and did not release well. Different processing methods minimally affected release profiles, highlighting HME's potential as a scalable, solvent-free method. These findings suggest that (R)-PZQ-HPMCAS is a promising alternative to commercial racemic PZQ formulations, potentially reducing side effects and improving patient compliance through allowing for a reduced pill burden.