Inmunogenicidad y capacidad protectora de variantes de la nueva vacuna antialérgica PROLINEM DS / mmunogeni city and protective efficacy of variants of a novel PROLINEM DS anti - allergic vaccine

Introducción: La vacuna antialérgica de segunda generación PROLINEM-DS está compuesta por alérgenos del ácaro Dermatophagoides siboney y la combinación de adyuvantes: proteoliposoma de N. meningitidis B y gel de hidróxido de aluminio. La adsorción del alérgeno es relevante para la seguridad y eficacia clínica de las vacunas adsorbidas en gel de hidróxido de aluminio en estudios previos se demostró la influencia negativa de los iones fosfato en la adsorción del alérgeno. Objetivo: Evaluar la inmunogenicidad y capacidad protectora de cuatro variantes de formulación obtenidas dentro del espacio de diseño de la vacuna PROLINEM DS. Métodos: Se emplearon 4 variantes de formulación con diferentes contenidos de tampón fosfato salino y gel de hidróxido de aluminio. Se administraron a ratones BALB/c 3 dosis subcutáneas una por semana. Luego, los ratones fueron sometidos a reto alergénico por aerosol. Resultados: Todas las variantes indujeron anticuerpos IgG1 e IgG2a alérgeno específico. Este efecto se correlacionó con el balance de citoquinas proinflamatorias Th1/Th2 en los pulmones y en los ganglios. La variante con reducción de tampón fosfato salino y gel de hidróxido de aluminio fue la de mayor índice IgG/IgE después de la vacunación. Esta relación muestra, en una variable, el equilibrio entre los componentes potencialmente bloqueadores y efectores. La tolerancia local en el lugar de la inyección mostró una reducción de los granulomas en los ratones vacunados con menos gel de hidróxido de aluminio. Conclusiones: La reducción del contenido de gel de hidróxido de aluminio y fosfatos se consideran mejoras farmacéuticas sin inconvenientes en cuanto a la inmunogenicidad de esta vacuna con un perfil de seguridad satisfactorio para futuros ensayos clínicos en humanos.

Introduction: The second generation anti allergic vaccine named PROLINEM DS is based on allergens from D. siboney house dust mite and a combination adjuvant containing PL and Alum. Allergen adsorption is relevant both safety and clinical efficacy in alum-adsorbed vaccines. Negative influence of phosphate ions on allergen adsorption was demonstrated in previous researches. Objective: To evaluate immunogenicity and protective efficacy of four variants obtained within design space of PROLINEM DS vaccine. Methods: Four variants were differentiated from each other by both phosphate and alum contents. Balb/c mice were administered with 3 doses by subcutaneous route. Further, mice were subjected to allergen aerosol challenge. Results: Specific IgG1 and IgG2a antibodies were induced by four vaccine variants. It was correlated with pro inflammatory cytokines balance Th1/Th2 both in lungs and lymphatic nodes. Formulation with lower PBS and Alum levels showed the highest IgG/IgE ratio at the end of vaccination schedule. This ratio shows in one variable the balance between potentially blocking and effector components. Mice injected with lower level of Alum showed a reduction of granuloma size in the site of vaccine administration. Conclusion: Decrease both alum and phosphate contents were a pharmaceutical improvement for antiallergic vaccines formulation. Safety and efficacy in this vaccine are crucial for future human clinical trials.

Research on feedforward control method of mixing process for compound Danshen Dripping Pills based on quality by design(QbD) / 中国中药杂志

