Wiergowska Gabriela, Stasiłowicz Anna, Miklaszewski Andrzej, Lewandowska Kornelia, Cielecka-Piontek Judyta
Tarchomin Pharmaceutical Works "Polfa" S.A., A. Fleminga 2, 03-176 Warsaw, Poland.
Department of Pharmacognosy, Faculty of Pharmacy, Poznań University of Medical Sciences, Święcickiego 4, 60-781 Poznań, Poland.
Pharmaceutics. 2021 Mar 13;13(3):384. doi: 10.3390/pharmaceutics13030384.
The presence of active pharmaceutical ingredients (APIs) in the forms of different polymorphic states can induce differences in their physicochemical properties. In the case of poorly soluble APIs, like the oncological drug sorafenib tosylate, small variations in solubility may result in large bioavailability differences. The control of its therapeutic dose is crucial from the effective pharmacotherapy point of view and the reduction of side effects. Therefore, this study aimed to assess the influence of sorafenib tosylate polymorphic forms on its solubility and, consequently, permeability, based on passive diffusion through membranes simulating the gastrointestinal tract (GIT) conditions. In the first part of the work, two crystalline forms of sorafenib tosylate were identified using the X-ray powder diffraction, FT-IR, and Raman spectroscopy. Subsequently, solubility studies were carried out. Both forms of sorafenib tosylate were insoluble in 0.1 N hydrochloric acid (HCl), in acetate buffer (pH 4.5), and in phosphate buffer (pH 6.8). Solubility (mg/mL) of form I and III of sorafenib tosylate in 0.1 N HCl + 1.0% SDS was 0.314 ± 0.006 and 1.103 ± 0.014, respectively, in acetate buffer pH 4.5 + 1.0% SDS it was 2.404 ± 0.012 and 2.355 ± 0.009, respectively, and in phosphate buffer pH 6.8 + 1.0% SDS it was 0.051 ± 0.005 and 1.805 ± 0.023, respectively. The permeability study was assessed using the parallel artificial membrane permeability assay (PAMPA) model. The apparent permeability coefficient (cm s) of form I and III in pH 1.2 was 3.01 × 10 ± 4.14 × 10 and 3.15 × 10 ± 1.89 × 10, respectively, while in pH 6.8 it was 2.72 × 10 ± 1.56 × 10 and 2.81 × 10 ± 9.0 × 10, respectively. Changes in sorafenib tosylate concentrations were determined by chromatography using the high-performance liquid chromatography (HPLC)-DAD technique. As a result of the research on the structural polymorphism of sorafenib tosylate, its full spectral characteristics and the possibility of using FT-IR and Raman spectroscopy for the study of polymorphic varieties were determined for the first time, and the HPLC method was developed, which is appropriate for the assessment of sorafenib solubility in various media. The consequences of various physicochemical properties resulting from differences in the solubility of sorafenib tosylate polymorphs are important for pre-formulation and formulation studies conducted with its participation and for the safety of oncological sorafenib therapy.
不同多晶型状态的活性药物成分（API）的存在会导致其物理化学性质产生差异。对于难溶性API，如肿瘤药物甲苯磺酸索拉非尼，溶解度的微小变化可能会导致生物利用度的巨大差异。从有效的药物治疗角度和减少副作用来看，控制其治疗剂量至关重要。因此，本研究旨在基于通过模拟胃肠道（GIT）条件的膜的被动扩散，评估甲苯磺酸索拉非尼多晶型形式对其溶解度以及进而对渗透性的影响。在工作的第一部分，使用X射线粉末衍射、傅里叶变换红外光谱（FT-IR）和拉曼光谱鉴定了甲苯磺酸索拉非尼的两种晶型。随后进行了溶解度研究。甲苯磺酸索拉非尼的两种晶型在0.1 N盐酸（HCl）、醋酸盐缓冲液（pH 4.5）和磷酸盐缓冲液（pH 6.8）中均不溶。甲苯磺酸索拉非尼晶型I和III在0.1 N HCl + 1.0%十二烷基硫酸钠（SDS）中的溶解度（mg/mL）分别为0.314±0.006和1.103±0.014，在pH 4.5 + 1.0% SDS的醋酸盐缓冲液中分别为2.404±0.012和2.355±0.009，在pH 6.8 + 1.0% SDS的磷酸盐缓冲液中分别为0.051±0.005和1.805±0.023。使用平行人工膜渗透性测定（PAMPA）模型评估渗透性研究。晶型I和III在pH 1.2时的表观渗透系数（cm/s）分别为3.01×10±4.14×10和3.15×10±1.89×10，而在pH 6.8时分别为2.72×10±1.56×10和2.81×10±9.0×10。使用高效液相色谱（HPLC）-二极管阵列检测（DAD）技术通过色谱法测定甲苯磺酸索拉非尼浓度的变化。作为对甲苯磺酸索拉非尼结构多晶型的研究结果，首次确定了其完整的光谱特征以及使用FT-IR和拉曼光谱研究多晶型变体的可能性，并开发了适用于评估甲苯磺酸索拉非尼在各种介质中溶解度的HPLC方法。甲苯磺酸索拉非尼多晶型溶解度差异导致的各种物理化学性质的结果对于在其参与下进行的制剂前和制剂研究以及肿瘤索拉非尼治疗的安全性很重要。
