Some Heteroskedasticity Consistent Covariance Matrix Estimators with Improved Finite Sample Properties

We examine several modified versions of the heteroskedasticity-consistent covariance matrix estimator of Hinkley and White. On the basis of sampling experiments which compare the performance of quasi t statistics, we find that one estimator, based on the jackknife, performs better in small samples than the rest. We also examine finite-sample properties using modified critical values based on Edgeworth approximations, as proposed by Rothenberg. In addition, we compare the power of several tests for heteroskedasticity and find that it may be wise to employ the jackknife heteroskedasticity-consistent covariance matrix even in the absence of detected heteroskedasticity.Jackknife, Heteroskedasticity, HCCME, Edgeworth approximations

Use of mathematical derivatives (time-domain differentiation) on chromatographic data to enhance the detection and quantification of an unknown 'rider' peak

Two samples of an anticancer prodrug, AQ4N, were submitted for HPLC assay and showed an unidentified impurity that eluted as a 'rider' on the tail of the main peak. Mathematical derivatization of the chromatograms offered several advantages over conventional skimmed integration. A combination of the second derivative amplitude and simple linear regression gave a novel method for estimating the true peak area of the impurity peak. All the calculation steps were carried out using a widely available spreadsheet program. (C) 2003 Elsevier B.V. All rights reserved

Inkjet printing scalable dosage forms capable of increasing the solubility of BCS Class II drugs

Oral drug delivery remains the preferred method of administration but BCS Class II drugs are not ideally suited to this due to their inherent poor solubility. Although a number of methods to increase solubility already exist, there is a need for manufacturing methods which are more flexible to the requirements of the individual patient. The current work aims to increase the solubility of poorly soluble drugs using the innovative manufacturing technique of inkjet printing with a view to creating formulations which are more easily tailored to the needs of the patient. Ultimately it has been established that printing the BCS Class II drug alone results in a crystalline product but on addition of a polymer this crystallinity is reduced and it is possible to print solid dispersions which are fully amorphous. Printing has also allowed greater control over drug distribution, which has allowed improved solubility overall. Additionally, the printer has proved itself capable of producing scalable products with a view to more patient centric dosage form manufacture

HUB Microfactory – PPA1 – Mefenamic acid – HME – 3D printing process stream

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Enabling future manufacture of dose forms: screening tools for an HME-3D printing process

Linking a hot-melt-extrusion (HME) process to 3D printing offers the ability for rapid prototyping of dose forms, whilst also allowing for personalisation of the dosage form to the patient's needs. However, process development can be lengthy and laborious since current technology involves process development for the HME and fused filament fabrication (FFF) process via the filament as an intermediate product. This work aims to develop screening tools to understand and predict API-polymer behaviour in HME and FFF processes and therefore reducing development time and resource

Achieving immediate release dosage forms using DoE and injection moulding

This study investigates a variety of disintegrating agents and small molecules to assess their suitability to increase the rate of the erosion process of Polyvinyl Alcohol (PVA)

The gut in the beaker : missing the surfactants

Gastrointestinal drug administration is the preferred route for the majority of drugs however, the natural physiology and physicochemistry of the gastrointestinal tract is critical to absorption but complex and influenced by factors such as diet or disease. The pharmaceutical sciences drive for product consistency has led to the development of in vitro product performance tests whose utility and interpretation is hindered by the complexity, variability and a lack of understanding. This article explores some of these issues with respect to the drug, formulation and the presence of surfactant excipients and how these interact with the natural bile salt surfactants. Interactions start in the mouth and during swallowing but the stomach and small intestine present the major challenges related to drug dissolution, solubility, the impact of surfactants and supersaturation along with precipitation. The behaviour of lipid based formulations and the influence of surfactant excipients is explored along with the difficulties of translating in vitro results to in vivo performance. Possible future research areas are highlighted with the conclusion that, “a great deal of work using modern methods is still required to clarify the situation”

Preparation and characterisation of free flowing solid lipid based drug delivery systems using a twin screw extruder

In this study, a continuous manufacturing process was developed for adsorbing liquid self-emulsifying drug delivery system (SEDDS) on mesoporous silica carriers in order to produce solid free flowing SEDDS powders. An optimized liquid SEDDS, consisting of Labrafil M 1944 CS, Labrasol and Capryol 90 (15, 80, 5 %w/w), was developed. The formulation spontaneously formed a homogenous emulsion with a droplet size of less than 200 nm (in water) and possessed pH robustness (pH 1.2, pH 6.8). Two grades of mesoporous silica were investigated as solid carriers, namely Syloid XDP 3050 and 3150. A twin screw extruder, setup in the granulation configuration, was employed to assess the mixing and adsorption of liquid SEDDS onto silica particles in a continuous process. Screw configuration, ratio of solid carrier to liquid SEDDS, powder and liquid feed rates and screw speed were identified as important parameters. These parameters were tested and optimized to achieve free flowing solid SEDDS. The maximum lipid loading of Syloid XDP 3050 and 3150 was 1:2 and 1:2 to less than 1:3 ratios, respectively. Although increasing liquid SEDDS loading increased the cohesive properties of the silica particles, the resulting powders afforded acceptable flow rate indexes as determined by powder rheometry. Similar self-emulsification behaviour was observed for solid and liquid SEDDS. With increasing lipid loading, the droplet size of emulsified solid SEDDS increased and changed from a unimodal to a bimodal size distributions. This effect was more pronounced for Syloid XDP3050. Syloid XDP 3150 was less sensitive to droplet size changes as its z-average diameters at 1:2-1:3 ratio were similar to the optimized liquid SEDDS. Targeting a lipid loading ratio of 2:1, process parameters were varied to maximise material throughput. The investigated continuous process of adsorbing liquid SEDDs onto solid carriers produced solid SEDDS with good flow properties. Syloid XDP 3150 seemed more robust to the process than Syloid XDP 3050

Explosivity : an unusual challenge in drug development

There remains an urgent global need for new drugs to combat diseases such as malaria, tuberculosis and cancer, as well as overcoming increasing antibiotic resistance. Chemists are moving into ‘new chemical space’ for drug design (1,2) and with this comes the possibility of traditional (and stable) ‘carbon-carbon’ bond structures being replaced by more ‘exotic’ bonding arrangements. While the implication of this on pharmaceutical stability can often be mitigated by suitable formulation and storage strategies, we came across an unusual case of chemical stability: the possibility that the drug was an explosive! By pushing drug designing into uncharted chemical space it could be argued that the possibility of finding explosive molecules of pharmaceutical interest will increase