Abstract
Objective
To perform the solid-state characterization and the in vitro-in vivo correlation (IVIVC) of three batches of efavirenz (EFV) active pharmaceutical ingredients.
Significance
EFV is an effective anti-HIV drug. Due to the poor aqueous solubility, the rate and extent of EFV absorption deeply depend on its dissolution characteristics.
Methods
Thermal analyses, x-ray diffraction, and particle size distribution were performed. The saturation solubility and dissolution profiles were assessed in 0.5% (w/v) sodium lauryl sulfate (SLS), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) using a flow-through cell. Each batch was orally administered to Wistar rats and the pharmacokinetic parameters were correlated with those obtained from in vitro dissolution.
Results
All batches of EFV consisted polymorph I. EFV-A presented the lowest particle size distribution [d(v,0.5) = 197.8 µm; d(v,0.9) = 444.6 µm] followed by EFV-B [d(v,0.5) = 223.9 µm; d(v,0.9) = 481.1 µm], and EFV-C [d(v,0.5) = 240.8 µm; d(v,0.9) = 497.3 µm]. The saturated solubility in FaSSIF was 36% and 40% of that in FeSSIF and SLS, respectively. EFV-A presented the fastest rate and largest extension of dissolution than EFV-B and C (79.15%, 69.93% and 54.22%, respectively, as well as the highest maximum plasma concentration. Levels B, C, and multiple-C of IVIVC models were achieved.
Conclusion
The FaSSIF medium discriminated the dissolution profiles of EFV APIs. Small differences in particle size distribution had a significant impact on the biopharmaceutical parameters of EFV, suggesting that strict control of such parameter is an important aspect during API development and drug formulation.
Acknowledgments
The authors wish to thank Certara® Corporation for kindly providing the License of Phoenix® WinNonlin® 64 (version 8.0), Cristália Produtos Químicos e Farmacêuticos LTDA, Centro de Tecnologias Estratégicas do Nordeste (CETENE), Instituto de Desenvolvimento e Estudos Farmacêuticos (IDEF-UFPB), Núcleo de Desenvolvimento Farmacêutico e Cosmético (NUDFAC-UFPE), Laboratório de Tecnologia de Medicamentos (LTM-UFPE), Faculté de Pharmacie, Université Clermont-Auvergne (ERT-CIDAM).
Ethical approval
This study protocol was approved by the Federal University of São João del-Rei Institutional Animal Care and Use Committee (Protocol 020/2015), and was in full compliance with the guidelines of the National Institutes of Health for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978).
Disclosure statement
No potential conflict of interest was reported by the author(s).