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Formulating Ternary Inclusion Complex of Sorafenib Tosylate Using β-Cyclodextrin and Hydrophilic Polymers: Physicochemical Characterization and In Vitro Assessment

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Abstract

Sorafenib tosylate (SFNT) is the first-line drug for hepatocellular carcinoma. It exhibits poor solubility leading to low oral bioavailability subsequently requiring intake of large quantities of drug to exhibit desired efficacy. The present investigation was aimed at enhancing the solubility and dissolution rate of SFNT using complexation method. The binary inclusion complex was prepared with β-cyclodextrin (β-CD). The molecular docking studies confirmed the hosting of SFNT into hydrophobic cavity of β-CD, while the phase solubility studies revealed the stoichiometry of complexation with a stability constant of 735.8 M−1. The ternary complex was prepared by combining the SFNT-β-CD complex with PEG-6000 and HPMC polymers. The results from ATR-IR studies revealed no interaction between drug and excipients. The decreased intensities in ATR-IR peaks and changes in chemical shifts from NMR of SFNT in complexes indicate the possibility of SFNT hosting into the hydrophobic cavity of β-CD. The disappearance of SFNT peak in DSC and XRD studies revealed the amorphization upon complexation. The ternary complexes exhibited improved in vitro solubility (17.54 µg/mL) compared to pure SFNT (0.19 µg/mL) and binary inclusion complex (1.52 µg/mL). The dissolution profile of ternary inclusion complex in 0.1 N HCl was significantly higher compared to binary inclusion complex and pure drug. In cytotoxicity studies, the ternary inclusion complex has shown remarkable effect than the binary inclusion complex and pure drug on HepG2 cell lines.

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Abbreviations

SFNT:

Sorafenib tosylate

β-CD:

Beta-cyclodextrin

HPMC:

Hydroxypropyl methyl cellulose

ATR-IR:

Attenuated total reflection infrared spectroscopy

NMR:

Nuclear magnetic resonance spectroscopy

DMEM:

Dulbecco’s Modified Eagle’s Medium high glucose

FBS:

Fetal bovine serum

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Author notes

  1. Sunil Kumar Dubey

    Present address: R&D Healthcare Division Emami Ltd., 13, BT Road, Belgharia, Kolkata, 700056, India

  2. Mahipal Reddy Donthi, Siva Ram Munnangi and Kowthavarapu Venkata Krishna contributed equally.

Authors and Affiliations

  1. Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan, India

    Mahipal Reddy Donthi, Siva Ram Munnangi, Kowthavarapu Venkata Krishna, Ranendra Narayan Saha, Gautam Singhvi & Sunil Kumar Dubey

  2. Department of Biological Sciences, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus, Rajasthan, India

    Sandhya Amol Marathe

  3. Department of Biotechnology, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Dubai Campus, Dubai, United Arab Emirates

    Ranendra Narayan Saha

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  1. Mahipal Reddy Donthi
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Contributions

Methodology, investigation, writing (original draft): Mahipal Reddy Donthi, Siva Ram Munnangi, and Kowthavarapu Venkata Krishna. Cell culture study: Sandhya Amol Marathe. Writing review, editing, and supervision: Ranendra Narayan Saha, Gautam Singhvi, and Sunil Kumar Dubey.

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Correspondence to Sunil Kumar Dubey.

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Donthi, M.R., Munnangi, S.R., Krishna, K.V. et al. Formulating Ternary Inclusion Complex of Sorafenib Tosylate Using β-Cyclodextrin and Hydrophilic Polymers: Physicochemical Characterization and In Vitro Assessment. AAPS PharmSciTech 23, 254 (2022). https://doi.org/10.1208/s12249-022-02406-6

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