In vitro dissolution enhancement of micronized l-nimodipine by antisolvent re-crystallization from its crystal form H

摘要

In order to enhance solubility and dissolution rate in water, micronized l-nimodipine (NMD) has been successfully prepared by antisolvent re-crystallization process using acetone as solvent and deionized water as antisolvent. The effects of five experimental parameters on the mean particle size (MPS) of NMD nanosuspension were investigated. It was found that the MPS of NMD nanosuspension decreased significantly when the concentration of NMD-acetone solution increased from 50 to 150 mg/mL along with the increase of volume ratio of antisolvent to solvent from 1 to 3, and then increased slightly with the following increase of them. By contrast, the MPS decreased with the increased feed rate of NMD-acetone solution and the amount of surfactant, from 1 to 3 mL/min and 0.025% to 0.2%, respectively. Thereafter, the MPS did not show any obvious change. The precipitation temperature had no significant effects on MPS. The optimum micronization conditions were determined as follows: NMD-acetone solution concentration of 150 mg/mL, the volume ratio of antisolvent to solvent of 3, the flow rate of NMD-acetone solution of 9 mL/min, the preparation temperature of 15 C and the amount of the surfactant of 0.2%. Under optimum conditions, micronized NMD with a MPS of 708.3 nm was obtained. The micronized product was characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), high performance liquid chromatography-mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermo gravimetric (TG), to verify the influences of micronization process on the final product. The results showed that the chemical structure of micronized NMD was not changed, but the crystalline structure had undergone transition during precipitation, which changed from form H into L. The dissolution test showed that micronized l-NMD exhibited enhanced dissolution rate and solubility of 5.22 folds compared to raw H-NMD. These results suggested that micronized l-NMD may have potential value to become a new oral NMD formulation with high bioavailability.