Solubilization of entecavir by povidone to overcome content uniformity challenges for low-dose tablet formulations

Development of 0.1, 0.5, and 1.0?mg entecavir tablet formulations for the treatment of hepatitis B virus was challenging for content uniformity. Entecavir with pK_a of 2.8 and 9.8 does not have sufficient solubility in acidic or alkaline medium or in common pharmaceutical solvents such as ethanol to dissolve the drug in granulating fluid to prepare the homogeneous granulation. Povidone (PVP), a commonly used binder, was found to increase entecavir solubility depending on the PVP concentration and temperature of the solution. At 15% w/w PVP concentration, entecavir solubility increased from 2?mg/mL to about 8?mg/mL at room temperature. When the PVP solution was heated to 50°C or 70°C, the solubility was increased to about 23 or 33?mg/mL, respectively. Based on Raman spectra of entecavir in PVP solution, the increase in entecavir solubility in the presence of PVP may not be due to any molecular interactions between them. Solubilization of entecavir in PVP and eventual granulation did not change the polymorphic form of the drug based on the powder X-ray and differential scanning calorimetric (DSC), and thermo-gravimetric analysis (TGA) of neat entecavir re-crystallized from the PVP solution. The enhancement in the solubility of entecavir by PVP was sufficient to keep the amount of solution, which was used for granulation, to be about 20% w/w of the batch size like the traditional aqueous granulation. The granulation manufactured using this approach provided better tablet content uniformity than one using micronized entecavir.     

感冒通片的含量均匀度考察

目的　测定感冒通片的含量均匀度。方法　采用紫外分光光度法检测 ,以双氯芬酸钠为含量测定指标 ,提取参数并进行相关性分析。结果　所用方法能理想地测定感冒通片中双氯芬酸钠的含量 ,3个厂家生产的感冒通片的含量均匀度参数之间有极显著性差异 (P <0 .0 1)。结论　有必要增加对该制剂含量均匀度的检查项目。     

HPLC法测定阿普唑仑片的含量及含量均匀度

目的建立HPLC法测定阿普唑仑的含量及含量均匀度。方法采用日本岛津VP-ODS色谱柱(250mm×4.6mm,5μm),以甲醇-水(65∶35)为流动相,检测波长254nm,流速:0.7mL.min-1,柱温:30℃,进样量:10μL。结果阿普唑仑线性范围为8.96～89.6μg.mL-1(r=0.9996),平均回收率为99.7%(RSD=1.2%)。结论本方法灵敏度高,操作简便、可靠,适用于阿普唑仑片的质量控制。     

替米沙坦片含量测定和含量均匀度方法的建立

目的：建立高效液相色谱法（HPLC）法测定替米沙坦片中替米沙坦的含量,并对其含量均匀度进行研究。方法：色谱柱：十八烷基硅烷键合硅胶为填充剂Waters Xbridge C18（4.6mm×150mm,5μm）,以2.0 g/L磷酸二氢铵溶液（用磷酸调节pH值至3.0）-甲醇（30:70）为流动相;流速1.0ml?min-1;检测波长为298nm;柱温40℃;进样体积10μl。测定34个厂家共43批样品。结果：在该色谱条件下,替米沙坦峰与已知杂质峰均能有效分离,辅料不干扰测定,替米沙坦在替米沙坦在0.103～205.7μg?ml-1的浓度范围内与峰面积的线性关系良好,线性方程为y =29927x+18031,r=0.9998（n=9）;回收率为99%（n=9）;稳定性和耐用性良好。结论：建立的含量测定方法专属性强,准确度高,重复性好,适用于替米沙坦片的含量测定和质量控制。     

HPLC法测定盐酸氯丙那林片的含量和含量均匀度

目的:建立HPLC法测定盐酸氯丙那林片的含量和含量均匀度的方法。方法:采用岛津Shim-pack C_(18)色谱柱(4.6mm×150mm,5μm),流动相为甲醇-磷酸盐缓冲液(pH7.0)(6∶4),流速为1.0mL·min~(-1),检测波长为213nm。结果:盐酸氯丙那林在21～420μg·mL~(-1)浓度范围内呈良好线性关系(r=0.9999);平均回收率为100.2%,RSD为1.3%(n=9)。结论:该方法简便、可靠、准确,可用于该制剂的质量控制。     

