注射用氨苄西林钠质量评价

目的 对注射用氨苄西林钠的质量进行评价。方法 采用法定标准结合探索性研究对95批次注射用氨苄西林钠进行检验,并与往年的两次国抽结果进行纵向比较,评价本品的质量状况。结果 按法定标准检验,95批次样品全部符合规定。原料为冷冻干燥和溶媒结晶工艺的产品在碱度、有关物质、水分、含量等方面存在明显差异。表现为冷冻干燥工艺的产品碱度相对较低,含量(按无水物计算)相对较低,杂质量、水分相对较高。探索性研究表明,在加速试验条件下放置,随着时间的增长,原料为冷冻干燥工艺的产品颜色加深,杂质增大;而溶媒结晶工艺的产品颜色和杂质变化较小。结论 注射用氨苄西林钠总体质量较好,采用溶媒结晶工艺为原料的产品质量相对更优,原料是影响本品质量的主要因素。     

注射用氨苄西林钠质量研究

目的:对不同生产工艺氨苄西林钠的质量进行对比研究。方法:采用粉末X-射线衍射、电镜扫描、红外光谱、有关物质等检测方法,同时进行加速试验,综合评价不同工艺产品。对产品中有机溶剂残留量和溶媒结晶工艺产品的2-乙基己酸残留进行检测。结果:溶媒结晶工艺样品为结晶型粉末,冷冻干燥和喷雾干燥工艺样品为无定型粉末。溶媒结晶工艺样品的有关物质明显较低,且产品稳定性好。结论:研究表明溶媒结晶工艺生产的原料最为稳定,应当引导企业主动使用该原料。     

注射用氨苄西林钠氯唑西林钠质量评价

目的 评价不同生产工艺的注射用氨苄西林钠氯唑西林钠的质量现状及存在问题。方法 按照国家评价性抽验计划总体要求，采用法定检验方法结合探索性研究进行样品研究，统计分析结果。结果 法定标准检验47批次样品，合格率100%。探索性研究建立了有关物质检查方法，对各杂质的来源与结构进行了确证；杂质主要由原料引入，不同生产工艺样品中杂质的种类基本一致，但杂质含量及分布有较大差异。结论 注射用氨苄西林钠氯唑西林钠质量总体较好，现行质量标准需进一步完善。原料药的质量影响制剂质量，采用不同生产工艺氨苄西林钠原料药生产的样品质量存在明显差异，冻干氨苄样品质量不及结晶氨苄样品，且更易受温度的影响。因此，应引导企业首选溶媒结晶工艺氨苄西林钠原料。     

注射用氨苄西林钠致过敏性休克病例分析

摘 要 目的：探讨注射用氨苄西林钠致过敏性休克的影响因素和救治合理性,为降低用药风险提供参考。方法：对河北省药品监测评价中心2015年1月～2017年6月收集到的注射用氨苄西林钠所致71例过敏性休克病例报告（包括5例死亡病例）按照患者性别、年龄、适应证、溶媒、单次剂量、给药频次、给药途径、医疗机构级别分层及预后等方面进行统计分析。结果：注射用氨苄西林钠导致过敏性休克与超说明书使用有一定的关联性,其中超单次剂量用药和超给药频次用药以及使用不适宜的溶媒、未按要求用药前进行皮试为发生过敏性休克的主要原因,预后与及时诊断和合理救治关系密切。结论：在实际使用中注射用氨苄西林钠导致过敏性休克发生率依然很高,开展注射用氨苄西林钠安全性监测,及时合理选择和使用救治药品是降低风险的有效途径。     

氨苄西林钠溶析结晶的工艺研究

氨苄西林钠是全世界第一个应用于临床的广谱半合成青霉素类药物,溶液结晶技术是决定氨苄西林钠产品质量的关键因素.为解决目前氨苄西林钠工业结晶产品聚结、粒度分布不均一等问题,本文提出了氨苄西林钠溶析结晶工艺,考察了晶种的加入量、结晶温度、溶析剂流加速度、表面活性剂对产品的主粒度和粒度分布的影响,实验结果表明晶种加入量为产品初始加入量的0.1%、结晶温度为288K、变速流加溶析剂以及加入十二烷基磺酸钠表面活性剂的条件下,可获得主粒度大、粒度分布均匀的晶体产品.     

