From a regulatory perspective,drug quality consistency evaluation must concern different processes used for the same drug.In this study,an assessment strategy based on quality by design(QbD)was developed for populatio...From a regulatory perspective,drug quality consistency evaluation must concern different processes used for the same drug.In this study,an assessment strategy based on quality by design(QbD)was developed for population pharmaceutical quality evaluation.A descriptive analysis method based on QbD concept was first established to characterize the process by critical evaluation attributes(CEAs).Then quantitative analysis method based on an improved statistical process control(SPC)method was established to investigate the process indicators(PIs)in the process population,such as mean distribution,batch-to-batch difference and abnormal quality probability.After that rules for risk assessment were established based on the SPC limitations and parameters.Both the SPC parameters of the CEAs and the risk of PIs were visualized according to the interaction test results to obtain a better understanding of the population pharmaceutical quality.Finally,an assessment strategy was built and applied to generic drug consistency assessment,process risk assessment and quality trend tracking.The strategy demonstrated in this study could help reveal quality consistency from the perspective of process control and process risk,and further show the recent development status of domestic pharmaceutical production processes.In addition,a process risk assessment and population quality trend tracking provide databased information for approval.Not only can this information serve as a further basis for decisionmaking by the regulatory authority regarding early warnings,but it can also reduce some avoidable adverse reactions.With continuous addition of data,dynamic population pharmaceutical quality is meaningful for emergencies and decision-making regarding drug regulation.展开更多
The study aims to prepare naproxen enteric-coated pellets(NAP-ECPs)by fluid-bed coating using QbD principle.Risk assessment was firstly performed by using failure mode and effect analysis(FMEA)methodology.A PlacketteB...The study aims to prepare naproxen enteric-coated pellets(NAP-ECPs)by fluid-bed coating using QbD principle.Risk assessment was firstly performed by using failure mode and effect analysis(FMEA)methodology.A PlacketteBurman design was then used for assessment of the most important variables affecting enteric-coated pellets characteristics.A BoxeBehnken design was subsequently used for investigating the main,interactive,and quadratic effects of these variables on the response.By FMEA we discovered that eight factors should be considered to be high/important risk variables as compared with others.The responses of acid resistance and cumulative drug release were taken as critical quality attributes(CQAs).Pareto ranking analyses indicated that the coating weight gain(X_(7)),triethyl citrate percentage(X_(1))and glycerol monostearate percentage(X_(2))were the most significant factors affecting the selected responses out of the eight high-risk variables.Optimization with response surface method(RSM)further fully clarified the relationship between X_(7),X_(1),X_(2) and CQAs,and design space was established based on the constraints set on the responses.Due to the extreme coincidence of the predicted value generated by model with the observed value,the accuracy and robustness of the model were confirmed.It could be concluded that a promising NAP-ECPs was successfully designed using QbD approach in a laboratory scale.展开更多
Objective This study aimed to design and optimize the water extraction process for Chuantieling(喘贴灵,CTL)based on the concept of quality by design(QbD).Methods The single-factor experiments were used to select the b...Objective This study aimed to design and optimize the water extraction process for Chuantieling(喘贴灵,CTL)based on the concept of quality by design(QbD).Methods The single-factor experiments were used to select the best experimental points of CTL water extraction.On this basis,the transfer rate of ephedrine hydrochloride and sin-apine thiocyanate,and the yield of the extract were evaluated as the evaluation indicators.The liquid-solid ratio,extraction time,and pH value were selected as the main factors to carry out the Box-Behnken design(BBD).A mathematical model of the critical process parameters(CPPs)and critical quality attributes(CQAs)was established,the interaction between CQAs and CPPs was examined,and the CTL extraction process design space was established and optimized,which guaranteed the stability of the process.The high performance liquid chro-matography(HPLC)was used to analyze the main active compounds in the CTL extract.Results Through single-factor experiments,the best experimental parameters were found to be a liquid-solid ratio of 8∶1,extraction time of 90 min,pH value of 4,and extraction times of three.The experimental variance analysis results of the BBD showed that the P value of the re-gression model was less than 0.05,and the lack-of-fit value was greater than 0.01,indicating that the constructed model had good predictive ability.The operating space of the CPPs of the CTL water extraction process was combined with the actual production situation.In the pro-duction situation,the best extraction process was nine times of water addition,72 min of ex-traction time,and 4.5 of pH value.The HPLC results showed that the peak areas of ephedrine hydrochloride,sinapine thiocyanate,tetrahydropalmatine,methyl eugenol,cinnamaldehyde,and 6-gingerol in the CTL extract accounted for 0.94%,14.32%,0.78%,31.23%,0.34%,and 0.44%of the total peak area,respectively.Conclusion The water extraction process design space of CTL based on QbD was conducive to actual production operations,ensuring the stability of the process.展开更多
