Marcel de Matas

The effect of zinc oxide and titanium dioxide nanoparticles in the Comet assay with UVA photoactivation of human sperm and lymphocytes

The present study has examined the effects of ZnO and TiO2 nanoparticles (40–70 nm range) in the presence and absence of UVA light in human sperm and human lymphocytes in the dark (D), after pre-irradiation with UV (PI) and simultaneous irradiation with UV (SI). For both ZnO and TiO2 nanoparticles, the percentage reduction in head DNA was greater for PI and SI samples compared with samples treated in the dark. However with regard to photogenotoxicity, sperm exhibited no significant differences when the results for PI and SI and the dark were compared, except at the lowest concentration for SI samples in the case of ZnO and the lowest concentration for PI in the case of TiO2. However for lymphocytes, responses were statistically significant at the highest concentration for both PI and SI samples. Thus, these studies suggest that there are photogenotoxic events in these cells in the absence of overt toxicity.

Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT)

Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals however have the potential to provide considerable challenges to the establishment of cost effective and robust supply chains. To guarantee product quality and surety of supply for essential medicines it is necessary that manufacturing science keeps pace with advances in pharmaceutical R&D. In this position paper, the EUFEPS QbD and PAT Sciences network make recommendations that European industry, academia and health agencies focus attention on delivering step changes in science and technology in a number of key themes. These subject areas, all underpinned by the sciences allied to QbD and PAT, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being established to gain commitment for inclusion of these themes into future funding priorities for the Innovative Medicines Initiative (IMI).

Characterization of thermal and rheological properties of zidovidine, lamivudine and plasticizer blends with ethyl cellulose to assess their suitability for hot melt extrusion

The influence of antiretroviral drugs and plasticizers on the rheological and thermal characteristics of ethyl cellulose formulations intended for hot melt extrusion has been investigated. Antiretroviral drugs used were zidovudine and lamivudine, whilst plasticizers included triethylcitrate (TEC) and polyethylene glycol (PEG-6000). Physical mixtures containing ethyl cellulose with varying concentrations of drugs and plasticizers were characterized using differential scanning calorimetry (DSC) and parallel plate oscillatory rheometry. The viscosity of physical mixtures containing both drugs was lower than observed for pure ethyl cellulose, indicating that the drugs had a plasticizing effect. This was confirmed by lowering of the glass transition temperature (Tg) of ethyl cellulose. At the highest loading of 40% by weight, lamivudine appeared to become saturated within the polymer, causing an increase in viscosity and showing evidence of recrystallization upon cooling. Both TEC and PEG-6000 were found to lower the Tg of ethyl cellulose, although PEG-6000 recrystallized upon cooling which makes it unsuitable for use in the proposed controlled release formulations. Both plasticizers were also shown to reduce the viscosity of ethyl cellulose, more significantly so for TEC. The results indicate that ethyl cellulose formulations containing up to 40% by weight of zidovudine, not more than 30% by weight of lamivudine, with 5-10% by weight of TEC as the plasticizer are suitable for processing by hot melt extrusion.

Multipronged evaluation of genotoxicity in Indian petrol‐pump workers

Petrol (gasoline) contains a number of toxicants. This study used human biomonitoring to evaluate the genotoxic effects of exposure to benzene in petrol fumes in 100 Indian petrol‐pump workers (PPWs) and an equal number of controls. The study was corroborated with in silico assessments of the Comet assay results from the human biomonitoring study. An in vitro study in human lymphocytes was also conducted to understand the genotoxicity of benzene and its metabolites. In a subset of the population studied, higher blood benzene levels were detected in the PPWs (n = 39; P < 0.01) than the controls (n = 18), and 100–250 ppb benzene was also detected in air samples from the petrol pumps. PPWs had higher levels of DNA damage than the controls (P < 0.01). In addition, the micronucleus assay was performed on lymphocytes from a subset of the subjects, and the micronucleus frequency for PPWs was significantly higher (n = 39; 14.79 ± 3.92‰) than the controls (n = 18; 7.54 ± 3.00‰). Human lymphocytes were treated in vitro with benzene and several of its metabolites and assayed for DNA damage with the Comet assay. Benzene and its metabolites produced significant (P < 0.05) levels of DNA damage at and above concentrations of 10 μM. The metabolite, p‐benzoquinone, produced the greatest amount of DNA damage, followed by hydroquinone > benzene > catechol > 1,2,4,‐benzenetriol > muconic acid. This study demonstrates that, using sensitive techniques, it is possible to detect human health risks at an early stage when intervention is possible. possible. Environ. Mol. Mutagen., 2008.

Granulation of increasingly hydrophobic formulations using a twin screw granulator.

The application of twin screw granulation in the pharmaceutical industry has generated increasing interest due to its suitability for continuous processing. However, an understanding of the impact of formulation properties such as hydrophobicity on intermediate and finished product quality has not yet been established. Hence, the current work investigated the granulation behaviour of three formulations containing increasing amounts of hydrophobic components using a Consigma™-1 twin screw granulator. Process conditions including powder feed rate, liquid to solid ratio, granulation liquid composition and screw configuration were also evaluated. The size of the wet granules was measured in order to enable exploration of granulation behaviour in isolation without confounding effects from downstream processes such as drying. The experimental observations indicated that the granulation process was not sensitive to the powder feed rate. The hydrophobicity led to heterogeneous liquid distribution and hence a relatively large proportion of un-wetted particles. Increasing numbers of kneading elements led to high shear and prolonged residence time, which acted to enhance the distribution of liquid and feeding materials. The bimodal size distributions considered to be characteristic of twin screw granulation were primarily ascribed to the breakage of relatively large granules by the kneading elements.

