Developing Quantitative In Vitro–In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method

This study is to evaluate 3 fenofibrate (FEN) formulations including Fournier® 200 mg capsule, Lipidil® 145 mg tablet, and a clinical HME 160 mg tablet by an in vitro biphasic method. Key experimental parameters were evaluated including the selection of biorelevant media, the United States Pharmacopeia IV flow rate, and the United States Pharmacopeia paddle speed. Varying the hydrodynamic condition resulted in a significant impact on FEN concentration time profiles in both aqueous and octanol phases for these formulations. In vivo pharmacokinetic profiles of the HME tablet, the Lipidil tablet, and Fournier capsule under the fasting and low-fat fed states are reported. Their corresponding absorption-time profiles were obtained through deconvolution by the Wagner-Nelson method. When fed state simulated intestinal fluid version 2 was used, the partitioned FEN amount–time profiles in octanol from the 3 formulations under an appropriate hydrodynamic condition exhibited a good agreement with their in vivo absorbed amount–time profiles, permitting a quantitative in vitro–in vivo correlation. When fasted state simulated intestinal fluid version 2 was used, partitioned FEN amounts into octanol from these formulations are significantly lower than those from in vivo data. Although no food effect was observed for both HME and Lipidil tablets, the positive food effect of the Fournier capsules significantly overestimated by the biphasic test.     

Stable and Fast-Dissolving Amorphous Drug Composites Preparation via Impregnation of Neusilin® UFL2

A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin^® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin^®. The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin^® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs.     

Mechanistic Basis of Cocrystal Dissolution Advantage

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.     

制片压力对不同厂家尼群地平片溶出度的影响

目的考查制片压力对市售不同厂家来源的尼群地平溶出度的影响,为片剂生产工艺流程提供参考。方法参考中国药典（2010版）方法,以0.1 mol·L-1盐酸溶液—乙醇（70∶30）900 mL为溶出介质,采用紫外—可见分光光度法,以尼群地平片含量为指标,测定不同厂家尼群地平片体外溶出度,并用相似因子法对实验数据进行统计分析。结果 5个厂家尼群地平片的溶出度存在差异,以金陵药业产品为对照,结果显示F2均小于50,而经过改进压片时压力后,溶出度基本一致。结论不同厂家生产的尼群地平溶出度有一定的差异,制片压力对其影响较大。在生产时应作参考,确保药品质量安全有效。     

高效液相色谱法测定甲硝唑片的溶出度

目的：采用高效液相色谱法测定甲硝唑片的溶出度。方法高效液相色谱法外标法,以C18化学键和硅胶为固定相,以甲醇-水（20：80）为流动相,检测波长320nm,柱温30℃,流速1.0ml/min。结果甲硝唑在线性范围0.05-0.5mg/ml内与峰面积有良好的线性关系（R=0.9999）。结论实验证明此方法简便并能准确测定甲硝唑片的溶出度。     

喷雾干燥法制备阿司匹林固体分散体及其胶囊制备与体外特性研究

目的 制备阿司匹林固体分散体及其胶囊,提高其溶出度。方法 以聚乙烯吡咯烷酮(PVP K 30)为载体,采用喷雾干燥法制备阿司匹林固体分散体,测定溶出度,采用X-射线衍射和扫描电镜(SEM)考察药物在载体中的分散状态,测定比表面积;制备阿司匹林固体分散体胶囊,考察胶囊的体外溶出度。结果 与阿司匹林原料药、阿司匹林物理混合物相比,阿司匹林固体分散体中药物的溶出度均有显著提高,且载体比例越大,药物溶出越快,但药物和载体比例达1∶6以上时,溶出度增加不再明显。阿司匹林以无定型或分子形式高度分散在载体中,药辅比在l∶6时,阿司匹林固体分散体比阿司匹林原料药的比表面积增大3.2倍;制成固体分散体胶囊后,30 min时药物累积溶出度达99.8%。结论 该固体分散体制备工艺可行,制备的胶囊质量可控。     

消渴脉康颗粒质量标准研 究简

目的 建立消渴脉康颗粒的质量控制方法.方法 采用薄层色谱（TLC）法对组方中牛膝、丹参、枸杞子、桑寄生、延胡索和黄芪进行定性鉴别,采用高效液相色谱（HPLC）法对芍药苷进行定量测定.结果 薄层色谱清晰,分离良好,阴性无干扰.芍药苷的平均回收率为96.95％,RSD为1.81％.结论 该方法简便易行、灵敏准确、专属性强,可用于消渴脉康颗粒的质量控制.     

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (T_g) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated.FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a T_g of 101.2 °C, whereas the T_g for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days.The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively.The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster T_max compared to the solution and amorphous and crystalline free acid. C_max for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster T_max compared to the amorphous and crystalline free acid.     

光纤传感过程分析利巴韦林片的溶出度

目的:建立过程分析利巴韦林片溶出度的方法。方法:参照《美国药典》中利巴韦林片的溶出条件,采用光纤传感药物溶出度实时测定仪建立利巴韦林片的溶出度分析方法(简称FODT法),并与《美国药典》方法进行比较;同时建立可测定3种不同规格(0.02、0.05、0.1 g)利巴韦林片溶出度的FODT法条件(探头规格、检测波长);另外对11批不同厂家产品进行了考察。结果:两种方法所得溶出度结果均符合要求,但采用FODT法可以观察不同厂家样品及同一厂家不同片之间药物实时溶出情况的差异;3种规格样品采用FODT法时的探头规格和检测波长分别为5、2、1 mm和210、228、234 nm。结论:所建立的测定利巴韦林片溶出度的FODT法能够直观有效地监测药物的溶出过程,连续定量地反映了样品的体外溶出特性。     

苯妥英钠片溶出度试验方法的改进

目的:建立测定苯妥英钠片溶出度新的、稳定的方法,同时考察12个厂家247批苯妥英钠片的溶出度。方法:以pH 10.0缓冲液(硼砂-氢氧化钠)500 ml代替《中国药典》中的水为溶出介质,转速为50 r/min,取样时间为30 min,光纤溶出仪测定,采用0.5 cm探头,检测波长为258 nm;同时比较苯妥英钠在水和缓冲液中24 h的稳定性及采用《中国药典》方法与新方法测得的溶出度结果。结果:苯妥英钠检测质量浓度线性范围为0.032⁰.320 mg/ml(r=0.999 9),回收率为101.5%(RSD=0.4%,n=3)。苯妥英钠在水和缓冲液中24 h的吸光度的RSD分别为2.9%、0.3%(n=6);新方法检测247批样品不合格率为8.1%,而《中国药典》方法检测样品全部合格。结论:新方法更能体现出不同厂家和批号之间样品的溶出差别,并且检测溶液的稳定性更好,能够更好地对全国样品进行监测。