The influence of deposition method on the packing uniformity of powder beds

A number of methods of preparing powder packings have been assessed in terms of the resulting variability of local porosity. Measurement of local porosity was carried out by a gamma-ray attenuation technique. It was found that overall porosity and the distribution of local porosity were highly dependent on particle properties and deposition method. Some deposition methods tended to give rise to the alternate formation and collapse of temporary structures within a growing bed, and in such cases, relatively high variability of local porosity was detected. More uniform packings could be formed by deposition of powder in even layers. In many cases, a significant relationship between local porosity and position within a packing was established, the central areas generally being of lowest porosity. This was true of packings both of high and low overall variability of porosity.     

The effect of sinusoidal vibration on the uniformity of packing of powder beds

Sinusoidal vibration, at a number of defined sets of conditions, has been applied to packings of certain particle size fractions of lactose. The distribution of local porosity within these vibrated packings was determined using a gamma-ray attenuation technique, and could be compared with porosity data for samples not subjected to vibration. It was found that the application of vibration in a vertical mode markedly increased the uniformity of packing; horizontal vibration was less effective in this respect. The relationship between local porosity and position with a packing, observed in most non-vibrated samples, was generally absent from vibrated packings.     

Acoustic assessment of mean grain size in pharmaceutical compacts

An ultrasonic non-destructive technique for the microstructure length-scale characterization of solid dosage pharmaceutical tablets is presented. The technique is based on the relationship between the attenuation of longitudinal ultrasonic elastic waves and the size of micro-structural features in the tablet material. In the reported experiments, the ultrasonic attenuation in microcrystalline cellulose (MCC)-lactose monohydrate (LMH) blended pharmaceutical compacts is measured by means of two pitch-catch experiments. The frequency dependent attenuation coefficient for the MCC-LMH compacts is then related to the mean grain diameter for each compact. For verification purposes, the mean grain diameter of the compacts was also established using micro-scale X-ray computerized tomography (MicroXCT). The mean grain diameters established by both routines agree well, and support the efficacy of the ultrasonic attenuation technique. The microstructure of a pharmaceutical compact (i.e., grain sizes and micro-feature size distribution) has been shown to have a profound effect on its mechanical properties, namely hardness, porosity, and mass density distribution, and in turn, can critically impact the dissolution profile and structural integrity of a compact. The ultrasonic technique presented provides a non-destructive and rapid method for determining the mean grain diameter size for powder compacts, thus providing a more timely and cost-effective method, compared to traditional techniques, of characterizing a compact's internal microstructure.     

A new technique for recording compliance of human hand veins.

1 A new technique for determining venous compliance at a standardized congestion pressure has been developed based on the optical method described by Nachev, Collier & Robinson (1971). It uses a linear variable differential transformer for a direct and continuous recording of venous compliance. 2 This method has been used to establish dose-response curves for the constrictor effects of noradrenaline, adrenaline, 5-hydroxytryptamine and dihydroergotamine after direct local infusion. 3 A parallel shift to the right of the noradrenaline dose-response curves was observed after local infusion of phentolamine, showing that the method can be used also to study interactions between agonists and antagonists on human veins in vivo. The usefulness of this technique for investigating the effects of orally administered drugs has also been established. The venoconstrictor action of dihydroergotamine reached its maximum after 1.5 h and remained almost constant for the period of observation (8 h).     

复方右美沙芬制剂的HPLC测定

采用反相高效液相色谱，以程序变换控制记录积分衰减因子的方法，达到一次实验同时对复方右美沙芬制剂中３个组分进行检测。方法快速、准确。     

Influence of elastic deformation of particles on Heckel analysis.