Objective:Quality by design integration is exceedingly imperative for industries dealing with pharmaceuticals,but it diminishes product variability and delivers an extraordinary degree of assurance that the product wo...Objective:Quality by design integration is exceedingly imperative for industries dealing with pharmaceuticals,but it diminishes product variability and delivers an extraordinary degree of assurance that the product would achieve the purpose for which it was formulated.The objective of the manuscript is to strengthen the understanding of the design of experimentation approach from the primary level.Hence,this review paper aims to get one experience with a course emphasizing product quality during its development process.Methods:The present work describes how experimental statistical designs can optimize the process.It is a strategy to improve the manufacturing of products and discuss the main factors involved in the production.The review describes different designs,advantages,disadvantages and design of experiments requirements concerning regulatory submissions.Results:Quality by design encourages the pharmaceutical industry to deal with risk management and proper understanding of products and manufacturing processes,assuring a good quality product.Having knowledge of quality by design and design of experiments in the formulation and process development will be beneficial for the optimization of drug delivery systems in upcoming times.Conclusion:Implementing quality by design at different phases in pharmaceutical manufacturing,the final product with a great degree of reproducible quality may be assured,depending upon experimental data.This contains valuable information in guiding new researchers about the importance and ways of using the design of experiments.展开更多
The double salt of glucosamine sulfate sodium chloride(glucosamine-SP) is an important pharmaceuticals ingredient for healing osteoarthritis. However, the study about its industrial production is rarely documented, le...The double salt of glucosamine sulfate sodium chloride(glucosamine-SP) is an important pharmaceuticals ingredient for healing osteoarthritis. However, the study about its industrial production is rarely documented, let alone the optimization over the whole process to produce glucosamine-SP using glucosamine hydrochloride and anhydrous sodium sulfate as synthetic raw materials. In order to improve the production efficiency, this study screened the process parameters based on the concept of quality by design(QbD), optimized 13 operational parameters related to reaction and separation in the process, and finally proposed the mixed dropping process. The reaction conditions for the preparation of glucosamineSP were found as follows: the molar ratio of anhydrous sodium sulfate to glucosamine hydrochloride is 0.42, the mass ratio of water to glucosamine hydrochloride is is 2.0, the reaction temperature is 50 ℃ and the reaction time is 1 h. Through step-by-step scaling up following QbD, the mixed dropping process was successfully applied to achieve a trial production of 200 kg products satisfying national quality standards.In all, the results of this study have high technical value and guiding significance for the industrial mass production of glucosamine-SP.展开更多
The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients,intended for coated tablets preparation and further transfer to industrial scale.The work aimed to prove t...The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients,intended for coated tablets preparation and further transfer to industrial scale.The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy.Moreover,an in-line Near-Infrared monitoring method was developed,which offered a real time overview of the moisture level along the granulation process,thus a reliable supervision and control process analytical technology(PAT)tool.The experimental design’s results showed that the use of apparently interchangeable active pharmaceutical ingredients(APIs)and filler sorts that comply with pharmacopoeial specifications,lead to different end-product critical attributes.By adapting critical granulation parameters(i.e.binder spray rate and atomising pressure)as a function of material characteristics,led to granules with average sizes comprised in a narrow range of 280–320μm and low nongranulated fraction of under 5%.Therefore,the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability.To complete the Quality by design(QbD)strategy,despite its limited spectral domain,the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process.展开更多
Over the recent few decades,many groups of formulation scientists are concentrating on rapid release dosage forms in oral cavity.Among all fast release dosage forms,orodispersible films are successful to attract pharm...Over the recent few decades,many groups of formulation scientists are concentrating on rapid release dosage forms in oral cavity.Among all fast release dosage forms,orodispersible films are successful to attract pharmaceutical industry due to ease of formulation and extension patent life.Films are popular in patients too because of quick onset and user friendliness of dosage form.From the beginning,solvent casting has been selected as method of choice for manufacturing of orodispersible films.Solvent casting has been proved as a benchmark technology because of ease in product development,process optimization,process validation and technology transfer to production scale despite of some drawbacks like more number of unit operations involved and consumption of large quantity of solvents with controlled limits of organic volatile impurities in final formulation.The application of hot-melt extrusion(HME)in the pharmaceutical industry is consecutively increasing due to its proven innumerable advantages like solvent free continuous process with fewer unit operations and better content uniformity.Very few development activities has been initiated in the field of hot melt extruded orodispersible films so far.This extensive review covers detailed discussion of heavy duty industrial extruders,selection of downstream equipments,selection of excipients,common problems found in formulations and their remedies.Successive part of review addresses identification of critical quality attributes,quality target profile of product,criticality in selection of process parameters and material for substantial simulation in laboratory scale and production for successful technology transfer.展开更多
