Model evaluation for the prediction of solubility of active pharmaceutical ingredients(APIs) to guide solid–liquid separator design

The assumptions and models for solubility modelling or prediction in systems using nonpolar solvents, or water and complex triterpene and other active pharmaceutical ingredients as solutes aren't well studied. Furthermore, the assumptions concerning heat capacity effects(negligibility, experimental values or approximations) are explored, using non-polar solvents(benzene), or water as reference solvents, for systems with solute melting points in the range of 306–528 K and molecular weights in the range of 90–442 g/mol. New empirical estimation methods for the Δ_(fus)C_(pi) of APIs are presented which correlate the solute molecular masses and van der Waals surface areas with Δ_(fus)C_(pi). Separate empirical parameters were required for oxygenated and non-oxygenated solutes. Subsequently, the predictive capabilities of the various approaches to solubility modelling for complex pharmaceuticals,for which data is limited, are analysed. The solute selection is based on a principal component analysis, considering molecular weights, fusion temperatures, and solubilities in a non-polar solvent, alcohol, and water, where data was available. New NRTL-SAC parameters were determined for selected steroids, by regression. The original UNIFAC, modified UNIFAC(Dortmund), COSMO-RS(OL), and COSMO-SAC activity coefficient predictions are then conducted, based on the availability of group constants and sigma profiles. These are undertaken to assess the predictive capabilities of these models when each assumption concerning heat capacity is employed. The predictive qualities of the models are assessed, based on the mean square deviation and provide guidelines for model selection, and assumptions concerning phase equilibrium, when designing solid–liquid separators for the pharmaceutical industry on process simulation software. The most suitable assumption regarding Δ_(fus)C_(pi) was found to be system specific, with modified UNIFAC(Dortmund) performing well in benzene as a solvent system, while original UNIFAC performs better in aqueous systems.Original UNIFAC outperforms other predictive models tested in the triterpene/steroidal systems,with no significant influence from the assumptions regarding Δ_(fus)C_(pi).

Analysis of the Current Situation of Active Pharmaceutical Ingredient (API) Export in China

Objective To analyze the problems of API export in China and to study the current international and domestic trading environment. Methods Data statistical analysis was used to study the export situation of APIs, and PEST was applied to analyze the current export problems. Results and Conclusion API export in China is now experiencing a growth period and the international trading environment is constantly improving.

Multiple Emulsions Able to Be Used for Oral Administration of Active Pharmaceutical Ingredients: Physico-Chemical Parameters Study of Different Phases

Multiple emulsions are of great therapeutic interest especially in the administration of medicines which can be inactivated by digestive enzymes;moreover the researches of formulation not being often easy, a control of the different phases physicochemical parameters would be of great interest in rapid formulations and at low cost. When formulating emulsions, the preliminary tests, also known as formulation tests, constitute a step which can be long and expensive because of the quantity of reagents that can be used. A rigorous methodology could thus be of great interest, which is at the aim of our study which consists of evaluating the physico-chemical parameters of different phases used to make thus multiple emulsions. In our study, physico-chemical parameters such as conductivity, pH, density, viscosity, and surface tension have been studied by direct measurement using equipment and also by means of suitable mounting. The results showed that the pH and the surface tension have an important role in the prediction of the stability of emulsions, these latter must be of the same order of magnitude. For all phases conductivity does not have too much interest apart from helping to determine the type of the emulsion.

Evaluation of Health and Environmental Risks of Pesticide Products Used in Market-Gardening in the City of Ngaoundere (Cameroon)

The aim of this survey?was to identify the active ingredients of phytosanitary products generally used in the market-gardening, to evaluate the behavior of market gardeners, environmental and sanitary risks link to the use of phytosanitary products. Results revealed that 8 actives ingredients are regularly used: paraquat, atrazine, glyphosate, chlorpyrifos-éthyl, cypermethrin, maneb, mancozeb and diuron. The contamination of running water and rivers is caused by the fact that 81.25% of them are washing their pulverization equipments in these last ones. Moreover, 72.90% release empty packages of pesticides in the farm which will be carried away by running water. 59.09% adopt the overdose strategy in case of insufficient treatment. The inadequate equipment of protection and the consumption of surrounding water by 51.10% represent a danger for the health of market gardeners. Thus, headache and stomachache are the most recorded intoxications.

