| Nitrendipine is a dihydropyridine calcium channel blocker for hypertension and coronary heart disease.However,its poor water solubility and oral bioavailability greatly limits the clinical effect.Therefore,how to improve its solubility and bioavailability has become an urgent problem.To make nitrendipine into inclusion complex with hydroxypropyl-β-cyclodextrin(HP-β-CD)can improve its solubility and bioavailability efficiently.The inclusion complex prepared by Solution Enhanced Dispersion by Supercritical Fluids(SEDS)has small particle size and narrow distribution.The SEDS technique can remove trace organic solvents and its process is simple,so it exhibits broad application prospects in the pharmaceutical field.So the nitrendipine-HP-β-CD inclusion complexes were prepared by using SEDS technology for improving its low bioavailability.In this dissertation,the inclusion stability constants K was measured by phase solubility method at different temperatures,and then the(35)H,(35)S and(35)G was calculated to judge the feasibility of the inclusion reaction.The calculation result was(35)G < 0,which indicates that the inclusion reaction is feasible.Nitrendipine-HP-β-CD inclusion complexs were successfully prepared by SEDS technique with HP-β-CD as carrier.The effects of process parameters such as solvent,the host-guest molar ratios,temperature,pressure and solution concentration on the particle size and dissolution of inclusion complexes were investigated.The distribution and average particle size were measured by using a laser particle size analyzer.The dissolution rate of nitrendipine,the physical mixture and the inclusion complexs in different dissolution medium were measured by an automatic sampling dissolution analyzer and ultraviolet spectrophotometer,respectively.The inclusion complexes were characterized by scanning electron microscopy,infrared spectroscopy,nuclear magnetic resonance,liquid chromatography-mass spectrometry,differential scanning calorimetry,and X-ray powder diffraction.The structure of inclusion complex was inferred according to the characterization results.The results of particle size showed that the average particle size of raw nitrendipine was 77.3 μm,and the minimum particle size of the inclusion complex was 10.18 μm.When using dichloromethane : methanol(25:15)as mixed solvent and the host-guest molar ratio is 1:1,the particle size of the inclusion complex is smallest.Under this condition,the average particle size of inclusion complexes decreases with the increase of pressure,increases and then decreases with the increase of temperature,decreases and then increases with the increase of solution concentration.The dissolution results indicate that the dissolution rate of nitrendipine was only 57.8% in mixed solution of pH1.2HCl:absolute ethanol(70:30),however,the dissolution of inclusion complex prepared at P=14 MPa was 61% at 5 minutes and reached 100% at 30 minutes.In mixed solution of pH1.2HCl: absolute ethanol(85:15),the dissolution of inclusion complex increased from 18.8% of the raw material to 56%.In the dissolution medium of pH1.2HCl,the dissolution of inclusion complex prepared at T=50°C improved by more than 5 times than that of the raw material.Therefore,the prepared inclusion complexes can significantly increase the dissolution of nitrendipine.It can be seen from the electron microscopy image that nitrendipine is short rod and HP-β-CD is porous sphere,and the morphology of inclusion complex is irregular flake,both of the two morphologies have disappeared.XRD and DSC results show that the crystallinity of the inclusion complex was reduced and there presents a new crystal form.The liquid chromatography-mass spectrometry results show that the forming process of inclusion complexes was a simple physical process,that is to say,the chemical structure of nitrendipine has not changed.Finally,the inclusion mechanism was speculated from four aspects: forming initial fog drops and expanding fog drops,HP-β-CD capture nitrendipine crystal nucleus and hardening into particles. |
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