Solid State Pharmaceutical Research Group (SSPRG), National Institute of Pharmaceutical Education and Research, Hyderabad, India.
School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Hyderabad, India.
J Pharm Biomed Anal. 2018 Feb 5;149:185-192. doi: 10.1016/j.jpba.2017.11.003. Epub 2017 Nov 6.
Rufinamide (R) is a triazole derivative approved for the management of partial seizures and seizures associated with Lennox-Gastaut Syndrome, in November 2007. Crystal structure, solid state characterization, drug-excipient compatibility and solubility play a pivotal role in formulation development. This work deals with the crystal structure elucidation of R by single crystal X-ray diffraction and solid state characterization by thermal, spectroscopic and crystallographic techniques. Drug- excipient compatibility was assessed by differential scanning calorimetry (DSC). New RP-HPLC method for quantification of R was developed with improved retention time. Solubility and dissolution of drug in different media was determined. Additionally, the flow behavior of the drug was evaluated by measuring Carr's index and Hausner's ratio, while the compressibility behavior was studied using Well's protocol. R crystallized from dimethylformamide (R-DMF) was utilized for single crystal analysis. The drug crystallized in triclinic crystal system with P-1 space group. Asymmetric unit cell consists of two molecules of R held by intermolecular hydrogen bond (connected by NH⋯O, which forms the catemeric chain). Analytical outcomes from DSC, thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD) revealed that the drug was present in pure crystalline form and was devoid of any polymorphic or pseudopolymorphic impurities. Influence of pH on the solubility and dissolution of R-DMF was found to be insignificant. The drug exhibited poor aqueous solubility, which was improved nearly 4.6 fold with the addition of 2% sodium lauryl sulphate (SLS). The drug exhibits poor flow and elastic compression nature. Excipients such as poly ethylene glycol (PEG) 8000, SLS, lactose monohydrate, starch and Hydroxypropyl methylcellulose (HPMC) E15 were incompatible with R-DMF as identified by thermal analysis. It is envisaged that these information regarding solid state properties of R-DMF would aid in identifying a logical path for formulation development.
鲁非尼胺（R）是一种三唑衍生物，于 2007 年 11 月获准用于治疗部分性发作和 Lennox-Gastaut 综合征相关的发作。晶体结构、固态特性、药物-赋形剂相容性和溶解度在制剂开发中起着关键作用。这项工作涉及通过单晶 X 射线衍射对 R 的晶体结构进行阐明，并通过热、光谱和晶体学技术对其固态特性进行研究。通过差示扫描量热法（DSC）评估药物-赋形剂的相容性。开发了新的反相高效液相色谱法（RP-HPLC），用于定量分析 R，同时改进了保留时间。测定了药物在不同介质中的溶解度和溶解情况。此外，通过测量 Carr 指数和 Hausner 比来评估药物的流动行为，同时使用 Well 方案研究药物的可压缩性行为。从二甲基甲酰胺（R-DMF）中结晶出的 R 用于单晶分析。药物结晶为三斜晶系，P-1 空间群。非对称单元由两个 R 分子组成，通过分子间氢键（通过 NH⋯O 连接，形成链状）相连。DSC、热重分析（TGA）和粉末 X 射线衍射（PXRD）的分析结果表明，药物以纯晶态存在，没有任何多晶或假多晶杂质。发现 pH 对 R-DMF 的溶解度和溶解影响不大。该药物的水溶性较差，加入 2%十二烷基硫酸钠（SLS）后，溶解度提高了近 4.6 倍。该药物的流动和弹性压缩性质较差。聚乙二醇（PEG）8000、SLS、一水乳糖、淀粉和羟丙基甲基纤维素（HPMC）E15 等赋形剂与 R-DMF 不兼容，这是通过热分析确定的。预计这些关于 R-DMF 的固态性质的信息将有助于确定合理的制剂开发途径。