A review on cocrystal of active ingredients in traditional Chinese medicine

In the development of new drugs products,especially the development of traditional Chinese medicine active ingredients,solubility and oral bioavailability are the main factors which are restricting the development of new drugs,whereas the physicochemical properties of active ingredients are the key element to affecting these factors.Pharmaceutical cocrystal provides an excellent opportunity to develop new drugs with excellent physical and chemical properties such as melting point,solubility,stability and bioavailability while retaining the pharmacological properties of individuals active pharmaceutical ingredients among pharmaceutical cocrystal compounds.Traditional Chinese herbal medicine has the characteristics of multiple pathways and multiple targets,mainly because it contains many active ingredients,like cocrystals thereof with many components.The active ingredients extracted from traditional Chinese herbal medicine have a wide range of pharmacological activities,but most of the active ingredients affect the development of traditional Chinese medicine active ingredients due to their physical and chemical properties such as solubility.Traditional Chinese medicine pharmaceutical cocrystals can not only improve the physical and chemical properties of drugs without changing the internal structure of drugs,so as to provide a new scheme for the development of traditional Chinese medicine active ingredients.This paper reviews the research progress of active ingredients of traditional Chinese medicine pharmaceutical cocrystal.The preparation methods of cocrystals are summarized and the advantages of cocrystals are illustrated with examples.

Removal of Pharmaceutically Active Compounds in Sequencing Batch Reactor

Biological treatment efficiency of six pharmaceutical compounds （acetazolamide, metronidazole, opipramol, piracetam, salicylamide and tinidazole） was evaluated using lab-scale Sequencing Batch Reactor （SBR）. Comparative biological degradation processes of two types of activated sludge from municipal and pharmaceutical industry sewage treatment plants were examined. Three different organic loadings （0.05 g COD/g MLSS.d, 0.1 g COD/g MLSS.d and 0.2 g COD/g MLSS-d） and reaction time on the efficiency of Active Pharmaceutical Ingredient （API） decomposition were examined. Chemical oxygen demand, non-purgeable organic carbon as well as ammonium nitrogen contents were monitored by standard methods. Percentage of API decomposition was analysed by High Performance Liquid Chromatography （HPLC）. The overall API removal efficiency was strictly dependent on the type of activated sludge origin. The main biodegradation products were identified using HPLC-MS,1H NMR and 13C NMR methods as e.g. （{4-[3-（5H-dibenzo[b,f]azepin-5-yl]piperazin-l-yl}methanamine） and （2-amino-1,3,4-thiadiazol-5-sulfonamide） for opipramol and acetazolamide respectively.

Modeling solubility of oxaprozin and irbesartan in biorelevant complex solutions based on a combination of pH-dependent and micellar solubilization models

Biological solubility is one of the important basic parameters in the development process of poorly soluble drugs,but the current measurement methods are mainly based on a large number of experiments,which are time-consuming and cost-intensive.There is still a lack of effective theoretical models to accurately describe and predict the biological solubility of drugs to reduce costs.Therefore,in this study,osaprazole and irbesartan were selected as model drugs,and their solubility in solutions containing surfactants and biorelevant media was measured experimentally.By calculating the parameters of each component using the perturbed-chain statistical associating fluid theory(PC-SAFT)model,combined with pH-dependent and micellar solubilization models,the thermodynamic phase behavior of the two drugs was successfully modeled,and the predicted results were in good agreement with the experimental values.These results demonstrate that the model combination used provides important basic parameters and theoretical guidance for the development and screening of poorly soluble drugs and related formulations.