高效液相色谱法测定硝酸毛果芸香碱片的含量及均匀度

目的：以HPLC法测定硝酸毛果芸香碱片的含量及均匀度。方法：采用Kromasil C18柱，以苯甲酸为内标物，醋酸钠2.94g与衡醋酸38.4ml，加水溶解成600ml(pH4.5)后，加甲醇400ml为流动相，检测波长230nm。结果：硝酸毛果芸香碱的平均回收率为100.5%，RSD为0.8%。结论：方法简便、准确。     

高效液相色谱法测定化痰平喘片中盐酸异丙嗪的含量及含量均匀度

目的建立化痰平喘片中盐酸异丙嗪的含量及含量均匀度的HPLC测定方法。方法色谱柱为DiamonsilC18柱,流动相为乙腈-水-三乙胺（40∶60∶0.3）（用磷酸调pH至4.0）,流速为1.0 mL.min-1,检测波长为249 nm,柱温：30℃,进样量：10μL。结果盐酸异丙嗪在0.61～2.44μg线性关系良好（r=0.9999,n=5）,平均加样回收率为97.6%（RSD=0.9%）。结论该方法简便、准确,可用于该制剂的质量控制。     

HPLC法测定息斯敏片的含量及含量均匀度

目的：建立高效液相色谱法测定息斯敏片的含量及含量均匀度的方法。方法：采用Hypersil—0DS—C18柱，甲醇-水(85：15)为流动相，检测波长为285nm。结果：线性范围40～200μg ml^-1；平均回收率：99．90％，RSD=0．80％。结论：方法快捷，准确，可信性强。     

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。     

Applications of NIR in early stage formulation development. Part I. Semi-quantitative blend uniformity and content uniformity analyses by reflectance NIR without calibration models

This article describes a semi-quantitative reflectance near infrared (SQ-NIR) method for blend uniformity (BU) and content uniformity (CU) analyses in early stage formulation development. Applicability of the method depends upon three factors: separation of NIR signals of the active pharmaceutical ingredient (API) from placebo; strength of the signal; and a quantitative relationship between API concentration and NIR signal. Based on these three criteria, suitable NIR signals of the API, separated from those of placebo through suitable pretreatment of the spectra, can be used for BU and CU calculations without calibration models. The method was applied to an early stage formulation development project. Multiple batches of tablets were prepared and analyzed using the SQ-NIR method and a validated UV–VIS reference method. The SQ-NIR method was able to distinguish between batches that had satisfactory and unsatisfactory content uniformity and potency. In addition, effects of compression force and API particle size on the SQ-NIR results are discussed. It is proposed that the SQ-NIR method may be used as an independent test in early stage formulation development. The advantages and limitations of the method compared with traditional HPLC or UV–VIS methods are also discussed.     

高效液相色谱法测定来曲唑口腔崩解片的含量及均匀度

目的:建立来曲唑口腔崩解片中来曲唑的含量及均匀度的测定方法。方法:以ZORBAXSB-C18(4.6mm×150mm,5μm)为色谱柱,水-乙腈(60∶40)为流动相,流速1.0mL.min-1,检测波长240nm,室温。结果:来曲唑在0.25～16mg.L-1范围内线性关系良好(r=0.9997),平均回收率为100.4%,RSD为0.27%。结论:本法简便,快速,准确,可用于该制剂的质量控制。     

不同过滤方法对富马酸酮替芬片含量和含量均匀度测定的影响

目的 探讨不同的过滤方法对富马酸酮替芬片含量及其均匀度测定的影响.方法 分别用滤纸（LPM-1：弃去初滤液40mL;LPM-2：弃去初滤液50mL）、混合纤维素酯膜微孔滤膜（CFMF）过滤,按〈中国药典〉二部依次测定富马酸酮替芬含量及含量均匀度,并对数据进行比较.结果 不同过滤方法测定4批样品,含量和含量均匀度均符合中国药典的规定,但测定结果存在显著性差异.结论 两种过滤方法操作方便均可选用.     

Determination of content uniformity and distribution characteristics of an investigational drug in its tablets dosage form and granule by ICP-AES

An investigational drug (A) in its calcium salt form has been developed as the tablet dosage form. Monitoring drug distribution and uniformity in granules and tablets during early stage formulation/process development is critical for drug product quality control and process robustness. In this report, an efficient and reliable analytical method for monitoring drug compound A uniformity and distribution has been developed by analyzing calcium, the counter ion of the drug substance, by Inductively Coupled Plasma Atomic Emission Spectrometer (ICP-AES). In this method, calcium in compound A granule and tablet samples was digested with 1 M hydrochloric acid by heating at 90 °C for 2 h. The resulting suspension was centrifuged, and the supernatant was directly aspirated into an ICP-AES. This method has been validated to demonstrate satisfactory precision, accuracy, specificity and sensitivity. Finally, this method has been used to analyze sieve fraction granules and tablets of drug compound A. The data generated were highly comparable to those by validated HPLC methods (UV method can not be applicable due to significant bias). In comparison with HPLC methods, this method demonstrates a significantly improved efficiency with very short analysis time (1 min per sample), and can be used as an excellent alternative for UV and HPLC methods to support formulation screening.     

