The stability of pharmaceutical powders: effect of additives and coating

The decomposition of drugs in the solid state has been studied using aspirin and salsalate as models. The feasibility of using suspension systems for predicting the stability of these drugs in the solid state has been investigated.. It has been found that such systems are inappropriate in defining the effect of excipients on 'the decomposition of the active drug due to chqnges in the degradation pathway. Using a high performance liquid chromatographic method, magnesium stearate was shown to induce the formation of potentlally immunogenic products in aspirin powders. These products which included salicylsalicylic acid .and acetylsalicyclsalicylic acid were not detected in aspirin suspensions which had undergone the same extent of decomposition. By studying the effect of pH and of added excipients on the rate of decomposition of aspirin in suspension systems, it has been shown that excipients such as magnesium stearate containing magnesium oxide, most probably enhance the decomposition of both aspirin and salsalate by alkalinising the aqueous phase. In the solid state, pH effects produced by excipients appear to be relatively unimportant. Evidence is presented to suggest that the critical parameter is a depression in melting point induced by: the added excipient. Microscopical examination in fact showed the formation of clear liquid layers in aspirin samples containing added magnesium stearate but not in control samples. Kinetic equations which take into account both the diffusive barrier presented by the liquid films and the. geometry of the aspirin crystals were developed. Fitting of the .experimental data to these equations showed good agreement. with the postulated theory. Monitorjng of weight issues during the decomposition of aspirin revealed that in the solid systems studied where the bulk of the decomposition product sublimes, it is possible to estimate the extent of degradation from the residual weight, provided the initial weight is known. The corollary is that in such open systems, monitoring of decomposition products is inadequate for assessing the extent of decomposition. In addition to the magnesium stearate-aspirin system, mapyramine maleate-aspirin mixtures were used to model interactive systems. Work carried out in an attempt to stabilise such systems included microencapsulation and film coating. The protection obtained was dependent on the interactive species used. Gelatin for example appeared to stabilise aspirin against the adverse effects of magnesium stearate but increased its decomposition in the presence of mapyramine maleate.

Quality control of pharmaceutical ingredients:developing a caking test for industry

Objectives - Powdered and granulated particulate materials make up most of the ingredients of pharmaceuticals and are often at risk of undergoing unwanted agglomeration, or caking, during transport or storage. This is particularly acute when bulk powders are exposed to extreme swings in temperature and relative humidity, which is now common as drugs are produced and administered in increasingly hostile climates and are stored for longer periods of time prior to use. This study explores the possibility of using a uniaxial unconfined compression test to compare the strength of caked agglomerates exposed to different temperatures and relative humidities. This is part of a longer-term study to construct a protocol to predict the caking tendency of a new bulk material from individual particle properties. The main challenge is to develop techniques that provide repeatable results yet are presented simply enough to be useful to a wide range of industries. Methods - Powdered sucrose, a major pharmaceutical ingredient, was poured into a split die and exposed to high and low relative humidity cycles at room temperature. The typical ranges were 20–30% for the lower value and 70–80% for the higher value. The outer die casing was then removed and the resultant agglomerate was subjected to an unconfined compression test using a plunger fitted to a Zwick compression tester. The force against displacement was logged so that the dynamics of failure as well as the failure load of the sample could be recorded. The experimental matrix included varying the number of cycles, the amount between the maximum and minimum relative humidity, the height and diameters of the samples, the number of cycles and the particle size. Results - Trends showed that the tensile strength of the agglomerates increased with the number of cycles and also with the more extreme swings in relative humidity. This agrees with previous work on alternative methods of measuring the tensile strength of sugar agglomerates formed from humidity cycling (Leaper et al 2003). Conclusions - The results show that at the very least the uniaxial tester is a good comparative tester to examine the caking tendency of powdered materials, with a simple arrangement and operation that are compatible with the requirements of industry. However, further work is required to continue to optimize the height/ diameter ratio during tests.

Measuring the flow properties of small powder samples using an avalanche tester

The feasibility of using a small-scale avalanche tester to measure the flow properties of pharmaceutical lactose powders was examined. The modes of behaviour observed in larger systems were displayed and showed a clear distinction between angular, free-flowing particles and more spherical particles of similar flow characteristics. Angular Lactohale LH100 particles showed slumping behaviour at a rotational frequency of 0.33Hz which disappeared at higher frequencies. Spherical lactose powder with a similar flow function to LH100 only showed rolling behaviour under the same conditions, as did more cohesive powders LH200 and LH300. Further investigation of the LH100 data using Fast Fourier analysis showed that the slumping frequency was 1/10th of the rotational frequency.

