(T1030-05-29) Improving the Drug Release of Clofazimine by Developing Amorphous Solid Dispersions via Hot-Melt Extrusion Using the Acid-Base Supersolubilization Principle

Purpose: Acid-base supersolubilization (ABS) is a novel approach for greatly increasing the aqueous solubility of basic drugs by interaction with weak acids that would not form salts. Rather, the solutions convert to amorphous solid dispersion (ASD) upon drying. (Singh et al., 2013) The ASDs can also be prepared in a dry state by hot melt extrusion (HME) of the mixtures. Earlier, this principle was successfully applied to a weakly basic haloperidol in the presence of weak acids (Patel and Serajuddin, 2021). In this study, ABS is applied to develop ASDs for clofazimine (CFZ), a weakly basic drug prescribed for the treatment of leprosy which exhibits poor aqueous solubility of less than 11 ng/ml (Verbić et al., 2023). Earlier, a lipid-based product was marketed and later withdrawn due to variability in bioavailability (Savla et al., 2017). Nevertheless, the escalating prevalence of drug-resistant tuberculosis has generated an imperative requirement for the development of efficacious anti-TB medications and alternative treatment regimes. Numerous studies assert that clofazimine maybe efficaciously for treatment of tuberculosis(Gopal et al., 2013). The goal of this work was to enhance the dissolution-limited solubility and develop amorphous solid dispersions (ASDs) of CFZ using glutaric acid as a weak acid. The development of CFZ oral formulation could be highly beneficial for the treatment of Tuberculosis.

Methods: Thermal stability of the CFZ and excipients was evaluated using thermogravimetric analysis (TGA) with a ramp rate of 10℃/min. Hot-stage microscopy (HSM) was used to test the miscibility of CFZ with glutaric acid. The melt viscosity of the drug-acid-surfactant-polymer physical mixture was investigated to optimize the HME processing conditions. The temperature sweep analysis was performed from 80℃ to 130℃ at 5℃/min with a constant angular frequency of 0.1 rad/s. The angular frequency analysis ranged from 0.1 to 100 rad/s, with a constant temperature of 120℃. Finally, a mixture containing CFZ, glutaric acid, poloxamer 407 (surfactant), and kollidon VA64 (polymer) was extruded through a Thermo Fisher Process-11 hot-melt extruder. The extrudates were then milled, and the solid-state properties of the extrudates were determined using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). In vitro dissolution testing was conducted using USP-II apparatus, at 50 RPM and 37°C, using 50 mg and 5 mg drug equivalents in 250 mL of pH 2.0 (0.01 M HCl), pH 6.8 USP phosphate buffer, FaSSGF (Fasted state simulated gastric fluid), and FeSSIF-V2 (Fed- state simulated intestinal fluid). In addition, the in vitro dissolution of a formulation comprising 50 mg drug equivalents was tested in 500 mL of FeSSIF-V2.

Results: Thermal stability of CFZ and excipients was confirmed by TGA, and no weight loss was observed until 150℃. Further, utilizing HSM, we confirmed that although CFZ has a high melting point of 224℃ a complete melting of CFZ was observed at a temperature below 100℃ in the presence of glutaric acid (GA) at a 1:4 (CFZ:GA) molar ratio. The melt viscosity analysis showed that the addition of glutaric acid and P407 have caused a substantial decrease in melt-viscosity, allowing the physical mixture to be processed at temperatures as low as 120°C. Based on preliminary studies, the processing parameters were optimized and by performing HME at 120°C and 100 rpm, extrudates were obtained that comprised of 10% CFZ, 11.16% glutaric acid (1:4 CFZ:GA molar ratio), 10% Poloxamer-407 and 68.84% Kollidon VA64. Further, the amorphous nature of the prepared formulation was confirmed by DSC and PXRD analysis. In vitro dissolution testing confirmed that CFZ in pH 2.0 HCl, pH 6.8 USP phosphate buffer and FaSSGF remained insoluble. In contrast, when 50 mg drug equivalents were utilized in FeSSIF-V2 32% of the drug was released in 250 mL of media, while 48% of the drug was released in 500 mL of FeSSIF-V2. Furthermore, complete drug release was achieved in 250 mL of FeSSIF-V2 by employing drug equivalents of 5 mg. Therefore, by employing the ABS concept, we effectively formulated ASD that substantially improved the dissolution profile of clofazimine.