The concept of Quality by Design was demonstrated in the development of a stability-indicating assay and related substances method by HPLC for Dabigatran Etexilate Capsules dosage form. Method design, method evaluatio...The concept of Quality by Design was demonstrated in the development of a stability-indicating assay and related substances method by HPLC for Dabigatran Etexilate Capsules dosage form. Method design, method evaluation, method control and life cycle management were explained by systematic flow chart. Analytical Target Product profile was defined. The method was developed using the Inertsil ODS-3V, 150 mm × 4.6 mm, 5 μm column using the gradient program with ammonium formate buffer as mobile phase A and acetonitrile as mobile phase B. Risk assessment was performed as part of method evaluation. Design of experiment tools was used to optimize the chromatographic conditions. A two-level Full Factorial Design along with Face Centered Central Composite design augmentation was employed and statistical analysis of the experimental data uncovered the significant influential of chromatographic factors. The design space and the contour plot suggest that the current center point parameters can be further modified, resulting in better acceptability of the response parameters. The performance of the optimized method was validated according to current ICH guidelines. Dabigatran Etexilate Capsules was subjected to various stress conditions like oxidative, acid, base, hydrolytic, thermal, humidity, and photolytic degradations and evaluated chromatograms at 220 nm. The degradation products were well separated from each other and main peak, demonstrating the stability-indicating power of the method. One of the major degradant impurities, which are forming in neutral hydrolysis stress condition, is isolated and characterized by using analytical techniques like IR, LC-MS and NMR. Degradation pathway for Dabigatran Etexilate was proposed based on forced degradation data along with reaction mechanism.展开更多
In recent times, the overall interest over Supercritical Fluid Chromatography (SFC) is truly growing within various domains but especially for pharmaceutical analysis. However, in the best of our knowledge modern SFC ...In recent times, the overall interest over Supercritical Fluid Chromatography (SFC) is truly growing within various domains but especially for pharmaceutical analysis. However, in the best of our knowledge modern SFC is not yet applied for drug quality control in the daily routine framework. Among the numerous reported SFC methods, none of them could be found to fully satisfy to all steps of the analytical method lifecycle. Thereby, the present contribution aims to provide an overview of the current and past achievements related to SFC techniques, with a targeted attention to this lifecycle and its successive steps. The included discussions were therefore structured accordingly and emphasizing the analytical method lifecycle in accord with the International Conference on Harmonisation (ICH). Recent and important scientific outputs in the field of analytical SFC, as well as instrumental evolution, qualification strategies, method development methodologies and discussions on the topic of method validation are reviewed.展开更多
Coptis chinensis(Huanglian) is a commonly used traditional Chinese medicine(TCM) herb and alkaloids are the most important chemical constituents in it. In the present study, an isocratic reverse phase high performance...Coptis chinensis(Huanglian) is a commonly used traditional Chinese medicine(TCM) herb and alkaloids are the most important chemical constituents in it. In the present study, an isocratic reverse phase high performance liquid chromatography(RP-HPLC) method allowing the separation of six alkaloids in Huanglian was for the first time developed under the quality by design(Qb D) principles. First, five chromatographic parameters were identified to construct a Plackett-Burman experimental design. The critical resolution, analysis time, and peak width were responses modeled by multivariate linear regression. The results showed that the percentage of acetonitrile, concentration of sodium dodecyl sulfate, and concentration of potassium phosphate monobasic were statistically significant parameters(P < 0.05). Then, the Box-Behnken experimental design was applied to further evaluate the interactions between the three parameters on selected responses. Full quadratic models were built and used to establish the analytical design space. Moreover, the reliability of design space was estimated by the Bayesian posterior predictive distribution. The optimal separation was predicted at 40% acetonitrile, 1.7 g·m L-1of sodium dodecyl sulfate and 0.03 mol·m L-1 of potassium phosphate monobasic. Finally, the accuracy profile methodology was used to validate the established HPLC method. The results demonstrated that the Qb D concept could be efficiently used to develop a robust RP-HPLC analytical method for Huanglian.展开更多