Quantitation of Genetox Impurities Using a Surrogate Standard Approach

With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are present in the final API’s, and if they are present, to ensure the levels are acceptable for any clinical uses. For PGI’s that have authentic standards available, quantitation can be accomplished in a straightforward manner. However, for PGI’s that are expected to form through rearrangements or side reactions, authentic standards may not be readily available, significantly complicating the analysis. In this study we describe a surrogate standard approach for quantifying PGI’s that allows for relative response factor calculations of PGI species utilizing both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).

气相色谱法检测阿普米司特原料药中有机溶剂残留

目的建立测定阿普米司特原料药中8种有机溶剂残留量的气相色谱法。方法色谱柱为DB-624石英毛细管柱(60 m×0.53 mm,3.00μm),程序升温,进样口温度为220℃,检测器为氢火焰离子化检测器(FID),检测器温度为250℃,载气为氮气,载气流速为4 mL/min,分流比为20∶1,直接进样,进样量为1μL。结果甲醇、乙醇、丙酮、乙酸甲酯、乙酸乙酯、乙酸、异丙叉丙酮、二丙酮醇的质量浓度分别在9.361~593.2μg/mL、10.01~984.6μg/mL、10.23~996.4μg/mL、14.31~971.5μg/mL、10.22~991.4μg/mL、7.313~983.3μg/mL、3.335~201.6μg/mL、10.12~202.4μg/mL范围内与峰面积线性关系良好(r≥0.9998,n=4);定量限分别为9.36,10.01,10.23,14.31,10.22,7.31,3.34,10.12μg/mL,检测限分别为2.81,3.00,3.07,4.29,3.07,2.19,1.01,3.37μg/mL;精密度、重复性试验结果的RSD均小于6.0%(n=6);平均加样回收率分别为103.25%,103.97%,101.51%,103.58%,102.63%,100.92%,103.67%,103.63%,RSD分别为2.24%,5.70%,2.15%,1.92%,2.25%,4.54%,3.28%,0.95%(n=9)。3批样品中乙醇和丙酮的检出量分别为0.17%,0.16%,0.19%和0.20%,0.17%,0.21%,其余溶剂均未检出。结论该方法操作简便、结果准确可靠、灵敏度高,可用于阿普米司特原料药中8种有机溶剂残留量的测定。拟订阿普米司特原料药中甲醇、乙醇、丙酮、乙酸甲酯、乙酸乙酯、乙酸、异丙叉丙酮、二丙酮醇的残留限度分别为0.3%,0.5%,0.5%,0.5%,0.5%,0.5%,0.1%,0.1%。

高效液相色谱法测定氟维司群原料药有关物质

为建立高效液相色谱法测定氟维司群原料药中有关物质的方法,采用Waters Symmetry C8(150 mm×4.6 mm,3.5μm)色谱柱,以水-乙腈-甲醇(41∶32∶27)为流动相A,以水-乙腈-甲醇(10∶49∶41)为流动相B,流速为2.0 mL·min-1进行梯度洗脱,柱温为40℃;检测波长为225 nm;样品温度为8℃;进样体积为10μL.结果表明:系统适应性试验氟维司群主峰和杂质A的分离度为3.03,大于1.5的标准要求;供试品溶液分别经强酸、强碱、高温、氧化、强光等条件破坏,主峰的纯度角均小于纯度阈值,主峰与相邻峰之间的最小分离度均大于1.5、杂质质量守恒均在在95%~105%之间;已知杂质B、C、D、F定量限分别为4.080、1.940、1.355、1.160μg·mL-1,小于报告阈值0.05%对应的样品浓度;所测单个未知杂质质量分数和总杂质量分数在小于0.1%的情况,重复性和中间精密度RSD分别为9.84%和12.49%;供试品在48 h内稳定.

