Biorefining and Remediation Laboratory, Department of Process Engineering and Applied Science, Dalhousie University, 1360 Barrington Street, Halifax, Nova Scotia B3J 1Z1, Canada; Solid State Pharma Inc., 1489 Hollis Street, Suite 300, Halifax, Nova Scotia B3J 3M5, Canada.
Solid State Pharma Inc., 1489 Hollis Street, Suite 300, Halifax, Nova Scotia B3J 3M5, Canada.
J Pharm Sci. 2021 May;110(5):2063-2073. doi: 10.1016/j.xphs.2020.11.036. Epub 2020 Dec 5.
In this work, a ternary phase diagram was developed for a Niclosamide-urea co-crystal (NCS-UR) in isopropanol (IPA) using a combination of slurry and solvent addition methods. The ternary phase diagram showed that solubility of Niclosamide and urea differed by an order of magnitude in IPA, leading to an incongruently saturating system. Spray drying was explored as a method to generate NCS-UR. Co-crystals with small, uniform particle size were successfully prepared by spray drying from equimolar solutions with yield up to 73%. Co-crystals were phase pure by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) from all conditions explored. Somewhat similar particles were obtained at inlet temperature of 70 °C (mean size of 2.0 μm) compared to 85 °C (2.8-3.4 μm). Based on the TPD, isolating phase pure co-crystal through solution crystallization in IPA would require excess urea. However, spray drying did not require excess co-former. The in-vitro solubility of NCS-UR was compared to anhydrous NCS in biorelevant media. NCS-UR did not give improvement in solubility at 1 h or 24 h. Overall, this work showed that spray drying is a feasible process for preparing phase pure co-crystals for an incongruently saturating system and simultaneously generating micron size particles.
在这项工作中，采用浆料法和溶剂添加法相结合的方法，在异丙醇（IPA）中开发了一种尼氯柳胺-尿素共晶（NCS-UR）的三元相图。三元相图表明，尼氯柳胺和尿素在 IPA 中的溶解度相差一个数量级，导致非共溶饱和体系。喷雾干燥法被探索用于生成 NCS-UR。通过喷雾干燥从等摩尔溶液中成功制备了具有小而均匀粒径的共晶，产率高达 73%。通过 X 射线粉末衍射（XRPD）和差示扫描量热法（DSC），从所有探索的条件下，共晶均为纯相。与 85°C（2.8-3.4μm）相比，在 70°C 的入口温度下获得了形状相似的较小颗粒（平均粒径为 2.0μm）。根据 TPD，通过 IPA 中的溶液结晶分离纯相共晶需要过量的尿素。然而，喷雾干燥不需要过量的共晶形成剂。在生物相关介质中，将 NCS-UR 的体外溶解度与无水 NCS 进行了比较。在 1 小时或 24 小时内，NCS-UR 的溶解度没有改善。总体而言，这项工作表明，喷雾干燥是一种用于制备非共溶饱和体系的纯相共晶并同时生成微米级颗粒的可行工艺。