Conclusion: The results of this study showed a successful application of ABS for developing amorphous solid dispersions of the poorly soluble drug CFZ. By reducing CFZ's melting temperature with glutaric acid, HME could be performed at a lower temperature of 120℃. The developed ASD using the concept of ABS substantially improved the dissolution profile of CFZ compared to the extremely low solubility of CFZ which was reported previously.

References: Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D., Serajuddin, A.T.M., 2013. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharm. Res. 30, 1561–1573. https://doi.org/10.1007/s11095-013-0994-7
Gopal, M., Padayatchi, N., Metcalfe, J.Z., O’Donnell, M.R., 2013. Systematic review of clofazimine for the treatment of drug-resistant tuberculosis [Review article]. Int. J. Tuberc. Lung Dis. 17, 1001–1007. https://doi.org/10.5588/ijtld.12.0144
Patel, N.G., Serajuddin, A.T.M., 2021. Development of FDM 3D-printed tablets with rapid drug release, high drug-polymer miscibility and reduced printing temperature by applying the acid-base supersolubilization (ABS) principle. Int. J. Pharm. 600, 120524. https://doi.org/10.1016/j.ijpharm.2021.120524
Savla, R., Browne, J., Plassat, V., Wasan, K.M., Wasan, E.K., 2017. Review and analysis of FDA approved drugs using lipid-based formulations. Drug Dev. Ind. Pharm. 43, 1743–1758. https://doi.org/10.1080/03639045.2017.1342654
Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D., Serajuddin, A.T.M., 2013. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharm. Res. 30, 1561–1573. https://doi.org/10.1007/s11095-013-0994-7
Verbić, T.Ž., Tam, K.Y., Veljković, D.Ž., Serajuddin, A.T.M., Avdeef, A., 2023. Clofazimine pKa Determination by Potentiometry and Spectrophotometry: Reverse Cosolvent Dependence as an Indicator of the Presence of Dimers in Aqueous Solutions. Mol. Pharm. 20, 3160–3169. https://doi.org/10.1021/acs.molpharmaceut.3c00172


Figure-1: Sub-figure (1A) provides the schematic representation of the interrelationship between the solubility of base and its salt form as a function of pH. Line AB represents free base as equilibrium species above the pHmax and line BC represents salt as equilibrium species below the pHmax. Sub-figure (1B) provides the pH vs solubility profile where acid added to increase the pH is weak so instead of forming salt, the solubility keeps increasing exponentially to form a supersolubilized system.


Figure 2: Sub-figure 2A represents the DSC scan and Sub-figure 2B represents the PXRD analysis of Neat CFZ (1) , neat P407 (2) , neat GA (3) , binary sample containing CFZ-VA64 (1:9 w/w) (4), CFZ-GA-P407-VA64 (1:2 Molar ratio of CFZ: GA) (5), and CFZ-GA-P407-VA64 (1:1.16:1:6.88% w/w) (6). Sub-figure (2C) represents the temperature sweep analysis and Sub-figure (2D) represents the angular frequency analysis of neat VA64 (1), binary mixture containing CFZ:VA64 [2 (1:9 w/w)] and quaternary mixture containing CFZ-GA-P407-VA64 [(3 (1:1.16:1:6.88 w/w)].


Figure-3: The dissolution profile of melt extrudates. Sub-figure 3A refers to the dissolution testing of 50 mg of CFZ equivalences in 250 mL of pH 5.8, FeSSIF-V2. Sub-figure 3B refers to dissolution testing of 50 mg CFZ equivalent in 500 mL of pH 5.8, FeSSIF-V2. Sub-figure 3C refers to dissolution testing of 5 mg CFZ equivalences in 250 mL of pH-5.8 FeSSIF-V2. For dissolution testing, a constant temperature and an RPM of 37°C and 50 rpm were used, respectively. The aliquots were filtered through 1.0-micron PTFE syringe filters. The black lines (-) represent the dissolution profile of CFZ-GA-P407-VA64 (1:1.16:1:6.88 w/w). The red lines (-) refer to the dissolution profiles of CFZ-VA64 (1:9 w/w).