(M1530-11-65) Investigation of Dissolution and Permeation Properties of Amorphous Drug Particles Dispersed in Wax-Based Formulations

Purpose: Many drug candidates have low solubility. Hence, improving solubility is still a challenging task in drug development. The amorphous state shows a high dissolution property compared to the crystalline state ¹⁾.Amorphous formulation of drugs alone poses challenges due to recrystallization during the dissolution process and storage, and limited dissolution caused by low glass transition temperatures. Therefore, hydrophilic polymers are often used as a dispersing agent to enhance the physicochemical stability of amorphs state. Wax-based formulation, prepared with oil and fat with a solid form at 37℃, is used for sustained drug release ²⁾. In this study, wax-based formulation was investigated as a dispersing agent of amorphous drugs. It was considered whether the dispersion of amorphous drug particles to fat enables improved dissolution and permeation properties.

Methods: Carvedilol was used as a model drug with low solubility. Amorphous carvedilol was prepared using the melt-quenching method, using a hot plate with a magnetic stirrer and liquid nitrogen. A stainless-steel cup was filled with carvedilol powder. A hot plate was used to heat the cup containing the sample for 5 minutes at 150°C. Furthermore, the cup containing the melted sample was submerged in liquid nitrogen for 30 seconds without exposing the melted samples. Quenched samples were removed from the stainless-steel cup and crushed with a pestle and mortar. The crystallinity was determined using an X-ray diffractometer. The glass transition temperature was evaluated by differential scanning calorimetry. A solubility test of the powder sample was performed using a phosphate buffer solution in a shaking bath. The wax-based formulation was prepared by dispersing amorphous carvedilol to glyceryl distearate. The dissolution and permeability of carvedilol from wax-based formulation was evaluated by the µFlux^TM system.

Results: The melt-quenched carvedilol powder showed an amorphous state in powder X-ray diffraction patterns (Figure 1). Its glass transition temperature was ca. 27℃. On the dissolution of the behavior of carvedilol from the powder samples, the melt-quenched carvedilol showed low solubility/dissolution properties to untreated carvedilol (Figure 2). It was thought that carvedilol, with low glass transition temperature, became oily in contact with the test solution, resulting in limited dissolution from powder. Therefore, we focused on the wax-based formulation containing amorphous drug particles. The dissolution and permeability of carvedilol were evaluated by the µFlux^TM system (Figure 3). The dissolution property of carvedilol was improved by the wax-based formulation compared to powder formulation. In the permeation process, sustained and constant membrane permeation of carvedilol was observed. The wax-based formulation enables a sustained drug release, thereafter the released drug proceeds to the membrane permeation process. Although the stability of a supersaturated state was known to be affected by parameter such as the degree of supersaturation, supersaturation of carvedilol was maintained until 360 min. It was estimated that a balance between drug release and membrane permeation processes was maintained, leading to the high supersaturation levels and constant membrane permeation.

Conclusion: The dispersion of amorphous drug particles to wax-based formulation enabled to realize both the supersaturation and constant membrane permeation.

References: 1) Andre H., Johanna M., Hanlin L., Christian J., Andrea M., Bart He., James M., Tian W., Michael C., 2023. Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations. The AAPS Journal 25.
2) Yasuhiko M., Toshio O., Yukiya Y., Masaharu Mi., Hiroshi S. Hisakazu S., 1996. Controlled-release of diclofenac sodium from wax matrix granule. International Journal of Pharmaceutics 138, 215-224.

Acknowledgements: There are no funding and conflict of interest.

Powder X-ray diffraction patterns of untreated and melt-quenched carvedilol powders.

Dissolution profiles of untreated and melt-quenched carvedilol powders.

Schematic presentation of one donor-acceptor pair of the µFlux apparatus separated by a membrane with UV-vis probes and dissolution and permeation profile of carvedilol from wax-based formulation.