Estimation of lurasidone hydrochloride equilibrium solubility in a polymeric solid dispersion using thermal analysis and thermodynamic modeling

Information on drug equilibrium solubility is crucial in producing a stable drug product, prolonging its shelf-life and maintaining its reported properties. Such data regarding the antipsychotic drug lurasidone hydrochloride (LRS HCl), were non-existent up to this date. We have presented results that could facilitate the formation of stable LRS HCl solid dispersions using amorphous poly(vinyl-pyrrolidone) (PVP) as a carrier. For the purpose of drug solubility enhancement, solid dispersions with different drug loads were prepared by solvent evaporation method and characterized by thermogravimetric analysis, differential scanning calorimetry, and Fourier-transform infrared spectroscopy (FT-IR). Thermal analysis has been used to detect the changes in heat capacity (<i>c_p</i>) occuring upon formation of a binary drug-polymer solid dispersion. Thermodynamic model accounting for those <i>c_p</i> changes is used to estimate the Gibbs free energy of mixing (<i>G</i>^M) and thus the equilibrium solubility of LRS HCl in PVP solid dispersions.

药物平衡溶解度数据对于制备稳定的药物制剂、延长药品保质期以及维持其标称特性至关重要。截至目前，尚无关于抗精神病药物盐酸鲁拉西酮（lurasidone hydrochloride, LRS HCl）的此类平衡溶解度数据。本研究提供的结果可助力以无定形聚乙烯吡咯烷酮（amorphous poly(vinyl-pyrrolidone), PVP）为载体，制备稳定的盐酸鲁拉西酮固体分散体。为提升药物溶解度，本研究采用溶剂蒸发法制备了不同载药量的盐酸鲁拉西酮固体分散体，并通过热重分析（thermogravimetric analysis）、差示扫描量热法（differential scanning calorimetry）以及傅里叶变换红外光谱（Fourier-transform infrared spectroscopy, FT-IR）对其进行表征。通过热分析手段检测二元药物-聚合物固体分散体形成过程中发生的定压热容（heat capacity, cₚ）变化。基于上述定压热容变化的热力学模型，可用于估算混合吉布斯自由能（Gibbs free energy of mixing, Gᴹ），进而得到盐酸鲁拉西酮在聚乙烯吡咯烷酮固体分散体中的平衡溶解度。