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<p>To develop and optimize zopiclone co-crystal loaded oral films with enhanced solubility and bioavailability for improved management of insomnia.&#xa0;Zopiclone co-crystals were prepared with various co-formers and characterized using DSC, FTIR, and molecular docking studies. The co-crystal with optimal solubility enhancement was incorporated into oral films using a 3² full factorial design with HPMC K15 and Ludiflash as independent variables, and disintegration time and tensile strength as responses. The films were characterized for physicochemical properties, in vitro dissolution, stability, and in vivo pharmacokinetics in Wistar rats.&#xa0;Zopiclone-caprylic acid co-crystals (1:2 ratio) exhibited exceptional aqueous solubility enhancement (20&#xa0;mg/mL, 241-fold solubility enhancement in water) compared to pure zopiclone (0.083&#xa0;mg/mL). Response surface methodology identified an optimized formulation (F3) containing HPMC K15 (400&#xa0;mg) and Ludiflash (300&#xa0;mg), with predicted values closely matching experimental outcomes (prediction error &lt; 0.6%). The optimized film demonstrated rapid disintegration (54&#xa0;s), adequate tensile strength (2.87&#xa0;N/mm²), and accelerated dissolution (75.8% in 5&#xa0;min). Stability studies confirmed negligible changes in critical attributes over 6 months under accelerated conditions. Pharmacokinetic studies revealed significantly enhanced bioavailability (C<sub>max</sub>: 106.38 ng/mL; AUC<sub>0 − 24</sub>h: 842.15 ng·h/mL) compared to conventional tablet (C<sub>max</sub>: 49.73 ng/mL; AUC<sub>0 − 24</sub>h: 356.85 ng·h/mL) with 2.6-fold increase in relative bioavailability compared to pure drug suspension.&#xa0;The innovative combination of co-crystallization and oral film technology successfully overcame zopiclone’s solubility limitations, offering potential clinical benefits including faster sleep onset, reduced dosing, and improved patient compliance. This approach represents a promising platform for addressing bioavailability challenges of poorly soluble hypnotic agents in clinical practice.</p>

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Formulation and Optimization of Zopiclone Co-Crystal Based Fast-Dissolving Oral Films for Insomnia Management

  • 期刊论文

  • 发表日期：

    2025年12月17日

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  • Rahul K. Godge,
  • Aditi Khatal,
  • Someshwar Mankar,
  • Kavita Vikhe,
  • Santosh Dighe

摘要

To develop and optimize zopiclone co-crystal loaded oral films with enhanced solubility and bioavailability for improved management of insomnia. Zopiclone co-crystals were prepared with various co-formers and characterized using DSC, FTIR, and molecular docking studies. The co-crystal with optimal solubility enhancement was incorporated into oral films using a 3² full factorial design with HPMC K15 and Ludiflash as independent variables, and disintegration time and tensile strength as responses. The films were characterized for physicochemical properties, in vitro dissolution, stability, and in vivo pharmacokinetics in Wistar rats. Zopiclone-caprylic acid co-crystals (1:2 ratio) exhibited exceptional aqueous solubility enhancement (20 mg/mL, 241-fold solubility enhancement in water) compared to pure zopiclone (0.083 mg/mL). Response surface methodology identified an optimized formulation (F3) containing HPMC K15 (400 mg) and Ludiflash (300 mg), with predicted values closely matching experimental outcomes (prediction error < 0.6%). The optimized film demonstrated rapid disintegration (54 s), adequate tensile strength (2.87 N/mm²), and accelerated dissolution (75.8% in 5 min). Stability studies confirmed negligible changes in critical attributes over 6 months under accelerated conditions. Pharmacokinetic studies revealed significantly enhanced bioavailability (Cmax: 106.38 ng/mL; AUC0 − 24h: 842.15 ng·h/mL) compared to conventional tablet (Cmax: 49.73 ng/mL; AUC0 − 24h: 356.85 ng·h/mL) with 2.6-fold increase in relative bioavailability compared to pure drug suspension. The innovative combination of co-crystallization and oral film technology successfully overcame zopiclone’s solubility limitations, offering potential clinical benefits including faster sleep onset, reduced dosing, and improved patient compliance. This approach represents a promising platform for addressing bioavailability challenges of poorly soluble hypnotic agents in clinical practice.