Establishment of Feedforward Control Model for Dry Granulation of Polysaccharide Components Based on Quality by Design / 中国实验方剂学杂志

ObjectiveA feedforward control model for dry granulation of polysaccharide components was established to guide the adjustment and optimization of critical process parameters （CPPs） in the design space， so as to reduce the impact of fluctuations in raw materials properties on the quality of medicines. MethodTaking Astragali Radix extract powder as the model drug， the design space of dry granulation CPPs was determined by Box-Behnken design. Astragali Radix mixed powder with different powder properties were prepared by mixture design， the variance inflation factor （VIF） was used to diagnose the multicollinearity of the powder properties， and principal component analysis （PCA） was used to extract the characteristic data of the model. Radial basis function neural network （RBFNN） was used to establish a feedforward control model for reflecting the relationship between the powder properties of polysaccharide components， dry granulation CPPs and one-time molding rate. ResultThe design space for dry granulation CPPs of polysaccharide components was 16-35 Hz for feeding speed， 10-23 Hz for roller speed， and 10-46 kg·cm-2 for roller pressure. The established RBFNN feedforward control model had a good predictive effect on the one-time molding rate of dry granulation of polysaccharide components， which could be used to guide the adjustment and optimization of CPPs in the design space， the relative error was 0.38%-6.73%， and the average relative error was 3.42%. ConclusionThe established feedforward control model can well reflect the relationship between the powder properties of the polysaccharide components， the dry granulation CPPs and the one-time molding rate of the granules， which can be used to guide the adjustment and optimization of CPPs in the design space， reduce the impact of material property fluctuation on product quality， and provide ideas for promoting the quality of traditional Chinese medicine from passive control to active control.

Exploratory study on preparation of high drug loading granules with traditional Chinese medicine raw powder as carriers / 中国中药杂志

With Sangtang Yin granule as model drug,and based on the strategy of " unification of medicines and excipients",the feasibility of preparing high drug loading granules with traditional Chinese medicine( TCM) raw powder as carrier was explored. The powder yield,particle size and particle size distribution,fillibility,flowability,hygroscopicity,reconstituability and other key physical properties relating to preparations of 8 herbs( Dioscoreae Rhizoma,Euryales Semen,Atractylodis Macrocephalae Rhizoma,Coicis semen,Poria,Puerariae Lobatae Radix,Puerariae Thomsonii Radix and Coicis Semen by stir-frying with bran) were studied after being smashed,and the feasibility of taking them as excipients of TCM granules was evaluated by co-spray drying,dry granulation and other preparation techniques. According to the results of the physical properties of raw powders,raw powders of Dioscoreae Rhizoma,Euryales Semen and Puerariae Thomsonii Radix had a high powder yield,uniform particle size distribution,good fillibility,poor hygroscopicity and good reconstitutability,with the feature of assisting granule forming. Compared with the prescription of spray dry powder Sangtang Yin without any excipient,the co-sprayed powder had a high yield,good fillibility and compressibility. The yield of dry granules prepared by co-spraying dry powder was increased by more than 10%,and the particles had a uniform color,good fluidity and dissolubility with the drug-loading rate up to 100%. Based on the physical characteristics of TCM raw powder combined with the analysis of the preparation process,Dioscoreae Rhizoma and Puerariae Thomsonii Radix raw powder were selected as the carriers of granule preparations,and Sangtang Yin granule without any excipient was successfully prepared. The findings provide a feasible idea for the preparation of TCM granules with a high drug loading capacity.

Optimization Of Roll Compactor Variables And Formulation Of Anti-Retroviral Tablet By Roll Compaction Method

