Granulation process analysis technologies and potential applications in traditional Chinese medicine

Pharmaceutical production is changing from batch production to continuous production,during which granulation is one of the most important unit operations.The quality of mass-produced products is traditionally guaranteed by conducting off-line testing,which cannot meet the demand of continuous production for real-time monitoring of critical process parameters and critical quality attributes(CQAs)of the pharmaceutical granulation technology.Since the U.S.Food and Drug Administration proposed process analytical technology(PAT)in 2004,many PAT tools have been developed to monitor the granulation process and provide information regarding the granulation operation conditions and endpoint determination.In this article,we review the recent research and application of two PAT modes in the granulation process,namely,single CQA and multi-CQA PAT,with the aim to provide references for comprehensively improving the technological level of the pharmaceutical granulation process.Furthermore,the potential applications in traditional Chinese Medicine are discussed.

Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis

The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr’s index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables(impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.

Developing super-hydrophobic and corrosion-resistant coating on magnesium-lithium alloy via one-step hydrothermal processing

Formation of super-hydrophobic and corrosion-resistant coatings can provide significant corrosion protection to magnesium alloys.However,it remains a grand challenge to produce such coatings for magnesium-lithium alloys due to their high chemical reactivity.Herein,a one-step hydrothermal processing was developed using a stearic-acid-based precursor medium,which enables the hydrothermal conversion and the formation of low surface energy materials concurrently to produce the super-hydrophobic and corrosion-resistant coating.The multiscale microstructures with nanoscale stacks and microscale spheres on the surface,as well as the through-thickness stearates,lead to the super-hydrophobicity and excellent corrosion resistance of the obtained coating.

A rapid one-step electrodeposition process for fabrication of superhydrobic surfaces on anode and cathode

This work presents a method to solve the weak solubility of zinc chloride(ZnCl_2) in the ethanol by adding some reasonable water into an ethanol electrolyte containing ZnCl_2 and myristic acid(CH_3(CH_2)_(12)COOH).A rapid one-step electrodeposition process was developed to fabricate anodic(2.5 min) and cathodic(40 s) superhydrophobic surfaces of copper substrate(contact angle more than 150°) in an aqueous ethanol electrolyte.Morphology,composition,chemical structure and superhydrophobicity of these superhydrophobic surfaces were investigated by SEM,FTIR,XRD,and contact angle measurement,respectively.The results indicate that water ratio of the electrolyte can reduce the required deposition time,superhydrophobic surface needs over 30 min with anhydrous electrolyte,while it needs only 2.5 min with electrolyte including 10 mL water,and the maximum contact angle of anodic surface is 166° and that of the cathodic surface is 168°.Two copper electrode surfaces have different reactions in the process of electrodeposition time,and the anodic copper surface covers copper myristate(Cu[CH_3(CH_2)_(12)COO]_2) and cupric chloride(CuCl);while,zinc myristate(Zn[CH_3(CH_2)_(12)COO]_2) and pure zinc(Zn) appear on the cathodic surface.

Fluidised bed granulation of two APIs:QbD approach and development of a NIR in-line monitoring method

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.

Pyramidal and Granule Cells Distribution through Hippocampal Fields: An Index for Sensory Information Processing

Background: This work aims at investigating the histology of hippocampus formation as structural model of information processing. The study addressed the question whether the pattern of cellular type distribution within hippocampal fields could be used as support of information processing in the hippocampus. Method: Pyramidal-shaped neurons presenting both cytoplasm and nucleus outlined clearly were measured systematically on brain slides, using a light microscope connected to a microcomputer equipped with a scanner software for measuring particles. Morphological types of cells were identified following class sizes and their distribution determined through hippocampal fields. Results: A battery of statistical tests: Sturges’ classification, class sizes distribution around overall mean, Bartlett’s sphericity test, principal components analysis (PCA) followed by correlations matrix analysis and ANOVA allowed two cellular groups to be identified in the hippocampus: large and small pyramidal-shaped cells. Conclusion: The results show that sensory information processing in the hippocampus could be built on two classes of pyramidal neurons that differed anatomically with probably different physiological functions. The study suggests combination ensembles clustering large and small pyramidal cells at different rates, as fundamental signaling units of the hippocampus.

Heat Transfer Analysis During "One-Step" Directional Solidification Process for Giant Magnetostrictive Materials

By theoretical analysis of heat transfer during the "one-step" directional solidification process, the functional relation between the temperature in solid-liquid interface and its effect factor was studied. The thermal gradient in solid liquid interface and heat transfer coefficient between the samples and surroundings were also calculated. On the basis of the above analysis, some suggestions for improving the thermal gradient in solid-liquid interface were put forward. It will provide a theoretical instruction for preparing high performance giant magnetostrictive materials (GMM).

