The assessment of in situ permeability of rock mass is challenging for large-scale projects such as reservoirs created by dams,where water tightness issues are of prime importance.The in situ permeability is strongly ...The assessment of in situ permeability of rock mass is challenging for large-scale projects such as reservoirs created by dams,where water tightness issues are of prime importance.The in situ permeability is strongly related to the frequency and distribution of discontinuities in the rock mass and quantified by rock quality designation(RQD).This paper analyzes the data of hydraulic conductivity and discontinuities sampled at different depths during the borehole investigations in the limestone and sandstone formations for the construction of hydraulic structures in Oman.Cores recovered from boreholes provide RQD data,and in situ Lugeon tests elucidate the permeability.A modern technique of multivariate adaptive regression splines(MARS)assisted in correlating permeability and RQD along with the depth.In situ permeability shows a declining trend with increasing RQD,and the depth of investigation is within 50 m.This type of relationship can be developed based on detailed initial investigations at the site where the hydraulic conductivity of discontinuous rocks is required to be delineated.The relationship can approximate the permeability by only measuring the RQD in later investigations on the same site,thus saving the time and cost of the site investigations.The applicability of the relationship developed in this study to another location requires a lithological similarity of the rock mass that can be verified through preliminary investigation at the site.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
Rock quality designation(RQD)has been considered as a one-dimensional jointing degree property since it should be determined by measuring the core lengths obtained from drilling.Anisotropy index of jointing degree(AI_...Rock quality designation(RQD)has been considered as a one-dimensional jointing degree property since it should be determined by measuring the core lengths obtained from drilling.Anisotropy index of jointing degree(AI_(jd))was formulated by Zheng et al.(2018)by considering maximum and minimum values of RQD for a jointed rock medium in three-dimensional space.In accordance with spacing terminology by ISRM(1981),defining the jointing degree for the rock masses composed of extremely closely spaced joints as well as for the rock masses including widely to extremely widely spaced joints is practically impossible because of the use of 10 cm as a threshold value in the conventional form of RQD.To overcome this limitation,theoretical RQD(TRQD_(t))introduced by Priest and Hudson(1976)can be taken into consideration only when the statistical distribution of discontinuity spacing has a negative exponential distribution.Anisotropy index of the jointing degree was improved using TRQD_(t) which was adjusted to wider joint spacing by considering Priest(1993)’s recommendation on the use of variable threshold value(t)in TRQD_(t) formulation.After applications of the improved anisotropy index of a jointing degree(AI'_(jd))to hypothetical jointed rock mass cases,the effect of persistency of joints on structural anisotropy of rock mass was introduced to the improved AI'_(jd) formulation by considering the ratings of persistency of joints as proposed by Bieniawski(1989)’s rock mass rating(RMR)classification.Two real cases were assessed in the stratified marl and the columnar basalt using the weighted anisotropy index of jointing degree(W_AI'_(jd)).A structural anisotropy classification was developed using the RQD classification proposed by Deere(1963).The proposed methodology is capable of defining the structural anisotropy of a rock mass including joint pattern from extremely closely to extremely widely spaced joints.展开更多
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
Northwest Electric Power Design Institute (NWEPDI)was established in 1956. The institute undertakes the engineering exploration, survey and design of thermal electric power plant, conventional island of nuclear power ...Northwest Electric Power Design Institute (NWEPDI)was established in 1956. The institute undertakes the engineering exploration, survey and design of thermal electric power plant, conventional island of nuclear power plant, power transmission and substation projects, design of the 1st and 2nd class pressure vessels, electric power system planning, environmental protection engineering monitoring, assessment and design, various industrial and civil architectural design and the scicntific research and technical development tasks of corresponding specialities. The institute展开更多
