激光散射法测定布洛芬混悬液粒度的研究

目的 建立激光散射法测定布洛芬混悬液中布洛芬的粒度及粒度分布的方法。方法 使用Malvern Mastersizer 2000激光粒度分析仪,Hydro 2000SM进样器;背景及样品的扫描时间为15 s,搅拌速率为850 r/min;分散剂为水,以辅料溶液为背景测试样品溶液;颗粒折射率为1.400～1.500;颗粒的吸收率为0.001;遮光度为5%～20%。结果 激光散射法可以测定布洛芬混悬液的粒度及其分布,由体积平均粒径D(4,3)可以直观地表征不同批号的布洛芬混悬液中布洛芬颗粒的大小差异,由d(0.1)、d(0.5)、d(0.9)数值表示其粒度分布的特征。方法学考察结果和样品测定结果的d(0.1)、d(0.5)和d(0.9)的RSD均小于8%。结论 本方法适合布洛芬混悬液中布洛芬药物的粒度及粒度分布的测定。     

叶酸粒度分布的激光衍射测定法研究

目的 建立一种激光衍射法用于测定叶酸粒度分布。方法 采用Malvern MS3000激光衍射法粒度分析仪和HYDRO EV湿法进样器,研究并优化重要的光学参数和样品分散条件(分散剂的选择、样品浓度、遮光度、搅拌速度、背景和样品测量时间、样品分散时间、超声方式),并对最终建立的方法进行验证。结果 参数设置确定为叶酸折射率1.76;叶酸吸收率0.1;分散介质水;水的折射率1.33;分析模式,通用模式;灵敏度普通;搅拌速度3000 r·min^-1;测量次数6;背景测量时间10 s;分散时间30 s;样品测量时间10 s;遮光度5%～7%。方法验证的d(0.1)和d(0.9)结果RSD≤15%(n=6),d(0.5)结果RSD≤10%(n=6),均符合USP〈429〉规范。结论 该法准确度、重现性和精密度良好,适用于各厂家叶酸原料药粒径的测定。     

激光粒度仪测定环索奈德粒度分布的应用研究

目的 建立激光粒度仪测定环索奈德粒度分布的测定方法。方法 采用马尔文2000激光粒度仪，以浓配法配制供试品溶液，表面活性剂浓度为0.01%(W/W)吐温20，分散介质水500mL，遮光度界限为10%~15%，泵转速为2000r/min，超声能量为12.5，超声定时120s，样品测量时间10s，样品测量快照10000，背景测量时间10s，背景测量快照10000。结果 3批样品中环索奈德粒径分布特征值d0.1、d0.5和d0.9平均值分别为1.215、2.726和5.734μm，平均标准差分别为0.086、0.186和0.251μm，测定结果与显微镜法基本一致。结论 本法快速、简便、重现性好、精密度高，适用于微粉化活性成份环索奈德的粒度测定。     

研究蒙脱石原料及其散剂的粒度与晶体杂质

目的:建立更为有效的激光粒度法与X-射线衍射法测定国产蒙脱石原料及其散剂的粒度与晶体杂质。方法:粒度测定:使用马尔文2000激光粒度仪,在800 mL水中以3000 r·min-1搅拌15 min,湿法测定。晶体杂质测定:采用X-射线衍射法;阴极:铜;滤过片:镍;电源:45 kV、40 mA;狭缝:0.1°;衍射角(2θ)从2°到80°扫描。结果:考察的5个企业15批蒙脱石原料中,60%均检出致癌物方英石;生产蒙脱石散的20个企业样品65%的产品检出方英石。结论:激光粒度法更为真实地反映了蒙脱石粒度的分布情况,可明显区分不同企业蒙脱石粒度的差别。X-射线衍射法可有效控制蒙脱石及其散剂中致癌物方英石的量。     

应用激光散射法测定西洛司特粒度分布

目的用激光散射法测定西洛司特粒度分布,考察不同试验条件对结果的影响。方法取西洛司特150mg,用0.1%吐温-20溶液20 m L预分散后以水为分散剂测定,泵速2 100 rpm,颗粒折射率1.52,颗粒吸收率0.1,分散剂折射率1.33,背景/样品测量时间12 s。结果 3批样品的测定结果,d(0.1)、d(0.5)和d(0.9)分别为16.552、16.235、16.417μm;38.775、38.426、38.302μm;71.455、71.487、71.279μm。结论本试验方法可用于测定西洛司特粒度分布,结果重现性好。     