The mixing process is one of the key operation units for solid preparation of traditional Chinese medicine. The physical properties such as particle size, density and viscosity of the mixture are key factors that need to be controlled, which will directly affect the performance of the preparation molding process and product quality. Subsequent dripping process performance and appearance qua-lity of dripping pills will be affected by dynamic viscosity of materials in the mixing process. Based on this, with mixing process of compound Danshen dripping pills as the object, a feedforward control method for the dripping pill mixing process was established based on the concept of quality by design(QbD). Firstly, critical quality attribute(CQA)-dynamic viscosity, critical material attributes(CMAs)-the moisture content of compound Danshen extract, average molecular weight of polyethylene glycol 6000 and critical process parameter(CPP)-mixing temperature were identified through the analysis of properties for multiple batches of the raw materials and excipients as well as technological mechanism. Then the Box-Behnken experimental design was used to establish the regression model among CMA, CPP and CMA(R■=0.972 0, RMSE =16.24) to obtain the design space. Finally, through the verification of three batches within the design space, the mixing process temperature was adjusted according to the properties of the raw materials and exci-pients to achieve accurate control of the dynamic viscosity attribute. The relative deviation between the actual dynamic viscosity value and the target value was less than 3.0 %. The feedforward control of the mixing process of compound Danshen dripping pills was rea-lized in this study, which can contribute to improving quality consistency of the mixing process intermediates, simultaneously provide a reference for the research on the process quality control of other Chinese medicine dripping pills.

Definitive screening design combined with design space for optimizing purification process of Scutellariae Radix extract / 中国中药杂志

In the pharmacopoeia, many process parameters for the purification process of Scutellariae Radix are unclear. In this study, deterministic screening design combined with design space method was used to optimize the purification process of Scutellariae Radix extract. Nine method parameters such as mass fraction of solution(X_1), first acid precipitation pH(X_2) and first holding time(X_3) in the purification process were firstly studied by definitive screening design. The yield of baicalin was defined as the evaluation index. A stepwise regression method was used then to build quantitative models between evaluation index and method parameters and the three most critical impact parameters were determined. Probability-based design space was calculated and successfully verified with the experimental error simulation method. Finally, the second standing temperature, the first standing temperature and the pH value of the second acid precipitation were determined as the three most critical method parameters. The recommended operating space was as follows: the second standing temperature 5-7 ℃, the first standing temperature 13-15 ℃, and the pH of the second acid precipitation 1.5-1.7. Within this operating space, the baicalin yield in the purification process was over 80%, and the probability of reaching the standard was over 0.96. In this study, we optimized the effect of various parameters for the purification process of the Scutellariae Radix extract in the pharmacopoeia on the yield of baicalin and provided a reference for industrial production of the exact of Scutellariae Radix.

Optimization of water-precipitation process in pretreatment process of Salviae Miltiorrhizae (Danshen) and Ligustrazine Hydrochloride Injection based on sequential central composite design / 中草药

Objective: To optimize the water-precipitation in the pretreatment manufacture process of Salviae Miltiorrhizae (Danshen) and Ligustrazine Hydrochloride Injection (SMLHI) based on the quality by design (QbD) concept and the sequential design. Methods: A design space was obtained by the global-type sequential design methodology combined with the fishbone-diagram risk analysis and central composite experiment based on global type sequential design method. The preliminary optimized zone of critical process parameters was extended in axial direction on the basis of the statistical result gained from the first central composite design. Then an updated multivariate linear regression model was fitted and a design space was delineated and verified. Results: According to the design space, the recommended operation space of the water-precipitation was as follows: when the pH value of the material was between 3.1 and 3.4, 3.25-5.00 times of water adding into the solution was recommened, the standing time was 7-17 h and the standing temperature was 7 ℃. Conclusion: This study introduces the sequential design into the process optimization of traditional Chinese medicine pharmaceuticals. Compared with the experimental design methods such as uniform space grid design and orthogonal design with a large number of samples, while samples cover the same feasible zone in a continuous operation form, sequential design methodology can effectively reduce the workload of the optimization experiment, avoid the waste of manpower and resources as well as guarantee the prediction ability of the fitting model.