The Qilian Mountain permafrost area located in the northern of Qinghai-Tibet Plateau is a favorable place for natural gas hydrate formation and enrichment,due to its well-developed fractures and abundant gas sources.U...The Qilian Mountain permafrost area located in the northern of Qinghai-Tibet Plateau is a favorable place for natural gas hydrate formation and enrichment,due to its well-developed fractures and abundant gas sources.Understanding the formation and distribution of multi-component gas hydrates in fractures is crucial in accurately evaluating the hydrate reservoir resources in this area.The hydrate formation experiments were carried out using the core samples drilled from hydrate-bearing sediments in Qilian Mountain permafrost area and the multi-component gas with similar composition to natural gas hydrates in Qilian Mountain permafrost area.The formation and distribution characteristics of multi-component gas hydrates in core samples were observed in situ by X-ray Computed Tomography(X-CT)under high pressure and low temperature conditions.Results show that hydrates are mainly formed and distributed in the fractures with good connectivity.The ratios of volume of hydrates formed in fractures to the volume of fractures are about 96.8%and 60.67%in two different core samples.This indicates that the fracture surface may act as a favorable reaction site for hydrate formation in core samples.Based on the field geological data and the experimental results,it is preliminarily estimated that the inventory of methane stored in the fractured gas hydrate in Qilian Mountain permafrost area is about 8.67×1013 m3,with a resource abundance of 8.67×108 m3/km2.This study demonstrates the great resource potential of fractured gas hydrate and also provides a new way to further understand the prospect of natural gas hydrate and other oil and gas resources in Qilian Mountain permafrost area.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
In th is study, a n e w m odel w as p re se n te d for com p u tin g stre n g th o f rock m asses based u p o n in -situo bservations o f RQD p o pularly kno w n as rock quality d esignation. This m odel links u p th ...In th is study, a n e w m odel w as p re se n te d for com p u tin g stre n g th o f rock m asses based u p o n in -situo bservations o f RQD p o pularly kno w n as rock quality d esignation. This m odel links u p th e rock m assp aram eters from in -situ investigations w ith th e stre n g th p a ram eters o f jo in ted rocks obtain ed fromlaboratory scale ex p erim en tal observations. Using th e co n stitu tiv e relation, th e a u th o r derived a p ressu reand d am age sensitive plastic p a ra m e te r to d ete rm in e stre n g th o f rock m asses for varied ex te n ts ofd isco n tin u ity an d p ressu re induced dam age. The te s t results show th a t plasticity characterized byhard en in g an d softening inclusive o f dam ag e invariably d e p en d s u p o n m ean p ressu re an d e x te n t ofdefo rm atio n s alread y experien ced by rock m asses. The p re se n t w ork explores th e te s t d a ta th a t revealth e d ep en d en c e o f in -situ stren g th on increm ental jo in t p ara m e te rs o b tain ed from th e jo in t num ber,jo in t orien tatio n , jo in t roughness, gouge p a ram eters an d w a te r pressure. S ubstituting th e relationshipb e tw e e n th e RQD and m odified jo in t factor w ith th a t b e tw e e n m odulus ratio an d stren g th ratio, th em odel show s successfully th a t using d am age inclusive plastic p a ra m e te r an d RQD provides a relationshipfor estim atin g th e stre n g th o f rock m asses. One o f th e m ain objectives o f this w ork is to illustrate th a t th ep re se n t m odel is sensitive to p la s tic ity a n d dam ag e to g e th e r in estim atin g in -situ stre n g th o f rock m assesin foundations, u n d e rg ro u n d excavation an d tunnels.展开更多
In the recent decades, effects of blast loads on natural and man-made structures have gained considerable attention due to increase in threat from various man-made activities. Site-specific empirical relationships for...In the recent decades, effects of blast loads on natural and man-made structures have gained considerable attention due to increase in threat from various man-made activities. Site-specific empirical relationships for calculation of blast-induced vibration parameters like peak particle velocity (PPV) and peak particle displacement (PPD) are commonly used for estimation of blast loads in design. However, these relation- ships are not able to consider the variation in rock parameters and uncertainty of in situ conditions. In this paper, a total of 1089 published blast data of various researchers in different rock sites have been collected and used to propose generalized empirical model for PPV by considering the effects of rock parameters like unit weight, rock quality designation (ROD), geological strength index (GSI), and uniaxial compressive strength (UCS). The proposed PPV model has a good correlation coefficient and hence it can be directly used in prediction of blast-induced vibrations in rocks. Standard errors and coefficient of correlations of the predicted blast-induced vibration parameters are obtained with respect to the observed field data. The proposed empirical model for PPV has also been compared with the empirical models available for blast vibrations predictions given by other researchers and found to be in good agreement with specific cases.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