Objective: This study emphasis on roll compaction variable and how the processing parameters influence the formation of granules in process of formulations of antiretroviral IR Tablet with help of optimization technique. Methods: In this present work we aimed to develop a stable pharmaceutical dosage form with anti-retroviral drug tenofovir disoproxil fumarate. % retention of granules over # 60 mesh in roll compaction method by sizing with 50G co-mill screen was assessed by optimization and results were evaluated by Design expert 12.0 software. Various parameters and optimization of the parameter for formulation for better product was done by using 23 factorial design and dry granulation technique for manufacturing tablets. Three operating parameters the roller speed, the hydraulic pressure and the gap width on the Chamunda CPMRC-200/150 Roll Compactor were varied. The planned response variable for study was % retention over #60 ASTM mesh. % retention of granules was calculated by weighing granules on digital electronic balance with respect to how much premix material was taken for compaction. Results: Excipients compatibility study gave positive way showing no change in physical appearance of drug-excipients mix. It reviled that drug was compatible with excipients used. By formation of granules with required ratio, the value of Compressibility index changed from 29 to 21.89, showed that flow properties were improved i.e. from poor to passable. Design expert 12.0 gave optimized solution for formation of required quantity of granules. Pareto chart showed envaulted positive and negative impact of factors on response as explained in results. The results clearly indicate that how granules manufacturing in roll compaction process are influenced by roller pressure, roller gap and speed. 70 % flakes formation and granules retention were observed with 4000 kg/cm2 pressure, 1 mm roller gap width and 6 rpm speed of roller. Pareto chart clearly indicate major impact is of roller pressure. Comparative dissolution profile graph showed that drug release pattern is similar with the innovator tablet. A stable, robust tablets were formed at the end of process. Conclusion: In this study, by optimizing processing variables stable antiretroviral immediate release oral solid dosage form was formed.

Research on Bayesian fault diagnosis model of traditional Chinese medicine dry granulation based on failure model and effect analysis (FMEA) / 中国中药杂志

This paper aims to construct a Bayesian(BN) fault diagnosis model of traditional Chinese medicine dry granulation based on the failure model and effect analysis(FMEA), effectively control risk factors and ensure the quality of granules.Firstly, the risk ana-lysis of dry granulation process was carried out with FMEA, and the selected medium and high risk factors were taken as node variables to establish corresponding BN network with causality.According to the mathematical reasoning method of probability theory, the model was accurately inferred and verified by Netica, and the granule nonconformance was used as the evidence for reversed reasoning to determine the most likely cause of the failure that affected the granule quality.The BN fault diagnosis model of traditional Chinese medicine dry gra-nulation was established based on the medium and high risk factors of process, prescription and equipment screened out by FMEA, such as roller pressure, raw material viscosity, clearance between rollers in the paper.The fault diagnosis of traditional Chinese medicine dry granulation process was then carried out according to the model, and the posterior probability of each node under the premise of nonconforming granule quality was obtained.This method could provide strong support for operators to quickly eliminate faults and make decisions, so as to improve the efficiency and accuracy for fault diagnosis and prediction, with innovation in its application.

Study on Preparation ，Quality Standard and Fingerprint of Ganshen Granules / 中国药房

OBJECTIVE： To prepare Ganshen granules， formulate its quality standards primarily and establish its HPLC fingerprint. METHODS： Using feeding speed， roller speed， roller pressure and roller clearance as factor， grain forming rate as index， single factor test and orthogonal test were used to optimize the granulation technology of Ganshen granules. According to 2015 edition of Chinese Pharmacopeia （part Ⅳ） （shorted for pharmacopeia）， moisture， granulation and dissolution were determined. TLC was used for the qualitative identification of Lycium barbarum， Astragalus membranaceus， Codonopsis pilosula in the Ganshen granules. HPLC method was used to determine the contents of betaine， calycosin-7-glucoside and lobetyolin in Ganshen granules. Fingerprints of 10 batches of Ganshen granules were drawn. RESULTS： The optimal dry granulation technology of Ganshen granules included that 25 r/min feeding speed， 8 r/min roller speed， 7 MPa roller pressure and 1.1 mm roller clearance， The grain forming rate is 85.83％. The moisture， granulation and solubility of Ganshen granule were all in line with pharmacopeia standard. TLC of L. barbarum， A. membranaceus and C. pilosula showed the same color spots on the corresponding positions of the reference chromatogram. The linear range of sample mass of betaine is 4.32-8.64 μg， and the linear range of mass concentration of calycosin-7-glucoside and lobetyolin were 5-30 and 10-60 μg/mL， respectively. RSDs of precision， reproducibility and stability tests （24 h） were all lower than 2.0％ （n＝5）. Average recoveries were 97.02％， 99.25％ and 101.04％ （all RSD＜1.7％， n＝6 or n＝9）. The contents of them were 4.298、0.054、0.025 mg/g， respectively. The similarity of HPLC fingerprints of 10 batches of Ganshen granules to control fingerprint was higher than 0.95. CONCLUSIONS： The optimal granulation technology of Ganshen granule is stable and feasible， and established quality standard and HPLC fingerprint can provide reference for quality control of Ganshen granule.