Quality control of ethanol extraction process of Corydalis Rhizoma based on quality by design (QbD) / 中草药

Objective: To improve the quality control level of ethanol extraction process of Corydalis Rhizoma (CR) by using quality by design (QbD), so as to meet the extraction requirements of Kedaling Tablets. Methods: The critical process parameters were solvent multiple, extraction time and soaking time, and the critical quality attributes were dry extract rate, content and transfer rate of dehydrocorydaline. The response surface methodology was used to establish the mathematical model between the critical process parameters and the critical quality attributes. The overlapping design space of multiple index design spaces was established to select the optimal operation space, where the process verification was carried out. Results: The operating space parameters of ethanol extraction of CR was 14-24 h of the immersion time, 3.0-4.0 times of the first time solvent multiple, 1.5-2.0 times of the second and third time solvent multiple, and 1.5-2.5 h of the extraction time. Under this operating space, the extraction yield of CR was ranged from 6%-8%, the content of dehydrocorydaline was more than 2.8%, and the transfer rate was not less than 85%. Conclusion: The concept of QbD is helpful to improve the ethanol extraction process of CR, and to obtain a reliable and suitable extraction operation space for the production of Kedaling Tablets.

Multi-index optimization of alcohol extraction and water precipitation processes of Shenmai Injection based on quality by design concept / 中草药

Objective: The alcohol extraction and water precipitation processes of Shenmai Injection were optimized based on quality by design (QbD) concept and satisfaction algorithm. Methods: Hazard and operational analysis method was applied to conduct risk assessment of various process parameters in alcohol extraction and water precipitation processes of Shenmai Injection. Ethanol concentration, extraction time and alcohol-material ratio were selected as the critical process parameters of alcohol extraction, and the material pH, temperature and time were selected as the critical process parameters of water precipitation. A multiple linear regression model of critical process parameters and critical quality attributes were established by using Box-Behnken design. A design space was delineated according to the level of each index. Finally, the optimum operating condition was determined by the multi-index optimization algorithm. Results: Within the scope of the design space, when the alcohol concentration was 89.0%, the extraction time was 110 min, the alcohol-material ratio was 2.99, the desirability function of alcohol extraction of 0.722 was the best. When the material pH was about 4, the time was 40 h, the temperature was 2.0 ℃, the desirability function of water precipitation of 0.995 was the best. When the material pH was about 5, the time was 35 h, the temperature was 2.0 ℃, the desirability function of water precipitation of 0.999 was the best. Conclusion: The optimal conditions were determined based on QbD and satisfaction algorithm were conducive to ensuring the product quality and reducing the cost of production. This study has reference value for the guidance of pharmaceutical process research and actual industrial production.

Real time release testing of disintegration time of uncoated Tianshu Tablets / 中国中药杂志

In this paper, a real time release testing(RTRT) model for predicting the disintegration time of Tianshu tablets was established on the basis of the concept of quality by design(QbD), in order to improve the quality controllability of the production process. First, 49 batches of raw materials and intermediates were collected. Afterwards, the physical quality attributes of all materials were comprehensively characterized. The partial least square(PLS) regression model was established with the 72 physical quality attributes of raw materials and intermediates as input and the disintegration time(DT) of uncoated tablets as output. Then, the variable screening was carried out based on the variable importance in the projection(VIP) indexes. Moisture content of raw materials(%HR), tapped density of wet masses(D_c), hygroscopicity of dry granules(%H), moisture content of milling granules(%HR) and Carr's index of mixed granules(IC) were determined as the potential critical material attributes(pCMAs). According to the effects of interactions of pCMAs on the performance of the prediction model, it was finally determined that the wet masses' D_c and the dry granules'%H were critical material attributes(CMAs). A RTRT model of the disintegration time prediction was established as DT=34.09+2×D_c+3.59×%H-5.29×%H×D_c,with R~2 equaling to 0.901 7 and the adjusted R~2 equaling to 0.893 3. The average relative prediction error of validation set for the RTRT model was 3.69%. The control limits of the CMAs were determined as 0.55 g·cm~(-3)<D_c<0.63 g·cm~(-3) and 4.77<%H<7.59 according to the design space. The RTRT model of the disintegration time reflects the understanding of the process system, and lays a foundation for the implementation of intelligent control strategy of the key process of Tianshu Tablets.

