Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation
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 bioav...
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MDPI AG
2021-03-01
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| Online Access: | https://www.mdpi.com/1999-4923/13/3/384 |
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| author | Gabriela Wiergowska Anna Stasiłowicz Andrzej Miklaszewski Kornelia Lewandowska Judyta Cielecka-Piontek |
| author_facet | Gabriela Wiergowska Anna Stasiłowicz Andrzej Miklaszewski Kornelia Lewandowska Judyta Cielecka-Piontek |
| author_sort | Gabriela Wiergowska |
| collection | DOAJ |
| description | 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 (<i>P<sub>app</sub></i><sub>—</sub>cm s<sup>−1</sup>) of form I and III in pH 1.2 was 3.01 × 10<sup>−5</sup> ± 4.14 × 10<sup>−7</sup> and 3.15 × 10<sup>−5</sup> ± 1.89 × 10<sup>−6</sup>, respectively, while in pH 6.8 it was 2.72 × 10<sup>−5</sup> ± 1.56 × 10<sup>−6</sup> and 2.81 × 10<sup>−5</sup> ± 9.0 × 10<sup>−7</sup>, 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. |
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| spelling | doaj.art-386ed478967743179accbb458609fcf52023-11-21T10:23:20ZengMDPI AGPharmaceutics1999-49232021-03-0113338410.3390/pharmaceutics13030384Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility DifferentiationGabriela Wiergowska0Anna Stasiłowicz1Andrzej Miklaszewski2Kornelia Lewandowska3Judyta Cielecka-Piontek4Tarchomin Pharmaceutical Works “Polfa” S.A., A. Fleminga 2, 03-176 Warsaw, PolandDepartment of Pharmacognosy, Faculty of Pharmacy, Poznań University of Medical Sciences, Święcickiego 4, 60-781 Poznań, PolandInstitute of Material Science and Engineering, Poznan University of Technology, Jana Pawła II 24, 60-965 Poznań, PolandInstitute of Molecular Physics, Polish Academy of Sciences, Smoluchowskiego 17, 60-179 Poznan, PolandDepartment of Pharmacognosy, Faculty of Pharmacy, Poznań University of Medical Sciences, Święcickiego 4, 60-781 Poznań, PolandThe 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 (<i>P<sub>app</sub></i><sub>—</sub>cm s<sup>−1</sup>) of form I and III in pH 1.2 was 3.01 × 10<sup>−5</sup> ± 4.14 × 10<sup>−7</sup> and 3.15 × 10<sup>−5</sup> ± 1.89 × 10<sup>−6</sup>, respectively, while in pH 6.8 it was 2.72 × 10<sup>−5</sup> ± 1.56 × 10<sup>−6</sup> and 2.81 × 10<sup>−5</sup> ± 9.0 × 10<sup>−7</sup>, 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.https://www.mdpi.com/1999-4923/13/3/384sorafenib tosylatepolymorphic formssolubilitypermeability |
| spellingShingle | Gabriela Wiergowska Anna Stasiłowicz Andrzej Miklaszewski Kornelia Lewandowska Judyta Cielecka-Piontek Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation Pharmaceutics sorafenib tosylate polymorphic forms solubility permeability |
| title | Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation |
| title_full | Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation |
| title_fullStr | Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation |
| title_full_unstemmed | Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation |
| title_short | Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation |
| title_sort | structural polymorphism of sorafenib tosylate as a key factor in its solubility differentiation |
| topic | sorafenib tosylate polymorphic forms solubility permeability |
| url | https://www.mdpi.com/1999-4923/13/3/384 |
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