激光散射法测定阿维A原料药粒度

目的：建立测定阿维A原料药的粒度及其分布的方法。方法：采用Malvern Mastersizer2000激光粒度分析仪、Hydro 2000MU湿法进样器,以《中国药典》粒度和粒度分布测定法中的光散射法进行阿维A原料药的粒度分析并进行方法学考察,泵速为1500r/min,遮光比为5%～15%,背景与样品的扫描时间为5s,样品折射率为1.569,样品吸光率为0.01。结果：方法学考察结果d（0.5）的RSD均〈3%,d（0.1）和d（0.9）的RSD均〈5%;4批阿维A原料药的d（0.1）均小于5μm,d（0.5）均小于10μm,d（0.9）均小于20μm,符合《中国药典》相关要求。结论：该方法简便、准确、重复性好,适用于阿维A原料药的粒度控制。     

布地奈德鼻喷雾剂粒度分布的测定及一致性分析

目的:建立布地奈德鼻喷雾剂样品粒度分布的测定方法,并分析其粒度分布的一致性。方法:以水为分散剂,搅拌(1 800 r/min)分散;分别以累积粒度分布为10%、50%、90%所对应的粒径[d(0.1)、d(0.5)、d(0.9)]为特征值。采用光散射法测定样品的粒度分布,并采用SAS 9.3统计软件分析2个厂家(A和B)样品间、同一厂家不同批次间及同一批次内样品粒度分布的一致性。结果:A厂3批样品d(0.1)平均值为3.96μm,d(0.5)平均值为29.58μm,d(0.9)平均值为67.10μm;B厂3批样品d(0.1)平均值为2.00μm,d(0.5)平均值为7.53μm、d(0.9)平均值为28.51μm。通过分析得出,2个厂家样品粒度分布差异较大,A厂样品的粒径大于B厂;B厂样品各批次之间的一致性好于A厂;2个厂家各批次内的一致性均较好。结论:所建立的方法适用于测定布地奈德鼻喷雾剂的粒度分布,并可用于分析其粒度分布的一致性。     

激光散射法测定替格瑞洛原料药的粒度分布

目的：建立激光散射法测定替格瑞洛原料药的粒度分布。方法：采用 Malvern Mastersizer 2000激光粒度分析仪;Hydro 2000MU湿法进样器。样品折射率：1.52;样品吸光率：0.1;分散介质(水)折射率：1.33;泵速：1800rpm/min;超声频率：10;测量次数：3次;测量时间：5S;背景时间：5S;遮光度：10%-20%。结果：方法学考察结果d(0.5)的RSD＜2%,d(0.1)和d(0.9)的RSD均＜2%,3批替格瑞洛中试样品的d(0.1)≤2μm,d(0.5)≤5μm及d(0.9)≤15μm,符合《中国药典》的要求。结论：该方法操作简便、准确度高、耐用性好,适合替格瑞洛原料药的粒度检测。     

激光散射法测定酪酸梭菌肠球菌三联活菌散粒度的探讨

摘 要 目的：建立测定酪酸梭菌肠球菌三联活菌散粒度分布的激光散射法,并与筛分法进行比较。方法: 激光散射法测试条件为：振动进样速度为80%,分散气压为0.05 MPa,背景及样品的扫描时间为15 s,遮光度为0.5%～5%,颗粒折射率为1.55,颗粒吸收率为0.01,进样量为0.1～0.2 g。测定粒度分布的特征值粒子体积累计分布图中10%、50%、90%处的粒径值[d（0.1）、d（0.5）、d（0.9）]和体积平均粒径D[4,3]。结果: 方法学考察中d（0.1）、d（0.5）、d（0.9）的RSD均小于5%。激光散射法结果显示93.3%的样品粒径小于250 μm,64.2%小于150 μm,51.4%小于125 μm,31.3%小于90 μm;筛分法结果显示96.6%的样品粒径小于250 μm,46.4%小于150 μm ,23.5%小于125 μm,1.4%小于90 μm。结论:筛分法和激光散射法均可以表征样品的粒度分布,但是激光散射法较筛分法的优点是样品量少、重复性好、测量速度快、测量范围广,可以全面表征样品的粒度分布。     