Spray drying technology of Shenpu Penyan Granule based on quality by design concept / 中草药

Design space approach was applied to optimize the spray drying process of Shenpu Penyan Granule (SPG) based on the concept of quality by design (QbD). The yield, moisture content, the content of paeoniflorin, chlorogenic acid, polydatin and salvianolic acid B were defined as the process critical quality attributes (CQAs). Based on the Plackett-Burman design, three critical process parameters (CPPs) including inlet temperature, specific gravity, and feeding speed were identified by using the weighted standardized partial regression coefficient method. And stepwise regression method was then used to establish the mathematical model between CQAs and CPPs in the Box-Behnken design. The variance analysis results showed that the P values of the five models were less than 0.05 and the mismatch values were all greater than 0.05, indicating that the model could describe the relationship between CQAs and CPPs. Probability based design space was obtained and verified using Monte-Carlo simulation method. According to the verification results, the robustness of first ethanol precipitation process of SPG can be guaranteed by operating within the design space parameters, which helps to improve the quality uniformity between batches of phenol extracts and provides data support for industrialization production.

Optimization of lime milk-sulfuric acid process of Salviae Miltiorrhizae Radix et Rhizoma aqueous concentrate based on quality by design concept / 中草药

Objective: To optimize the lime milk-sulfuric acid process of Salviae Miltiorrhizae Radix et Rhizoma (SMRR) aqueous concentrate in the pretreatment of the manufacture of Danshen Chuanxiongqin Injection (DCI) based on the quality by design (QbD) concept. Methods Fishbone diagram method was applied to conduct preliminary risk assessment of various process parameters in lime milk-sulfuric acid process of SMRR aqueous extracts. Nine potential critical process parameters (CPP), including mass fraction of lime milk, flow rate of the lime milk addition, stirring speed, stirring time after lime milk addition, mass fraction of sulfuric acid, flow rate of the acid addition, stirring time after acid addition, standing time, and standing temperature, were identified. Plackett-Burman (PB) experiment design method was used to further screen the nine potential CPPs. As the result, the mass fraction of lime milk, stirring time after lime milk addition, stirring time after acid addition, and the standing time were filtered as CPPs of the lime milk-sulfuric acid process. A partial least squares regression models of critical process parameters and critical quality attributes were established using the central composite design and the design space methodology. Results: The recommended operation space of the lime milk-sulfuric acid process in the pretreatment of the manufacture of DCI was as follow: mass fraction of lime milk of 12.0%-13.0%, stirring time after lime milk addition of 40-50 min, stirring time after acid addition of 30-35 min, and standing time of 16-20 h. Conclusion: Operation in the design space is helpful to improve the consistency of lime milk-sulfuric acid process. This study is of valuable reference to actual industrial production.

Design and Optimization of the Formulation and Technology of Theophylline Gel Matrix Sustained-release Tablets Based on QbD Concept / 中国药房

OBJECTIVE： To design and optimize the formulation and technology of Theophylline hydrophilic gel matrix sustained-release tablets （self-made sustained-release tablets for short） based on the concept of “Quality by Design” （QbD）. METHODS： Diluent type， tablet diameter， the property of adhesive （ratio of different adhesive types）， the amount of adhesive were regarded as critical process parameters （CPPs）. Similarity factor of dissolution curves of self-made Theophylline sustained-release tablets and reference preparation and its accumulative release rate at different time points were regarded as critical quality attributes （CQAs）. L18（34） orthogonal tablet was adopted for design and trial， and secondary polynomial regression model was established. By using Modde 12.0 software， the design space and its acceptable range （PAR） were calculated through the optimal model. The optimal formulation and technology of Theophylline sustained-release tablets was determined， and validation test and Monte Carlo simulation verification were conducted. RESULTS： The optimal model with good coincidence， accuracy， validity and reproducibility was obtained， which could better fit the relationship between CQAs and CPPs. The design space and PAR value were obtained by further calculation （The optimum value of diluent was lactose； tablet diameter was 9.07-9.33 mm， and the optimal value was 9.20 mm； ratio of HPMC K4M to HPMC was 0.50-0.83， and the optimal value was 0.80； total amount of HPMC was 0.036 0-0.041 3 g per tablet， and the optimal value was 0.038 g per tablet）. The optimal formulation and technology included that ratio of theophylline， HPMC K4M and HPMC K100M were 50％， 15.48％ and 3.87％， respectively； the rest was filled with lactose and the diameter of the tablet was 9.20 mm. The results of validation confirmed that self-made Theophylline sustained-release tablets had similar in vitro release behavior compared with reference preparation. CONCLUSIONS： Based on the concept of QbD， the formulation and technology of Theophylline sustained-release tablets can meet the requirements of design， and the CPPs can be adjusted within the PAR range to meet the requirements of CQAs. This shows that the QbD concept is scientific and effective in the design and optimization of the formulation and technology of sustained and controlled release preparations.