Global concerns toward environmental issues have induced growing demand for new approaches in the construction because of its considerable impact on the environment and use of natural resources. Through using construc...Global concerns toward environmental issues have induced growing demand for new approaches in the construction because of its considerable impact on the environment and use of natural resources. Through using construction sustainability tools, methods and techniques, a greener design can be applied during various building phases. In this connection, it is argued that the analytical and integrated models applied by Building Information Modelling (BIM) may also facilitate this process to be performed more efficiently. BIM and construction sustainability are quite different initiatives, but both have received much attention in recent years in the architecture, engineering and construction (AEC) industry. A rigorous analysis of the interactions between them implies that a synergy exists which, if properly it is understood that can be helpful to reduce the environmental impacts of the AEC industry. A BIM-based design model can contribute to sustainability through its three main dimensions which are environmental, economic and social. In this paper, by reviewing the existing literature on BIM and construction sustainability and using a matrix to analyze construction sustainability dimensions and BIM functionalities a number of interactions have been discussed. It can be concluded that despite there are many improvements in implementation of BIM in environmental and economic aspects of sustainability, its potential impact on social dimension has not been explicitly explored hence further studies need to be undertaken in this area.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
The aim of this study is to identify and analyze ways to increase usage of destination website and motivate website visitors’intention to actually visit the destination.The sample population is South Koreans who visi...The aim of this study is to identify and analyze ways to increase usage of destination website and motivate website visitors’intention to actually visit the destination.The sample population is South Koreans who visit the VisitBritain website,the homepage of Britain’s national tourism agency.The data for this study were collected by a self-participated online survey on the blog of VisitBritain Korea,which is directly linked to the VisitBritain Korea website.Using structural equation modeling,six hypotheses were tested.The results show that the destination image on the destination marketing organization(DMO)website,quality of the destination website design including three dimensions(information quality,system quality,and service quality),and customers’satisfaction formed by high quality of the website design have a significant impact on website visitors’use intention and increase their visiting intention to the destination.Based upon the results of the analysis,managerial implications and areas for future research are proposed.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
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
Animal studies play a vital role in validating the concept,feasibility,safety,performance and efficacy of biomaterials products during their bench-to-clinic translation.This article aims to share regulatory considerat...Animal studies play a vital role in validating the concept,feasibility,safety,performance and efficacy of biomaterials products during their bench-to-clinic translation.This article aims to share regulatory considerations for animal studies of biomaterial products.After briefly emphasizing the importance of animal studies,issues of animal studies during biomaterial products’translation are discussed.Animal studies with unclear purposes,flawed design and poor reporting quality could significantly reduce the translation efficiency and create regulatory challenges.Regulatory perspectives on the purpose,principle,quality and regulatory science of animal studies are also presented.Animal studies should have clear purposes,follow principles of 3R+DQ(replacement,reduction,refinement,design and quality)and execute under an efficiently operating quality management system.With the advancement of regulatory science,National Medical Products Administration of China has been developing a series of standards and guidance documents on animal studies of medical devices.Case studies of making decisions on whether to conduct animal studies are provided in the end with drug-eluting stents as examples.In summary,animal studies of biomaterial products should pay close attention to the rationale,design and quality in order to achieve their purposes.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indebted to the Sohar University and the University of Buraimi, Oman, to support this study
文摘The assessment of in situ permeability of rock mass is challenging for large-scale projects such as reservoirs created by dams,where water tightness issues are of prime importance.The in situ permeability is strongly related to the frequency and distribution of discontinuities in the rock mass and quantified by rock quality designation(RQD).This paper analyzes the data of hydraulic conductivity and discontinuities sampled at different depths during the borehole investigations in the limestone and sandstone formations for the construction of hydraulic structures in Oman.Cores recovered from boreholes provide RQD data,and in situ Lugeon tests elucidate the permeability.A modern technique of multivariate adaptive regression splines(MARS)assisted in correlating permeability and RQD along with the depth.In situ permeability shows a declining trend with increasing RQD,and the depth of investigation is within 50 m.This type of relationship can be developed based on detailed initial investigations at the site where the hydraulic conductivity of discontinuous rocks is required to be delineated.The relationship can approximate the permeability by only measuring the RQD in later investigations on the same site,thus saving the time and cost of the site investigations.The applicability of the relationship developed in this study to another location requires a lithological similarity of the rock mass that can be verified through preliminary investigation at the site.
