Application Of JMP Software In The Formulation And Process Optimization Of Tenofovir Disoproxil Fumatate Tablets

JMP software is an interactive visual statistical discovery software,which is used in pharmaceutical industry of experimental design and statistical analysis of data.Quality by Design(QbD)theory focuses on increasing understanding of drug and productive processes.According to QbD theory,the quality of drug can be improved by scientific management and risk management.The Food and Drug Administration(FDA)only accepted the statistical analytical report by SAS and JMP's analysis on new drugs.More than 40%of drug reviewers were JMP users.Based on the QbD theory,the quality target profile and critical quality attributes(CQAs)of the generic drug were determined though the full analysis of reference listed drug.The prescription and process optimization of tenofovir disoproxil fumarate tablets were investigated by the experimental design of JMP.The main contents are summarized as follows:1.Based on the QbD theory,prescription screening study was applied by the mixture design of JMP software.This design was based on systematic comprehensive research on the properties and risk assessment of APIs,the compatibility of raw and auxiliary materials,the risk assessment of prescription variables and the reaseach of API's particle size.The ratio of lactose monohydrate,pregelatinized starch,microcrystalline cellulose and croscarmellose sodium was the design factor,and the dissolution rate,disintegration time and tablet hardness was the dependent variables,the design space model consisting of the prescription components was established.The established model R~2 was higher than 0.9,which indicated that the model could explain most of the variations.The appropriate ratio of prescription composition was selected by this model.Based on the QbD theory,the single factor test was used to select the appropriate internal and external proportions of croscarmellose sodium and dosage of magnesium stearate.Through experimental verification,the prescription composition of each tablet was determined as:tenofovir disoproxil fumarate was 300mg,microcrystalline cellulose was 93 mg,lactose monohudrate was 164 mg,pregelatinized starch was71 mg,magnesium stearate was 10.05mg,croscarmellose sodium was 32mg,the ratio of internal and external croscarmellose sodium was 1:2.2.Based on the QbD theory,the above-mentioned optimized prescription and the initial risk and variable risk assessment of the production process,the wet granulation process was studied by custom design of JMP software.The speed of cutter and rotating,the granulation time,the amount of water was the design factor.The Karl coefficient,bulk density,and dissolution was the dependent variables.The design space model of the wetting granulation process was established.The established model R~2 was basically higher than 0.9,which indicated that the model could explain most of the variation.The appropriate process parameters were obtained by the process model:the stirring speed was3r/s,the cutter speed was 25r/s,the water consumption was 250mg/tablet and the granulating time was 8min.Through experimental verification,the optimal wetting granulation process paramenter by this model was feasible.Based on the QbD theory,the single factor method was applied to determine drying process parameters,lubrication process parameters and tableting process parameters.The drying process parameters was that drying temperature range was 55-60?and drying time was less than 7h.The lubrication process parameter was that number of revolutions was40-100.The tableting process parameters was that tablet machine speed range was 15-25rpm and tablet hardness was maintained to 100-140N by adjusting the main tablet thickness.Based on the quality standard of tenofovir disoproxil fumarate tablets in USP,the self-made drug and the reference drug was evaluated.The experimental results showed that the self-made drug was consistent with the reference listed drug.Therefore,the formulation and process of tenofovir disoproxil fumarate tablets which was based on QbD theory and the experimental design of JMP software could produce qualified products.The design concept and optimization method had an important application and promotion significance in the research of generic drug in china.