Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA.
Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
AAPS PharmSciTech. 2021 Jan 6;22(1):31. doi: 10.1208/s12249-020-01875-x.
Aripiprazole (APZ) has poor physicochemical properties and bitter taste. The current study aimed to prepare salts of APZ with polycarboxylic acids (citric, malic, and tartaric acids) to improve physicochemical properties and impart sour taste to the drug. The salts were prepared by solubilization-crystallization method, and characterized by electron microscopic, spectroscopic, diffractometry, and thermal methods. The salts were assessed for pH solubility, pH-stability, dissolution, and solid-state stability. Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry data indicated formation of new solid phases. APZ and the salts exhibited pH-dependent solubility. The pH solubility curve shape was inverted "V," inverted "W," and inverted "U" for APZ, APZ-Citrate, and APZ-Malate and APZ-Tartrate, respectively. Compared to APZ, the solubility of salts at pH 4, 5, and 6 was 3.6-7.1, 23.9-31.5, and 143.4-373.3 folds of APZ. Increase in solubility in water by citrate, malate, and tartrate salts was 5562.8, 21,284.7, and 22,846.7 folds of APZ. The salt formation also leads to an increase in rate and extent of dissolution. The dissolution extent was 3.5 ± 0.5, 71.3 ± 1.2, 80.1 ± 6.2, and 86.1 ± 1.1% for APZ, APZ-Citrate, APZ-Malate, and APZ-Tartrate, respectively. Liquid and solid-state stabilities of the salts were comparable to APZ. In conclusion, salts of APZ with polycarboxylic acids improved solubility, and dissolution, and impart sour taste, which may improve palatability of the drug.
阿立哌唑（APZ）具有较差的理化性质和苦味。本研究旨在制备 APZ 与多元羧酸（柠檬酸、苹果酸和酒石酸）的盐，以改善理化性质并使药物具有酸味。盐通过溶解-结晶法制备，并通过电子显微镜、光谱、衍射和热方法进行表征。评估了盐的 pH 溶解度、pH 稳定性、溶解和固态稳定性。傅里叶变换红外、X 射线粉末衍射和差示扫描量热法数据表明形成了新的固相。APZ 及其盐表现出 pH 依赖性溶解度。APZ、APZ-柠檬酸、APZ-苹果酸和 APZ-酒石酸盐的 pH 溶解度曲线形状分别为倒“V”形、倒“W”形和倒“U”形。与 APZ 相比，盐在 pH 4、5 和 6 时的溶解度分别是 APZ 的 3.6-7.1、23.9-31.5 和 143.4-373.3 倍。柠檬酸、苹果酸和酒石酸盐盐在水中的溶解度增加了 5562.8、21284.7 和 22846.7 倍。盐的形成还导致溶解速率和程度的增加。APZ、APZ-柠檬酸、APZ-苹果酸和 APZ-酒石酸盐的溶解程度分别为 3.5±0.5、71.3±1.2、80.1±6.2 和 86.1±1.1%。盐的液体和固体稳定性与 APZ 相当。总之，APZ 与多元羧酸的盐提高了溶解度和溶解速度，并赋予了酸味，这可能提高了药物的适口性。