Study on famous prescription of prestigious traditional Chinese medicine master Lu Zhizheng based on QbD concept: optimization of extraction process and granule forming process of Meiyan Shuqi Prescription / 中国中药杂志

Based on the concept of quality by design( QbD),the design space of Meiyan Shuqi Prescription extraction process was established,and its granules forming process was optimized. The content of total flavonoids was the critical quality attribute( CQA).The amount of water,extraction time and frequency were used as the critical process parameters( CPPs). Box-Behnken experimental design was used to optimize the extraction process. The design space of Meiyan Shuqi Prescription extraction process was established and verified. The results of variance analysis showed that the P value of the quadratic regression model was less than 0. 01,which indicated that the model had a statistical significance,and the relationship between each factor and response value could be functionalized by the established model. Through further optimization of design space,the optimal extraction process of Meiyan Shuqi prescription was13-fold volume of water,extraction for 3 times and each extraction time of 1. 4 hours. Furthermore,the forming process optimized by single factor was as follows: the excipient was dextrin; the ratio of extract powder to excipient was 1 ∶1; the wetting agent was 70% ethanol; and the amount of wetting agent was 0. 3 m L·g-1. The Meiyan Shuqi Prescription extraction process and the forming process based on QbD concept provide reference for the study of other traditional Chinese medicine prescriptions.

Research of classical prescription based on QbD concept:optimization of extraction process for modified Siwu Decoction / 中国中药杂志

As an advanced concept in international pharmaceutical research,quality by design( QbD) can fulfill the strategic requirements of drug quality from testing to design. In this paper,the extraction process of Yanggong Prescription which was the modified Siwu Decoction was optimized based on QbD concept. With the extraction amount of solid matter,the content of ferulic acid and the content of paeoniflorin as critical quality attributes( CQAs),the failure mode and effect analysis( FMEA) was used to screen potential critical process parameters( p CPPs). The mathematical model was established by Box-Behnken experimental design to investigate the interaction between critical process parameters( CPPs) and CQAs. Then the design space for the extraction process of Yanggong Prescription was further established and optimized. Analysis of variance showed that the variance of all models was significant( P<0. 01),and the lack-of-fit value was not significant,indicating that the model was statistically significant. The relationship between various factors and the response values could be functionalized by the established models. Finally,through the optimization of the design space,the optimum extraction process of Yanggong Prescription was obtained as follows: 3 extraction times,122 minutes extraction,and 7 times of water adding. The extraction process of Yanggong Prescription based on the QbD concept was robust and reliable,which would provide guidance for the process development and quality control of its formulations.

Quantitative chromatographic fingerprint analysis of Sanye Tangzhiqing Decoction based on quality by design concept / 中国中药杂志

In this work,a high performance liquid chromatography-ultraviolet( HPLC-UV) detection technology was used to establish fingerprint analysis method for Sanye Tangzhiqing Decoction following an analytical quality by design( AQb D) approach. Firstly,column temperature,flow rate,and gradient elution conditions were determined as the method parameters needing to be optimized. Then according to the results of definitive screening design,three critical method attributes( CMAs) were identified,including peak number,the percentage of common peak area to total peak area,and retention time of the last peak. A stepwise regression method was used then to build quantitative models between CMAs and method parameters. Probability-based design space was calculated and successfully verified using the experimental error simulation method. After the analysis conditions were optimized,the contents of six components,namely chlorogenic acid,paeoniflorin,rutin,hyperoside,quercetin-3-O-β-D-glucuronide,and salvianolic acid B were simultaneously determined. There were 19 common peaks in the fingerprint and their common peak area accounted for 96% of the total peak area. Both fingerprint and quantitative analysis methods were validated applicable in methodology study,and they can be applied to determine new samples.

