| Traditional Chinese medicine dosage forms are composed of the raw materials and excipients.The quality of the raw materials of traditional Chinese medicine(TCM)extracts fluctuates by a variety of factors including planting,harvesting,processing,storage and so on.In contrast,on account of extensive sources,various forms,complex manufacturing processes and different scales,source-to-source and batch-to-batch variation also can be seen in pharmaceutical excipients.In the process of pharmaceutical products,the raw materials and excipients are taken as the input of the process,the variation of which can be delivered to the final product,resulting in batch-to-batch differences in the quality of the products.In this paper,taking the matrix tablet of Panax notoginseng saponins as an example,based on the physical properties of materials,the effect of the variability of raw materials and excipients on the consistency of TCM tablet was studied.A robust formulation is defined as,"A formulation that is able to accommodate the typical variability seen in active pharmaceutical ingredients,excipients and processes without compromising the manufacture,stability,performance or any other attribute of the product critical to the patient's care or well being." Therefore,the reliability-oriented optimal control method was established,providing new insights into the quality control of TCM dosage forms and manufacturing process.The main research contents were as follows:?.Establishment of Physical Quality Attribute Evaluation of Raw Materials and Excipients1.The physical properties of both raw materials and excipients have high impacts on the quality of Chinese medicine preparations with oral solid dosage forms.Based on the concept of the chemical fingerprint for quality control of Chine medicine products,the method of physical fingerprint for quality evaluation of Chinese herbal extract powders was innovately proposed.This novel physical fingerprint was displayed by the radar map,and consisted of five primary indexes(i.e.stackablity,homogeneity,flowability,compressibility and stability)and twelve secondary indexes(i.e.bulk density,tapped density,particle size,homogeneity index,Hausner ratio,angle of repose,powder flow,inter-particle porosity,Carr index,cohesion index,moisture content,hygroscopicity).The method can also be applied to quality evaluation of excipient powders.2.Taking the Panax Notoginseng Saponins(PNS)extract,HPMC K4M and HPMC K15M as examples,physical fingerprints were built to evaluate source-to-source and batch-to-batch quality consistence of raw material and excipient powders.The fluctuation range and characteristics of variability were then identified.Results showed that the physical properties of source-to-source PNS extracts,HPMC K4M and HPMC K15M were dramatically different.The physical properties of batch-to-batch PNS extracts from the same vendor were similar,while with respect to HPMC K4M and HPMC K15M,they had different degrees of differences.In addition to the Hausner ratio,the other physical attributes were dispersed on the PNS extracts.As to HPMC K4M and HPMC K15M,except for the bulk density,tapped density and Hausner ration,the rest of the physical indicators were dispersed from different batches Through the integration of 12 secondary indexes,the index of parameter,the index of parametric profile and the index of good compressibility were calculated to predict the compressibility of the powders.Results indicated that the compressibility of PNS extracts,HPMC K4M and HPMC K15M was poor and they need diluent excipients to improve this deficiency to meet the requirements of direct compression.?.Study on the Effect of Raw Material and Excipient Variability on the Quality Consistency of TCM tablet1.Content determination results of batches of PNS extract from various sources showed that Heptosaponin Ri,Ginsenoside Rgi,Ginsenoside Re,Ginsenoside Rb1,Ginsenoside Rd and total content of PNS extracts from different batches and vendors were basically accorded with pharmacopoeia specification.2.PNS extracts from different vendors and batches were employed to stimulate the raw material variability to study the effect of which on the quality of the PNS controlled release matrix tablet.In addition to the indexes included in the physical fingerprints of PNS extracts,the particle size and particle size distribution,specific surface area and skeleton density of PNS extracts were measured,and the apparent morphology and thermodynamic properties of the PNS extracts were also analyzed.PLS models were built to relate the physical properties to the dissolution and tensile strength of the matrix tablet.The results showed that the moisture,hygroscopicity and specific surface area of PNS extract were the key factors that affect the dissolution of PNS matrix tablets.The tensile strength of matrix tablet was mainly determined by the cohesion index,specific surface area,percentage of particle size less than 50 ?m,D10,D50,D90 and relative homogeneity index of PNS extracts.3.HPMC K4M from different vendors and batches were employed to stimulate the excipient variability to study the effect on the quality of the PNS extended release matrix tablet.The particle size and particle size distribution of HPMC K4M were also measured,and the content of substituent and viscosity of each batch were collected based the certificate of analysis.PLS models were built to relate the physical properties to the dissolution and tensile strength of the matrix tablet.The results showed that the D10,D90,Span and moisture of HPMC K4M were the main factors affecting the dissolution of the matrix tablet,while the tensile strength was apt to be affected by the amount of methoxy and the hygroscopicity of HPMC K4M.?.Study on the formulation optimization of TCM tablet1.Through the established MBPLS model,chemical properties of raw materials and excipients,physical properties of raw materials and physical properties of excipients were divided into different blocks to obtain profound understanding of the influence of input materials on the in-vitro dissolution of the tablet.Results showed that the number of latent variables of the built MBPLS model was two,and the accumulated R2Y and Q2Y were 91.3%and 83.8%,respectively,indicating good explanatory and predictive ability.The BIP values of these three blocks were 0.87,0.92,and 1.18,respectively.It demonstrated that the physical properties of the materials had greater effects on the dissolution of the tablets compared to the chemical properties.In particularly,the physical properties of the excipients have a significant effect on the dissolution with the BIP value over 1.0.2.Based on the physical attributes of the input materials,the mixture-property PLS model was established,with two latent variables.The model captured 60.9%of the total variability in the physical properties of the raw materials and excipients and was able to predict 68.5%of the variability in the dissolution profile of Ginsenoside Rgi from the final formulation.Then the formulation optimization and control method was created by combining the objective function and the restriction conditions.Taking the DIS02?15%,DIS06?40%,and DIS12?90%as the optimization goals,results showed that the optimized formulations could meet the desired target.The SPE and hoteling T2 were less than their respective 95%confidence limits,ensuring that the properties of the new were close to that of the existed formulations.This also illustrated that the physical fingerprint of the raw materials and excipients can be applied to the initial stage of the process and reduce the influence of the input material variability on the critical quality attribute of the final product,ensuring uniform and stable quality. |
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