采用不同介质中的溶出曲线评价硫酸氢氯吡格雷片的内在质量

目的 比较硫酸氢氯吡格雷片仿制药与原研药在4种不同溶出介质中溶出曲线的相似性。方法 分别以pH 2.0盐酸缓冲液、pH 4.5磷酸盐缓冲液、pH 6.8磷酸盐缓冲液和水为溶出介质测定2种片剂的体外溶出曲线,并采用f₂相似因子法考察其相似性。结果 在4种不同溶出介质中,2种片剂溶出曲线的f₂值分别为56,80,78和75。结论 2种片剂的体外溶出曲线在4种不同溶出介质中均相似。     

硫酸氢氯吡格雷杂质D的合成

目的 合成硫酸氢氯吡格雷杂质D。方法 以右旋邻氯苯甘氨酸为原料,经过氨基保护、与(R)-2-氯扁桃酸甲酯成酯、脱保护后得到(2R)-(2-氯苯基)-[(2S)-(2-氯苯基)-(2-氨基)乙酸酯基]乙酸甲酯,再与2-(2噻吩)乙醇对甲苯磺酸酯发生亲核取代反应后,经成盐、环合反应得到硫酸氢氯吡格雷杂质D。结果 设计合成杂质D路线总收率为54%,杂质D纯度在99.0%以上。结论 合成杂质D产品纯度较高,可用作硫酸氢氯吡格雷杂质研究对照品。     

硫酸氢氯吡格雷片的制剂工艺研究

目的：本论文通过对硫酸氢氯吡格雷片制剂工艺研究,找到最佳原辅料配比。方法对硫酸氢氯吡格雷片的脆碎度、溶出度进行检测,评价包衣效果。结果开发出最优处方：硫酸氢氯吡格雷原料药32.75%、羟丙甲纤维素K4M 1%、微晶纤维素55%、羧甲基淀粉钠7%、十二烷基硫酸钠4%和硬脂酸镁0.25%。结论硫酸氢氯吡格雷片符合标准。     

提高硫酸氢氯吡格雷片内在质量

目的比较硫酸氢氯吡格雷片在研药与原研药在四种溶出介质中的溶出曲线,计算f2相似因子,从而提高在研硫酸氢氯吡格雷片内在质量。方法分别测定2种片剂在p H 1.2盐酸缓冲液、p H 6.8磷酸盐缓冲液、p H4.5磷酸盐缓冲液和水中的溶出曲线,通过f2相似因子确定相似性。结果在四种溶出介质中的f2相似因子分别为71.4、51.8、86.8、60.1。结论在研药与原研药在四种溶出介质中的溶出曲线相似。     

硫酸氢氯吡格雷片剂的体外溶出度测定

目的 以原研厂家的市售品为参比制剂,测定自制硫酸氢氯吡格雷片剂的溶出曲线,并比较体外溶出行为的相似性.方法 参考USP31-NF26版硫酸氢氯吡格雷片剂质量标准,分别测定规定时间点的累积溶出度,采用f2因子来评价体外溶出行为的相似性.结果 自制品和参比制剂在30 min内,累积溶出度均达到90%以上,符合规定的限度(80%);当参比制剂平均溶出度分别为60%和85%的两个时间点时,自制片和参比片溶出度比较,分别相差8.2%和5.2%.结论 自制硫酸氢氯吡格雷片剂和参比制剂体外溶出行为一致.     