Research Progress of Granulation Technology for Taste Masking of Pharmaceutical Preparation / 中国实验方剂学杂志

In commonly used oral solid preparations, poor mouthfeel results in poor patient compliance with the drug, which in turn reduces the market competitiveness of the drug. The problem of taste masking of pharmaceutical preparations has always been one of the important problems faced by pharmaceutics. With the increasing demand for the taste of drugs, the methods of masking bad taste of drugs have gradually increased in recent years. By summarizing the relevant literature covering the bad taste of drugs, the commonly used taste masking techniques include the addition of taste masking agents, inclusion techniques, microsphere/microcapsule technology, solid dispersion technology, ion exchange technology and the like. However, in addition to the above taste masking techniques, in the manufacturing process of the solid preparation, the granulation technique also can achieve the shielding of the bad taste of the medicine, and the granulation technique is simple, and can well achieve the effect of masking the bad taste of the medicine. This paper systematically introduces the research progress of granulation technology in drug taste masking, in order to provide reference for the selection of drug taste masking technology. With the increasing demand for drug taste, drug masking technology has been paid more and more attention by the majority of preparation workers, however, there are still some problems, such as imperfect taste evaluation system and low specificity of methods. This series of problems need to be further studied and solved by relevant pharmaceutical researchers.

Discussion on research thought of dry granulation of traditional Chinese medicine: research progress at home and abroad based on dry granulation technology / 中国中药杂志

Dry granulation technology is a great innovation in granulation technology,which saves many intermediate links and reduces many intermediate costs. It is closely related to the characteristics of materials,dry granulation equipment and process. Dry granulation technology is a systematic engineering science covering many technical fields. The process of dry granulation involves complex mathematical model mechanisms of temperature field,pressure field and velocity field,closely related to the characteristics of materials and drying equipment. However,due to the late start of research on dry granulation technology of traditional Chinese medicine,basic research is still weak. The research on dry granulation technology has achieved great results in the fields of food,chemical industry,agriculture and forestry,showing great reference significance. The advantage of dry granulation of traditional Chinese medicine is that it can be directly granulated by adding an appropriate amount of auxiliary materials in the extract powder of traditional Chinese medicine,without the need of wetting,mixing,drying and other processes. The process is simple and can effectively guarantee the quality of traditional Chinese medicine. The granules obtained by the dry granulation technique are important intermediates for preparing the solid preparations of traditional Chinese medicines,which would directly affect the subsequent molding process and the quality of the preparation products. Therefore,based on the characteristics of dry granulation method in traditional Chinese medicine and by referring to the advanced research results of dry granulation technology in other fields,we would discuss the research ideas of dry granulation in traditional Chinese medicine in terms of the mechanism of dry granulation equipment,technology,on-line detection technology and mathematical model of dry granulation process,hoping to provide reference for the research of dry granulation method in traditional Chinese medicine.

Optimization of dry granulation prescription and technology of Anti-Hashimoto’s Thyroiditis Formula Granules based on physical characteristics of raw materials in preparations / 中草药

Objective To optimize the prescription of dry granulation process of Anti-Hashimoto’s Thyroiditis Formula Granules. Methods Regarding primary formation rate, friability, and dissolubility and comprehensive in granulation process as indexes, the physical properties of water content, the angle of repose and the degree of compression were investigated to select dry granulation prescription. The technological parameters including horizontal speeds, rotate speed of roller and pressure rollers were screened by L9(34) orthogonal experiment were composed to be optimal technological prescription, and the optimum process was verified. Results The optimum lubricant and accessories ratio were 0.5% magnesium stearate and 20% dextrin respectively. The optimized dry granulation process parameters: horizontal speed 30 r/min, press roll speed 5 r/min and press roll pressure 7 MPa. Conclusion The optimized dry granulation preparation technology is feasible and reasonable, which shows good flakes continuous and granules with color uniformity, suitable rigidity and well formability in dry granulation preparation. After three batches of pilot-scale test, the dry granulation preparation technology is stable and feasible.

