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Pharmaceutical Co-crystal of Antiviral Agent Efavirenz with Nicotinamide for the Enhancement of Solubility, Physicochemical Stability, and Oral Bioavailability

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Abstract

The present research work attempted to improve the oral bioavailability of the antiviral drug Efavirenz (EFV) using a pharmaceutical cocrystallization technique. EFV comes under BCS-II and has extremely low water solubility, and results in low oral bioavailability. EFV and nicotinamide (NICO) were selected in a (1:1) stoichiometric ratio and efavirenz nicotinamide cocrystal (ENCOC) was prepared through the liquid-assisted grinding method (LAG). The confirmation of the formation of a new solid phase was done through spectroscopic techniques like Fourier transmission infrared (FTIR), Raman, and 13C solid-state nuclear magnetic resonance (13C ssNMR). Thermal techniques like differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM) illustrated the thermal behavior and melting patterns of ENCOC, EFV, and NICO. The X-ray powder diffraction (XRPD) confirms the formation of a new crystalline phase in ENCOC. The Morphology was determined through scanning electron microscopy (FESEM). The results of saturated solubility studies and in vitro drug release studies exhibited 8.9-fold enhancement in solubility and 2.56-fold enhancement in percentage cumulative drug release. The percentage drug content of ENCOC was found higher than 97% and cocrystal exhibits excellent accelerated stability. The oral bioavailability of EFV (Cmax, 799.08 ng/mL) exhibits significant enhancement after cocrystallization (Cmax, 5597.09 ng/mL) than EFV and Efcure®-200 tablet (2896.21 ng/mL). The current work investigates the scalable and cost-effective method for enhancement of physicochemical stability, solubility, and oral bioavailability of an antiviral agent EFV.

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Acknowledgements

Authors are thankful to Nirma University, Ahmedabad, for providing facilities for conducting research work, which is part of Doctor of Philosophy (PhD) of Dattatraya Yadav (18FTPHDP50), to be submitted to Nirma University, Ahmedabad, India. Authors are also thankful to Vaibhav Analytical Laboratory Ahmedabad for their kind support in analysis of the samples through gas chromatography. Authors are also thankful to Emcure R&D Center Gandhinagar, Ahmedabad, for their facilities for conducting research work.

Funding

The author of this article Dattatraya Yadav received a Chhatrapati Shahu Maharaj National Research fellowship (CSMNRF-2019) from the Chhatrapati Shahu Maharaj Research Training and Human Development Institute (SARTHI), Pune, Government of Maharashtra, India.

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  1. Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University Ahmedabad, Ahmedabad, Gujarat, India, 382481

    Dattatraya Yadav & Jignasa Savjani

  2. Emcure Pharmaceuticals, Gandhinagar, Gujarat, India, 382423

    Ketan Savjani

  3. Department of Pharmacology, Institute of Pharmacy, Nirma University Ahmedabad, Ahmedabad, Gujarat, India, 382481

    Aakash Kumar & Snehal Patel

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DY: experimental work, methodology, validation, formal analysis, investigation, data curation, analysis and interpretation, writing—original draft, visualization; JS: methodology, formal analysis, analysis and interpretation, resources, writing—review and editing, supervision, project administration, revision and approval of the final version; KS: analysis, and interpretation of data for the work; AK: substantial contribution in an in vivo pharmacokinetic study; SP: substantial contribution in an in vivo pharmacokinetic study; all the authors read and approved the final manuscript.

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Correspondence to Jignasa Savjani.

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Yadav, D., Savjani, J., Savjani, K. et al. Pharmaceutical Co-crystal of Antiviral Agent Efavirenz with Nicotinamide for the Enhancement of Solubility, Physicochemical Stability, and Oral Bioavailability. AAPS PharmSciTech 24, 7 (2023). https://doi.org/10.1208/s12249-022-02467-7

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