激光散射法测定乳糖的粒度

目的：确定激光散射法测定乳糖粒度分布，并与传统的筛分法进行比较。方法：Malvem Mastersizer 2000激光粒度分析仪，Scirocco 2000干法进样器；振动进样速度为50％；分散气压，60目和200目为2×10^5Pa，70目、80目、100目为5×10^4Pa；背景及样品的扫描时间为15s；遮光度为0．5％～5％；颗粒折射率为1．347；颗粒吸收率为0．1。Sympatec Helos＆Rodos激光粒度分析仪，振动进样速度为60％；分散气压为5×10^4Pa；透镜为2．5mm，遮光度为4％～10％。OCTAGON DIGITAL高速筛分机；筛分时间2min；振动幅度9。结果：激光散射法可以测定各种规格的乳糖样品，由体积平均粒径D[4，3]可以直观地表征不同规格的乳糖颗粒大小的差异，由d（0．1）、d（0．5）和d（0．9）可以看出其粒度分布特征。基于米氏理论或弗朗霍夫理论进行运算的激光粒度仪均可用于乳糖的粒度分析，两者的测定结果无显著性差异。结论：虽然筛分法与激光散射法均可以表征乳糖的粒度分布，但激光散射法能更好地表征样品的粒度分布，同时可减少测量过程中人为操作误差的影响。     

激光粒度仪测定单硝酸异山梨酯缓释片中间产品粒度的方法学研究

目的 建立测定单硝酸异山梨酯缓释片中间产品粒度分布的方法。方法 采用Malvern Mastersizer 3000型激光粒度分析仪,Aero S型干法进样器。激光散射法干法检测参数为：样品折射率1.52、漏斗池高度1.0 mm、遮光度范围0.8%～3.0%、分散气体压力2.0 bar、进样速度50%、样品测量时间25 s。结果 同一批供试品,平行测定6次,不同操作人员在不同时间、使用相同仪器和相同方法,测得粒度分布结果的RSD值小于1.0%;三个批次供试品,相同操作人员使用相同仪器和相同方法测得批次间粒度分布结果的RSD值小于2.0%。结论 该方法重现性好、准确度高,操作简便,可用于单硝酸异山梨酯缓释片中间产品粒度分析。     

Protein Spray-Freeze Drying. Effect of Atomization Conditions on Particle Size and Stability

Purpose. To investigate the effect of atomization conditions on particle size and stability of spray-freeze dried protein. Methods. Atomization variables were explored for excipient-free (no zinc added) and zinc-complexed bovine serum albumin (BSA). Particle size was measured by laser diffraction light scattering following sonication in organic solvent containing poly(lactide-co-glycolide) (PLG). Powder surface area was determined from the N₂ vapor sorption isotherm. Size-exclusion chromatography (SEC) was used to assess decrease in percent protein monomer. Fourier-transform infrared (FTIR) spectroscopy was employed to estimate protein secondary structure. PLG microspheres were made using a non-aqueous, cryogenic process and release of spray-freeze dried BSA was assessed in vitro. Results. The most significant atomization parameter affecting particle size was the mass flow ratio (mass of atomization N₂ relative to that for liquid feed). Particle size was inversely related to specific surface area and the amount of protein aggregates formed. Zinc-complexation reduced the specific surface area and stabilized the protein against aggregation. FTIR data indicated perturbations in secondary structure upon spray-freeze drying for both excipient-free and zinc-complexed protein. Conclusions. Upon sonication, spray-freeze dried protein powders exhibited friability, or susceptibility towards disintegration. For excipient-free protein, conditions where the mass flow ratio was > 0.3 yielded sub-micron powders with relatively large specific surface areas. Reduced particle size was also linked to a decrease in the percentage of protein monomer upon drying. This effect was ameliorated by zinc-complexation, via a mechanism involving reduction in specific surface area of the powder rather than stabilization of secondary structure. Reduction of protein particle size was beneficial in reducing the initial release (burst) of the protein encapsulated in PLG microspheres.     

Guidance in the Setting of Drug Particle Size Specifications to Minimize Variability in Absorption

Purpose. To provide guidance in setting particle size specifications for poorly soluble drugs to minimize variability in absorption. Methods. A previously reported computer method was used to simulate the percent of dose absorbed as a function of solubility, absorption rate constant, dose, and particle size. Results. The simulated percent of dose absorbed was tabulated over a realistic range of solubilities, absorption rate constants, and doses using drug particle sizes that might be typically found in a dosage form. Conclusions. The greatest effect of particle size on absorption was simulated for low dose- low solubility drugs. In general, the sensitivity of absorption to particle size decreased with increasing dose or solubility. At a solubility of 1 mg/mL, particle size had practically no effect on the percent of dose absorbed over the range of doses simulated (1–250 mg).     