Optimization of Dry Granulation Technology of Typha Pollen Granules by Box-Behnken Design and Response Surface Method / 中国中医药信息杂志

Objective To optimize the dry granules process of Typha Pollen. Methods The particle size and particle friability were selected as evaluation indexes. The inspect factors were water content, compression frequency, and granulation frequency. Influence of inspect factors on evaluation indexes was investigated by single factor test, the influence of inspect factors on OD value was investigated by Box-Behnken design, and response surface method was adopted to predict, analyze and choose optimal process. Results The optimal dry granulation technology was as follows: the water content was 35.0%; the frequency of tabletting was 27 Hz; the granulating frequency was 15 Hz. Conclusion The selected process is stable, feasible and reproducible, which can be used for granulation of Typha Pollen granules.

Optimization of dry granulation prescription and technology of Xiaochuan Granules based on physical characteristics of raw materials in preparations / 中草药

Objective: To utilize powder physical characteristics, optimize prescription of dry granulation process of Xiaochuan Granules (XG). Methods: Filtering of granulation prescription was guided by investigating of powder material physical characteristics such as angle repose, compression degree, water content, etc; With one time forming rate, friability and quality score of granulation process as indexes, L9(34) orthogonal test which based on the evaluation method of information entropy was used to optimize the process parameters in XG dry granulation. Results: The optimum accessory is CD, optimum dry granulation technology parameters was as follows: roll wheel pressure of 7 MPa, roll wheel speed of 10 r/min, and feed speed of 18 r/min. Conclusion: Study of physical property of preparation materials could guide filtering prescription of dry granulation preparation; The prepared granules have high forming rate with moderate hardness and good flowability, and this optimized dry granulation technology is stable and reasonable.

Optimization of Dry Granulation Technology for Yinqiao Baidu Tablet by Orthogonal Test / 中国药房

OBJECTIVE:To optimize the dry granulation technology conditions for Yinqiao baidu tablet. METHODS:Using granulating difficulty degree and disintegration time as investigation indexes,ratio and amount of accessories microcrystalline cellu-lose and compressible starch in Yinqiao baidu tablet,moisture content of the sprayed powder were screened. Using yield of particle and angle of repose as indexes,L9(34)orthogonal test was used to optimize the wheel pressure,rotating speed and feeding speed in dry granulation technology,and verification test was conducted. RESULTS:The ratio of microcrystalline cellulose and compress-ible starch was 7:3,and mixing ratio of the two with spray powder+inclusion compound was 1:5. The moisture content of spray powder was controlled in 1％-2％. The optimal technology was as follow as wheel pressure of 3.5 MPa,roller speed of 4 r/min and feeding speed of 10 r/min. In verification test,average yield of particle was 69.2％ and angle of repose was 31.5 °. Transfer rate of chlorogenic acid had reached over 92％,and RSD of each index was below 2.53％(n=3). CONCLUSIONS:Each index of parti-cle prepared by optimized accessories formulation and technology shows good reproducibility and feasibility,and the technology is stable and suitable for production.

Preparation of Valsartan Tablets and evaluation of quality consistency / 药物评价研究

Objective To develop a formulation of generic Valsartan Tablets and evaluate the quality consistency in vitro.Methods Diovan(R)~ HCT (80 mg) was used as the reference drug.In order to determine the best formulation and the best preparation processing,the single factor experiments were applied to determining the best formulation and the best preparation processing.And dissolution test was used as the evaluation index in the single factor experiments.Meanwhile the dissolubility of generic Valsartan Tablets and original preparation was investigated in four different media to evaluate the similarity of dissolution by calculating similar factor (f2).Results The dissolution was above 85％ of three batches of generic Valsartan Tablets in the phosphate buffer (pH 6.8).The similar factors were all more than 50 in the water,hydrochloric acid solution (pH 1.2),and acetate buffer solution (pH 4.5).Conclusion The f2 similarity factor results indicate a similarity in the reference drug and generic Valsartan Tablets which were developed by single factor experiments,which means the quality of genetic Valsartan Tablets is qualified.

