Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation

Abstract

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 (Papp—cm s−1) of form I and III in pH 1.2 was 3.01 × 10−5 ± 4.14 × 10−7 and 3.15 × 10−5 ± 1.89 × 10−6, respectively, while in pH 6.8 it was 2.72 × 10−5 ± 1.56 × 10−6 and 2.81 × 10−5 ± 9.0 × 10−7, 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.

Exploring Taxifolin Polymorphs: Insights on Hydrate and Anhydrous Forms

“…Since dissolution kinetics are affected by crystalline form, it is important to investigate the presence of polymorphs obtained following Tax purification/crystallization. Over past decades, the number of papers investigating the solid state of active pharmaceutical ingredients (API) has tremendously increased, and in particular, the identification of polymorphs or pseudopolymorphs of API is gaining the interest of the scientific community [ 14 , 15 , 16 ]. Indeed, it is known that the presence of different crystalline forms can dramatically affect fundamental characteristics of the API such as chemical (reactivity), physical (shape, hygroscopicity, conductivity, density), thermodynamic (free energy, solubility, melting point, vapor pressure, and others), and mechanical (compressibility, friability, hardness, and flux) properties [ 17 , 18 , 19 ].…”

Enhancing the Biopharmacological Characteristics of Asperosaponin VI: Unveiling Dynamic Self-Assembly Phase Transitions in the Gastrointestinal Environment

“…The PAMPA model was conducted to evaluate In vitro gastrointestinal (GIT) permeability. 52 Results shown in ( Figure 9B and C ), the effective permeability of ASP VI-NaTC-DOPC-SAN increased 13.33 times after 12 h compared to the self-assembled micelles formed by ASP VI in aqueous solution (1.71% ± 0.13 and 24.52% ± 1.86, respectively). Notably, the effective in vitro permeability of the free drug was slightly lower than the self-assembly of ASP VI in water.…”

Study on Novel Solid-State Forms of Sorafenib with Advantages in Terms of Solubility

“…2 drug for advanced hepatocellular carcinoma [20,21] . Sorafenib belongs to a Biopharmaceutics Classification System (BCS) class II with high permeability but poorly aqueous solubility, with a low bioavailability of 8.4% [22,23] .…”

“…Sorafenib belongs to a Biopharmaceutics Classification System (BCS) class II with high permeability but poorly aqueous solubility, with a low bioavailability of 8.4% [22,23] . The marketed active substance sorafenib tosylate (SFN) is also BCS class II with low aqueous solubility (insoluble in pH 1~6) [24] . It is common knowledge that the solubility and dissolution rate of oral drugs in the gastrointestinal tract is one of the most important factors regulating their bioavailability [25,26] .…”