Design And Control Of High-speed Shear Wet Granulation Process For Ginkgo Leaves

High shear wet granulation converts fine powder into granules by raw material powder,mixing,extrusion,wet massing and shearing under the function of binder agent wetting and paddle force.The technology has obtained extensive application,since it has advantages such as high efficiency,low energy,green,closure.Production operations of high shear wet granulation for Traditional Chinese medicine fluctuate with raw material variation,time lapse and uneven spatial distribution,which could lead to quality fluctuation.Quality by design method system highlights a thorough process and product understanding.In this paper,the high shear wet granulation process of the Ginkgo tablet was taken as research object.Using its process concepts and design elements including risk assessment,process characterization,mathematic model,critical process parameter,critical quality attribute,design space,control strategy,etc.,its relationships among raw material,granule and tablet were deeply analyzed and the quality consistency control was established.The main research contents are as follow:?.Comprehensive characterization of granulated products of Traditional Chinese medicineMicromeritics evaluation method was performed to characterize stackability,homogeneity,flowability,compressibility and stability of granules.The physical fingerprint of granules was constructed by 16 indexes including bulk density,tapped density,span,width,relative homogeneity index,aspect ratio,hausner ratio,angle of repose,granule flow time,inter-particle porosity,Carr index,specific surface area,pore volume,pore size distribution,loss on drying and hygroscopicity.Furthermore,compressibility parameters(i.e.index of parameter,index of parametric profile and index of good compression)were employed to analyze the compressibility characteristics of the granules.Two principal components,dimension parameter and morphology parameter,could be extracted from the physical fingerprint by the principal component analysis(PCA).?.Identification of critical quality attributes of granules of Traditional Chinese medicineQuality by design(QbD)highlights the concept of "begin with the end" which means thoroughly understand the target product quality and then guides pharmaceutical process development and quality control throughout the whole manufacturing process.Tablet compactability was taken as target and back analysis was executed to identify granules'critical quality attributes(CQAs)of and CQAs' limits using mathematical model.Firstly,the orthogonal partial least square(OPLS)model was adopted to build the relationship between the physical properties of granules and the tensile strength of tablets and thereby the potential critical quality attributes(pCQAs)were screened by variable importance in the projection(VIP)indexes.Then,a series of OPLS models were rebuilt by reducing pCQAs variables one by one in view of the rule of VIP values from low to high in sequence.The model performance indices demonstrated that calibration and predictive performance of the model had no decreasing trend after variables reduction.In consideration of the results from variables selection as well as the collinearity test and testability of the pCQAs,the median particle size(D50)and the bulk density(Da)were identified as critical quality attributes(CQAs).The design space of CQAs was developed based on a multiple linear regression model established between the CQAs(D50 and Da)and the tensile strength.The control constraints of the CQAs that were 170 ?m<D50<500 ?m and 0.30 g·cm-3<Da<0.44 g·cm-3 were determined within the design space.?.Design space approach to optimize high shear wet granulation process of Traditional Chinese medicineThe median granule size(D50)and bulk density(Da)of granules were identified as critical quality attributes(CQAs).The Failure mode and Effects analysis(FMEA)was used to quantitative risk assessment.The Plackeet-Burmann experimental design was used to screen pCPPs and the results demonstrated that the binder amount,the wet massing time and the wet mixing impeller speed were critical process parameters(CPPs).The design space of the high shear wet granulation process was developed based on the Box-Behnken design and quadratic polynomial regression models.Since the p-values of model were less than 0.05 and the values of lack of fit test were more than 0.1,the relationship between CQAs and CPPs could be well described by the mathematical models.D50 could be controlled within 170 to 500 ?m,and the bulk density could be controlled within 0.30 to 0.44 g·cm-3 using any CPPs' combination within the scope of design space,which effectively controls high-risk factors and avoids potential hazard.Besides,granules produced by process parameters within the design space region could also meet the requirement of tensile strength of the Ginkgo tablet.IV.Quality consistency control of high shear wet granulation process of Traditional Chinese medicineExcipients and Ginkgo biloba extracts collected from various sources and batches were used to simulate raw materials' quality variation.Online torque was recorded to analyze viscosity of the wetting mass,and thereby the impact of physical quality variation of powders on granule properties could be investigated combining with physical fingerprint.Based on regime map thesis,granules' nucleation mode belonged to mechanical dispersion regime by calculating dimensionless parameters,which would lead to the unstable output in considerations of granule yield ratio and particle size distribution(PSD)curve.The orthogonal partial least square(OPLS)model was adopted to build the relationship between the physical properties of powders and the median granule size of Ginkgo biloba granules and then the critical material attributes(CMAs)were screened by variable importance in the projection(VIP)indexes.The results demonstrated that the properties of powders including hygroscopicity,angle of repose,hausner ratio,Carr index,D10 and loss on drying affected the granule size increase.Besides,Ginkgo biloba granules were compressed into tablet.In view of tensile strength analysis,the decrease of tensile strength of the Ginkgo tablet could not be attributed to the raw materials' quality variation.The design space of critical quality attributes(CQAs)and the process design space which could cope with raw materials' quality variation were proved to be robust.In conclusion,the physical fingerprint was firstly incorporated into granules'characterization.The research introduced the method for identification of granules' CQAs using the "begin with the end" principle.Besides,the FMEA approach was performed to identify systematic and unsystematic risk.Uniting the design space of critical quality attributes and the process design space,quality consistency could be ensured.Last,feedforward control would be explored by locating and adjusting nucleation mode within the scope of design space according to regime map theory.Based on QbD concepts,the high shear wet granulation process of the Ginkgo tablet would be designed and optimized.The established method performed well and process performance met expectations.