Formula Optimization of Minocycline Hydrochloride Sustained Release Tablets by Central Composite De-sign-Response Surface Methodology / 中国药师

Objective:To prepare minocycline hydrochloride sustained release tablets and optimize the formula .Methods: The method of dry granulation tabletting was used to prepare minocycline hydrochloride sustained release tablets .With the cumulative re-lease rate in 1, 2, 4 and 8 h as the index, the amount of HPMC E50 and HPMC K100LV was studied by central composite design re-sponse surface methodology .The in vitro release similarity of the sustained-release tablets and the reference tablets was compared .Re-sults:The optimized formula contained 35 mg HPMC E50 and 70 mg HPMC K100LV.The f2 for the sustained release tablets and the reference tablets in the different dissolution media was 79.06, 84.62, 75.46 and 72.95, respectively.Conclusion: Minocycline hydrochloride sustained release tablets with the formula optimized by central composite design response surface methodology meet the requirements.The results can provide evidence for the next industrial production .

Application of Dry Granulation Technology in Production of Lianhua Qingwen Capsules / 中国中医药信息杂志

Objective To solve the agglomeration problem in the former process, dry granulation technology was used to prepare the granules of Lianhua Qingwen Capsules. Methods Complexity and granule yield coefficient were set as inspection indexes. The optimum subsidiary material and its amount were optimized. The parameters of dry granulation technology were optimized by orthogonal test. Then, granule yield, angle of repose, and bulk density were compared with those of wet granulation technology. Results Starch was set as subsidiary material. The optimum technology is roll pressure of 12 MPa, rotation speed of 5 r/min, and feed speed of 10 r/min. The yield of granules prepared by dry granulation technology was significantly higher than that of wet granulation technology. Conclusion The dry granulation technology can effectively improve the agglomeration of the granulation process of Lianhua Qingwen Capsules, and was suitable for granulating process of Lianhua Qingwen Capsules.

Study on dry granulation technology for Ejiao granules / 中草药

Objective: To study the optimal technological conditions of Ejiao granules by dry granulation. Methods: The effects of rolling wheel press, speed, and powder feeding rate on grain yield were studied, and the dry granulation technology for Ejiao granules was optimized using L9(34) orthogonal test. Results: The optimal granulating conditions for the roll pressure was 60-70 kgf/cm2, powder feeding rate was 17-19 r/min, and rolling speed was 10-12 r/min. Conclusion: The study on the dry granulation technology for Ejiao granules provides the experimental basis for industrial application and spread of dry granulation technology in Chinese animal medicines.

Effect of superdisintegrants and their mode of incorporation on disintegration time and release profile of carbamazepine from immediate release tablet.

In this experiment the effect of mode of incorporation of some superdisintegrants such as sodium starch glycolate, croscarmellose sodium, crospovidone (kollidon CL), ludiflash and Xanthan gum (XG) on dissolution profile and disintegration time of carbamazepine (CBZ), apoorly water soluble drug was studied. The superdisintegrants were incorporated by extragranularly, intragranularly and in direct compression method. Different amount of superdisintegrants (1%, 3% and 6%) was incorporated in different formulations whereas all the other excipients as well as the active drug remained same. The results indicated that sodium starch glycolate, when incorporated extragranularly in wet granulation method significantly enhanced the release profile of CBZ. Kollidon CL was the most effective superdisintegrant in decreasing disintegration time of different tablet formulations (1.95 minutes when extragranularly incorporated). On the other hand, tablets prepared with SSG were found most effective in % drug release irrespective of its mode of incorporation (99.99% when extragranularly incorporated and 99.75 when intragranularly incorporated within one hour). Tablets prepared by direct compression method also showed similar drug release with other methods but tablet hardness was found lower. So addition of superdisintegrants in tablet formulation may be an effective technique to comply compendial drug release.

