美国药典ⅩⅪ版片剂含量均匀度检验方案的统计特性分析

本文根据实测片剂批的含量分布曲线,采用计算机模拟随机抽样方法对USP ⅩⅪ版片剂含量均匀度检验方案诸统计特性进行了分析,并与USP ⅩⅩ版相应方案的统计特性比较,获得了一系列定量结果。结果表明,由于引入统计量RSD,属于计数—计量混合型的USP ⅩⅪ版方案,在判断可靠性上优于属于计数型的USP ⅩⅩ版方案。     

片剂含量均匀度计量检验新方案的研究

本文通过大量测试工作,查明10批国产小剂量片剂的含量分布,在此基础上提出了计量检验新方案。采用计算机模拟随机抽样的方法,通过计算绘制了USP XX,BP,JP和新方案在正态分布和10批实际分布下的OC曲线。结果表明,当用于测定生产规模的片剂批时,与国外片剂含量均匀度计数检验方案中统计特性最优的USP XX方案相比,新方案NEW能在化验工作量相近的前提下,作出更准确的判断;新方案SMA能在不降低判断准确性的前提下,减少化验工作虽约三分之一。新方案还可减免分析方法误差对判定结果的影响。     

美国药典21版及国家药方集16版简介

美国药典(USP)21版及国家药方集(NF)16版已于1985年1月起施行。全书仍将两者合在一起(USPⅩⅪ-NFⅩⅥ)同时改版,这个版本是其历史上规模最大的一部,收载范围划分仍同上版,USP 是药物和制     

片剂含量均匀度试验的初步综述

<正> 一、概述长期以来药典用重量差异限度作检验片剂质量的主要方法。1960年 F.Wiley 提出片重差异不等于有效药物成分的含量差异,他建议采用含量均匀度试验控制片剂质量,这项创见为后来许多研究所证实。1965年美国药典(USP17版)首先采用含量均匀度于8种片剂,USP18版推广应用于     

论校正分析方法系统误差对含量均匀度的影响

用化学统计学方法,研究了药物制剂含量均匀度检查和含量测定,所用不同分析方法之间的系统误差及其校正方法。对中国药典(1985,1990),USP(ⅩⅫ)和JP(Ⅺ)收载的7个片剂品种的研究表明,地高辛片和硝酸甘油片各该不同分析方法之间存在的系统误差包括恒差和比例误差。本文扼要地讨论了确定恒差和比例误差的理论,并提出了相应的实验方法,从而提高了含量均匀度检查的判定准确性。给出的校正公式比USP(ⅩⅪ,ⅩⅫ)的对应公式更合理,更有说服力。     

分光光度法测定复方盐酸苯丙醇胺片含量

复方盐酸苯丙醇胺片是一种防治感冒药。每片由盐酸苯丙醇胺12.5mg,扑尔敏2mg和适量辅料组成。盐酸苯丙醇胺在USP(ⅩⅩ)与BP(1980)上均有收载,含量测定均采用非水滴定法。但扑尔敏的存在会影响片剂测定结果。张景钊等曾报道用二阶导数光谱法进行含量测定,但由于仪器等问题,目     

美国药典29版与中国药典含量均匀度检查方法的比较分析

含量均匀度检查方法在美国药典第17版（USP17）中首次有规定，采用的方法为计数型二次抽样检查法。USP21版中采用的方法由计数型修订为计量-计数混合型二次抽样检查法，由于在USP17～20版的基础上，增加了一个计量参数-相对标准偏差S，USP21版方法判断准确性高于USP17版。目前美国药典（USP）28～29版中颁布了将于2006年4月1日生效的剂量单位含量均匀度检查方法又有了新的修订，引人注目的修改为首次采用了计量型二次抽样检查法（保留了部分特殊剂型如透皮制剂仍采用计量一计数型方法），由于计量型含量均匀度检查方法综合考虑各样本测定值的均值和标准差的关系，在判断可靠性、效率等方面明显优于计数型方法，又一次体现了美国药典修订含量均匀度检查方法的必然性，预计该方法将成为国际药典讨论小组（PDG）和ICH等寻求的统一的含量均匀度检查方法。     

