de Paiva Lacerda Suênia, Espitalier Fabienne, Hoffart Valérie, Ré Maria Inês
a Mines Albi, CNRS, Centre RAPSODEE, Université de Toulouse , Albi , France and.
b "Conception, Ingénierie et Développement de l'Aliment et du Médicament" (EA CIDAM), UFR Pharmacie, Université d'Auvergne , Clermont-Ferrand , France.
Drug Dev Ind Pharm. 2015;41(11):1910-20. doi: 10.3109/03639045.2015.1020812. Epub 2015 Mar 20.
This study concerns a new compound named CRS 74 which has the property of inhibiting Human Immunodeficiency Virus (HIV) protease, an essential enzyme involved in HIV replication process. It is proved in this study that the original CRS 74 exhibits poor aqueous solubility and a very low dissolution rate, which can influence its bioavailability and clinical response. In an attempt to improve the dissolution rate, CRS 74 was recrystallized by liquid anti-solvent (LAS) crystallization. Ethanol was chosen as solvent and water as the anti-solvent. Recrystallized solids were compared with the original drug crystals in terms of physical and dissolution properties. Recrystallization without additives did not modify the CRS 74 dissolution profile compared to the original drug. CRS 74 was then recrystallized using different additives to optimize the process and formulate physicochemical properties. Steric stabilizer in organic phase ensured size-controlling effect, whereas electrostatic stabilizer in aqueous phase decreased particle agglomeration. Cationic additives avoided drug adsorption onto stainless steel T-mixer. In general, additive improved drug dissolution rate due to improvement of wetting properties by specific interactions between the drug and the additives, and ensured continuous production of CRS 74 by electrostatic repulsion.
本研究涉及一种名为CRS 74的新化合物，它具有抑制人类免疫缺陷病毒（HIV）蛋白酶的特性，HIV蛋白酶是HIV复制过程中一种必不可少的酶。本研究证明，原始的CRS 74表现出较差的水溶性和极低的溶解速率，这可能会影响其生物利用度和临床反应。为了提高溶解速率，采用液体反溶剂（LAS）结晶法对CRS 74进行重结晶。选择乙醇作为溶剂，水作为反溶剂。将重结晶后的固体与原始药物晶体在物理性质和溶解性质方面进行了比较。与原始药物相比，无添加剂的重结晶并未改变CRS 74的溶解曲线。然后使用不同的添加剂对CRS 74进行重结晶，以优化工艺并形成理化性质。有机相中的空间稳定剂确保了粒径控制效果，而水相中的静电稳定剂减少了颗粒团聚。阳离子添加剂避免了药物吸附到不锈钢T型混合器上。一般来说，添加剂通过药物与添加剂之间的特定相互作用改善了润湿性，从而提高了药物溶解速率，并通过静电排斥确保了CRS 74的连续生产。
