| Objective:To prepare 200mg BT307 sustained release tablets,study the relationship between micromeritics properties of intermediate granules and quality of tablet,investigated release mechanism,provide data and establish the foundation for industrialized production,enhance controllability and uniformity of the tablet.Methods:The effort of viscosity of HPMC,diluents,adhesives and compression pressure for the release of tablet was studied,basic formula was determined.Under base of signal factor experiment,with impacted preparation as reference,release result was calculated to choose optimization formula by orthogonal design.Used particle size distribution?repose angle?compressibility degree as indexes,the relationship with tablet appearance?tensile strength?friability?tablet weight variation was fitted.Three batches of samples were prepared,and mechanism for release was investigated.By study of release?content and related substance of samples,stability test was investigated preliminarily.Results:The optimized formulation was:30%HPMCK4M,15%lactose,5%kollidon(?)SR,wetting granulating procedure was employed with 5%PVP 50%ethanol as adhesives,compression pressure and tablet weight was 8-10kg/cm2 and 400mg.Test of micromeritics parameter and drug release show:intermediate granules have good flowability(repose angle less than 40°)and compressibility(compression degree less than 20%),little discrete for particle size distribution,craft repetitiveness for batches is good.The release behavior is ideal.By measurement of weight gain of granules under different RH for 5 days,the critical relative humidity is RH 67-68%.compared with 0 day,micromeritics parameter of granules under RH 60%for 10 days changed significantly(repose angle more than 40°,compression degree more than 40%),so enviroment relative humidity for manufacture and storage should less than 60%.The mathematical fit result is Y1=0.192X1+0.092 X2-7.398(r=0.9921),Y2=0.0348 X1+0.174 X2-3.58(r=0.9543),Y3=0.0384X1-0.0699 X2-0.0731 X3-0.0036 X4+8.891(r=0.8997)when compression degree as X1,repose angle as X2,particle size distribution? as X3,water content as X4,and tablet weight variation as Y1,friability as Y2,tensile strength of tablet as Y3.Confidence coefficient for all mathematical relational expression is 0.001,linear correlation is significant.Release mechanism of the sustained tablet show that,the mechanism of tablet fit Higuchi equation well.When cumulative release of the drug is under 80%,Ritger-Peppas equation was used to fit,the result is In Q =0.555 lnt +3.366(r=0.9970),hint that the release of drug is by diffusion and erosion.when compared with HPMC tablet,the erosion rate of mixed matrix tablet decreased,and the time for diffusion is dominant is increased.Methodology for content,release and related substance was investigated.Influencing factor experiment of 10 days show that sustained release tablets is stable under light?humidity and heat.Result of accelerated test(30?±2?,RH65%±5%)and 6 months long term test(25 ?±2?,RH60%±10%)show that although content of related substance raised,the content?release and related substance of drug are not changed significantly.Conclusion:Formulation of BT307 sustained release tablet is reasonable,prepare craft is feasible,quality is controllable and stable.By control of micromeritics parameter,quality of tablet can be assured. |
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