Preparation Of Nimodipine Solid Dispersion And Tablets By Hot Melt Extrusion

In modern pharmacy research,the in vitro dissolution and bioavailability of poorly soluble drugs have been receiving much attention.It was an effective method that transforming crystalline drugs into amorphous forms for improving its solubility.However,controlling the recrystallization for drugs after dissolution was the most important problem.In this paper,nimodipine?NM?,which had a very low solubility in vitro,was selected as a model drug to prepare solid dispersion and tablets with the excipient of Hypromellose methylcellulose acetate succinate?HPMCAS?by hot-melt extrusion.Thereby,not only the solubility of the drug was improved but also the recrystallization was inhibited.Futhermore,the bioavailability of the drug was also increased?In this study,the excipient of HPMCAS,which has strong inhibition of crystallization,were selected by crystallization inhibition experiments.The prescription and process of preparing solid dispersion by hot melt extrusion were selected by single factor investigation?The fomulation was NM-HPMCAS?3:7?,an extrusion temperature of110?,speed of 70 rpm/min,and granules passed through a 200 mesh sieve.NM was confirmed to exist as an amorphous state in NM-SD by differential scanning calorimetry?DSC?and powder X-ray diffraction?PXRD?.Hot stage microscopy?HSM?and scanning electron micrographs?SEM?observed the dispearence of the crystalline drug.FT-IR analysis illustrated hydrogen bond interaction between drugs and excipients in NM-SD.NM-SD tablets and NM sustained-release tablets were prepared with NM solid dispersion.The release behavior of NM-SD tablets was investigated in the dissolution medium of pH 6.8 for the in vitro study,which showed that the release of nimodipine could be realized in vitro without recrystallization within two hours.The formulation of NM sustained-release tablets exhibited good release profile,and the investigation on the drug release mechanisms indicated that the drug release profile closed to the first-order release equation.Accelerated experimental results showed that the stability was very good,and no crystallization occured during placement.The in vivo pharmacokinetic profiles study in Sprague-Dawley rats was also determined.The pharmacokinetic parameters of NM-SD tablets and the reference formulation Nimtop^?was that T_maxax of?0.5±0.085?h and?0.5±0.109?h,C_maxax of?570.6±11.55?ng/mL,?500.5±16.33?ng/mL,and AUC_?0-??of?8473.5±266.58?ng-hr/mL,?7144.2±286.74?ng-hr/mL.The results showed that the absorption of the self-made tablets was the same as Nimotop^?,and the AUC of them were similar.The C_maxax of the NM-SD tablets was higher than Nimotop^?,In short,the NM-SD tablets could produce similar treatment effects compared to those of Nimotop^?.Thus,in spite of the poor in vitro release profiles for NM-SD tablets at pH 1.2,the enhanced dissolution at pH 6.8 and superior recrystallization behavior contributed significantly to improve its bioavailability.