高效液相色谱法测定苯甲酸利扎曲普坦片含量及含量均匀度

目的采用高效液相色谱法测定苯甲酸利扎曲普坦片含量及含量均匀度.方法色谱条件为Prodigy ODS C18硅烷键合硅胶填充柱(150 mm×4.6 mm,5 μm);流动相为乙腈-0.025%磷酸二氢钾-三乙胺(36∶264∶1),10%磷酸调pH 5.0;检测波长为225 nm;进样量为20 μL;流速为1.0 mL*min-1.结果在进样量为0.101～1.01 μg,样品浓度和峰面积成良好线性关系,r=0.999 9,平均回收率为101.20%,RSD为2.2%. 结论方法灵敏可靠,选择性高.     

RP-HPLC-FLD法测定盐酸氟桂利嗪片中盐酸氟桂利嗪的含量及含量均匀度

目的 RP-HPLC-FLD法测定盐酸氟桂利嗪片中盐酸氟桂利嗪的含量及含量均匀度.方法 采用DiamonsilTM C18柱（250mm×4.6mm,5μm）,以甲醇：0.02mol·L-1磷酸二氢铵（0.1%三乙胺,磷酸调pH至3.0）（70：30）为流动相,流速为1mL·min-1,激发波长260nm,发射波长310nm,柱温为25℃,进样体积10μL.结果 盐酸氟桂利嗪在6.1～122ng（r=0.9992）范围内呈良好的线性关系;平均回收率为100.07%（RSD=1.38%）;LOD和LOQ分别为2.44ng、8.13ng;3批样品的含量均匀度：A＋1.8S分别为5.644、4.194、7.160,均小于15.结论 该方法快速、准确,无内源物质干扰,可为盐酸氟桂利嗪片的质量标准的建立与完善提供科学依据,并指导临床合理用药.     

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.     

复方卡马西平片中氢溴酸东莨菪碱的含量均匀度测定

目的研究复方卡马西平片中氢溴酸东莨菪碱的含量均匀度。方法色谱柱HypersilC6H5(10μm,4.6mm×25cm);流动相0.005mol·L     

高效液相色谱法测定多潘立酮片的含量及含量均匀度

目的建立高效液相色谱法测定多潘立酮片的含量及含量均匀度。方法采用C18(200mm×4.6mm,5μm)色谱柱,甲醇-0.05mol.L-1磷酸二氢钾溶液(55∶45)(用磷酸调节pH值为4.0±0.05)为流动相,检测波长为286nm,流速为0.8mL.m in-1。结果多潘立酮在0.19264μg~2.50432μg范围内与峰面积呈良好的线性关系(r=1.0000,n=7),平均回收率为100.26%(n=7),RSD为0.49%。结论本方法快速、简便,结果准确,可用于多潘立酮片的质量控制。     

Understanding the mechanism for paradoxical effect of ionized and unionized chitosan: Orodispersible tablets of Ondansetron Hydrochloride

The objective of the present investigation was to formulate and evaluate orodispersible tablets (ODTs) of ondansetron HCl possessing sufficient mechanical strength by wet granulation or direct compression method. A combination of glycine and chitosan was employed for providing a sweet tasting disintegrating system. The evaluation of ODTs prepared by a wet granulation method revealed that in vitro disintegration time (DT) as well as wetting time (WT) increased and water absorption ratio (WAR) decreased with an increase in concentration of chitosan (as binder). However, an opposite relationship was obtained when ODTs were prepared by direct compression method. The FTIR spectra and DSC analysis indicated that the ?NH₃⁺ moieties of chitosan interacted with COO^? moieties of glycine in ODTs prepared by the wet granulation method. However, chitosan was found to be present in the unionized state in ODTs prepared by direct compression method. Furthermore, in vitro as well as in vivo disintegration tests revealed that ODTs containing the chitosan-glycine mixture were superior to those containing well known superdisintegrants. The results suggested that the chitosan-glycine system not only improved disintegration time but also made it possible to prepare ODTs with higher crushing strength as compared to tablets containing superdisintegrants.