Relationship Between Drug Percolation Threshold and Particle Size in Matrix Tablets

Purpose. Since a previous qualitative study carried out by us showed the existence of an important influence of the particle size on the percolation thresholds and taking into account that the existing theoretical models can only provide qualitative explanation to this influence, the purpose of this work is to carry out the first quantitative study of the influence of the particle size over the drug percolation thresholds. Methods. Matrix tablets have been elaborated using potassium chloride as drug model and Eudragit RS-PM as matrix forming material. Five different KC1 particle size fractions have been employed whereas the Eudragit^® RS-PM particle size was kept constant. In-vitro release assays were carried out for all the elaborated lots. The drug percolation thresholds were estimated following the method proposed by Bonny and Leuenberger. Results. A linear relationship has been found between the drug particle size and the corresponding drug percolation threshold. Conclusions. This finding confirms the results previously obtained in our qualitative study and has important repercussions in the design of pharmaceutical solid dosage forms. If this linear behaviour is general, the percolation threshold can soon become a useful preformulation parameter.     

In Situ Determination of Delavirdine Mesylate Particle Size in Solid Oral Dosage Forms

Purpose. The in-situ particle size of delavirdine mesylate in dry mix and tablets was determined. Methods. Optical microscopy and fluorescence microscopy combined with image analysis were used for qualitative and quantitative measurements. Results. Using optical microscopy, it was demonstrated qualitatively that fragmentation of the large drug particles was occurring during tablet compression. Quantitative comparisons between dry mix and tablet samples showed that in the dry mix, drug particles remain intact, with particle lengths exceeding 200 m. In the tablets, no particles longer than 100 m had been observed. Analysis of multiple tablet lots revealed consistent in-situ drug particle size distributions, regardless of the original bulk drug particle size. Conclusions. Bulk drug particle size of delavirdine mesylate is not predictive of the particle size in the tablet due to fragmentation of particles during compression. Optical and fluorescence microscopy are valuable tools for probing in-situ particle size in complex matrices.     

Influence of Particle Size,Air Flow,and Inhaler Device on the Dispersion of Mannitol Powders as Aerosols

Purpose. To study the effect of particle size, air flow and inhaler type on the dispersion of spray dried mannitol powders into aerosols. Methods. Mannitol powders were prepared by spray drying. The solid state properties of the powders were determined by laser diffraction, X-ray powder diffraction, scanning electron microscopy, freeze fracture, Karl Fischer titration and gas pycnometry. The powders were dispersed using Rotahaler^® and Dinkihaler^®, connected to a multistage liquid impinger at different air flows. Results. Three crystalline mannitol powders with primary particle size (MMD) 2.7, 5.0, 7.3 m and a similar polydispersity were obtained. The particles were spherical with a density of 1.5 g/cm³ and a moisture content of 0.4 wt.%. At an air flow of 30 L/min all the powders were poorly dispersed by both inhalers. With the Rotahaler^® increasing the flow (60–120 L/min) increased the fine particle fraction (FPF) in the aerosols for the 2.7 m powder, and decreased the FPF for the 7.3 m powder; whereas the FPF for 5.0 m powder was unaffected. With the Dinkihaler^®, all the powders were near complete dispersion at 60 L/min. Conclusions. The FPF in the mannitol powder aerosols was determined by an interplay of the particle size, air flow and inhaler design.     

The Role of the Drug/Excipient Particle Size Ratio in the Percolation Model for Tablets

Purpose. In previous papers, a linear relationship between drug particle size and drug percolation threshold was found in inert matrix tablets. The main objectives of the present work are: to study the influence of the excipient particle size on the drug percolation threshold and to investigate if the change in the drug percolation threshold is due either to the absolute or to the relative drug particle size. Methods. Matrix tablets have been prepared using KC1 (7 different particle size fractions) as a drug model and Eudragit^® RS-PM (4 granulommetric fractions) as matrix forming material. In vitro release assays were carried out on the 66 lots of tablets. The drug percolation thresholds were estimated following the method of Bonny and Leuenberger. Results. The particle size of the excipient has shown an opposite effect to the drug size on the drug percolation threshold. Nevertheless, the influence of drug and excipient sizes on the drug percolation threshold are of the same magnitude. Conclusions. The drug percolation threshold depends linearly on the relative drug particle size. This finding is in agreement with percolation theory and can facilitate the use of the percolation threshold as a preformulation parameter to improve the pharmaceutical dosage forms design.