原料药减压蒸馏系统的共性问题及解决方案

深入分析了原有减压蒸馏系统存在问题及产生原因。在减少蒸馏罐和真空泵的前提下,通过合理设计系统的设备配置流程,选购新型换热设备,自制高效分离设备,提高了系统的冷凝(冷却)性能、气液分离性能和管道通量。有效利用真空系统的额定抽气能力,使蒸馏速度数倍提高、蒸馏温度明显下降,进而提高了产品产量、质量和收率。同时,提高溶剂回收率,降低水电汽冷和设备维保费用及人工费用,大幅降低三废排放和后续处理费用,节能减排效果显著。

高效液相色谱法测定氟苯尼考原料药

本研究建立了氟苯尼考药的液相色谱测定方法。通过研究色谱柱分离、定性波长、流动相选择等条件确定检测方法。并通过检出限、定量限、回收率和重复性实验评价方法。结果表明,选择TC-C18柱作为分离柱,最佳波长为223 nm,最佳流动相为25%乙腈水溶液,氟苯尼考线性达到0.99975,检出限为0.05μg/mL,定量限为0.15μg/mL,添加量为0.5~3μg时回收率达到88.7%~100%,重复性RSD达到0.64%。此方法高效准确,能为氟苯尼考药主含量测定提供参考,也能为其他兽药氟苯尼考的测定提供思路。

膜分离技术在中药现代化中的应用:进展、难点及发展方向

综述了膜技术在中药现代化进程中包括有效成分的提取和浓缩、中药制剂的制备等方面的应用,探讨了膜技术在中药制药中面临的挑战,基于膜污染与使用寿命、规模化应用等提出了解决思路。针对目前膜技术在中药现代化中的应用多数仍处于实验探索研究阶段这一现状,从膜材料创新等角度结合可持续发展、绿色制药等理念对未来的发展方向作了展望。

腐殖质土添加杉木屑对金线莲生长及活性成分的影响

目的:研究腐殖质土添加不同腐熟程度杉木屑对金线莲生长与活性成分的影响。方法:以金线莲组培苗为材料,设置100%腐殖质土(处理A)、40%腐熟杉木屑+60%腐殖质土(处理B)、40%未腐熟杉木屑+60%腐殖质土(处理C)3个处理,测定金线莲生长指标以及活性成分含量,分析腐殖质土中添加不同腐熟程度杉木屑对杉木下仿野生栽培金线莲生长及活性成分的影响。结果:种植在处理B中的金线莲幼苗保存率最高,达到了84.80%;幼苗茎粗、叶片数、叶片长、叶片宽、根长的增长量均高于其余2个处理;总黄酮与生物碱含量分别比处理A与处理C高出1.17%、25.63%和3.55%、11.34%。结论:腐殖质土中添加杉木屑可提高金线莲保存率,促进金线莲生长,其中60%腐殖土+40%腐熟杉木屑栽培效果最佳,值得进一步推广。

我国化学药改良型新药临床试验最新进展研究

目的:总结已公开的化学药改良型新药临床试验开展情况,以期为后续化学药改良型新药临床试验的顺利开展提供参考。方法:通过国家药品监督管理局药品审评中心药物临床试验登记与信息公示平台并结合药智、丁香园等第三方数据库,检索2020年1月1日至2023年12月31日期间的化学药改良型新药临床试验信息,并采用Excel等方法进行统计分析,研究其临床试验开展情况。结果:自2020年1月1日至2023年12月31日,化学药改良型新药临床试验公示的数量逐年上升,3年时间总计公示了548次。其中,2.2类改良型新药占比最高,超过50%,2.1类改良型新药占比最少。开展的临床试验分期主要以Ⅰ期临床研究为主。结论:化学药改良型新药可借鉴已上市产品的临床开发数据,减免部分临床研究,缩短研发周期,这些是目前新药研发的热点。

黄酮类化合物的含N杂环共晶形成物研究概况

黄酮类化合物是一类受到广泛的研究天然化合物,具有十分广泛的药理作用,但是水溶性差,生物利用度低等缺点限制了其在临床的应用。药物共晶是指活性药物成分(APIs)在氢键等非共价键的作用下,与共晶形成物(CCFs)生成的新型晶体,并可在不改变化学结构的前提下改善药物的理化性质。由于含N杂环中的N原子可以参与氢键的生成,故本文将以N杂环结构为依据,对近年来参与黄酮共晶的CCFs进行综述,为黄酮共晶的进一步研究提供参考。