具有区分力的罗红霉素片体外溶出度方法研究

目的 研究罗红霉素片的溶出行为,确定有区分力的溶出度检查方法。方法 考察罗红霉素在不同pH溶液中的稳定性及溶解度,测定不同处方自研制剂与参比制剂在4种不同溶出介质中的溶出度,绘制溶出曲线,用相似因子法进行拟合。结果 罗红霉素在pH6.8和7.4磷酸盐缓冲液中8 h内稳定性较好,自研制剂A与参比制剂在4种溶出介质中的溶出曲线均具有较好的相似性,自研制剂B与参比制剂在pH 6.8磷酸盐缓冲液中的溶出曲线不相似。结论 以pH 6.8磷酸盐缓冲液为溶出介质,采用浆法测定,75 r/min对本品溶出具有较好的区分力,可为本品的质量控制和一致性评价提供参考。     

伊潘立酮片溶出度一致性评价研究

目的 考察自制伊潘立酮片（1 mg规格）与参比制剂的溶出度一致性。方法 用HPLC法测定伊潘立酮在不同pH溶出介质中的溶解度,绘制伊潘立酮“pH-溶解度”曲线,测定自研制剂与参比制剂在4种不同pH溶出介质（0.1 mol/L HCl溶液、pH 4.5醋酸盐缓冲液、pH 6.8磷酸盐缓冲液、水）中的溶出度,绘制溶出曲线,用相似因子法进行拟合。结果 在所选4种溶出介质下,自研制剂与参比制剂的溶出曲线相似因子f₂值均大于50。结论 自研制剂与参比制剂能够达到体外溶出一致。     

复方硫酸氢氯吡格雷阿司匹林双层片的制备和溶出度测定

目的建立复方硫酸氢氯吡格雷阿司匹林双层片的制备和溶出度测定方法,通过比较自制品和市售产品的体外溶出行为,考察其有效性。方法制备复方硫酸氢氯吡格雷双层片,采用反相高效液相色谱法测定含量。色谱条件:色谱柱为Ultimate XB-C18柱(250mm×4.6mm,5μm),流动相为乙腈-水-磷酸(体积比40∶60∶2),检测波长为235nm,流速为1.0mL·min-1;采用桨法,以pH值2.0盐酸缓冲液为溶出介质,转速为75 r·min-1测定溶出度;采用f2因子比较法,考察体外溶出行为。结果硫酸氢氯吡格雷和阿司匹林的质量浓度在20~200mg·L-1内与峰面积具有良好的线性关系(r=0.999 9)。硫酸氢氯吡格雷与阿司匹林的平均回收率分别为100.2%和99.8%。自制品和市售品的溶出曲线一致。结论制备方法简单易行。所建立的溶出度测定方法专属、高效、简便,可用于测定复方硫酸氢氯吡格雷阿司匹林双层片的溶出度。     

氯氮平片的溶出曲线考察

摘 要 目的： 考察氯氮平片在4种不同pH溶出介质中的溶出行为与参比制剂之间的差异,比较不同厂家药品的内在品质,为药品质量控制提供参考。方法: 通过体外溶出度试验,测定18家企业生产的46批氯氮平片在4种不同pH的溶出介质中的溶出曲线,用相似因子（f₂）法与参比制剂进行比较。结果: 共绘制46条溶出曲线,与参比制剂完全相似的批次仅占4%（一个企业的2个批次）,其余样品与参比制剂的溶出行为不一致。结论:目前国内该品种生产工艺差异较大,溶出行为与参比制剂存在差异。生产企业应加强处方工艺的筛选、优化,提高改进生产工艺。     

硫酸氢氯吡格雷片的制备及其处方工艺优化

目的:制备硫酸氢氯吡格雷片并优化其处方工艺。方法:采用单因素试验联合相容性试验对片剂的填充剂、崩解剂、黏合剂、润滑剂和制备方法进行筛选;以黏冲情况和崩解时间的综合评分为指标,采用正交试验优选崩解剂[低取代羟丙基纤维素(L-HPC)]、润滑剂(氢化植物油和聚乙二醇6000)的用量,并进行验证;考察所制片剂与进口制剂(波立维)在水、p H 2.0盐酸盐缓冲液、p H 4.5磷酸盐缓冲液(PBS)、p H 6.8 PBS中的溶出情况并进行影响因素试验。结果:采用干法制粒,最优处方(1 000片)为硫酸氢氯吡格雷97.8 g、甘露醇84 g、预胶化淀粉36 g、L-HPC 8 g、氢化植物油8 g、聚乙二醇6000 6 g;所制片剂压片无黏冲现象且崩解时间适中,其与波立维在4种溶出介质中溶出曲线均相似;影响因素试验结果与波立维比较无明显差异。结论:成功制得硫酸氢氯吡格雷片,且处方合理、工艺可行、质量稳定可控。     