氨苄青霉素钠溶媒喷雾干燥工艺的研究

喷雾干燥目前仍是生产氨苄青霉素钠的常用方法,它有操作简便,异物、澄明度易控制,收率高,成本低的优点。因此,在研究氨苄青霉素溶媒结晶工艺的同时,对喷雾工艺亦继续进行研究。目前溶媒喷雾工艺取得了成功,对生产起了重大推动作用。     

氨苄西林钠在不同pH值5%葡萄糖注射液中稳定性研究

目的探讨氨苄西林钠在不同pH值5%葡萄糖注射液中的稳定性。方法分别用pH值为3.2、4.2、5.4、6.0、6.5的5%葡萄糖注射液作为溶媒制备1%氨苄西林钠溶液,温度20℃,用高效液相色谱法法分别测定氨苄西林钠的浓度在0、0.5、1、2、4、6 h变化情况,计算降解速率。结果在pH 3.2~6.5的5%葡萄糖注射液中,氨苄西林钠的分解基本符合零级动力学方程,其速率随着pH值增大而减小,其稳定性随着pH值增大逐步增强。结论 5%葡萄糖注射液的pH值对氨苄西林钠的稳定性影响较大,静脉滴注使用氨苄西林钠可以选择pH值相对较大(在合格范围)的5%葡萄糖注射液,以减少氨苄西林钠的降解,确保疗效,降低药品不良反应的发生率。     

注射用泮托拉唑钠在专用溶媒、0．9％氯化钠及5％葡萄糖中的稳定性研究

目的研究注射用泮托拉唑钠专用溶媒、0．9％氯化钠（NaCl）及5％葡萄糖（Gs）溶液中的稳定性。方法测定不同时间供试品溶液的澄清度与颜色、pH值、含量及有关物质，比较泮托拉唑钠在3种溶液中的稳定性。结果泮托拉唑钠在专用溶媒中的颜色无变化，pH值、含量和有关物质改变最小。结论泮托拉唑钠在专用溶媒中稳定性最好。     

养肝增免合剂澄清工艺的优选

目的 优选养肝增免合剂的澄清工艺。方法 以澄清度和阿魏酸含量为指标,在单因素试验基础上,采用正交试验考察壳聚糖加入量、pH、温度等因素对絮凝澄清工艺的影响;考察醇沉浓度、pH、醇沉时间等因素对醇沉工艺的影响。比较2种工艺在最优条件下的澄清效果。结果 壳聚糖絮凝澄清法为最佳工艺,优化工艺为壳聚糖加入量0.1%,体系pH 5.0,絮凝时体系温度为45℃。结论 优选的工艺条件稳定、可行,缩短了生产周期,降低了成本,可作为养肝增免合剂的澄清工艺。     

正交试验法优选“艾辛止痛膏”提取工艺的研究

目的“艾辛止痛膏”有效成分的提取工艺条件。方法以总浸膏得率、复方提取物中桂枝主要成分桂皮酸和桂皮醛的总吸收度A(权重系数分别为0.7和0.3)为综合考察指标,采用正交实验法对提取工艺的溶媒用量、提取时间、提取次数、溶媒浓度4个因素进行考察,优选出"艾辛止痛膏"的最佳提取工艺条件。结果影响提取的主次因素为:溶媒浓度>提取次数>提取时间>溶媒用量;最佳提取工艺条件是:A3B2C3D3,即乙醇用量10倍,提取2次,时间为60m in,55%乙醇。结论优选得到的提取工艺稳定可行。     

头孢羟氨苄单水合物反应结晶工艺优化

利用头孢羟氨苄N,N-二甲基甲酰胺(DMF)溶剂化物在水溶液中反应结晶得到头孢羟氨苄单水合物晶体,产品往往存在聚结、松紧密度小、粒度分布不均匀、晶习不稳定等问题。本文考察了结晶过程中温度、搅拌速率、溶剂配比、溶液pH值等因素对产品粒度分布、晶习及晶体聚结的影响。研究结果表明,结晶温度对产品粒度、晶习和晶体聚结都有影响,搅拌速率和溶剂配比主要影响产品的粒度分布。实验优化得到了头孢羟氨苄单水合物反应结晶的最佳操作工艺并为工业化生产提供了重要的参考价值,利用该工艺得到的头孢羟氨苄单水合物产品为四方片状晶体、晶习完整、粒度分布均匀、产品不聚结,松紧密度分别为0.37g/mL和0.57g/mL,产品质量达国际水平。     

Effects of harvesting and cooling on crystallization and transformation of orthorhombic paracetamol in ethanolic solution.