The Heckel equation is one of the most useful equations for describing the compaction properties of pharmaceutical powders. Important material properties (e.g., yield strength) of powders can be derived using Heckel analysis. Two types of Heckel analysis are in common use. One is the "out-of-die," or "zero-pressure" method, the other is the "in-die" or "at-pressure" method. Because particles undergo elastic deformation under pressure, which tends to lower the porosity of the powder bed, the "out-of-die" method describes powder consolidation and compaction more accurately than the "in-die" method. However, "in-die" Heckel analysis has been widely used because of the speed and ease of data collection. Using L-lysine monohydrochloride dihydrate as a model compound, this work analyzes quantitatively the effects of elastic deformation on the calculation of porosity of a tablet, and therefore on the Heckel analysis. The effects of a small change in porosity, epsilon, on Heckel analysis are presented mathematically. It is found that a decrease in porosity of 0.001, when the porosity is lower than 0.05, causes a significant increase in the value of -ln epsilon. Therefore, data at epsilon < 0.05 should be interpreted with caution when using Heckel analysis. Elastic deformation causes positive deviations in the Heckel plot, and therefore leads to a yield strength that is lower than the true value. The lower the elastic modulus of the powder, the greater is the deviation from the true value. Therefore, the "in-die" method gives values of yield strength that are significantly lower than the true values for most pharmaceutical powders.     

Local drug delivery to the inner ear using biodegradable materials

The lack of an effective method of drug delivery has been a considerable obstacle in the development of novel therapeutics for inner ear diseases. However, several strategies have been investigated to achieve drug delivery to the inner ear, particularly for local application. Here, we review recent advances in the development of inner ear drug-delivery systems, focusing on biodegradable materials. Both synthetic and natural biodegradable materials have shown efficacy for inner ear drug delivery, resulting in an attenuation of hearing loss in animal models. We expect the further development of such drug-delivery systems to help translate the findings of experimental studies to clinical applications.     

Validation of a capillary electrophoresis method for the enantiomeric purity testing of ropivacaine,a new local anaesthetic compound

A capillary electrophoresis method for the determination of the enantiomeric purity of ropivacaine, a new local anaesthetic compound developed by Astra Pain Control AB, has been validated. The method showed the required limit of quantitation of 0.1% enantiomeric impurity and proved to be robust. Good performances were also shown for specificity, linearity, system repeatability and accuracy. The same capillary electrophoresis method can also be used to simultaneously chirally resolve homologues and impurities of ropivacaine.     

A Fast and Non-destructive Terahertz Dissolution Assay for Immediate Release Tablets

There is a clear need for a robust process analytical technology tool that can be used for on-line/in-line prediction of dissolution and disintegration characteristics of pharmaceutical tablets during manufacture. Tablet porosity is a reliable and fundamental critical quality attribute which controls key mass transport mechanisms that govern disintegration and dissolution behavior. A measurement protocol was developed to measure the total porosity of a large number of tablets in transmission without the need for any sample preparation. By using this fast and non-destructive terahertz spectroscopy method it is possible to predict the disintegration and dissolution of drug from a tablet in less than a second per sample without the need of a chemometric model. The validity of the terahertz porosity method was established across a range of immediate release (IR) formulations of ibuprofen and indomethacin tablets of varying geometries as well as with and without debossing. Excellent correlation was observed between the measured terahertz porosity, dissolution characteristics (time to release 50% drug content) and disintegration time for all samples. These promising results and considering the robustness of the terahertz method pave the way for a fully automated at-line/on-line porosity sensor for real time release testing of IR tablets dissolution.     

A radioisotope method for assessing the anaphylactogenicity of polymer drugs

A radioisotope technique has been developed for the quantitative assessment of microcirculation disorder in a local anaphylactic focus of guinea pigs sensitized with horse immunoglobulin G and polyethyleneoxide conjugate with 2,4-dinitrophenol. The technique is based on the use of a radioactive tracer, dextran derivative, labelled with radionuclide 125I. The method can be used for studying a safety of new polymer-containing drugs.     

The non-structural proteins of RSV: targeting interferon antagonists for vaccine development

Over fifty years have passed since the identification of respiratory syncytial virus (RSV) as an important pediatric pathogen. However, an effective vaccine is still lacking. Immunization with formalin-inactivated RSV resulted in vaccine-enhanced disease; thus, a greater focus has been placed more recently on developing live attenuated RSV vaccines. The difficulty in identifying a live attenuated vaccine candidate has been balancing appropriate attenuation with sufficient immunogenicity. With the advent of reverse genetics systems for RSV, researchers have been able to generate recombinint vaccine candidates by introducing specific mutations into the genome wild-type RSV. These systems provide a means to determine the effects of known attenuating mutations and identifying novel methods of attenuating the virus without decreasing immunogenicity. In addition, different mutations can be combined in a single genome to fine-tune the level of attenuation and immunogenicity to achieve the proper balance in a viable vaccine candidate. Among the targets for attenuation are the small RSV nonstructural (NS) proteins. The NS proteins have multiple functions during the virus life cycle, including antagonizing the antiviral effects of interferon and directly augmenting virus replication. This review will outline the progress in understanding the functions of the NS proteins and how altering these functions by reverse genetic manipulation can be a useful path toward rationally designing a safe and effective live-attenuated RSV vaccine.     