两种晶型硫酸氢氯吡格雷片稳定性的比较

目的建立高效液相色谱法测定硫酸氢氯吡格雷片中的有关物质,并对2种晶型片剂的稳定性进行考察。方法采用ULtron ES-OVM手性色谱柱(150 mm×4.6 mm,5μm),流动相:0.01 mol.L-1磷酸二氢钾溶液-乙腈(体积比为75∶25),流速:1.0 mL.min-1,进样量:10μL,检测波长:220 nm,柱温:25℃。结果在该色谱条件下,杂质A、杂质B的第一个异构体(杂质B1)、杂质C质量浓度分别在0.3～3.0、0.45～4.50、1.4～14.0 mg.L-1内与峰面积呈良好的线性关系,硫酸氢氯吡格雷与杂质B1之间的分离度大于2.5。稳定性试验表明,在高温条件下,两种晶型硫酸氢氯吡格雷片中杂质B、C含量明显增加,晶型I杂质A略有增加;在高湿条件下2种晶型均易产生杂质A;在光照条件2种晶型的杂质均未明显增加。结论高温是影响2种晶型硫酸氢氯吡格雷片稳定性的主要因素,2种晶型中Ⅱ型硫酸氢氯吡格雷片稳定性更佳。     

Comparison of antiplatelet effect and safety of clopidogrel napadisilate with clopidogrel bisulfate in stroke patients: multicenter,randomized, open-label,phase 4, non-inferiority clinical trial

Objective:

Clopidogrel napadisilate has better chemical stability than clopidogrel bisulfate. Our trial’s objective was to compare the efficacy and safety of clopidogrel napadisilate with clopidogrel bisulfate in participants with ischemic stroke.

Research design and methods:

The study was a phase 4, 4 week, randomized, parallel-group, non-inferiority trial. Patients with ischemic stroke were randomized to receive either clopidogrel napadisilate 75?mg or clopidogrel bisulfate 75?mg. The primary study endpoint was change from baseline in P2Y12 percentage inhibition at week 4. The primary analysis was conducted in the per-protocol population. Non-inferiority was confirmed if the lower limit of the 95% confidence interval (CI) of the treatment difference was greater than or equal to ?9.0% points.

Results:

Sixty-one participants were randomly assigned clopidogrel napadisilate and 60 were randomly assigned clopidogrel bisulfate. Thirty-nine participants in the clopidogrel napadisilate group and 39 in the clopidogrel bisulfate group were analyzed for the primary endpoint. At 4 weeks, mean P2Y12 percentage inhibition had increased in both treatment groups. The estimated mean change from baseline was 22.3% with clopidogrel napadisilate and 21.4% with clopidogrel bisulfate; the estimated treatment difference of 0.9% (95% CI, ?8.6 to 10.4) confirmed the non-inferiority of clopidogrel napadisilate to clopidogrel bisulfate.

Conclusions:

Clopidogrel napadisilate was non-inferior to clopidogrel bisulfate as assessed by change in P2Y12 percentage inhibition. Rates of adverse events were similar between the two groups. Therefore, clopidogrel napadisilate is a useful alternative option for the dosing of ischemic stroke patient populations.     