日本药典ⅩⅢ版含量均匀度检查法的统计特性分析

采用计算机模拟随机抽样方法,分析了日本药典第１３版,ＪＰ（ⅩⅢ）,含量均匀度检查法的统计特性,并与其它药典的相应检查法进行了比较．ＪＰ（ⅩⅢ）的含量均匀度检查法为计数－计量混合型的,它采用了样本中单剂含量超出合格限的数目和包括标示量、均值、标准差、接受度系数ｋ不同的两个直线判别式．计量型因素的引入使它的统计特性比ＪＰ（Ⅹ～Ⅻ）大为改善,从而使它继中国药典１９９０,１９９５版之后,再一次显示了以标示量为参考值、二次抽样、计量型含量均匀度检查法的优越性．进一步肯定计量型这个含量均匀度检查法改进方向的正确．     

高效液相色谱法测定格列吡嗪片含量

格列吡嗪为新一代降血糖药,其片剂的含量测定中国药典是UV法[1],USP24版为HPLC法[2]。本文采用HPLC法,以羟苯丙酯为内标,考察了色谱条件和定量的线性范围,对片剂进行了含量测定,结果表明,本法简便,专属性强,利于更好地控制产品质量。     

中国药典（1990）中复方炔诺酮片含量均匀度检查法的统计特性分析

通过大容量样本实验，考察了复方炔诺酮片重和炔诺酮含量的分布类型以及片重与含量的相关性；借助计算机模拟随机抽样方法，绘制出ＵＳＰ（ＸＶＩＩ～ＸＸ），ＢＰ（１９８８）、新方案、中国药典（ｌ９９０，限度为±１５％和±２０％）等含量均匀度检查法的抽样特性曲线，并进行了统计特性分析，表明计量型的含量均匀度检查法优于计数型的。     

八氢吲(口朶)并[2,3-a]喹嗪衍生物的合成

本文报道简化长春胺结构、寻找治疗脑血管疾病有较好疗效的药物。以烯胺Ⅰa,Ⅰb和Ⅰc为起始原料,在C₁位引进羟甲基和羟丙基以及进行酰化等反应,立体选择性地合成了17个结构比长春胺少一个E环的1,2,3,4,6,7,12,12b-八氢-吲哚并[2,3-a]喹嗪衍生物,并分离到3个五环稠合化合物。对于副产物Ⅱ,ⅩⅠⅩ和ⅩⅩ的生成机理作了推测。所合成的化合物进行了小白鼠耐缺氧初筛试验,发现有11个化合物有明显的生物活性,对其它动物的脑血流动力学试验尚在进行中。     

Parametric Two-Stage Sequential Quality Assurance Test of Dose Content Uniformity

The United States Pharmacopeia (USP) content uniformity sampling acceptance plan consisting of a two-stage sampling plan with criteria on sample mean and number of out-of-range tablets is the standard for compendium. It is, however, often used mistakenly for lot quality assurance. In comparison to the Japan Phamacopeia (JP) procedure, USP procedure is less discriminative between lots with on-target mean and small variance and lots with off-target mean and large variance. The new European Pharmacopeia (EP) and USP harmonized test adopted a tolerance interval approach. But the “no-difference zone” criteria modification for off-target products make the approaches biased in favor of off-target products. We propose a parametric tolerance interval procedure to test a two-sided specification that is equivalent to the test of two one-sided hypotheses. Testing against a lower specification is to assure that the drug product is not under-dosed for the sake of efficacy. On the other hand, testing against an upper specification is to assure that the drug product is not over-dosed for the sake of safety. The operating curves of the proposed procedure are compared with those of the USP test to illustrate the difference in acceptance probability against the mean and variance of the lot.     

Parametric two-stage sequential quality assurance test of dose content uniformity

The United States Pharmacopeia (USP) content uniformity sampling acceptance plan consisting of a two-stage sampling plan with criteria on sample mean and number of out-of-range tablets is the standard for compendium. It is, however, often used mistakenly for lot quality assurance. In comparison to the Japan Phamacopeia (JP) procedure, USP procedure is less discriminative between lots with on-target mean and small variance and lots with off-target mean and large variance. The new European Pharmacopeia (EP) and USP harmonized test adopted a tolerance interval approach. But the "no-difference zone" criteria modification for off-target products make the approaches biased in favor of off-target products. We propose a parametric tolerance interval procedure to test a two-sided specification that is equivalent to the test of two one-sided hypotheses. Testing against a lower specification is to assure that the drug product is not under-dosed for the sake of efficacy. On the other hand, testing against an upper specification is to assure that the drug product is not over-dosed for the sake of safety. The operating curves of the proposed procedure are compared with those of the USP test to illustrate the difference in acceptance probability against the mean and variance of the lot.     