Research on extraction process of Digeda-4 flavored decoction based on QbD concept / 中国中药杂志

To establish and validate the design space of the Digeda-4 flavored decoction( DGD-4D) extraction process by using the quality by design( Qb D) concept. With DGD-4D decoction pieces as a model drug,with the transfer rate of aesculin,picroside I,picroside Ⅱ,geniposide and the yield of extract as critical quality attributes( CQAs),the single factor experiment design was used to determine the level of each factor; the Plackett-Burman experiment design was used to select the critical process parameters( CPPs);and the Box-Behnken experiment design was used to optimize the extraction process. The design space of the DGD-4D extraction process was established,and finally,four experimental points were selected to verify the established model. The single factor experiment determined the levels of each factor,including soaking time 60 min and 30 min,water adding volume 12 times and 8 times,extraction time 90 min and 30 min,number of extraction times 3 times and 1 time,as well as extraction temperature 100 ℃ and 90 ℃.By Plackett-Burman experimental design,the DGD-4D water addition,extraction time and number of extraction times were determined to be CPPs. The Box-Behnken experimental variance analysis showed that P of the regression model was less than 0. 01 and the misstated value was more than 0. 01,indicating that the model had good predictive ability,and the operation space of CPPs in the DGD-4D extraction process was determined as follows: the amount of water addition was 10-12 times; extraction time 50-80 min; and number of extraction times was 3 times. The design space of DGD-4D extraction process based on the concept of Qb D is conducive to improving the stability of product quality and laying a foundation for the future development of DGD-4D.

Design space method for optimizing extraction process of Carthami Flos / 中草药

Objective To establish and verify the design space for the extraction process of Carthami Flos (CF) based on the concept of quality by design (QbD). Methods The safflower was used as a model drug. The critical evaluation indicators were determined through literature and previous research experience. Fishbone diagram and Failure Mode Effect Analysis (FMEA) were carried out to determine the critical process parameters (CPPs). The mathematical models of CPPs and critical evaluation indicators were established using the Box-Behnken experimental design method. Results The critical evaluation indicators were the extraction amount of total flavonoid, hydroxysafflor yellow A (HSYA), and total solids. The water-adding amount, extraction temperature, extraction time, and extraction times were determined as the CPPs by the fishbone diagram and FMEA. The variance analysis results of Box-Behnken experiments showed that the P values of established models were less than 0.000 1, indicating that the models have good prediction ability. The recommended operating space were as follows: the extraction times were twice and 2.5 h for each time, the water-adding amount was 23.5-25 mL/g crude drug and the temperature was 65-71 ℃. Conclusion The establishing of design space for CF extraction improves the correlation between the extraction process parameters and extract quality, which provides a reference for the applicability of the design space approach in the field of CMM.

Multivariate modeling to evaluate effect of fabricating process on product profile of high shear granulation / 中草药·英文版

Objective: To investigate the feasibility of high shear granulation (HSG) for agglomeration of Crataegi Folium extract (Chinese edible herbal), and explore the effect of process variables on granule critical quality attributes (CQAs) by three different models, i.e., response surface methodology (RSM), multilayer perceptron neural networks (MLP), and partial least squares method (PLS). Methods: RSM, MLP, and PLS complementary to design of experiment (DoE) were utilized to investigate the influence of granulation time, impeller speed, and binder amount on the products. Crataegi Folium extract was employed as granulation powder. RSM was further carried out to develop design space of HSG. Results: The results indicated that RSM, MLP, and PLS modeling techniques enhanced the understanding and controlling of granules produced via HSG. The granule CQAs were mainly influenced by granulation time, impeller speed, and binder amount. Overlay plots of the RSM indicated that design space for the operating ranges of impeller speed and binder amount at high levels of granulation time was the smallest. Conclusion: The study showed that these models were useful to characterize the granulation process, and was particularly important to understand the process.