Orthorhombic paracetamol (form II) can be obtained from ethanolic solution when seeding technique is applied although it converts to monoclinic (form I) upon contact with the solvent. In the present work different cooling temperature T(C) (-20, -10 and 0 degrees C) was applied under fixed agitation (700 rpm) and the crystalline product was harvested after different crystallization time t(H) (20, 30 and 40 min). Crystal yield (Y%), micromeritic properties and orthorhombic content of the crystalline product were evaluated and related to T(C) and t(H). Conditions for optimal crystal yield and orthorhombic content were elucidated and kinetic parameters of solvent mediated transformation (induction times, t(it), and activation energy, E(a)) were determined. It was found that crystal yield (Y%) increases with t(H) and decreases with T(C). The mean crystal size and size distribution is affected linearly by T(C), probably due to alterations in the nucleation and growth processes. The effects on the crystal shape can be elucidated only after size classification. As the crystals grow, they become more elongated, with rougher surface due to secondary nucleation and alteration in growth rate of different crystal faces. Induction times for solvent mediated transformation (t(it)), were remarkably longer than those corresponding to appearance of monoclinic form, when large scale collection and drying of crystalline product was applied, probably due to residual solvent evaporation. The activation energy of solvent mediated transformation (E(a)=62.9 kJ/mol) is between those for nucleation in the solid state and in a solvent, indicating the operation of a mixed mechanism.     

Freeze-Drying From Organic Co-Solvent Systems,Part 2: Process Modifications to Reduce Residual Solvent Levels and Improve Product Quality Attributes

The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various cosolvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert-butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low-melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation.     

Kinetics of solvent extraction/evaporation process for PLGA microparticle fabrication

Organic solvent extraction/evaporation from an o/w-dispersion has been widely used for the fabrication of PLGA microparticles. The purpose of this work was to elucidate the kinetics of the solvent extraction/evaporation process. A mathematical diffusion model was developed and applied to predict the duration of the solvent extraction. As the diffusion coefficient, D(p), plays a major role in the modeled process, a new and experimentally simple method for estimating D(p) was developed. Both the experimental method and the mathematical model were validated through PLGA microparticle fabrication experiments. For microparticles of mode diameters of 2 and 20 microm, the solvent was extracted in approximately 10 s. Sufficient hardening of the microparticles required, however, the evaporation of solvent from the extraction phase. Residual solvent in extraction phase exerted a strong effect on the morphology of the final product as demonstrated by scanning electron microscopy. Only if most solvent was removed from the aqueous extraction phase, a powdery product of individual microparticles was obtained. At residual organic solvent concentration of above 0.2% in the extraction phase, the microparticles strongly aggregated during collection on a membrane filter and final drying. The presented methods may be useful for better controlling microparticle fabrication processes by solvent extraction/evaporation.     

Particle size control of poly(dl-lactide-co-glycolide) nanospheres for sterile applications

Parameters affecting the particle sizes of poly(DL-lactide-co-glycolide) (PLGA) nanospheres produced by the Emulsion Solvent Diffusion (ESD) method were evaluated in this study, so that suitable PLGA nanospheres could be prepared to pass through a membrane filter with 0.2 μm pore size and used as a sterile product. Experimental results demonstrated that the particle sizes of PLGA nanospheres could be reduced by the following efforts.

(1) Increase stirring rate of poor solvent.

(2) Decrease feed rate of good solvent.

(3) Increase poor solvent ratio.

(4) Increase the temperature of poor solvent.

(5) Decrease polyvinyl alcohol concentration in poor solvent.

(6) Increase ethanol concentration in good solvent.

(7) Decrease PLGA concentration in good solvent.

After optimization, PLGA nanospheres with a mean particle size of 102–163 nm and the 100–98% of filtration fraction could be produced and passed the bacteria challenge tests. This study found PLGA nanospheres can be efficiently prepared as a sterile product.     

Identification of a novel in vitro metabonate from liver microsomal incubations.