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supports from the General Directorate of ETIMADEN enterprises during the field studies at Simav open pit mine。
文摘Rock quality designation(RQD)has been considered as a one-dimensional jointing degree property since it should be determined by measuring the core lengths obtained from drilling.Anisotropy index of jointing degree(AI_(jd))was formulated by Zheng et al.(2018)by considering maximum and minimum values of RQD for a jointed rock medium in three-dimensional space.In accordance with spacing terminology by ISRM(1981),defining the jointing degree for the rock masses composed of extremely closely spaced joints as well as for the rock masses including widely to extremely widely spaced joints is practically impossible because of the use of 10 cm as a threshold value in the conventional form of RQD.To overcome this limitation,theoretical RQD(TRQD_(t))introduced by Priest and Hudson(1976)can be taken into consideration only when the statistical distribution of discontinuity spacing has a negative exponential distribution.Anisotropy index of the jointing degree was improved using TRQD_(t) which was adjusted to wider joint spacing by considering Priest(1993)’s recommendation on the use of variable threshold value(t)in TRQD_(t) formulation.After applications of the improved anisotropy index of a jointing degree(AI'_(jd))to hypothetical jointed rock mass cases,the effect of persistency of joints on structural anisotropy of rock mass was introduced to the improved AI'_(jd) formulation by considering the ratings of persistency of joints as proposed by Bieniawski(1989)’s rock mass rating(RMR)classification.Two real cases were assessed in the stratified marl and the columnar basalt using the weighted anisotropy index of jointing degree(W_AI'_(jd)).A structural anisotropy classification was developed using the RQD classification proposed by Deere(1963).The proposed methodology is capable of defining the structural anisotropy of a rock mass including joint pattern from extremely closely to extremely widely spaced joints.
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.
文摘Northwest Electric Power Design Institute (NWEPDI)was established in 1956. The institute undertakes the engineering exploration, survey and design of thermal electric power plant, conventional island of nuclear power plant, power transmission and substation projects, design of the 1st and 2nd class pressure vessels, electric power system planning, environmental protection engineering monitoring, assessment and design, various industrial and civil architectural design and the scicntific research and technical development tasks of corresponding specialities. The institute
基金the financial support of the National Natural Science Foundation of China(42176212,41976074 and 41302034)the Marine S&T Fund of Shandong Province for Laoshan Laboratory(2021QNLM020002)the Marine Geological Survey Program(DD20221704)。
文摘The Qilian Mountain permafrost area located in the northern of Qinghai-Tibet Plateau is a favorable place for natural gas hydrate formation and enrichment,due to its well-developed fractures and abundant gas sources.Understanding the formation and distribution of multi-component gas hydrates in fractures is crucial in accurately evaluating the hydrate reservoir resources in this area.The hydrate formation experiments were carried out using the core samples drilled from hydrate-bearing sediments in Qilian Mountain permafrost area and the multi-component gas with similar composition to natural gas hydrates in Qilian Mountain permafrost area.The formation and distribution characteristics of multi-component gas hydrates in core samples were observed in situ by X-ray Computed Tomography(X-CT)under high pressure and low temperature conditions.Results show that hydrates are mainly formed and distributed in the fractures with good connectivity.The ratios of volume of hydrates formed in fractures to the volume of fractures are about 96.8%and 60.67%in two different core samples.This indicates that the fracture surface may act as a favorable reaction site for hydrate formation in core samples.Based on the field geological data and the experimental results,it is preliminarily estimated that the inventory of methane stored in the fractured gas hydrate in Qilian Mountain permafrost area is about 8.67×1013 m3,with a resource abundance of 8.67×108 m3/km2.This study demonstrates the great resource potential of fractured gas hydrate and also provides a new way to further understand the prospect of natural gas hydrate and other oil and gas resources in Qilian Mountain permafrost area.
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In th is study, a n e w m odel w as p re se n te d for com p u tin g stre n g th o f rock m asses based u p o n in -situo bservations o f RQD p o pularly kno w n as rock quality d esignation. This m odel links u p th e rock m assp aram eters from in -situ investigations w ith th e stre n g th p a ram eters o f jo in ted rocks obtain ed fromlaboratory scale ex p erim en tal observations. Using th e co n stitu tiv e relation, th e a u th o r derived a p ressu reand d am age sensitive plastic p a ra m e te r to d ete rm in e stre n g th o f rock m asses for varied ex te n ts ofd isco n tin u ity an d p ressu re induced dam age. The te s t results show th a t plasticity characterized byhard en in g an d softening inclusive o f dam ag e invariably d e p en d s u p o n m ean p ressu re an d e x te n t ofdefo rm atio n s alread y experien ced by rock m asses. The p re se n t w ork explores th e te s t d a ta th a t revealth e d ep en d en c e o f in -situ stren g th on increm ental jo in t p ara m e te rs o b tain ed from th e jo in t num ber,jo in t orien tatio n , jo in t roughness, gouge p a ram eters an d w a te r pressure. S ubstituting th e relationshipb e tw e e n th e RQD and m odified jo in t factor w ith th a t b e tw e e n m odulus ratio an d stren g th ratio, th em odel show s successfully th a t using d am age inclusive plastic p a ra m e te r an d RQD provides a relationshipfor estim atin g th e stre n g th o f rock m asses. One o f th e m ain objectives o f this w ork is to illustrate th a t th ep re se n t m odel is sensitive to p la s tic ity a n d dam ag e to g e th e r in estim atin g in -situ stre n g th o f rock m assesin foundations, u n d e rg ro u n d excavation an d tunnels.
