(T1430-07-41) Preparation of Telmisartan Nanoparticles by the Supercritical Antisolvent Process: Effect of Particle Size on the Dissolution and Oral Bioavailability

Purpose: The purpose of this study was to enhance the solubility and oral bioavailability of telmisartan through preparation of its amorphous nanoparticles using the supercritical antisolvent (SAS) process. In addition, this study was aimed to investigate the effect of SAS process parameters such as solvent composition, concentration of drug solution, temperature, pressure, injection rate of drug solution, and CO2 flow rate on telmisartan particle formation using design of experiment.

Methods: A screening study was performed with a fractional factorial design using variables such as temperature, pressure, concentration of drug solution, injection rate of drug solution, dichloromethane and methanol ratio as a solvent composition and CO2 injection rate to investigate the effect of parameters on nanoparticle preparation of SAS process. An optimization study was conducted based on the results of the screening study, wherein the parameters of the SAS process were altered to produce the optimum particle size and morphology. The solid-state properties of telmisartan particles were characterized by using scanning electron microscopy (SEM), dynamic light scattering (DLS), powder x-ray diffraction (PXRD), and fourier-transform infrared (FT-IR) spectroscopy. The effect of particle size on the kinetic solubility, dissolution, and oral bioavailability of telmisartan was also investigated.

Results: In a screening study, the unprocessed telmisartan had an average particle size of 2 μm and appeared as a rod-like structure with an irregular length. Conversely, the processed telmisartan obtained by SAS process had a particle size that ranged from 362 to 1900 nm, which was relatively small compared to that of unprocessed telmisartan. Based on the results to screening study, the optimization study continued to investigate the effect of other parameters. Solid particles with different particle sizes of 198 to 1290 nm was prepared by SAS at various concentration of the drug solution. The lower ratio of dichloromethane in the solvent mixture, the higher the likelihood of preparing particles that are either close to the spherical shape or spherical. It was confirmed by FT-IR spectroscopy and PXRD analysis that all particles produced through the SAS process were prepared in an amorphous form. The solubility and dissolution rate of the SAS processed samples increased when compared to those of the unprocessed telmisartan, and it was found that they depend on the particle size. The oral bioavailability of processed telmisartan with a particle size of 198 nm was 4.3-fold higher than that of the unprocessed telmisartan. As the C_max and AUC_{0-48 h} of the processed telmisartan increased with a decrease in particle size, it is suggested that the oral absorption of telmisartan can be controlled by particle size.

Conclusion: In this study, amorphous telmisartan nanoparticles with particle size ranging from 198 nm to 1201 nm were manufactured using the SAS process and a mixture of dichloromethane and methanol. According to the screening experiments, particle size was mainly controlled by temperature and concentration of drug solution. Moreover, the size and morphology of particles were demonstrated to be tailored by the concentration of drug solution and the solvent compositions (ratio) at a fixed temperature along with the pressure conditions of the precipitation vessel. Compared to the crystalline microparticles, the amorphous nanoparticles had higher solubility and a rapid dissolution rate. In addition, the dissolution rate and oral absorption of telmisartan increased when the particle size of the amorphous nanoparticles decreased. Such findings confirm that the size and morphology of particles can be controlled by the solvent compositions of dichloromethane and methanol, and the preparation of amorphous telmisartan nanoparticles could be an effective approach to enhance the solubility, dissolution, and oral absorption of telmisartan.

Acknowledgments: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C4002166).