Content uniformity testing: suitability of different approaches for marketed low dose tablets

Context: Content uniformity (CU) testing was developed and improved to control the effectiveness and safety of dosage units. Many modifications of compendial CU test have been introduced and several alternatives have been suggested.

Objectives: This study aims to evaluate the degree of suitability of current USP CU test for low dose tablets and to compare the performance of the current test with that of the former USP27-NF22 and other alternatives for different sample sizes.

Methods: All locally marketed risperidone (RSP) tablets were analyzed using newly developed and validated isocratic UPLC method. The CU results were statistically analyzed in groups with sample sizes comparable to the USP sampling plans.

Results: Seven out of eleven products failed the different requirements of the former and current USP <905>chapters as well as of several alternative CU tests with several substantial deviations.

Conclusion: The current USP <905> chapter was found to have some deficiencies that allowed such failed products to exist in the market. The dependence of compendial CU test on two-staged sampling plan and the use of arithmetic mean to calculate the reference and acceptance values were obvious shortcomings.     

Lack of medication dose uniformity in commonly split tablets

OBJECTIVE: To divide 11 commonly split tablets and evaluate the resulting half-tablets for content uniformity. DESIGN: Pre-post comparison. SETTING: Laboratory. Interventions: A trained individual split tablets of 11 products using a single-edged razor blade and 3 products by hand alone. MAIN OUTCOME MEASURES: The Uniformity of Dosage Units test published in the United States Pharmacopeia 24 (USP), which applies to whole tablets, was adapted liberally to assess the dose uniformity of the resulting split tablets. RESULTS: Of the 11 razor-split products, 8 failed the liberal adaptation of the USP uniformity test. No visible tablet features (e.g., scoring) predisposed a product's split tablets to pass or fail the uniformity test. All three hand-split tablets failed the uniformity test and yielded worse results than did razor-split tablets. CONCLUSION: The majority of the 11 drug products we tested, when assessed for their ability to be split into half-tablets of equal dose, failed a liberally interpreted USP uniformity test. The practice of dividing tablets to save costs or to improve a dosage regimen may not cause problems for patients using drugs with low toxicity and relatively flat dose-response relationships, but it is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.     

Comparison of high-performance liquid chromatography and radioimmunoassay in the determination of content uniformity of digoxin tablets

Digoxin 0.25-mg tablets were dissolved and assayed by the standard high-performance liquid chromatography (HPLC) method specified in USP XX and by a radioimmunoassay (RIA) method modified for the assay of tablet solutions. For the RIA method, the filtrate was diluted to a theoretical concentration of 5 ng/ml. Aliquots of this dilution were then assayed for digoxin content using a commercial digoxin 125I RIA kit. Results from both methods were extrapolated to total tablet content and compared with the labeled amount for 20 individual tablets. All tablet assay results were within the USP standards for content uniformity of individual tablets. The individual tablet deviations from labeled amount by the RIA method were smaller when compared with the USP XX-specified HPLC method. Comparison of individual tablet assays show the RIA method to be both as precise and as accurate as the USP XX-specified HPLC method.     

Quality Assurance Test of Delivered Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products

The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products–Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.     

Stability of prednisone tablets submitted by U.S. hospitals

The stability of prednisone tablets that had been stored in hospitals across the United States was studied. Through a voluntary FDA drug stability program, all hospital pharmacies in the United States were asked in October 1982 to complete a response card indicating information about prednisone tablets they had in stock. Based on the responses, FDA selected 117 samples (representing 18 manufacturers and all available tablet strengths) from pharmacies that represented an adequate cross section of the country. The samples were analyzed for content uniformity, strength, identification, dissolution, and the presence of other steroids. All samples met USP requirements for content uniformity and strength. Four samples failed to meet USP requirements for dissolution. Prednisone tablets appear to be stable when stored under actual marketplace conditions.