文摘In the recent decades, effects of blast loads on natural and man-made structures have gained considerable attention due to increase in threat from various man-made activities. Site-specific empirical relationships for calculation of blast-induced vibration parameters like peak particle velocity (PPV) and peak particle displacement (PPD) are commonly used for estimation of blast loads in design. However, these relation- ships are not able to consider the variation in rock parameters and uncertainty of in situ conditions. In this paper, a total of 1089 published blast data of various researchers in different rock sites have been collected and used to propose generalized empirical model for PPV by considering the effects of rock parameters like unit weight, rock quality designation (ROD), geological strength index (GSI), and uniaxial compressive strength (UCS). The proposed PPV model has a good correlation coefficient and hence it can be directly used in prediction of blast-induced vibrations in rocks. Standard errors and coefficient of correlations of the predicted blast-induced vibration parameters are obtained with respect to the observed field data. The proposed empirical model for PPV has also been compared with the empirical models available for blast vibrations predictions given by other researchers and found to be in good agreement with specific cases.
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Global concerns toward environmental issues have induced growing demand for new approaches in the construction because of its considerable impact on the environment and use of natural resources. Through using construction sustainability tools, methods and techniques, a greener design can be applied during various building phases. In this connection, it is argued that the analytical and integrated models applied by Building Information Modelling (BIM) may also facilitate this process to be performed more efficiently. BIM and construction sustainability are quite different initiatives, but both have received much attention in recent years in the architecture, engineering and construction (AEC) industry. A rigorous analysis of the interactions between them implies that a synergy exists which, if properly it is understood that can be helpful to reduce the environmental impacts of the AEC industry. A BIM-based design model can contribute to sustainability through its three main dimensions which are environmental, economic and social. In this paper, by reviewing the existing literature on BIM and construction sustainability and using a matrix to analyze construction sustainability dimensions and BIM functionalities a number of interactions have been discussed. It can be concluded that despite there are many improvements in implementation of BIM in environmental and economic aspects of sustainability, its potential impact on social dimension has not been explicitly explored hence further studies need to be undertaken in this area.
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.
文摘The aim of this study is to identify and analyze ways to increase usage of destination website and motivate website visitors’intention to actually visit the destination.The sample population is South Koreans who visit the VisitBritain website,the homepage of Britain’s national tourism agency.The data for this study were collected by a self-participated online survey on the blog of VisitBritain Korea,which is directly linked to the VisitBritain Korea website.Using structural equation modeling,six hypotheses were tested.The results show that the destination image on the destination marketing organization(DMO)website,quality of the destination website design including three dimensions(information quality,system quality,and service quality),and customers’satisfaction formed by high quality of the website design have a significant impact on website visitors’use intention and increase their visiting intention to the destination.Based upon the results of the analysis,managerial implications and areas for future research are proposed.
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 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.
文摘Animal studies play a vital role in validating the concept,feasibility,safety,performance and efficacy of biomaterials products during their bench-to-clinic translation.This article aims to share regulatory considerations for animal studies of biomaterial products.After briefly emphasizing the importance of animal studies,issues of animal studies during biomaterial products’translation are discussed.Animal studies with unclear purposes,flawed design and poor reporting quality could significantly reduce the translation efficiency and create regulatory challenges.Regulatory perspectives on the purpose,principle,quality and regulatory science of animal studies are also presented.Animal studies should have clear purposes,follow principles of 3R+DQ(replacement,reduction,refinement,design and quality)and execute under an efficiently operating quality management system.With the advancement of regulatory science,National Medical Products Administration of China has been developing a series of standards and guidance documents on animal studies of medical devices.Case studies of making decisions on whether to conduct animal studies are provided in the end with drug-eluting stents as examples.In summary,animal studies of biomaterial products should pay close attention to the rationale,design and quality in order to achieve their purposes.
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.