Design and in vitro evaluation of oral colon targeted drug delivery systems for tinidazole

The aim of the present investigation is to develop colon targeted drag delivery sytems for tinidazole using guar gum as a carrier in the treatment of amoebiasis. Fast-disintegrating tinidazole core tablets were compression-coated with 55, 65 and 75% of guar gum. All the formulations were evaluated for the hardness, drug content uniformity, and subjected to in vitro drug release studies. The amount of tinidazole released from tablets at different time intervals was estimated by HPLC method. The compression-coated formulations released < 0.5% of tinidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 55% of guar gum coat released 99% of tinidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 65 and 75% of guar gum coat released about 67 and 20% of tinidazole, respectively in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated tinidazole tablets with either 55 or 65% of guar gum coat is most likely to provide targeting of tinidazole for local action in the colon owing to its minimal release of the drug in the first 5 h of physiological environment of stomach and small intestine. The tinidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months.     

枸橼酸他莫昔芬片的制备及质量评价

目的 探索枸橼酸他莫昔芬片的处方和制备工艺,并对其进行质量评价。方法 通过考察填充剂比例、黏合剂浓度、崩解剂用量、润滑剂用量、颗粒大小和水分含量等,筛选最优处方比例及制备工艺。制备若干批枸橼酸他莫昔芬片（1 000片/批）,对颗粒休止角、药物晶型、片质量差异、硬度、崩解时限、含量等进行质量评价;同时,建立多条溶出曲线利用相似因子法评价自制片与参比制剂的相似性。结果 选用本处方和工艺条件制备的枸橼酸他莫昔芬片质量符合中国药典2015年版中的相关质量要求;4种溶出介质中溶出曲线的相似因子f₂值均>50。结论 枸橼酸他莫昔芬自制片与参比制剂具有体外溶出一致性。     

Stability of sodium valproate tablets repackaged into dose administration aids

Objectives Since sodium valproate, a commonly used antiepileptic drug, has been reported to be unstable in the presence of moisture, our objective was to investigate the effect of repackaging into dose administration aids. Methods Sodium valproate 100 mg immediate‐release tablets were repackaged and stored for 56 days at accelerated conditions (40°C/75% relative humidity), room temperature (25°C) and under refrigeration (2–8°C). Samples were analysed at 3, 7, 10, 14, 21, 35, 49 and 56 days to determine chemical stability using high‐performance liquid chromatography, while physical testing included assessment of weight changes and dissolution behaviour. Key findings The results revealed that the sodium valproate content in the tablets remained within the acceptable range of 90–110% under all storage conditions for 56 days. Physical stability, however, was not maintained, with a total weight gain of 12.36% under accelerated conditions over the 56 days. Samples stored under all conditions showed variable dissolution compared to the controls, with the amount of sodium valproate in solution following 45 min of dissolution testing below 75% for half of all the intervals determined. Conclusions Repackaging sodium valproate tablets into dose administration aids results in unacceptable weight variation and changes in the dissolution profiles.     

Correlation and Prediction of Moisture-Mediated Dissolution Stability for Benazepril Hydrochloride Tablets

PURPOSE: This report investigated dissolution stability of benazepril hydrochloride tablets. METHODS: Reduction in dissolution rate was observed for benazepril hydrochloride tablets when they were subjected to stressed storage condition (40 degrees C/75% RH) for prolonged periods of time (1-3 months). Moisture contents of initial and stressed tablets were measured by Karl Fischer method. Comparative thermal and physical characterizations of initial and stressed tablets were also performed. A mathematical model that was used to predict possible reduction in dissolution rate was proposed and validated using experimental data. RESULTS: It was found that there was a direct correlation between moisture content of benazepril hydrochloride tablets and their percentage of dissolution at 10 min. At moisture content below 3.5%, there were no significant changes in dissolution values. Beyond that point, however, a close to linear decrease in dissolution was observed as a function of increase in moisture content. Results from thermal and X-ray analysis have ruled out possible changes in drug substance. Other physical characterization, such as scanning electron microscope and mercury porosimetry measurements, revealed changes in core structure of stressed tablets vs. initial tablets. Based on results from these measurements, "preactivation" of disintegrant was identified as the mechanism for reduction in dissolution rate above critical moisture content. A simple physical model for moisture uptake of benazepril hydrochloride tablets was also proposed for predicting when, based on water vapor transmission and critical moisture content, dissolution rate will decline. CONCLUSIONS: Physical changes of tablets mediated by moisture were the main cause for reduction in dissolution. Inclusion of desiccant, although beneficial, cannot prevent reduction in dissolution completely. The simple physical model proposed in this report was found to be useful in predicting the dissolution stability of the dosage form.     

