Expanding the Crystal Structure Landscape of Pravastatin Complexes: Tuning Solubility, Diffusion, and Pharmacokinetics

Pravastatin (PRV), a lipid-lowering medication, is prescribed to treat cardiovascular disease and dyslipidemia. Due to its low permeability and high solubility, the biopharmaceutics classification system (BCS) class III drug exhibits poor bioavailability. To overcome the bottlenecks of PRV, novel complexes with Zn and Cu along with a zwitterionic cocrystal with l-proline (PRO) were synthesized. These new solid forms were characterized by SC-XRD, PXRD, DSC, TGA, FT-IR, DVS, and SEM images. Rietveld refinement was used to obtain the 3D coordinates of the PRV–Na–PRO ionic cocrystal hydrate from high-resolution PXRD data. PRV–Cu and Zn complexes were obtained by substituting PRV sodium salt with a Cu/Zn metal. In PRV–Na–PRO cocrystal hydrate, each Na metal is coordinated from carboxylates of PRV (2) and zwitterionic PRO (1) and three water molecules result in an octahedron geometry. Cu is coordinated with two carboxylate anions of PRV (2) and three water molecules, forming a square pyramidal geometry. The PRV–Zn complex maintains an octahedral geometry using four coordination from two carboxylate anions of PRV (2) and two water molecules. The PRV–Na–PRO cocrystal hydrate exhibited higher solubility (1.7-fold) and diffusion profile (1.1-fold) compared to the commercial PRV–Na salt hydrate, whereas PRV–Cu/Zn complexes showed controlled drug release. Surprisingly, the PRV–Na–PRO cocrystal hydrate enhanced peak plasma concentration Cmax (50 fold) and AUC (14.4 fold) compared to the commercial PRV–Na salt during pharmacokinetics study in rats. The stability of the PRV complexes was supported by ground-state optimization energy calculations. Unlike the moisture-sensitive PRV–Na salt hydrate and PRV–Na–PRO cocrystal hydrate, PRV–Zn/Cu complexes exhibited far superior moisture stability and may offer extended drug release. On the other hand, the PRV–Na–PRO cocrystal hydrate with significantly improved bioavailability can be commercialized following proper formulation that offers moisture stability.