Development of advanced capillary electrophoresis techniques with UV and mass spectrometry detection for forensic, pharmaceutical and environmental applications

Capillary electrophoresis (CE) is a modern analytical technique, which is electrokinetic separation generated by high voltage and taken place inside the small capillaries. In this dissertation, several advanced capillary electrophoresis methods are presented using different approaches of CE and UV and mass spectrometry are utilized as the detection methods. ^ Capillary electrochromatography (CEC), as one of the CE modes, is a recent developed technique which is a hybrid of capillary electrophoresis and high performance liquid chromatography (HPLC). Capillary electrochromatography exhibits advantages of both techniques. In Chapter 2, monolithic capillary column are fabricated using in situ photoinitiation polymerization method. The column was then applied for the separation of six antidepressant compounds. ^ Meanwhile, a simple chiral separation method is developed and presented in Chapter 3. Beta cycodextrin was utilized to achieve the goal of chiral separation. Not only twelve cathinone analytes were separated, but also isomers of several analytes were enantiomerically separated. To better understand the molecular information on the analytes, the TOF-MS system was coupled with the CE. A sheath liquid and a partial filling technique (PFT) were employed to reduce the contamination of MS ionization source. Accurate molecular information was obtained. ^ It is necessary to propose, develop, and optimize new techniques that are suitable for trace-level analysis of samples in forensic, pharmaceutical, and environmental applications. Capillary electrophoresis (CE) was selected for this task, as it requires lower amounts of samples, it simplifies sample preparation, and it has the flexibility to perform separations of neutral and charged molecules as well as enantiomers. ^ Overall, the study demonstrates the versatility of capillary electrophoresis methods in forensic, pharmaceutical, and environmental applications.^

Development of Advanced Capillary Electrophoresis Techniques with UV and Mass Spectrometry Detection for Forensic, Pharmaceutical and Environmental Applications

Capillary electrophoresis (CE) is a modern analytical technique, which is electrokinetic separation generated by high voltage and taken place inside the small capillaries. In this dissertation, several advanced capillary electrophoresis methods are presented using different approaches of CE and UV and mass spectrometry are utilized as the detection methods. Capillary electrochromatography (CEC), as one of the CE modes, is a recent developed technique which is a hybrid of capillary electrophoresis and high performance liquid chromatography (HPLC). Capillary electrochromatography exhibits advantages of both techniques. In Chapter 2, monolithic capillary column are fabricated using in situ photoinitiation polymerization method. The column was then applied for the separation of six antidepressant compounds. Meanwhile, a simple chiral separation method is developed and presented in Chapter 3. Beta cycodextrin was utilized to achieve the goal of chiral separation. Not only twelve cathinone analytes were separated, but also isomers of several analytes were enantiomerically separated. To better understand the molecular information on the analytes, the TOF-MS system was coupled with the CE. A sheath liquid and a partial filling technique (PFT) were employed to reduce the contamination of MS ionization source. Accurate molecular information was obtained. It is necessary to propose, develop, and optimize new techniques that are suitable for trace-level analysis of samples in forensic, pharmaceutical, and environmental applications. Capillary electrophoresis (CE) was selected for this task, as it requires lower amounts of samples, it simplifies sample preparation, and it has the flexibility to perform separations of neutral and charged molecules as well as enantiomers. Overall, the study demonstrates the versatility of capillary electrophoresis methods in forensic, pharmaceutical, and environmental applications.

Particle number and mass emission factors from combustion of wood samples collected from Queensland forest

Knowledge of particle emission characteristics associated with forest fires and in general, biomass burning, is becoming increasingly important due to the impact of these emissions on human health. Of particular importance is developing a better understanding of the size distribution of particles generated from forest combustion under different environmental conditions, as well as provision of emission factors for different particle size ranges. This study was aimed at quantifying particle emission factors from four types of wood found in South East Queensland forests: Spotted Gum (Corymbia citriodora), Red Gum (Eucalypt tereticornis), Blood Gum (Eucalypt intermedia), and Iron bark (Eucalypt decorticans); under controlled laboratory conditions. The experimental set up included a modified commercial stove connected to a dilution system designed for the conditions of the study. Measurements of particle number size distribution and concentration resulting from the burning of woods with a relatively homogenous moisture content (in the range of 15 to 26 %) and for different rates of burning were performed using a TSI Scanning Mobility Particle Sizer (SMPS) in the size range from 10 to 600 nm and a TSI Dust Trak for PM2.5. The results of the study in terms of the relationship between particle number size distribution and different condition of burning for different species show that particle number emission factors and PM2.5 mass emission factors depend on the type of wood and the burning rate; fast burning or slow burning. The average particle number emission factors for fast burning conditions are in the range of 3.3 x 1015 to 5.7 x 1015 particles/kg, and for PM2.5 are in the range of 139 to 217 mg/kg.

