Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439, United States.
Department of Chemical and Materials Engineering, National Central University, 300 Zhongda Road, Zhongli District, Taoyuan City 320317, Taiwan, ROC.
Mol Pharm. 2023 Oct 2;20(10):5160-5172. doi: 10.1021/acs.molpharmaceut.3c00511. Epub 2023 Aug 30.
Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pH of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state C and N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.
为了避免涉及到各种环境、安全和制造成本问题，制造药物盐需要使用无有机溶剂工艺或绿色化学。在这项研究中，通过双螺杆挤出（TSE）并用水分协助，成功制备了 1:1 摩尔比的肉桂嗪（CNZ）与苹果酸盐。首先通过在研钵中用纯研磨（NG）和液辅助研磨（LAG）筛选几种羧酸，评估了盐形成的可行性，结果表明苹果酸和琥珀酸可以与 CNZ 形成盐。进一步使用苹果酸进行了盐形成的研究。热台显微镜检查表明，尽管 CNZ 的水溶性较差，但添加水可以促进 CNZ-苹果酸盐的形成和结晶。通过确定 CNZ 和苹果酸之间的 pH-溶解度关系，证实了盐形成的可行性，观察到 pH 值为 2.7 和盐溶解度为 2.47mg/mL。通过有机溶剂溶液结晶制备了真正的盐晶体，用于通过差示扫描量热法（DSC）、粉末 X 射线衍射（PXRD）、傅里叶变换红外（FTIR）光谱、固态 C 和 N 核磁共振（NMR）以及单晶 X 射线衍射（SXD）来检查晶体性质和结构。这些技术还确定形成了盐，而不是共晶。然后通过 1:1 CNZ-苹果酸混合物的 TSE 制备 CNZ 盐晶体，其中添加少量水可使混合物完全转化为盐形式。通过溶剂结晶和水辅助 TSE 制备的盐具有相同的性质，其水分吸附曲线也相似，这表明 TSE 是通过绿色化学制备盐的可行方法。由于 TSE 可以连续进行，如果将本研究的结果与其他连续过程相结合，则表明从活性药物成分（API）的合成到最终剂型的生产，连续制造药物产品的可能性。