Preparation,properties and ageing of tablets prepared from the chlorpropamide-urea solid dispersion

Tablets have been prepared from the solid dispersion of 30% chlorpropamide and 70% urea. Granulation was accomplished using two formulations at 100°C. The melt acted as binder and hard tablets were produced whose dissolution properties were superior to those of traditional wet granulated products. Initial dissolution rates of 11.5 and 7.5 mg min^?1 were obtained from tablets containing the solid dispersion of chlorpropamide and compressed at 150 MNm^?2 whereas a rate of only 3.2 mg min^?1 was obtained from the wet granulated product similarly compressed. During dry storage the melt-granulated tablets became harder due to crystallization of the melt. Disintegration times generally decreased and dissolution rates decreased during the intitial two months of storage at 25°C and 35°C but, thereafter increased. Subsequently, the melt-formulated tablets were more sensitive to moisture during storage than the wet-granulated tablets.     

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

Purpose

This study aims to investigate the influence of different storage humidity conditions on crystallization and aerosol performance of inhalable spray dried amorphous powder formulations (Ciprofloxacin hydrochloride as the model drug).

Methods

The spray dried samples were stored at 20%, 55% and 75% relative humidity (RH). Crystallinity was monitored by Powder X-ray diffraction (PXRD), and particle morphology was measured by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Aerosol performance was evaluated using a multi-stage liquid impinger (MSLI).

Results

PXRD diffractograms showed the spray dried Ciprofloxacin stored at 20% RH for three weeks were amorphous; whereas those stored at 55% RH and 75% RH started crystallizing after one hour. Fine particle fraction (FPF) of the particles was improved from 28% to 42% after storage at 55% RH for three days. Such improvement was attributed to the crystallization of amorphous powders, which led to increased particle roughness and reduced particulate contact area, as visualized by SEM and quantified by AFM. A linear relationship was observed between degree of crystallinity/crystallite size and FPF (R²?=?0.94 and R²?=?0.96, respectively). However, deterioration in aerosol performance was observed after storage at 75% RH due to formation of inter-particulate liquid/solid bridges, as confirmed by SEM.

Conclusions

This study provides a fundamental understanding in moisture-induced physical and aerosol instability of the spray dried powder formulations.

     

Gastroretentive mucoadhesive tablet of lafutidine for controlled release and enhanced bioavailability

Abstract

Lafutidine a newly developed histamine H2-receptor antagonist having biological half-life of 1.92?±?0.94?h due to its selective absorption from upper part of gastrointestinal tract the development of mucoadhesive sustained release drug delivery system is recommended in order to enhance the bioavailability. A mucoadhesive tablets was developed using the natural polymer, sodium alginate, xanthan gum and karaya gum. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. The prepared tablets of various formulations were evaluated for a total mucoadhesion time, buoyancy lag time and percentage drug released. The formulation with xanthan gum showed better results. Thus, it may be useful for prolonged drug release in stomach to improve the bioavailability and reduced dosing frequency. Non-fickians release transport was confirmed as the drug release mechanism from the optimized formulation by Korsmeyer–Peppas. The optimized formulation (B3) showed a mucoadhesive strength >35?g. In vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences suggest that, a formulated tablet was well adhered for >10?h in rabbit’s stomach. Optimized lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug content, mucoadhesive properties and in vitro dissolution pattern after storage at 40?°C temperature 75?±?5% relative humidity for 3 months.