Achyrocline satureioides (Lam.) DC., Asteraceae: development of granules from spray dried powder

Achyrocline satureioides (Lam.) DC., Asteraceae, is a herbal specie widely used in folk medicine in the south of Brazil, Uruguay, Argentina and Paraguay. The technological characteristics of an Achyrocline satureioides spray dried extract powder, produced in semi-industrial scale, as well as the feasibility of the granules are reported in the present work. The spray dried powder was characterized as a fine powder consisting of small spherical particles with rough and porous surface. The Hausner's factor, Carr's index, and densification index of the spray dried powder were, respectively, 1,23, 18,9 percent, and 27,2 mL, characterizing it as a poor flow and low density powder. The preparation of granules from this spray dried powder, through dry disaggregation method, yielded irregularly shaped granules, with a rough surface, but with better flow and compactability characteristics. These granules presented a Hausner's factor, a Carr's index, and a densification index of, respectively, 1,09, 8,16 percent, and 12,33 mL. The LC assay of the main polyphenols, quercetin, luteolin, and 3-O-methylquercetin revealed that the granulation process did not changed the quantitative and qualitative profile of these constituents originally present in the spray dried powder. The comparative evaluation of the physical stability of both the spray dried powder and the granules, under relative humidity conditions of 65 percent and 99 percent, showed an expressive reduction in the humidity sorption on the granules as compared to the spray dried powders.

Achyrocline satureioides (Lam.) DC., Asteraceae, é uma planta amplamente utilizada na medicina popular no sul do Brasil, Uruguai, Argentina e Paraguai. As características tecnológicas do extrato seco por aspersão de Achyrocline satureioides, produzido em escala semi-industrial, assim como a viabilidade da produção de granulados são relatadas no presente trabalho. O extrato seco por aspersão foi caracterizado como um pó fino, composto por pequenas partículas esféricas com superfície rugosa e porosa. O fator de Hausner, índice de Carr e o índice de densificação das partículas foram, respectivamente, 1,23, 18,9 por cento e 27,2 mL, caracterizando-o como um pó com fluxo pobre e de baixa densidade. A preparação dos granulados a partir deste extrato seco por aspersão, através do método de desagregação por via seca, originou grânulos com forma irregular, superfície rugosa, mas com melhor fluxo e melhores características de compactabilidade. Estes grânulos apresentaram fator de Hausner, índice de Carr e índice de densificação de 1,09, 8,16 por cento e 12,33 mL, respectivamente. A análise por de CLAE dos polifenóis principais quercetina, luteolina e 3-O-metilquercetina revelou que o processo de granulação não altera o perfil quantitativo e qualitativo dos constituintes inicialmente presentes no extrato seco. A avaliação da estabilidade física do extrato seco por aspersão e do granulado, em condições de unidade relativa de 65 e 99 por cento, mostrou uma expressiva redução na absorção de umidade dos grânulos quando comparados com o extrato seco.

Development of granules from phyllanthus niruri spray-dried extract / Desenvolvimento dos grânulos de extrato phyllanthus niruri seco por aspersão

The aim of this study was to develop granules from Phyllanthus niruri spray-dried extract using dry and wet granulation and to assess techniques to enable the production of granules with improved technological characteristics and yields. Granules were characterized by granulometry, reological parameters, compression and hygroscopic behavior. Independent of the granulation technique, technologically developed granules presented particle diameter, bulk and tapped densities and compressibility indexes suitable for a solid dosage form. The compression behavior showed plastic and fragmentary deformation for granules produced by the dry granulation technique and predominantly plastic deformation for wet granulation. Concerning the humidity sorption, the study showed that granules absorb less humidity than the spray-dried extract. However, granules with Eudragit® E 100 were the least hygroscopic.

O objetivo deste estudo foi desenvolver grânulos de extrato Phyllantus niruri seco por aspersão e por granulação úmida e avaliar técnicas que possibilitem a produção de grânulos com características tecnológicas e rendimentos aperfeiçoados. Os grânulos foram caracterizados por granulometria, parâmetros reológicos, compressão e comportamento higroscópico. Independentemente da técnica de granulação, os grânulos tecnologicamente desenvolvidos apresentaram diâmetro de partículas, densidades aparente e compactada e índices de compressibilidade adequados para a formulação sólida. O comportamento de compressão mostrou deformação plástica e elástica para os grânulos produzidos por técnicas de granulação seca e, predominantemente, deformação plástica para a granulação úmida. Com relação à absorção da umidade, o estudo mostrou que os grânulos absorvem menos umidade do que o extrato seco por aspersão. Entretanto, os grânulos com Eudragit E 100 foram os menos higroscópicos.