Study on Preparation Process and Quality Standard of Tianlu Tongluo Granules

[Objectives]This study was conducted to optimize the preparation process of Tianlu Tongluo Granules and establish its quality standard.[Methods]Tianlu Tongluo Granules was prepared by an orthogonal test.TLC was used to identify Radix Astragali preparata,Radix Paeoniae Alba,Scutellariae Radix and Acori Tatarinowii Rhizoma in the granules,and the content of paeoniflorin in the finished product was determined by HPLC.[Results]The extraction process of Tianlu Tongluo Granules was as follows:adding 6 times of water,and decocting twice,1 h/time.In the forming process,the optimal ratio of thick paste to excipients as 10∶8.6,and the optimal ratio of excipients dextrin:starch:colloidal silicon dioxide was 6.5∶0.5∶1.6.The results showed that TLC spots were obvious,the separation was significant,and the specificity was strong.The paeoniflorin content had a good linear relationship in the concentration range of 5.9048-590.48 mg/L(r=0.9999).The average sample recovery was 101.10%,and the RSD was 1.18%.[Conclusions]The preparation process is stable and reasonable,and the established quality control method is specific and reproducible,and can be used for the quality control of Tianlu Tongluo Granules.

Study on the Forming Process of Yi Medicine Tongfeng Granules

[Objectives]To optimize the forming process of Yi medicine Tongfeng Granules.[Methods]The forming process of Yi medicine Tongfeng Granules was optimized,with paste density,ethanol volume fraction,and type and proportion of excipient as influencing factors,and granule formability,solubility,moisture absorption,and angle of repose as evaluation indicators.Critical relative humidity(CRH)was investigated to select optimal storage conditions.[Results]Maltodextrin was selected as the excipient,and the best process parameters was the ratio of drug to excipient at 1∶2(g/g),under which the forming rate,solubility,moisture absorption rate,and angle of repose were 81.38%,98.90%,8.81%,and 27.5°,respectively.The critical relative humidity was 72%.[Conclusions]The forming process adopted is reasonable and feasible,and can provide a reference for large-scale production of Yi medicine Tongfeng Granules.

Effects of Post-expanding Lower Temperature Granulating Process on Growth Performance of Piglets

[Objective] The paper was to compare the effects of traditional granulating process and post-expanding lower temperature granulating process on starch gelatinization degree and in vitro protein digestibility of conversation feed, and growth performance of piglets. [Method] Sixty weaned piglets, 25 days old, were randomly divided into two groups, six replicates each group, and each replicate contained five piglets. Piglets in control group were fed with the conversation feed developed by traditional granulating process, and those in experimental group were fed with the conservation feed developed by post-expanding lower temperature granulating process. The trial lasted 28 d. [Result] Compared to traditional granulating process, post-expanding lower temperature granulating process significantly enhanced starch gelatinization degree of conservation feed by56.9%（P〈0.05）, and significantly improved in vitro protein digestibility of conservation feed by 11.48%（P〈0.05）. Compared to the control group, the feed intake of piglets in experimental group was increased by 21.63%（P〈0.05）; the average daily gain was increased by 27.61%（P〈0.05）; the diarrhea rate was lowered; and the feed gain ratio was improved by 4.51%（P〉0.05）. The results suggested that post-expanding lower temperature granulating process effectively enhanced feed digestion and absorption of piglets. [Conclusion] The paper provides a theoretical basis and practical reference for improvement of production process of conservation feed.

Preparation of Ephedra houttuynia Granule and Its Therapeutic Mechanism of Anti-Mycoplasma gallisepticum Infection Based on Network Pharmacology

The use of Chinese herbal medicines can replace antibiotics that cause drug-resistance problems,which are currently necessary for disease control.In this paper,a traditional Chinese medicine compound named Ephedra houttuynia granule for the treatment of Mycoplasma galliscepticum(MG)infection was prepared.Furthermore,its action mechanism was explored through network pharmacology.The optimal extraction and granulation processes of the compound were determined by high performance liquid chromatography(HPLC)method and L9 orthogonal test,and in the treatment experiment,Ephedra houttuynia granule showed a significant therapeutic effect on MG infection.In the study of network pharmacology,the results showed that the core targets of Ephedra houttuynia granule against MG infection were vascular endothelial growth factor(VEGFA),fos proto-oncogene(FOS),prepro-coagulation factor II(F2),etc.,the gene ontology/kyoto encyclopedia of genes and genomes(GO/KEGG)analysis results indicated that the signaling pathways of neuroactive ligand receptor interaction,cAMP,IL-17,T cell receptor,and tumor necrosis factor(TNF)might involve in anti-MG infection.In conclusion,this study would provide a new idea for elucidating the action mechanism of other diseases in veterinary clinic,which had a certain guiding significance.

