Structural analysis of anti-retroviral drug raltegravir and its potential impurity C: investigation of solubility and stability

Fayaz, T. K. S.; Chanduluru, Hemanth Kumar; Lal, Puja; Ghosh, Animesh; Chernyshev, Vladimir; Sanphui, Palash

doi:10.1039/d3ce01071f

Cited by 1 publication

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“…Hydrogen bonding interactions are summarized in Table S1, Supporting Information. The Mercury 2021.2.0 software was employed to make hydrogen-bonded interactions of the PRV complexes …”

Section: Methodsmentioning

confidence: 99%

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

Varsa S,

Priya Katukam,

Kole

et al. 2024

Crystal Growth & Design

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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 C max (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.

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“…Hydrogen bonding interactions are summarized in Table S1, Supporting Information. The Mercury 2021.2.0 software was employed to make hydrogen-bonded interactions of the PRV complexes …”

Section: Methodsmentioning

confidence: 99%

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

Varsa S,

Priya Katukam,

Kole

et al. 2024

Crystal Growth & Design

Self Cite

View full text Add to dashboard Cite

show abstract

Structural analysis of anti-retroviral drug raltegravir and its potential impurity C: investigation of solubility and stability

Abstract: Raltegravir (hereafter RLT) is a human immunodeficiency virus integrase strand transfer inhibitor that is prescribed for the treatment of HIV-1 infection. The drug belongs to biopharmaceutics classification system (BCS) class...

Cited by 1 publication

References 30 publications

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

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

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