中心复合设计法制备盐酸奈福泮微孔渗透泵控释片

目的以盐酸奈福泮为模型药物制备微孔渗透泵,控制其在24 h内维持零级释放,且最终释药量达90%以上。方法采用中心复合设计法优化处方。以24 h累计释药量和释药速率为考察指标对包衣膜PEG-400含量和包衣膜厚度2个自变量进行多元线性回归和二项式拟合,并进行预测分析。结果2个影响因素和2个评价指标之间存在定量关系,优化处方各指标的预测值和目标值接近。结论经中心复合设计优化的盐酸奈福泮微孔渗透泵片能24 h零级释药。     

Use of mercury porosimetry, assisted by nitrogen adsorption in the investigation of the pore structure of tablets

The microstructure of pharmaceutical solid dosage forms (porosity, pore volume-size distribution, specific surface area) can be investigated by different methods. Mercury porosimetry and nitrogen gas adsorption have been widely used to characterize the pore structure of tablets because these methods enable the determination of porosity and pore size distribution in one step. The two techniques are based on different physical interactions and cover specific ranges of pore size. Mercury porosimetry determines mesopores and macropores, whereas gas adsorption covers the micropore range. The aim of this study was to investigate the relationship between the compression force and the structure of tablets containing theophylline. The porosity parameters determined with mercury porosimetry and nitrogen adsorption were compared. The results indicated a good correlation between the applied compression forces and the porosity parameters of the tablets. The pore volume-size distributions, the pore size frequencies and the specific surface areas obtained with mercury porosimetry and nitrogen adsorption were not equal, which can be attributed to the different measurement ranges and to the complexity of the pore structures. Our results allow the conclusion that mercury porosimetry, assisted by nitrogen adsorption as a complementary technique, is an acceptable method to achieve a proper characterization of the internal structure of tablets.     

二苯胺用作重氮滴定法的内指示剂

利用重氮化反应测定芳香氨基化合物含量的方法,在药物分析上及有机定量上应用至为广泛。重氮法测定含量虽以简单迅速著称,但至今尚缺乏适当的内指示剂。在操作上普通采用淀粉碘化钾滤袄或糊浆为外用指示剂,此法不易掌握,且需时时取出部分溶液与淀粉作用,以决定终点是否到达,不但操作麻烦,抑且影响滴定之准确性。而于生     

The Preparation of Rapidly Disintegrating Tablets in the Mouth

Elderly people, children and patients sometimes have difficulties swallowing tablets. To solve this problem, a novel method of preparing tablets that disintegrate rapidly in the mouth was developed. A tablet with high porosity is required for rapid disintegration, but such a tablet is generally fragile. To make a tablet having both high porosity and practical strength, amorphous sucrose, which has good compactability, was used. Mannitol powder with freeze-dried amorphous sucrose was tabletted at low compression and stored under certain conditions. The tablet disintegrated rapidly in the mouth, because of its high porosity. The tensile strength of the tablet increased remarkably during storage, while the porosity of the tablet seemed almost unchanged. The results of thermal analysis and powder x-ray diffraction measurement showed that the amorphous sucrose in tablet crystallized during storage. The increase in the tensile strength of the tablet was due to crystallization of the amorphous sucrose and formation of new internal contact points in the tablet. It was concluded that this crystalline transition method is a very useful method to prepare a rapidly disintegrating tablet.     

The preparation of rapidly disintegrating tablets in the mouth.