SNP technologies for drug discovery : a current review

Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.

Development of a biaxial compression device for biological samples : preliminary experimental results for a closed cell foam

Biological tissues are subjected to complex loading states in vivo and in order to define constitutive equations that effectively simulate their mechanical behaviour under these loads, it is necessary to obtain data on the tissue's response to multiaxial loading. Single axis and shear testing of biological tissues is often carried out, but biaxial testing is less common. We sought to design and commission a biaxial compression testing device, capable of obtaining repeatable data for biological samples. The apparatus comprised a sealed stainless steel pressure vessel specifically designed such that a state of hydrostatic compression could be created on the test specimen while simultaneously unloading the sample along one axis with an equilibrating tensile pressure. Thus a state of equibiaxial compression was created perpendicular to the long axis of a rectangular sample. For the purpose of calibration and commissioning of the vessel, rectangular samples of closed cell ethylene vinyl acetate (EVA) foam were tested. Each sample was subjected to repeated loading, and nine separate biaxial experiments were carried out to a maximum pressure of 204 kPa (30 psi), with a relaxation time of two hours between them. Calibration testing demonstrated the force applied to the samples had a maximum error of 0.026 N (0.423% of maximum applied force). Under repeated loading, the foam sample demonstrated lower stiffness during the first load cycle. Following this cycle, an increased stiffness, repeatable response was observed with successive loading. While the experimental protocol was developed for EVA foam, preliminary results on this material suggest that this device may be capable of providing test data for biological tissue samples. The load response of the foam was characteristic of closed cell foams, with consolidation during the early loading cycles, then a repeatable load-displacement response upon repeated loading. The repeatability of the test results demonstrated the ability of the test device to provide reproducible test data and the low experimental error in the force demonstrated the reliability of the test data.

Osteryoung square wave voltammetric determination of lactose in food samples by a derivative procedure

A method for determination of lactose in food samples by Osteryoung square wave voltammetry (OSWV) was developed. It was based on the nucleophilic addition reaction between lactose and aqua ammonia. The carbonyl group of lactose can be changed into imido group, and this increases the electrochemical activity in reduction and the sensitivity. The optimal condition for the nucleophilic addition reaction was investigated and it was found that in NH4Cl–NH3 buffer of pH 10.1, the linear range between the peak current and the concentration of lactose was 0.6–8.4 mg L−1, and the detection limits was 0.44 mg L−1. The proposed method was applied to the determination of lactose in food samples and satisfactory results were obtained.

Simultaneous kinetic-spectrophotometric determination of maltol and ethyl maltol in food samples by using chemometrics

A fast and accurate procedure has been researched and developed for the simultaneous determination of maltol and ethyl maltol, based on their reaction with iron(III) in the presence of o-phenanthroline in sulfuric acid medium. This reaction was the basis for an indirect kinetic spectrophotometric method, which followed the development of the pink ferroin product (λmax = 524 nm). The kinetic data were collected in the 370–900 nm range over 0–30 s. The optimized method indicates that individual analytes followed Beer’s law in the concentration range of 4.0–76.0 mg L−1 for both maltol and ethyl maltol. The LOD values of 1.6 mg L−1 for maltol and 1.4 mg L−1 for ethyl maltol agree well with those obtained by the alternative high performance liquid chromatography with ultraviolet detection (HPLC-UV). Three chemometrics methods, principal component regression (PCR), partial least squares (PLS) and principal component analysis–radial basis function–artificial neural networks (PC–RBF–ANN), were used to resolve the measured data with small kinetic differences between the two analytes as reflected by the development of the pink ferroin product. All three performed satisfactorily in the case of the synthetic verification samples, and in their application for the prediction of the analytes in several food products. The figures of merit for the analytes based on the multivariate models agreed well with those from the alternative HPLC-UV method involving the same samples.