Characteristics of high-sulfate wastewater treatment by two-phase anaerobic digestion process with Jet-loop anaerobic fluidized bed

A new anaerobic reactor, Jet-loop anaerobic fluidized bed （JLAFB）, was designed for treating high-sulfate wastewater. The treatment characteristics, including the effect of influent COD/SO42 ratio and alkalinity and sulfide inhibition in reactors, were discussed for a JLAFB and a general anaerobic fiuidized bed （AFB） reactor used as sulfate-reducing phase and methane-producing phase, respectively, in two-phase anaerobic digestion process. The formation of granules in the two reactors was also examined. The results indicated that COD and sulfate removal had different demand of influent COD/SO4^2- ratios. When total COD removal was up to 85%, the ratio was only required up to 1.2, whereas, total sulfate removal up to 95% required it exceeding 3.0. The alkalinity in the two reactors increased linearly with the growth of influent alkalinity. Moreover, the change of influent alkalinity had no significant effect on pH and volatile fatty acids （VFA） in the two reactors. Influent alkalinity kept at 400-500 mg/L could meet the requirement of the treating process. The JLAFB reactor had great advantage in avoiding sulfide and free-H2S accumulation and toxicity inhibition on microorganisms. When sulfate loading rate was up to 8. 1 kg/（m^3.d）, the sulfide and free-H2S concentrations in JLAFB reactor were 58.6 and 49.7 mg/L, respectively. Furthermore, the granules, with offwhite color, ellipse shape and diameters of 1.0-3.0 mm, could be developed in JLAFB reactor. In granules, different groups of bacteria were distributed in different layers, and some inorganic metal compounds such as Fe, Ca, Mg etc. were found.

One-step Synthesis of ε-Caprolactam by the Liquid Phase Nitrosation of Cyclohexane over the Catalysts Containing CH_3COO^- or —COOH

ε-Caprolactam（CL or CPL） is one of the most important intermediates used in polymer industry for the production of several million tons of nylon-6 every year^[1]. All current commercial processes for the production of caprolactam are based on either benzene or tolueneI21. Caprolactam is synthesized by the Beckmann rearrangement of cyclohexanone oxime with fuming sulfuric acid or sulfuric acid as the reaction medium, and cyclohexanone oxime is produced by the reaction between cyclohexanone and hydro- xylamine（only one exception is the Toray PNC process）.

The development of Fructus corni quality standard considering the effects of processing

The quality standards for Fructus Comi have been established based on the effects of the manufacturing processes.Three critical process parameters(CPPs)of extraction,filtration,and concentration to prepare Fructus Comi concentrate were identified by Plackett-Burman design with a single batch of Fructus Corni,which were heating medium temperature,extraction time,and water addition.Morroniside yield,loganin yield,and dry matter yield were process critical quality attributes(CQAs).CPPs arranged with a Box-Behnken design were applied to treat different batches of Fructus Comi After constructing a model that included CPPs,material propertie s,and process CQAs,loganin content was found to be the critical material attribute(CMA).The design space was calculated with a probability method.According to the limits of process CQAs,the minimum content of loganin in Fructus Corni was calculated with an error propagation method,which was 6.92 mg·g^(-1).When the content of loganin in Fructus Corni reaches up to 6.92 mg·g^(-1),the material is considered high-quality and is most suitable for the process.High-quality material can be used for production of Fructus Comi concentrate.This method can also be used to set material quality standards for other Chinese medicines.

Process Auxiliary Decision-making Based on Rough Sets and Regulation Distance Computing

Computer aided process planning（CAPP） is an important content of computer integrated manufacturing, and intelligentizing is the orientation of development of CAPP. Process planning has characters of empirical and time-consuming to finalize, and the same technical aim always can be achieved by different process schemes, so intelligentizing of process decision making always be a difficult point of CAPP and computer integrated manufacturing （CIM）. For the purpose of intelligent aided process decision making and reuse of process resource, this paper proposed a decision making method based on rough sets（RS） and regular distance computing. The main contents and methods of process planning decision making are analyzed under agile response manufacturing environment, the concept of process knowledge granule is represented, and the methods of process knowledge granule partitioning and granularity analysis are put forward. Based on the theory of RS and combined the method of process attributes importance identification, the paper brought forward a computing model for process scheme regulation distance under the same attribute conditions, and conflict resolution strategy was introduced to acquire process scheme fit for actual situation of enterprise＇s manufacturing resources, so as to realize process resources＇ conflict resolution and quick excavate and reuse of enterprises＇ existing process knowledge, to advance measures of process decision making and improve the rationality and capability of agile response of process planning.

