This paper concerns optimization and experimental validation of coprecipitation process parameters for preparing particles of Pyrazinamide and Polyvinylpyrrolidone using gas anti-solvent supercritical method. Mixtures of organic solvents (acetone and ethanol) were selected with various combinations of the drug and the polymer. The central composite design (CCD) was adopted to explore the effect of temperature, pressure, antisolvent addition rate, polymer fraction, and ethanol fraction on particle size distribution (PSD) and solubility. The strong likelihood models were developed for all the responses using Design-Expert software. Polymer fraction was the most important (p<0.0001) factor influencing PSD, while pressure and interaction between temperature and polymer fraction significantly affected solubility. The optimal condition was specified at temperature of 50 °C, pressure of 120 bar, antisolvent rate of 16 bar/min, polymer fraction of 30%, and ethanol fraction of 50%. The model was then validated experimentally under the optimal condition and compared with pure PZA and particles obtained from the physical mixture. According to DLS, XRD, FTIR, and FESEM analyses, the crystallinity of PZA-PVP particles was reduced in optimum conditions, leading to higher solubility. Also, the results suggest that it is feasible to produce coprecipitated particles with narrower size distribution by optimized GAS process.

本文研究了气体反溶剂超临界法制备吡嗪酰胺和聚乙烯吡咯烷酮颗粒的共沉淀工艺参数的优化和实验验证。选择有机溶剂（丙酮和乙醇）的混合物以及药物和聚合物的各种组合。采用中心复合设计 (CCD) 来探索温度、压力、抗溶剂添加速率、聚合物分数和乙醇分数对粒径分布 (PSD) 和溶解度的影响。使用 Design-Expert 软件为所有响应开发了强似然模型。聚合物分数是影响 PSD 的最重要 (p<0.0001) 因素，而压力和温度与聚合物分数之间的相互作用显着影响溶解度。最佳条件为温度 50 °C、压力 120 bar、抗溶剂速率 16 bar/min、聚合物分数 30% 和乙醇分数 50%。然后在最佳条件下对该模型进行实验验证，并与纯 PZA 和从物理混合物中获得的颗粒进行比较。根据 DLS、XRD、FTIR 和 FESEM 分析，在最佳条件下 PZA-PVP 颗粒的结晶度降低，从而导致更高的溶解度。此外，结果表明，通过优化的 GAS 工艺生产具有较窄尺寸分布的共沉淀颗粒是可行的。然后在最佳条件下对该模型进行实验验证，并与纯 PZA 和从物理混合物中获得的颗粒进行比较。根据 DLS、XRD、FTIR 和 FESEM 分析，在最佳条件下 PZA-PVP 颗粒的结晶度降低，从而导致更高的溶解度。此外，结果表明，通过优化的 GAS 工艺生产具有较窄尺寸分布的共沉淀颗粒是可行的。然后在最佳条件下对该模型进行实验验证，并与纯 PZA 和从物理混合物中获得的颗粒进行比较。根据 DLS、XRD、FTIR 和 FESEM 分析，在最佳条件下 PZA-PVP 颗粒的结晶度降低，从而导致更高的溶解度。此外，结果表明，通过优化的 GAS 工艺生产具有较窄尺寸分布的共沉淀颗粒是可行的。