Study On Prescription Development Of Compound Diphenoxylate Tablets

Compound Diphenoxylate Tablets,a kind of antidiarrheal drugs,was developed by the United States GD SEARLE LLC for the treatment of acute and chronic functional diarrhea and chronic enteritis.Its active ingredients are diphenoxylate hydrochloride and atropine sulfate.FDA first approved Compound Diphenoxylate Tablets to sell in American in 1960 under the trade name Lomotil(?).Then in 1982,CFDA first approved its listing in China,and Changzhou Kangpu Pharmaceutical Co.,Ltd.was the listed company and used Compound Diphenoxylate Tablets as the trade name.The dosage form was tablet with 2.5 mg diphenoxylate hydrochloride and 25μg atropine sulfate.Currently,the Compound Diphenoxylate Tablets are widely produced and sold in the United States and Europe.This study was commissioned by Changzhou Kangpu Pharmaceutical Co.,Ltd.to carry out consistency evaluation research on its pillar product—the Compound Diphenoxylate Tablets.In order to fully meet the quality requirements of the United States originator product.The main content was divided into three parts:Firstly,we imitated compound diphenoxylate tablets referring to the United States’reference preparation Lomotil formulation.We investigated original prescriptions and Analyzed its composition.Then we use analytical tools to quantified the main excipients in the prescriptions.The sucrose content of reference preparation was measured using high performance liquid chromatography with differential refractive index detector;the sorbitol was quantified using a liquid chromatography-mass spectrometer;and the content of corn starch in the reference preparation was determined by starch iodine coloration method.According to the mesurement results of these excipients,we have basically identified more than 96%of the composition in the prescription.Next,based on the specific content of most ingredients in the reference prescription,we used the dissolution curve in vitro as an index to screen out the prescriptions with the consistent dissolution behavior with the reference.Then we designed a series of self-prepared prescription to screen the most suitable formulations and process.Through screening,we determined wet granulation as the granulation method of the formulation,and acacia solution as the adhesive.The optimal concentration and amount of the adhesive was further studied to finally determine the composition of the adhesive and the amount of the added adhesive.At last,the lubricant of the prescription was screened to determine the composition and amount of each lubricant in the prescription.Given all the above,the self-prepared prescription and technology was basically established.In the third part,we prepared samples of test batch and tested the dissolution curve.The Original US drug Lomotil was used as a reference preparation for in vitro bioavailability comparison.500mL pH 1.2 hydrochloric acid solution,0.2M acetic acid solution,pH 3.8 acetate buffer,and pH 4.5 acetate buffer were selected as dissolution medium at speed of 100 r/min,then sampled and tested at 5,10,15,30,45 minutes respectively.We then measured the dissolution rate of self-prepared tablets and the reference preparations at each time points,calculated the corresponding f2 factor,and accordingly estimate the similarity of in vitro bioavailability.To scale-up and verify the process of final prescription,we prepared three batches of amplified samples and selected one of the three amplified batches as the final process validation batch.The premixing,granulation,drying,total mixing,tableting,and other steps of the amplification process were sampled respectively and the relevant parameters were tested,and finally our prescription and technology could be confirmed.As a result,our prescription showed great similarity with the original product.The f2 factors of the two active ingredients were both larger than 50 in each dissolution medium;the results of the pilot batch process validation were all in line with the requirements.In conclusion,the prescriptions we designed shared good similarities with original product,all process parameters of the amplified samples met the requirements,which provides a reliable guarantee for the production of the Compound Diphenoxylate Tablets.