Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 701 Alfenas, Minas Gerais 37130-001, Brazil; Novartis Pharmanalytica AS, Via Serafino Balestra, 31, 6600 Locarno, Switzerland.
Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 701 Alfenas, Minas Gerais 37130-001, Brazil.
Int J Pharm. 2020 Nov 15;589:119840. doi: 10.1016/j.ijpharm.2020.119840. Epub 2020 Sep 2.
Buclizine (BCZ) is a chiral synthetic piperazine derivative which has antihistaminic, anti-muscarinic and antiemetic properties, and has been reintroduced as an appetite stimulant, especially for pediatric patients. Structural information about this drug, as well as other buclizine crystalline forms (solvates, salts and co-crystals) including the BCZ free-base (BCZ-FB), is non-existent. Here, we present for the first time the crystal structure of the monohydrochloride monohydrate salt of BCZ (BCZHCl·HO), and of its anhydrous form, BCZHCl. Interestingly, BCZHCl·HO was obtained by recrystallization from the raw material (BCZHCl) in ethanol:water solution showing that BCZ anhydrous dihydrochloride salt changes easily to a monohydrochloride monohydrate salt modification, which raise concerns about formulation quality control. BCZHCl·HO and BCZHCl crystallize in the orthorhombic space groups (Pna2 and Pca2) belonging to the mm2 point group and are thus classified as non-centrosymmetric achiral structures (NA). Intuitively, we expect these salts to crystallize in a space group with a center of symmetry, since less than 5% of the known racemic compounds crystallize in the NA type. The crystal structures of BCZHCl and BCZ-FB were not determined, but their existence was verified by other techniques (chloride ion analysis, PXRD, HPLC, FT-IR, DSC, TGA) and by comparison of the obtained results with those found for BCZHCl. Additionally, we have also performed an evaluation of the equilibrium solubility (at six different aqueous media) and the dissolution profile of the BCZHCl salt compared to the raw material and BCZ-FB. Different equilibrium solubility values were found comparing the three forms in acidic and neutral pH ranges and all of them were insoluble at pH > 7.0. Moreover, tablets prepared with BCZHCl, BCZHCl or BCZ-FB show significant differences in terms of dissolution profile.
布克利嗪（BCZ）是一种手性合成哌嗪衍生物，具有抗组胺、抗毒蕈碱和止吐作用，并被重新引入作为食欲刺激剂，特别是用于儿科患者。关于这种药物的结构信息，以及其他布克利嗪晶型（溶剂化物、盐和共晶），包括布克利嗪游离碱（BCZ-FB），都不存在。在这里，我们首次展示了布克利嗪单盐酸单水合物盐（BCZHCl·HO）及其无水形式 BCZHCl 的晶体结构。有趣的是，BCZHCl·HO 是通过在乙醇：水溶液中从原料（BCZHCl）重结晶得到的，这表明 BCZ 无水二盐酸盐容易转化为单盐酸单水合物盐修饰，这引起了对配方质量控制的关注。BCZHCl·HO 和 BCZHCl 结晶于正交晶系空间群（Pna2 和 Pca2），属于 mm2 点群，因此被归类为非中心对称手性结构（NA）。直观地说，我们期望这些盐在具有对称中心的空间群中结晶，因为少于 5%的已知外消旋化合物在 NA 类型中结晶。BCZHCl 和 BCZ-FB 的晶体结构没有被确定，但通过其他技术（氯离子分析、PXRD、HPLC、FT-IR、DSC、TGA）以及通过比较获得的结果与 BCZHCl 的结果，验证了它们的存在。此外，我们还评估了 BCZHCl 盐的平衡溶解度（在六种不同的水性介质中）和与原始材料和 BCZ-FB 的溶解曲线。在酸性和中性 pH 范围内，比较三种形式发现了不同的平衡溶解度值，所有形式在 pH>7.0 时都不溶解。此外，用 BCZHCl、BCZHCl 或 BCZ-FB 制备的片剂在溶解曲线方面表现出显著差异。