Compared with traditional drug therapy,nanomedicines exhibit intriguing biological features to increase therapeutic efficiency,reduce toxicity and achieve targeting delivery.This review provides a snapshot of nanomedi...Compared with traditional drug therapy,nanomedicines exhibit intriguing biological features to increase therapeutic efficiency,reduce toxicity and achieve targeting delivery.This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials,which manifests a diversified trend in carrier types,applied indications and mechanisms of action.From the perspective of indications,this article presents an overview of the applications of nanomedicines involving the prevention,diagnosis and treatment of various diseases,which include cancer,infections,blood disorders,cardiovascular diseases,immuno-associated diseases and nervous system diseases,etc.Moreover,the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.展开更多
Scale-up of the high shear wet granulation （HSWG） process is considered a challenge because HSWG is complex and influenced by numerous factors, including equipment, formulation, and process variables. For a system o...Scale-up of the high shear wet granulation （HSWG） process is considered a challenge because HSWG is complex and influenced by numerous factors, including equipment, formulation, and process variables. For a system of microcrystalline cellulose and water, HSWG experiments at three scales （1, 2, and 4 L working vessel） were conducted with a granulator. Scale-up was implemented on the basis of a nucleation regime map approach. To keep dimensionless spray flux and drop penetration time constant, water addition time at three processing scales were 300, 442, and 700 s, respectively. The other process parameters were kept unchanged. Granule size distributions were plotted and compared, and scanning electron microscopy was used to analyze granule surface morphology. Physical characterization was undertaken using a modified SeDeM method. At nearly all scales, granule yield was greater than 85% and all the cosine values were larger than 0.89. At the same experiment points, granules at all scales had similar surface morphology and similar physical characteristics. The results demonstrate that a rational scaling-up of the HSWG process is feasible using a regime map approach.展开更多
基金The National Major Scientific and Technological Special Project for‘Significant New Drugs Development’(Grant No.:2017ZX0901001-007)provides support for this study.
文摘From a regulatory perspective,drug quality consistency evaluation must concern different processes used for the same drug.In this study,an assessment strategy based on quality by design(QbD)was developed for population pharmaceutical quality evaluation.A descriptive analysis method based on QbD concept was first established to characterize the process by critical evaluation attributes(CEAs).Then quantitative analysis method based on an improved statistical process control(SPC)method was established to investigate the process indicators(PIs)in the process population,such as mean distribution,batch-to-batch difference and abnormal quality probability.After that rules for risk assessment were established based on the SPC limitations and parameters.Both the SPC parameters of the CEAs and the risk of PIs were visualized according to the interaction test results to obtain a better understanding of the population pharmaceutical quality.Finally,an assessment strategy was built and applied to generic drug consistency assessment,process risk assessment and quality trend tracking.The strategy demonstrated in this study could help reveal quality consistency from the perspective of process control and process risk,and further show the recent development status of domestic pharmaceutical production processes.In addition,a process risk assessment and population quality trend tracking provide databased information for approval.Not only can this information serve as a further basis for decisionmaking by the regulatory authority regarding early warnings,but it can also reduce some avoidable adverse reactions.With continuous addition of data,dynamic population pharmaceutical quality is meaningful for emergencies and decision-making regarding drug regulation.
基金This study is financially supported by the major project of National College Students Innovation Project for the R&D of Novel Drugs(No.J1030830).
文摘The study aims to prepare naproxen enteric-coated pellets(NAP-ECPs)by fluid-bed coating using QbD principle.Risk assessment was firstly performed by using failure mode and effect analysis(FMEA)methodology.A PlacketteBurman design was then used for assessment of the most important variables affecting enteric-coated pellets characteristics.A BoxeBehnken design was subsequently used for investigating the main,interactive,and quadratic effects of these variables on the response.By FMEA we discovered that eight factors should be considered to be high/important risk variables as compared with others.The responses of acid resistance and cumulative drug release were taken as critical quality attributes(CQAs).Pareto ranking analyses indicated that the coating weight gain(X_(7)),triethyl citrate percentage(X_(1))and glycerol monostearate percentage(X_(2))were the most significant factors affecting the selected responses out of the eight high-risk variables.Optimization with response surface method(RSM)further fully clarified the relationship between X_(7),X_(1),X_(2) and CQAs,and design space was established based on the constraints set on the responses.Due to the extreme coincidence of the predicted value generated by model with the observed value,the accuracy and robustness of the model were confirmed.It could be concluded that a promising NAP-ECPs was successfully designed using QbD approach in a laboratory scale.
