The Study Of Propafenone Hydrochloride Sustained-release Tablets

1 ObjectiveThe project intended to prepare propafenone hydrochloride hydrophilic matrix sustained tablets, complete the new quality standards and stability studies of the new drug registration, evaluate the release mechanism and release effect by in vitro release and in vivo pharmacokinetic studies.2 Methods and Results2.1 The study of the pre prescriptionsUV is used to determine the solubility and oil/water partition of propafenone hydrochloride in 0.1mol·L-1 hydrochloric acid, pH4.0 acetate buffer, pH6.8 phosphate buffer solution and pH7.4 phosphate buffer, and study the bulk density, mobility and compressibility of propafenone hydrochloride. The results showed that the solubility of propafenone hydrochloride in 0.1mol·L-1 hydrochloric acid, pH4.0 acetate buffer, pH6.8, pH7.4 phosphate buffer were 1090.91、3621.13、3525.25、 2575.76mg·L-1,oil/water partition were 2.31、1.562、1.825、2.013;bulk density was 0.72g·cm-3, angle of repose was 40.7°.compressibility was poor.2.2 The study of prescription and technologyThe in vitro cumulative release as the indicator, investigated the prescription, technology of sustained-releasetablets. Finally, the amount of HPMC K100Lv and lactose was31.19%-32.16% and 8.67%-14.7% of the weight of the tablet; process:alcohol solution of 5% PVP-K30 as binder,20 mesh extrusion granulation, dried in 65℃ 1.5h, mixed with 0.5% magnesium stearate, compressed with Φ9mm shallow concave molded, control the tablets hardness from 60N-80N; in vitro release conditions:basket method,900ml pH6.8 phosphate buffer as the release medium, the speed was 50rpm, temperature was 37±0.5℃.2.3 The research of release mechanismEstablish the analysis of propafenone hydrochloride sustained release tablets in vitro release method. Three batches as samples, study the in vitro release, and a kinetic equation, zero order kinetics equation, Hixson,-Crowell equation, Higuchi model and Peppas equation were used for resolving the release mechanism.The chromatographic conditions were:Dikma ODS of C18(4.6×250mm,5μm); mobile phase:0.03mol·L-1 (NH4)2HPO4-Acetonitrile(65:35);flow rate:1.0mL·min-1; detection wavelength:220nm;column temperature:25℃;injection volume:10μL;the RSD of precision, stability and recovery were less than 5%. The model fitting results were as following:zero order kinetics:M,/M-=0.076t+0.114(R2=0.986, AIC-29.13); kinetic:ln(1-Mt/M∞)=-0.263t+0.346(R2=0.948, AIC=6.67);Higuchi:M,/M-=O.348t0.5-0.225(R2=0.995, AIC=-37.15);Hixson:(10-Mt) 1/3=-0.273t+4.838(R2=0.973, AIC=-40.9); Peppas:M,/M.=0.153t0.761(R2=0.998, AIC=-39.27). The results showed that the release mechanism of the preparation was the irregular proliferation, drugs and skeleton dissolution at the same time.2.4 Quality Assessment and Preliminary stability testInvestigated sustained-release tablets appearance, character, release and content limits, establish the quality standards of propafenone hydrochloride sustained release tablets, and research the preliminary stability.Quality standards results showed that the appearance of propafenone hydrochloride sustained release tablets was white, the uniformity and reproducibility of release were good (RSD<5%), the influence of medium pH did not effect the release behavior; the amount of the labeled content was from 95% to 105%; the indicators of tablet were in line with the requirements of the 2010 edition of the "Chinese Pharmacopoeia". Preliminary stability tests showed that the light, temperature had no effect, the humidity caused slight expansion of the tablet surface, but release and content had no significant changes. Accelerated test preliminary forecast the valid was two years.2.5 Pharmacokinetic StudyHPLC was used for determining concentration of the New Zealand rabbit oral test formulations and reference formulation at 0.5,1,2,4,6,8,10,12,24h pharmacokinetic parameters and relative bioavailability degree were calculated, and study the in vivo correlation.The results of pharmacokinetic study:the AUC0-t of reference preparation and the test preparation were 6.5mg-h/L,6.8mg-h/L, Cmax, were 1.42mg·L-1,0.65mg·L-1,tmax was 2h、6h, compared to the reference formulation, relative bioavailability was 105.9%, retention time extended from 3.7 to 9. 1h, and in vivo correlation Fa=1.039F-10.67 (R2=0.996).showing a correlation, indicating good in vivo correlation.3 ConclusionPropafenone hydrochloride sustained release tablets were prepared. The process was mature and reliable, and the drug released steadily in 12h in vivo, the effect of release reached the goal.