桑树抗肿瘤药用活性物质研究进展

近年来,抗肿瘤领域所面临的最棘手问题之一便是肿瘤的耐药性和药物的毒副作用,这些因素极大地影响到肿瘤治疗的效果,引起了人们的高度关注。为解决这一难题,科研人员积极寻找新的抗肿瘤药物,希望能找到对肿瘤有良好疗效、毒副作用小、不易产生耐药性的化合物。在这一探索过程中,来自植物的天然药用活性物质成为了重要的研究方向。桑树作为一种传统药用植物,在抗肿瘤领域的应用研究逐渐受到重视。桑树中含有丰富的生物活性成分,例如黄酮类化合物、生物碱和多糖等,这些成分被证实具有显著的抗肿瘤活性。本文旨在综述桑树中发现的天然抗肿瘤活性成分及其抗肿瘤机制,以期为开发桑树药用资源和探究桑树在中药现代应用中的确切证据提供支持,同时为进一步发掘桑树药用活性成分提供参考。

“OCS”控制系统在原料药项目设计中的应用研究

针对目前原料药项目控制系统普遍存在的问题提出了一种新的“OCS”控制系统,通过对“OCS”控制系统基本原理的介绍,阐述了“OCS”控制系统较PLC系统及DCS系统的优势,并通过项目实例佐证了“OCS”控制系统的优越性。总之“OCS”控制系统主要通过组件iDTU和RJU的组合,将传输信号由传统的电信号转换成光信号,完美地解决了原料药项目控制系统设计中防爆、线缆过多等诸多难题。

一种非奈利酮消旋体的制备方法

以4-氰基-2-甲氧基苯甲醛和乙酰乙酸叔丁酯为原料,通过缩合、关环、氧烷基化、水解以及氨解反应,得到了非奈利酮消旋体。考察了不同取代酯在碱性条件下的水解,发现常规酯在NaOH等多种碱性条件下均未水解,而在酸性条件下则可发生水解,在三氟乙酸(TFA)的作用下,二氯甲烷(DCM)作溶剂,室温下可实现叔丁基4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-羧酸酯(Ⅶ)的水解,重点优化了中间体Ⅶ的水解条件。结果表明,在n(Ⅶ)∶n(TFA)=1∶10、n(Ⅶ)∶n(DCM)=1∶18、室温(25℃)条件下反应3 h,即可得到收率为68%的4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-羧酸(Ⅷ)(HPLC纯度98%)。该法突破了常规酯在碱性条件下难以水解的困难,反应放大到百克级,最终以约35%的总收率得到非奈利酮消旋体(HPLC纯度99%)。产物经^(1)HNMR、^(13)CNMR和HRMS确定结构。

拜登政府重塑原料药供应链:进展与前景

美国在新药研发上长期占据领先优势,但在原料药生产能力方面较为薄弱,对外依赖性较强且集中度高,这被美国政府视为存在供应链风险。这种风险产生的原因有三:一是美国制药产业转移导致的客观风险,二是新冠疫情暴露了美国在大宗原料药上对中国的依赖,三是美国将原料药对华依赖定性为国家安全威胁。拜登政府执政后,通过评估和管理原料药供应链、投资生物技术和连续生产工艺等先进制造、以“友岸外包”和“近岸外包”推动原料药供应链多元化等举措,来增强美国本土生产能力,重塑原料药供应链,缓解药品短缺等问题。从前景看,拜登政府重塑原料药生产能力恐难达到预期,清晰掌握原料药供应链信息的难度较大。从中国竞争优势、大国技术竞争和市场格局变化来看,拜登政府的政策举措对中国大宗原料药生产的负面影响不大,对特色原料药和专利原料药的消极影响将逐渐增强。