基金Hunan University of Traditional Chinese Medicine Graduate Training Quality Engineering Project(2019CX57)the First-class Discipline Project on Chinese Pharmacology of Hunan University of Chinese Medicine (201803)。
文摘Objective This study aimed to design and optimize the water extraction process for Chuantieling(喘贴灵,CTL)based on the concept of quality by design(QbD).Methods The single-factor experiments were used to select the best experimental points of CTL water extraction.On this basis,the transfer rate of ephedrine hydrochloride and sin-apine thiocyanate,and the yield of the extract were evaluated as the evaluation indicators.The liquid-solid ratio,extraction time,and pH value were selected as the main factors to carry out the Box-Behnken design(BBD).A mathematical model of the critical process parameters(CPPs)and critical quality attributes(CQAs)was established,the interaction between CQAs and CPPs was examined,and the CTL extraction process design space was established and optimized,which guaranteed the stability of the process.The high performance liquid chro-matography(HPLC)was used to analyze the main active compounds in the CTL extract.Results Through single-factor experiments,the best experimental parameters were found to be a liquid-solid ratio of 8∶1,extraction time of 90 min,pH value of 4,and extraction times of three.The experimental variance analysis results of the BBD showed that the P value of the re-gression model was less than 0.05,and the lack-of-fit value was greater than 0.01,indicating that the constructed model had good predictive ability.The operating space of the CPPs of the CTL water extraction process was combined with the actual production situation.In the pro-duction situation,the best extraction process was nine times of water addition,72 min of ex-traction time,and 4.5 of pH value.The HPLC results showed that the peak areas of ephedrine hydrochloride,sinapine thiocyanate,tetrahydropalmatine,methyl eugenol,cinnamaldehyde,and 6-gingerol in the CTL extract accounted for 0.94%,14.32%,0.78%,31.23%,0.34%,and 0.44%of the total peak area,respectively.Conclusion The water extraction process design space of CTL based on QbD was conducive to actual production operations,ensuring the stability of the process.
文摘Objective:Quality by design integration is exceedingly imperative for industries dealing with pharmaceuticals,but it diminishes product variability and delivers an extraordinary degree of assurance that the product would achieve the purpose for which it was formulated.The objective of the manuscript is to strengthen the understanding of the design of experimentation approach from the primary level.Hence,this review paper aims to get one experience with a course emphasizing product quality during its development process.Methods:The present work describes how experimental statistical designs can optimize the process.It is a strategy to improve the manufacturing of products and discuss the main factors involved in the production.The review describes different designs,advantages,disadvantages and design of experiments requirements concerning regulatory submissions.Results:Quality by design encourages the pharmaceutical industry to deal with risk management and proper understanding of products and manufacturing processes,assuring a good quality product.Having knowledge of quality by design and design of experiments in the formulation and process development will be beneficial for the optimization of drug delivery systems in upcoming times.Conclusion:Implementing quality by design at different phases in pharmaceutical manufacturing,the final product with a great degree of reproducible quality may be assured,depending upon experimental data.This contains valuable information in guiding new researchers about the importance and ways of using the design of experiments.
基金supported by the Science and Technology Program of Xiamen, China (No. 3502Z20173018)。
文摘The double salt of glucosamine sulfate sodium chloride(glucosamine-SP) is an important pharmaceuticals ingredient for healing osteoarthritis. However, the study about its industrial production is rarely documented, let alone the optimization over the whole process to produce glucosamine-SP using glucosamine hydrochloride and anhydrous sodium sulfate as synthetic raw materials. In order to improve the production efficiency, this study screened the process parameters based on the concept of quality by design(QbD), optimized 13 operational parameters related to reaction and separation in the process, and finally proposed the mixed dropping process. The reaction conditions for the preparation of glucosamineSP were found as follows: the molar ratio of anhydrous sodium sulfate to glucosamine hydrochloride is 0.42, the mass ratio of water to glucosamine hydrochloride is is 2.0, the reaction temperature is 50 ℃ and the reaction time is 1 h. Through step-by-step scaling up following QbD, the mixed dropping process was successfully applied to achieve a trial production of 200 kg products satisfying national quality standards.In all, the results of this study have high technical value and guiding significance for the industrial mass production of glucosamine-SP.
