Study On Production Technology Of Danqi Powder Based On QbD Concept

OBJECTIVE:1.Based on the concept of quality by design(QbD),the production process of Danqi powder is designed from the source;the influence of different process parameters on the quality attributes of Danqi powder is studied from the perspective of pharmaceutics;the mathematical model of key process parameters and key quality attributes is explored,and the operation space of production process is constructed and verified to be scientific.2.Methods for the determination of Danqi powder was established,and the range of the content of active components was determined.3.The HPLC fingerprint of Danqi powder was studied and established.4.The packaging materials,storage conditions and expiration date of Danqi powder were studied and determinedMETHODS:1.Based on the concept of QbD,taking the clean index,water content,powder yield,effective component content,dissolution,uniformity and effective component transfer rate of Salvia miltiorrhiza and Panax notoginseng as evaluation indexes,the method,frequency,power,time,drying method,temperature,power,time,grinding method,temperature,time,fineness and mixture of Salvia miltiorrhiza and Panax notoginseng were carried out Methods,frequency,time and other single factor screening and multi factor significance test to determine the key process parameters.The mathematical model between the key process parameters and the key quality attributes was established by using the center point composite design test,and the multiple quadratic regression equation was established for the test results;the optimal model was calculated by using Minitab 15 software,and the production process operation space and its acceptable scope were obtained,and the obtained process operation space was verified.Ten batches of Danqi powder were prepared from Salvia miltiorrhiza and Panax notoginseng from different origins to confirm the scientific production process.2.To establish and verify Tanshinone ?A,Cryptotanshinone,Tanshinone I,Salvianolic acid B,Notoginsenoside R1,Ginsenoside Rg1 and Ginsenoside RB1 content determination method:determine the content of active ingredients in 10 batches of Danqi powder,and determine the change range of active ingredients by adding and subtracting 3 times of standard deviation from the mean value.3.The fingerprints of 10 batches of Danqi powder were studied by HPLC,and the HPLC fingerprints were analyzed by the similarity evaluation software of the National Pharmacopoeia Committee(2012 Edition),so as to establish the HPLC fingerprints of Danqi powder.4.High temperature,high humidity and strong light tests were used to determine the storage conditions of the products.The accelerated and long-term stability tests were carried out on the Danqi powder packed in polyethylene composite film,tin composite film and aluminum foil composite film respectively,so as to select the appropriate packaging materials and determine the validity period of the products.RESULTS:1.Based on the concept of QbD,the production process parameters of Danqi powder were identified comprehensively,and the regression equations of key process parameters and key quality attributes were established,namely:(1)The transfer rate of Tanshinone ? A,Cryptotanshinone,Tanshinone ? and Salvianolic acid B Y1=83.365-0.035X1+1.082X2-0.165X4-1.088×10-4X1X2+1.833 × 10-5 X1X4+3.967×10-4X2X4+4.027 × 10-5X12-0.011X22+3.113 × 10-4X42;(2)Transfer rate of Notoginsenoside R1,ginsenoside Rg1 and ginsenoside Rb1 Y2=64.071—0.07X1-0.069X3+0.763X4—9.638 × 10-5X1X3+5.611 × 10-4 X1X4+2.804×<10-4X3X4+3.477 × 10-5X12+4.149 × 10-5X32—3.436 × 10-3X42;(3)Mixing uniformity Y3=81.929—0.341X5+2.323X6—0.029X5X6+0.025X52—0.052X62(X1,X2,X3,X4,X5 and X6 represent net washing power,drying temperature,drying power,grinding fineness,mixing frequency and mixing time respectively).The mathematical model of Danqi powder production process was established and verified,and the operation space of Danqi powder production process was established.2.The results were as follows:(1)Tanshinone ? A,Cryptotanshinone and Tanshinone ? were determined by gradient elution with acetonitrile as mobile phase A and 0.02%phosphoric acid as mobile phase B,and the detection wavelength was 270nm;(2)Determination of Salvianolic acid B with acetonitrile-0.1%phosphoric acid(22:78)as mobile phase and detection wavelength of 286nm;(3)Salvianolic acid B was determined by gradient elution with acetonitrile as mobile phase a Water as mobile phase B for gradient elution,detection wavelength of 203nm Notoginsenoside R1,Ginsenoside Rg1 and Ginsenoside Rb1 content determination method.The content range of Tanshinone I,Cryptotanshino-ne,Tanshinone ?A,Salvianolic acid B,Ginsenoside Rg1,Ginsenoside Rb1 and Notoginsenoside R1 were 2.57mg/g-3.35mg/g,23.98mg/g-27.46mg/g,37.89mg/g-42.69mg/g,respectively.3.The HPLC fingerprint of Danqi powder was established and 19 common peaks were identified.The chromatographic peaks of Cryptotanshinone,Tanshinone I,Tanshinone ?A,Salvianolic acid B,Notoginsenoside R1,Ginsenoside Rg1 and Ginsenoside Rb1 were identified.The similarity of the fingerprint of 10 batches of Danqi powder was above 0.980.4.The storage conditions of Danqi powder were determined as follows:put it in a cool and dry place,keep it away from light,the best packaging material was medical aluminum foil composite film,and the validity of the product was more than 18 monthsCONCLUSION:The production technology of Danqi powder based on QbD is stable,reliable and reproducible,which can provide scientific basis for large-scale production of Danqi powder.The HPLC method is accurate,stable and repeatable.The storage conditions and validity period of Danqi powder were determined preliminarily.The selected packaging materials can ensure the stability of product quality.It can provide reference for the quality control and clinical application of Danqi powder.