In vitro drug metabolism studies during the early drug discovery stage are becoming increasingly important. With the increasing demand for high throughput and quick turnaround time for in vitro metabolism studies, however, careful examination of the results and proper design of the experiments are still crucial. In this communication, we report the identification and mechanism of formation of a novel metabonate from incubations of a diamine-containing compound with liver microsomes. The metabonate appeared to be the major product, and its formation was NADPH- and microsomal protein-dependent. Liquid chromatography/mass spectrometry and NMR analysis of the metabonate indicated an extra carbon and unusual formation of an imidazolidine ring. Further studies revealed that this metabonate was not a true biotransformation product from the diamine compound itself in the microsomal incubation, but rather a product resulting from a condensation reaction between the compound and a metabolite of the solvent (alcohol) used in the incubation. When the microsomal incubations contained a small amount of methanol or ethanol as solvent, the alcohols were metabolized to formaldehyde or acetaldehyde, which then condensed with the diamine compound through an imine intermediate to form the metabonate. The compound itself was metabolically stable in vitro when acetonitrile or dimethyl sulfoxide was used as solvent. During the study of in vitro microsomal stability and metabolite identification of amine-containing compounds, the use of alcohol as solvent should be avoided.     

高碳醇复合溶剂萃取麦白霉素工艺研究

研究用异辛醇和稀释荆（4：1，V／V）的混合物代替醋酸丁酯萃取麦白霉素的工艺条件及其经济和技术的优越性。实验结果表明，麦白霉素的萃取溶剂消耗由6．7kg／十亿降至2．4kg／十亿，其生产成本降低达42元／十亿，提取的总收率与用醋酸丁酯时相当，产品质量合格、稳定。同时，革除了从萃余液中回收溶剂的工艺步骤，大大降低了能耗。     

国产伏立康唑调配方法优化及其稳定性研究

目的 筛选注射用伏立康唑的最优调配方法及配伍溶媒,确保用药安全、有效,提高静脉用药调配中心(PIVAS)药品调配的工作效率。方法 采用3种不同的调配方法,方法 A按说明书方法;方法 B专用溶剂反复冲洗西林瓶约6～7次至溶液澄清透明;方法 C注入专用溶剂,强力振荡至溶液澄清透明;并检测各调配方法下药品的残留量、成品输液质量及各调配方法所耗时间;以及模拟成品输液运送过程,观察不同条件下配伍液的外观,检测其pH值、不溶性微粒数和伏立康唑含量变化。结果三种调配方法下,残留量合格率均为100%,方法 A、B、C组残留量分别为(0.004 3±0.000 1)g、(0.004 2±0.000 1)g、(0.0040±0.000 0)g,组间比较,差异无统计学意义(P>0.05);方法 A、B、C组调配时间分别为(33.616 0±0.887 3)s、(2.648 0±0.428 8)s、(1.670 0±0.326 9)s,组间比较,差异有统计学意义(P<0.05)。选用5%葡萄糖注射液作为溶媒,三种调配方法下所得配伍液在8 h内,其外观、pH值、不溶性微粒、主药百分含量均符合规定;与...     

An efficient method for the synthesis of sulbactam pivoxil

Sulbactam pivoxil, a prodrug of the beta-lactamase inhibitor sulbactam, was prepared in high yield by reacting the sodium salt of sulbactam with chloromethyl pivalate in a polar solvent, then diluting the reaction mixture with water and isolating the product by filtration. Dimethyl sulfoxide was found to be the solvent of choice among several aprotic organic solvents.     

Factors Influencing the Retention of Organic Solvents in Products Freeze-Dried From Co-Solvent Systems

Controlling residual solvent levels is a major concern in pharmaceutical freeze-drying from co-solvent systems. This review provides an overview of the factors influencing this process and estimates their potential to reduce residual solvents in freeze-dried products. Decreased solvent contents are potentially correlated with the lower solid content, complete excipient crystallization, higher water solubility, and smaller molecular sizes of the solvent. Although no general rule can be derived for the selection of appropriate freezing conditions, the freezing stage appears to play a major role in subsequent volatile retention. In contrast, diverse secondary drying conditions do not appear to impact the amount of solvent retained in lyophilisates, and modification of this stage is thus not assumed to be expedient. Co-solvents are strongly entrapped in an amorphous product matrix as soon as the local moisture content decreases below a certain level. Thus, the moisture content in the dried product layer adjacent to the sublimation interface might be a key factor. Therefore, extension of the high moisture content period during the primary drying phase as well as a postlyophilization humidification of the dried products are presumably promising approaches to promote solvent release.