基金This work was supported by the Romanian National Authority for Scientific Research and Innovation,CNCS-UEFISCDI[project number PN-III-P2-2.1-BG-2016-0201].
文摘The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients,intended for coated tablets preparation and further transfer to industrial scale.The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy.Moreover,an in-line Near-Infrared monitoring method was developed,which offered a real time overview of the moisture level along the granulation process,thus a reliable supervision and control process analytical technology(PAT)tool.The experimental design’s results showed that the use of apparently interchangeable active pharmaceutical ingredients(APIs)and filler sorts that comply with pharmacopoeial specifications,lead to different end-product critical attributes.By adapting critical granulation parameters(i.e.binder spray rate and atomising pressure)as a function of material characteristics,led to granules with average sizes comprised in a narrow range of 280–320μm and low nongranulated fraction of under 5%.Therefore,the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability.To complete the Quality by design(QbD)strategy,despite its limited spectral domain,the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process.
文摘Over the recent few decades,many groups of formulation scientists are concentrating on rapid release dosage forms in oral cavity.Among all fast release dosage forms,orodispersible films are successful to attract pharmaceutical industry due to ease of formulation and extension patent life.Films are popular in patients too because of quick onset and user friendliness of dosage form.From the beginning,solvent casting has been selected as method of choice for manufacturing of orodispersible films.Solvent casting has been proved as a benchmark technology because of ease in product development,process optimization,process validation and technology transfer to production scale despite of some drawbacks like more number of unit operations involved and consumption of large quantity of solvents with controlled limits of organic volatile impurities in final formulation.The application of hot-melt extrusion(HME)in the pharmaceutical industry is consecutively increasing due to its proven innumerable advantages like solvent free continuous process with fewer unit operations and better content uniformity.Very few development activities has been initiated in the field of hot melt extruded orodispersible films so far.This extensive review covers detailed discussion of heavy duty industrial extruders,selection of downstream equipments,selection of excipients,common problems found in formulations and their remedies.Successive part of review addresses identification of critical quality attributes,quality target profile of product,criticality in selection of process parameters and material for substantial simulation in laboratory scale and production for successful technology transfer.
文摘The concept of Quality by Design was demonstrated in the development of a stability-indicating assay and related substances method by HPLC for Dabigatran Etexilate Capsules dosage form. Method design, method evaluation, method control and life cycle management were explained by systematic flow chart. Analytical Target Product profile was defined. The method was developed using the Inertsil ODS-3V, 150 mm × 4.6 mm, 5 μm column using the gradient program with ammonium formate buffer as mobile phase A and acetonitrile as mobile phase B. Risk assessment was performed as part of method evaluation. Design of experiment tools was used to optimize the chromatographic conditions. A two-level Full Factorial Design along with Face Centered Central Composite design augmentation was employed and statistical analysis of the experimental data uncovered the significant influential of chromatographic factors. The design space and the contour plot suggest that the current center point parameters can be further modified, resulting in better acceptability of the response parameters. The performance of the optimized method was validated according to current ICH guidelines. Dabigatran Etexilate Capsules was subjected to various stress conditions like oxidative, acid, base, hydrolytic, thermal, humidity, and photolytic degradations and evaluated chromatograms at 220 nm. The degradation products were well separated from each other and main peak, demonstrating the stability-indicating power of the method. One of the major degradant impurities, which are forming in neutral hydrolysis stress condition, is isolated and characterized by using analytical techniques like IR, LC-MS and NMR. Degradation pathway for Dabigatran Etexilate was proposed based on forced degradation data along with reaction mechanism.
文摘In recent times, the overall interest over Supercritical Fluid Chromatography (SFC) is truly growing within various domains but especially for pharmaceutical analysis. However, in the best of our knowledge modern SFC is not yet applied for drug quality control in the daily routine framework. Among the numerous reported SFC methods, none of them could be found to fully satisfy to all steps of the analytical method lifecycle. Thereby, the present contribution aims to provide an overview of the current and past achievements related to SFC techniques, with a targeted attention to this lifecycle and its successive steps. The included discussions were therefore structured accordingly and emphasizing the analytical method lifecycle in accord with the International Conference on Harmonisation (ICH). Recent and important scientific outputs in the field of analytical SFC, as well as instrumental evolution, qualification strategies, method development methodologies and discussions on the topic of method validation are reviewed.
