The Study Of Preparation Of Nitrendipine Solid Dispersion And It’s Performance By Supercritical CO₂ Anti-solvent Method

Nitrendipine（NT）is a calcium channel blocker,a second-generation dihydropyridine compound,mainly used for the treatment of hypertension and coronary heart disease.However,NT has poor water solubility and bioavailability,which greatly limits its absorption in the human body.Therefore,using hydroxypropyl methyl cellulose（HPMC）and polyvinylpyrrolidone（PVP K30）with good water solubility,many hydrophilic groups and high swelling properties as carriers,the solid dispersion is prepared by the supercritical CO₂ antisolvent method（SAS）to improve the bioavailability of NT.The NT/HPMC binary solid dispersion and NT/HPMC/PVP K30 ternary solid dispersion were successfully prepared by the SAS method.The effects of process parameters such as temperature,pressure,concentration and solvent on the dissolution and particle size were investigated,and the process parameters were optimized.using infrared spectroscopy（FITR）,scanning electron microscopy（SEM）,liquid-mass spectrometry（LC-MS）,thermogravimetric and differential scanning calorimetry（TG/DSC）,X-ray powder diffraction（XRD）,nuclear magnetism resonance（¹H NMR）,etc.,performed characterization and analysis of solid dispersions,and speculated on the mechanism of binary and ternary solid dispersions to increase the dissolution rate.The best process conditions for the preparation of solid dispersions by the SAS process single-factor optimization method are:NT:HPMC mass ratio 1:2/3,operating pressure 14 MPa,operating temperature 40℃,drug concentration 25 mg/m L,mixed solvent The volume ratio of methanol:dichloromethane（DCM）is 10:10.The in vitro dissolution results show that the dissolution rate of NT is 25.5%under p H=1.2hydrochloric acid buffer solution,the dissolution rate of NT/HPMC physical mixture is28%,the dissolution rate of NT/HPMC binary solid dispersion is up to 94.8%,NT/HPMC binary solid dispersion under different p H buffers,the dissolution rate was found to be93.55%,91.15%and 72.2%under p H=1.2,4.5 and 7.4 buffers,it shows that the lower the p H of the buffer is,the better the solubility and dissolution rate are.The solubility of NT,NT/HPMC physical mixture,NT/HPMC binary solid dispersion,NT/HPMC/PVP K30physical mixture and NT/HPMC/PVP K30 ternary solid dispersion in distilled water are1.72μg/m L,2.3μg/m L,6.44μg/m L,3.91μg/m L,5.75μg/m L,the solubility of NT/HPMC binary solid dispersion and NT/HPMC/PVP K30 ternary solid dispersion in distilled water is 3.7and 3.3 times higher than that of NT,respectively.It can be seen that the solubility of NT can be significantly improved by preparing solid dispersions through the SAS process.XRD analysis showed that the solid dispersion was in an amorphous state,and the crystal form of NT disappeared;SEM shows that the morphology of the solid dispersion is quite different from that of the raw material,which is coral-like;LC-MS analysis shows that the retention time of the solid dispersion and NT is the same,and the[M+H]⁺ion peak of the solid dispersion and NT is the same,which is m/z=360.3,it shows that there is no chemical change in NT after solid dispersion is prepared by SAS process;TG/DSC,¹H NMR and FITR analysis found that there are hydrogen bonds or van der Waals forces between the benzene ring,methyl group,imino group and other groups of NT and the hydroxyl group,methyl group,methoxy group and other groups of HPMC.