Study On The Specification Of SCB Drug Substance And In Vitro And In Vivo Evaluation Of SCB Solid Dispersion

The purpose of this study was to investigate the specification of innovative drug the SCB drug substance,including the characteristics?identification?examination?relative substance and assay according to the technical requirements of drug research and development.Also analysis methods were established.Then,the SCB solid dispersion was produced by spray drying to improve the solubility and bioavaibility of SCB,meanwhile,dynamic solubility in vitro and absorption in vivo were evaluated.The main contents include the following five parts:The study of specification of SCB drug substanceAccording to the Chinese Pharmacopoeia,the characteristics of SCB API were observed and detected,the results showed that it was white powder and odorless;easily dissolved in DMSO,soluble in methanol or ethanol,insoluble in water;the melting point of three batches of samples was between 161?¹67?.The features of SCB such as HPLC,IR,UV and XRD were identified,the results showed those samples were the same as references substance.The examination of SCB drug substanceAccording to the Chinese Pharmacopoeia,the chloride,loss on drying,residue on ignition,heavy metals,arsenic salt of SCB API were examined and determined,the results showed that the chloride was less than 0.01%,the loss on drying was less than 0.1%,the residue on ignition was less than 0.1%,the heavy metal was less than 20ppm,the arsenic salt was less than 2ppm.An HPLC method was developed to determine the related substance of SCB,the chromatographic conditions were as follow,chromatographic column was DiMa Platisil PH?4.6×250mm 5?m?;mobile phase was acetonitrile-0.1%TFA solution,gradient elution;flow rate was 1ml/min;detection wavelength was 236nm.The results showed that,the specificity test suggested that the main peak and the impurity peaks were separated,the resolution of was more than 1.5;the LOD and LOQ were 6.2ng/ml?6.0ng/ml and 7.4ng/ml?7.0ng/ml separately;the single impurity was no more than 0.3%and the total impurities were no more than 0.5%.An GC method was developed to determine the residual solvents in SCB,the chromatographic conditions were as follow,Agilent GC-MS7697A-7890B-5977A,chromatographic column was DB-624?30m×0.32m×1.8?m?with the FID detector and nitrogen as the carrier gas,air flow rate was 400ml/min,hydrogen gas flow rate was 30ml/min and tail-blowing flow rate was 25ml/min.Column temperature was 40?and kept 5min,then increased to 120?at the rate of 40?/min,and then increased to 230?at the rate of 40?/min and kept 10min.The inlet temperature was 220?,the pressure of the head of the column was15.5psi and the split ratio was 10:1.The results showed that four kinds of residual solvents acetone,tetrahydrofuran,n-heptane and toluene showed a good linearity in the experimental concentration.The LOD of acetone,tetrahydrofuran,toluene and n-heptane were 0.05?g/ml?0.04?g/ml?0.05?g/ml?0.01?g/ml separately,the LOQ of acetone,tetrahydrofuran,n-heptane and toluene were 0.2?g/ml?0.18?g/ml?0.05?g/ml?0.22?g/ml separately.The average recovery of acetone,tetrahydrofuran,n-heptane and toluene at various concentrations was between 90%¹08%,and the residual solvents in the three batches of samples were acetone less than0.006%,tetrahydrofuran less than 0.002%,n-heptane less than 0.04%and toluene was not detected.The assay of SCB drug substanceThe assay determination method was the same as the related substances determination method.The results showed that a good linearity of SCB was observed in the range of 0.2495mg/ml⁰.6986mg/ml and the regression equation was A=17568830C+26442,R²=1,the precision RSD was 0.42%;the recovery was between98%¹02%and the assay of the three batches of samples were more than99.0%.The study on formulation of SCB SD and the evaluation of SCB SDThe optimal prescription composition and preparation process of SCB SD were determined by orthogonal test.The phase identification was determined though DSC?XRD analysis.The dynamic dissolution process of SD in gastrointestinal was simulated by the dynamic solubility test.The results showed that optimal prescription of SD was S-630 as the carrier,the drug and carrier ratio was 1:3?w/w?,the preparation process was spray drying,inlet liquid rate was 15ml/min,inlet temperature was75?,adding 5%HPMC E3 and mixing;the phase identification results showed that SCB exists in an amorphous state in the carrier,SCB and S-630 formed the solid dispersion;the dynamic solubility test results showed that the dissolution in simulated intestinal juice of SCB-SD at40min is more than 80%,and with the time increases,there was no drug precipitation,the dissolution of SD maintains more than 90%in the simulated intestinal juice within 3 hours.The study on stability and pharmacokinetics in rats of SCB SDSCB-SD was stored under the condition of temperature 40?±2??RH 60%±5%for 1 month?2 month,the stability of SD were evaluated by DSC and HPLC.The results showed that there was no melting peak of SCB in the DSC diagram,suggesting that SCB still exists in an amorphous state in the carrier;there was no significant change in the assay of SCB,the above results showed the good stability of SCB-SD.Sprague-Dawley rat models were used to evaluate the absorption rate and bioavailability between SCB-SD and SCB API.The plasma samples were analyzed by LC-MS/MS.The results showed that the C_maxax and AUC_0?t?t of SCB SD were 7.5 times and 6.3 times higher than those of bulk drug,respectively,indicating that the oral bioavailability was improved significantly by SCB SD.