基金supported by National Natural Science Foundation of China(No.81403112)Beijing Natural Science Foundation(No.7154217)+1 种基金Scientific Research Program of Beijing University of Chinese Medicine(No.2015-JYB-XS104)Special Program for Beijing Key Laboratory of Chinese Medicine Manufacturing Process Control and Quality Evaluation(No.Z151100001615065)
文摘Coptis chinensis(Huanglian) is a commonly used traditional Chinese medicine(TCM) herb and alkaloids are the most important chemical constituents in it. In the present study, an isocratic reverse phase high performance liquid chromatography(RP-HPLC) method allowing the separation of six alkaloids in Huanglian was for the first time developed under the quality by design(Qb D) principles. First, five chromatographic parameters were identified to construct a Plackett-Burman experimental design. The critical resolution, analysis time, and peak width were responses modeled by multivariate linear regression. The results showed that the percentage of acetonitrile, concentration of sodium dodecyl sulfate, and concentration of potassium phosphate monobasic were statistically significant parameters(P < 0.05). Then, the Box-Behnken experimental design was applied to further evaluate the interactions between the three parameters on selected responses. Full quadratic models were built and used to establish the analytical design space. Moreover, the reliability of design space was estimated by the Bayesian posterior predictive distribution. The optimal separation was predicted at 40% acetonitrile, 1.7 g·m L-1of sodium dodecyl sulfate and 0.03 mol·m L-1 of potassium phosphate monobasic. Finally, the accuracy profile methodology was used to validate the established HPLC method. The results demonstrated that the Qb D concept could be efficiently used to develop a robust RP-HPLC analytical method for Huanglian.
基金Financial supports by the National Natural Science Foundation of China(32071385,31771092,31930066)Shandong Provincial Natural Science Foundation of China(ZR2019ZD25)Fudan-SIMM Joint Research Fund(FU-SIMM20182005,China)。
文摘Compared with traditional drug therapy,nanomedicines exhibit intriguing biological features to increase therapeutic efficiency,reduce toxicity and achieve targeting delivery.This review provides a snapshot of nanomedicines that have been currently launched or in the clinical trials,which manifests a diversified trend in carrier types,applied indications and mechanisms of action.From the perspective of indications,this article presents an overview of the applications of nanomedicines involving the prevention,diagnosis and treatment of various diseases,which include cancer,infections,blood disorders,cardiovascular diseases,immuno-associated diseases and nervous system diseases,etc.Moreover,the review provides some considerations and perspectives in the research and development of nanomedicines to facilitate their translations in clinic.
基金The authors acknowledge research funding support from the Beijing Natural Science Foundation of China： study on the dimensionless modeling of high shear wet granulation process for Tanshinone extract （No. 7154217）, joint development program funding from the Beijing Municipal Education Commission of China （Key Laboratory Construction Project： study on the integrated modeling and optimization technology of the pharmaceutical process of Chinese medicine preparations）, and the program funding from the National Natural Science Foundation of China： study on the quality transfer model and global optimization method of the chained pharmaceutical process of Chinese medicine products （No. B1403112）.
文摘Scale-up of the high shear wet granulation （HSWG） process is considered a challenge because HSWG is complex and influenced by numerous factors, including equipment, formulation, and process variables. For a system of microcrystalline cellulose and water, HSWG experiments at three scales （1, 2, and 4 L working vessel） were conducted with a granulator. Scale-up was implemented on the basis of a nucleation regime map approach. To keep dimensionless spray flux and drop penetration time constant, water addition time at three processing scales were 300, 442, and 700 s, respectively. The other process parameters were kept unchanged. Granule size distributions were plotted and compared, and scanning electron microscopy was used to analyze granule surface morphology. Physical characterization was undertaken using a modified SeDeM method. At nearly all scales, granule yield was greater than 85% and all the cosine values were larger than 0.89. At the same experiment points, granules at all scales had similar surface morphology and similar physical characteristics. The results demonstrate that a rational scaling-up of the HSWG process is feasible using a regime map approach.