预造球强化难制粒精矿烧结工艺

随着进口铁矿石价格的增长,充分利用廉价的难处理铁矿资源成为钢铁企业降本增效的关键。本文针对难制粒精矿在烧结中利用率低的问题,在复合造块法的基础上开发了预造球工艺,显著提高了难制粒精矿的配入量,有效改善了制粒效果与烧结产、质量指标。研究表明,在难制粒精矿配比达到36%时,采用预造球制粒可以使准颗粒平均粒径提高1.53 mm,透气性指数提高0.17。在此基础上,垂直烧结速度提高13.97 mm/min,利用系数提高0.815 t/(m^(2)·h),转鼓强度提高3.39%。预造球烧结中,由于难制粒精矿的分离,常规制粒料部分的制粒性能得到优化,局部碱度得到提高,形成大量的针柱状铁酸钙。在常规制粒料与球团料交界处固相固结与液相固结同时存在,铁酸钙与铁氧化物相互交织,形成球团嵌入式分布的成品矿结构,具有良好的成矿效果和强度性能。

复方老鹳草颗粒制备工艺研究

目的研究复方老鹳草的制备工艺。方法以没食子酸和总多糖的保留率及浸膏的降低率为指标,对水提液进行精制,得到最佳的精制工艺,研究复方老鹳草的成型工艺。结果水提液精制工艺为将水提液70℃减压浓缩至药材:药液为1∶1.1,在4℃的低温环境下放置24 h;水提与醇提液的最佳浓缩工艺均为(70±2)℃(-0.08~0.07Mpa)减压浓缩,分别浓缩至相对密度为1.15~1.20及1.20~1.25;干燥工艺均定为70℃真空干燥。最佳成型工艺为以93%乙醇为黏合剂,加入浸膏细粉、浸膏粉量8%的独活细粉混匀制粒。结论复方老鹳草颗粒的制备工艺合理、可行,可为复方老鹳草颗粒的制备提供依据。

参杞强精颗粒成型工艺优化与稳定性研究

目的探讨参杞强精颗粒成型工艺优化方案,并考察其成品稳定性。方法采用单因素试验考察湿法制粒工艺。以浸膏粉与辅料的配比(A)、乙醇浓度(B)、润湿剂用量(C)为主要影响因素,以吸湿率、溶化率、成型率、休止角为评价指标,采用L9(34)正交试验法优选参杞强精颗粒成型工艺。同时,考察参杞强精颗粒的长期稳定性和加速稳定性。结果正交试验法优选的最佳成型工艺为浸膏粉与辅料配比为1∶1,乙醇浓度为65%,0.3%甜菊素的颗粒口感较好,润湿剂用量为15~20 mL,生产环境的相对湿度应控制在70%以下。在稳定性考察过程中加速试验和长期试验均符合规定。结论优化后的成型工艺方法科学合理,稳定可行,操作简便,所制得颗粒符合各项指标的相关规定,且稳定性好,可为参杞强精颗粒的生产及其后续研究开发提供实验依据。

基于正交实验优化中药配方颗粒调剂工艺

目的:探讨影响中药配方颗粒药品下药量因素,优化最佳配药、储存条件,保证患者用药安全、有效,提高患者对中药配方颗粒药品的满意度。方法:通过正交实验法优化最佳配药、储存条件,对中药配方颗粒进行质量监管。结果:配方颗粒调剂工艺的影响因素依次为:湿度>粒径>温度;最佳调剂工艺为温度21℃,湿度45%,粒径为全部通过2号筛且不通过3号筛。结论:温度、湿度、粒径三者对配方颗粒的调剂工艺都有显著影响,依据本实验所得最佳配药条件,能达到最准确配药量。

桂附颗粒提取工艺研究

目的:选取桂附颗粒最佳提取工艺。方法:以加水量,煎煮时间,煎煮次数作为参考因素,以肉桂酸含量及浸膏得率作为综合指标评分,选用L_(9)(3^(4))正交试验优化桂附颗粒的提取制备工艺。结果:优选桂附颗粒提取工艺的最佳条件为煎煮两次,每次加入10倍的水,并且每次煎煮1.5 h。结论:该试验结果合理、可行,有效成分率高,适合工业生产的需要。