Varsa S Richu Bagya, Pandey Noopur, Ghosh Animesh, Srivastava Anubha, Puram Pavan Kumar, Meka Sai Teja, Chernyshev Vladimir V, Sanphui Palash
Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Chennai, Tamil Nadu 603203, India.
Solid State Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
ACS Omega. 2023 Sep 7;8(37):34120-34133. doi: 10.1021/acsomega.3c05263. eCollection 2023 Sep 19.
Allopurinol (ALO) is a medication that treats gout and kidney stones by lowering uric acid synthesis in the blood. The biopharmaceutics classification system (BCS) IV drug exhibits poor aqueous solubility, permeability, and bioavailability. To overcome the bottlenecks of ALO, salts with maleic acid (MLE) and oxalic acid (OXA) were synthesized using the solvent-assisted grinding method. The novel multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SEM images. The crystal structures of these salts with variable stoichiometry were obtained using Rietveld refinement from the high-resolution PXRD data. The proton from the dicarboxylic acid is transferred to the most basic pyrimidine "N" of ALO. The N-H···N hydrogen-bonded ALO homodimer is replaced by the N-H···O ionic interactions in ALO-OXA (2:1:0.4) and ALO-MLE (1:1:1) salt hydrates. The organic salts improved solubility and dissolution up to 5-fold and the diffusion permeability up to 12 times compared to the native drug in a luminal pH 6.8 phosphate buffer medium. The salt hydrates were exceptionally stable during storage at 30 ± 5 °C and 75 ± 5% relative humidity. Superior dissolution and diffusion permeability of the ALO-MLE salt resulted in improved pharmacokinetics (peak plasma concentration) that offers a promising solid dosage form with enhanced bioavailability and lower dosage formulation.
别嘌醇（ALO）是一种通过降低血液中尿酸合成来治疗痛风和肾结石的药物。生物药剂学分类系统（BCS）IV类药物表现出较差的水溶性、渗透性和生物利用度。为了克服ALO的瓶颈，采用溶剂辅助研磨法合成了与马来酸（MLE）和草酸（OXA）形成的盐。通过粉末X射线衍射（PXRD）、差示扫描量热法（DSC）、热重分析法（TGA）、傅里叶变换红外光谱法（FT-IR）和扫描电子显微镜（SEM）图像对新型多组分固体进行了表征。利用高分辨率PXRD数据通过Rietveld精修获得了这些不同化学计量比盐的晶体结构。二元羧酸中的质子转移到ALO最碱性的嘧啶“N”上。在ALO-OXA（2:1:0.4）和ALO-MLE（1:1:1）盐水合物中，N-H···N氢键连接的ALO同二聚体被N-H···O离子相互作用取代。与天然药物相比，在肠腔pH 6.8的磷酸盐缓冲介质中，有机盐的溶解度和溶出度提高了5倍，扩散渗透率提高了12倍。在30±5℃和75±5%相对湿度下储存期间，盐水合物异常稳定。ALO-MLE盐优异的溶出度和扩散渗透率导致药代动力学改善（血浆峰浓度），提供了一种具有提高生物利用度和更低剂型剂量的有前景的固体剂型。