Elderly people, children and patients sometimes have difficulties swallowing tablets. To solve this problem, a novel method of preparing tablets that disintegrate rapidly in the mouth was developed. A tablet with high porosity is required for rapid disintegration, but such a tablet is generally fragile. To make a tablet having both high porosity and practical strength, amorphous sucrose, which has good compactability, was used. Mannitol powder with freeze-dried amorphous sucrose was tableted at low compression and stored under certain conditions. The tablet disintegrated rapidly in the mouth, because of its high porosity. The tensile strength of the tablet increased remarkably during storage, while the porosity of the tablet seemed almost unchanged. The results of thermal analysis and powder x-ray diffraction measurement showed that the amorphous sucrose in tablet crystallized during storage. The increase in the tensile strength of the tablet was due to crystallization of the amorphous sucrose and formation of new internal contact points in the tablet. It was concluded that this crystalline transition method is a very useful method to prepare a rapidly disintegrating tablet.     

Capture–recapture estimates of the local and national prevalence of problem drug use in Scotland

Estimates of the prevalence of problem drug use, defined within this study as the illicit use of opiates or benzodiazepines, have been provided for all 32 local government areas in Scotland. A national prevalence estimate has been derived as the sum of the local estimates.Data on individual drug users were collated from the police, social work departments, general practitioners, drug treatment services. These data were augmented by the Scottish Drug Misuse Database. In total 22,795 individuals were identified as opiate or benzodiazepine users. This figure corresponds to 0.8% of the population aged 15 to 54.In terms of the national prevalence of problem drug use, it was estimated that there were 55,800 individuals illicitly using opiates and benzodiazepines in Scotland in the year 2000 (95% CI: 43,591–77,697%). That figure corresponds to 2.0% (95% CI: 1.5–2.7%) of the population aged 15 to 54. The local prevalence rates, derived from capture–recapture estimates, ranged from 0.8 to 3.8%.This study has demonstrated that it is possible to use the capture–recapture method in urban and rural areas and, by systematically applying this method at the local level, a national prevalence estimate can be obtained.     

Fluorimetric determination of procaine in pharmaceutical preparations based on its reaction with fluorescamine

A simple spectrofluorimetric analysis of a local anaesthetic named procaine using a specific labelling reagent for primary amino groups, has been developed. Because procaine shows very weak native fluorescence, the technique of spectrofluorimetry has been very much limited for its determination. A detail study of the variables affecting the derivatisation reaction (pH, fluorescamine (FC) concentration, temperature, reaction time), have minuciously been studied. The minimum detectable quantity is estimated as 7.7 ng ml(-1), with a relative standard deviation of 2.16% (ten determinations) for a procaine concentration of 100 ng ml(-1). The present method can be employed for the analysis of procaine by direct fluorescence measurements, without the interference from other compounds. The applicability of the present methodology have been demonstrated analysing three pharmaceutical preparations containing the analyte with satisfactory results.     

The formulation and sterilization of a surgical lubricant gel based on carboxypolymethylene

A lubricant gel of optimal consistency containing a local anaesthetic (lignocaine) has been formulated which can be sterilized by gamma irradiation. A rheological specification was obtained by examination of some currently used preparations. The variation in their consistency was large but all exhibited pseudoplastic flow with a yield value. Gels based on tragacanth, the methylcelluloses and the Carbopols were suitable as lubricants before sterilization and after autoclaving, but on gamma irradiation the gel structure was destroyed. Ethanol (5–10%) protected the Carbopol formulations. Irradiation of lignocaine solutions caused some cloudiness and a small drop in pH. Ethanol and metabisulphite acted as protective agents. A final formulation was developed consisting of a Carbopol gel (1%) neutralized by lignocaine base (2%) and the biological availability of the local anaesthetic was assessed using an in vitro method.     

A chemometrics method for separation of size dependent and size independent attributes of microspheres for medical ultrasound imaging

The size dependent and size independent contributions to the mechanical properties of poly(ethyleneglycol) microspheres with encapsulated air, made for medical ultrasound imaging, have been studied. A relation between the size of microspheres in a reference group and their acoustic attenuation efficacy was derived by partial least square regression. The developed model was used to estimate acoustic attenuation as a function of the measured size distribution for various preparations made during formulation and process studies. The ratio between the measured attenuation and model estimated attenuation was then used to evaluate variations in the mechanical properties of the polymer shell and the contribution of such variations to the acoustical properties of the substance. The statistical parameter was compared with results for the mechanical compressibility derived from a theoretical approach and the results from the two methods mutually confirmed each other. The statistical procedure outlined has been found applicable for studies of other particulate products with size dependent in vitro or in vivo properties.