Comparison of methods for processing drinking water samples for the isolation of Myocbacterium avium and intracellulare

Several protocols for isolation of mycobacteria from water exist, but there is no established standard method. This study compared methods of processing potable water samples for the isolation of Mycobacterium avium and Mycobacterium intracellulare using spiked sterilized water and tap water decontaminated using 0.005% cetylpyridinium chloride (CPC). Samples were concentrated by centrifugation or filtration and inoculated onto Middlebrook 7H10 and 7H11 plates and Lowenstein-Jensen slants and into mycobacterial growth indicator tubes with or without polymyxin, azlocillin, nalidixic acid, trimethoprim, and amphotericin B. The solid media were incubated at 32°C, at 35°C, and at 35°C with CO2 and read weekly. The results suggest that filtration of water for the isolation of mycobacteria is a more sensitive method for concentration than centrifugation. The addition of sodium thiosulfate may not be necessary and may reduce the yield. Middlebrook M7H10 and 7H11 were equally sensitive culture media. CPC decontamination, while effective for reducing growth of contaminants, also significantly reduces mycobacterial numbers. There was no difference at 3 weeks between the different incubation temperatures.

A spectroscopic investigation of pigment and ceramic samples from Copán, Honduras

A combination of micro-Raman spectroscopy, micro-infrared spectroscopy and SEM–EDX was employed to characterize decorative pigments on Classic Maya ceramics from Copán, Honduras. Variation in red paint mixtures was correlated with changing ceramic types and improvements in process and firing techniques. We have confirmed the use of specular hematite on Coner ceramics by the difference in intensities of Raman bands. Different compositions of brown paint were correlated with imported and local wares. The carbon-iron composition of the ceramic type, Surlo Brown, was confirmed. By combining micro-Raman analysis with micro-ATR infrared and SEM–EDX, we have achieved a more comprehensive characterization of the paint mixtures. These spectroscopic techniques can be used non-destructively on raw samples as a rapid confirmation of ceramic type.

Concentrations of polybrominated diphenyl ethers (PBDEs) in matched samples of human milk, dust and indoor air

Polybrominated diphenyl ethers (PBDEs) are lipophilic, persistent pollutants found worldwide in environmental and human samples. Exposure pathways for PBDEs remain unclear but may include food, air and dust. The aim of this study was to conduct an integrated assessment of PBDE exposure and human body burden using 10 matched samples of human milk, indoor air and dust collected in 2007–2008 in Brisbane, Australia. In addition, temporal analysis was investigated comparing the results of the current study with PBDE concentrations in human milk collected in 2002–2003 from the same region. PBDEs were detected in all matrices and the median concentrations of BDEs -47 and -209 in human milk, air and dust were: 4.2 and 0.3 ng/g lipid; 25 and 7.8 pg/m3; and 56 and 291 ng/g dust, respectively. Significant correlations were observed between the concentrations of BDE-99 in air and human milk (r = 0.661, p = 0.038) and BDE-153 in dust and BDE-183 in human milk (r = 0.697, p = 0.025). These correlations do not suggest causal relationships — there is no hypothesis that can be offered to explain why BDE-153 in dust and BDE-183 in milk are correlated. The fact that so few correlations were found in the data could be a function of the small sample size, or because additional factors, such as sources of exposure not considered or measured in the study, might be important in explaining exposure to PBDEs. There was a slight decrease in PBDE concentrations from 2002–2003 to 2007–2008 but this may be due to sampling and analytical differences. Overall, average PBDE concentrations from these individual samples were similar to results from pooled human milk collected in Brisbane in 2002–2003 indicating that pooling may be an efficient, cost-effective strategy of assessing PBDE concentrations on a population basis. The results of this study were used to estimate an infant's daily PBDE intake via inhalation, dust ingestion and human milk consumption. Differences in PBDE intake of individual congeners from the different matrices were observed. Specifically, as the level of bromination increased, the contribution of PBDE intake decreased via human milk and increased via dust. As the impacts of the ban of the lower brominated (penta- and octa-BDE) products become evident, an increased use of the higher brominated deca-BDE product may result in dust making a greater contribution to infant exposure than it does currently. To better understand human body burden, further research is required into the sources and exposure pathways of PBDEs and metabolic differences influencing an individual's response to exposure. In addition, temporal trend analysis is necessary with continued monitoring of PBDEs in the human population as well as in the suggested exposure matrices of food, dust and air.

Using samples to estimate the sensitivity and specificity of a surveillance process

Determining sensitivity and specificity of a postoperative infection surveillance process is a difficult undertaking. Because postoperative infections are rare, vast numbers of negative results exist, and it is often not reasonable to assess them all. This study gives a methodological framework for estimating sensitivity and specificity by taking only a small sample of the number of patients who test negative and comparing their findings to the reference or “gold standard” rather than comparing the findings of all patients to the gold standard. It provides a formula for deriving confidence intervals for these estimates and a guide to minimum requirements for sampling results.