Quantitative analysis method of Shengxuebao Mixture by HPLC-UV-MS based on quality by design concept / 中国中药杂志

In this study, the HPLC-UV-MS method for the simultaneous determination of eight active ingredients of Shengxuebao Mixture were developed based on the concept of quality by design（QbD）with a stepwise optimization approach. After the analytical target profile（ATP）had been defined, albiflorin, paeoniflorin, 2, 3, 5, 4'-tetra-hydroxy-stilbene-2-O-β-D-glucopyranoside, specnuezhenide, ecliptasaponin D, emodin, calycosin-7-glucoside, and astragaloside Ⅳ were identified as the indicator components. The resolution and the signal-to-noise ratio of indicator components were then selected as critical method attributes (CMA) for the first step optimization. According to the results collected from fractional factorial design, critical method parameters (CMP) were determined with a multiple linear regression method, which included the amount of acid addition in the mobile phase, temperature, gradient, and wavelength. After that, the amount of acid addition and the wavelength were optimized to improve the resolution and the signal-to-noise ratio of the indicator components. The peak symmetry factors of specnuezhenide and emodin were then set as CMA for the second step optimization. The Box-Behnken designed experiments were conducted. The temperature and gradient were optimized after modelling. The design space were calculated and verified. The optimized analytical method was validated, and the results showed a good precision, accuracy and stability, which means that it can be used for the quantification of the indicator components in Shengxuebao Mixture.

Comparison of two algorithms for development of design space-overlapping method and probability-based method / 中国中药杂志

In this work, two algorithms (overlapping method and the probability-based method) for design space calculation were compared by using the data collected from extraction process of Codonopsis Radix as an example. In the probability-based method, experimental error was simulated to calculate the probability of reaching the standard. The effects of several parameters on the calculated design space were studied, including simulation number, step length, and the acceptable probability threshold. For the extraction process of Codonopsis Radix, 10 000 times of simulation and 0.02 for the calculation step length can lead to a satisfactory design space. In general, the overlapping method is easy to understand, and can be realized by several kinds of commercial software without coding programs, but the reliability of the process evaluation indexes when operating in the design space is not indicated. Probability-based method is complex in calculation, but can provide the reliability to ensure that the process indexes can reach the standard within the acceptable probability threshold. In addition, there is no probability mutation in the edge of design space by probability-based method. Therefore, probability-based method is recommended for design space calculation.

Optimize dropping process of Ginkgo biloba dropping pills by using design space approach / 中国中药杂志

In this paper, a design space approach was applied to optimize the dropping process of Ginkgo biloba dropping pills. Firstly, potential critical process parameters and potential process critical quality attributes were determined through literature research and pre-experiments. Secondly, experiments were carried out according to Box-Behnken design. Then the critical process parameters and critical quality attributes were determined based on the experimental results. Thirdly, second-order polynomial models were used to describe the quantitative relationships between critical process parameters and critical quality attributes. Finally, a probability-based design space was calculated and verified. The verification results showed that efficient production of Ginkgo biloba dropping pills can be guaranteed by operating within the design space parameters. The recommended operation ranges for the critical dropping process parameters of Ginkgo biloba dropping pills were as follows: dropping distance of 5.5-6.7 cm, and dropping speed of 59-60 drops per minute, providing a reference for industrial production of Ginkgo biloba dropping pills.

Study on spray drying technology of Fengke Granule based on QbD concept / 中草药

Objective: To establish and validate the design space of spray drying process of Fengke Granule using the concept of quality by design (QbD). Methods: Using Fengke Granule formula to extract the concentrated solution as model drug, the risk assessment and Plackeet-Burmann design on influence factors of screening, to determine the liquid inlet velocity and pressure of atomization is the critical process parameters. Then, the central composite design was used to optimize the key parameters and establish the process design space. Finally, four experimental points were selected to test the predictive power of the model. Results: Analysis of variance results showed that regression model P values were less than 0.01, which showed that the model had a good prediction, and the optimal range of key parameters of inlet velocity was determined and pressure of atomization were 11%-14% and 41.3-45.0 mmHg, the process parameters in this range could meet the target requirements. Conclusion: The design space of spray drying process is established based on QbD, which could improve the flexibility and stability of spray drying process, and provide reference for the pilot study in the future.