Prediction of the mechanical behaviour of crystalline solids.

ABSTRACTPurposeTo explore the use of crystal inter-planar d-spacings and slip-plane interaction energies for predicting and characterising mechanical properties of crystalline solids.MethodsPotential relationships were evaluated between mechanical properties and inter-planar d-spacing, inter-planar interaction energy, and dispersive surface energy as determined using inverse gas chromatography (IGC) for a set of pharmaceutical materials. Inter-planar interaction energies were determined by molecular modelling.ResultsGeneral trends were observed between mechanical properties and the largest inter-planar d-spacing, inter-planar interaction energies, and IGC dispersive surface energy. A number of materials showed significant deviations from general trends. Weak correlations and outliers were rationalised.ConclusionsResults suggest that the highest d-spacing of a material could serve as a first-order indicator for ranking mechanical behaviour of pharmaceutical powders, but with some reservation. Inter-planar interaction energy normalised for surface area shows only a weak link with mechanical properties and does not appear to capture essential physics of deformation. A novel framework linking mechanical properties of crystals to the distinct quantities, slip-plane energy barrier and inter-planar interaction (detachment) energy is proposed.

Quantification of Swelling and Erosion in the Controlled Release of a Poorly Water-Soluble Drug Using Synchrotron X-ray Computed Microtomography

The hydration layer plays a key role in the controlled drug release of gel-forming matrix tablets. For poorly water-soluble drugs, matrix erosion is considered as the rate limiting step for drug release. However, few investigations have reported on the quantification of the relative importance of swelling and erosion in the release of poorly soluble drugs, and three-dimensional (3D) structures of the hydration layer are poorly understood. Here, we employed synchrotron radiation X-ray computed microtomography with 9-μm resolution to investigate the hydration dynamics and to quantify the relative importance of swelling and erosion on felodipine release by a statistical model. The 3D structures of the hydration layer were revealed by the reconstructed 3D rendering of tablets. Twenty-three structural parameters related to the volume, the surface area (SA), and the specific surface area (SSA) for the hydration layer and the tablet core were calculated. Three dominating parameters, including SA and SSA of the hydration layer (SAhydration layer and SSAhydration layer) and SA of the glassy core (SAglassy core), were identified to establish the statistical model. The significance order of independent variables was SAhydration layer > SSAhydration layer > SAglassy core, which quantitatively indicated that the release of felodipine was dominated by a combination of erosion and swelling. The 3D reconstruction and structural parameter calculation methods in our study, which are not available from conventional methods, are efficient tools to quantify the relative importance of swelling and erosion in the controlled release of poorly soluble drugs from a structural point of view.

Determination of the relative bioavailability of salbutamol to the lungs following inhalation from dry powder inhaler formulations containing drug substance manufactured by supercritical fluids and micronization

PurposeThe relative lung bioavailability of salbutamol sulfate particles produced using supercritical fluids (SEDS™) and delivered by dry powder inhaler (DPI) was compared with the performance of a conventional micronized drug DPI using the same device design (Clickhaler™, Innovata Biomed).Materials and MethodsTwelve healthy volunteers and 11 mild asthmatic patients completed separate four-way randomised cross-over studies, assessing the relative bioavailability of salbutamol sulfate (urinary excretion method), formulated as SEDS™ particles (three batches) and micronized particles (Asmasal™ inhaler, UCB Pharma Ltd). Post-treatment improvements in patient lung function were assessed by measuring FEV1. Physicochemical evaluation of the three SEDS™ batches revealed inter-batch differences in particle size and shape.ResultsThere was no significant difference in the relative lung bioavailability of salbutamol and its bronchodilator response between the best performing SEDS™ formulation and the Asmasal™ inhaler in volunteers and patients, respectively. SEDS™ salbutamol sulfate showing wafer like morphology gave greater fine particle dose, relative lung bioavailability and enhanced bronchodilation compared to other SEDS™ batches containing elongated particles.ConclusionsActive Pharmaceutical Ingredient (API) manufactured using supercritical fluids and delivered by DPI can provide similar lung bioavailability and clinical effect to the conventional micronized commercial product. Product performance is however notably influenced by inter-batch differences in particle characteristics.

Influence of Solvent on the Morphology and Subsequent Comminution of Ibuprofen Crystals by Air Jet Milling

Crystal morphology plays an important role in drug processing and delivery, which may be controlled during crystallisation. In this study, ibuprofen particles with different size and morphology were produced by controlled crystallisation in order to evaluate their impact on particle size reduction. Results suggest that the micronisation behaviour of ibuprofen was markedly influenced by the morphology and size of starting materials. It was possible to reduce the size of ibuprofen particles to sizes less than 5 µm during dry milling, which is markedly below the reported brittle-ductile transition size. Results also indicate that the particle size reduction mechanism is influenced by the size and morphology of the starting ibuprofen crystals. Dissolution behaviour of ibuprofen was shown to be influenced by the solid surface chemistry of micronised drug particles. The molecular modelling study provided deeper understanding of the experimental findings observed in this study.

A quality by design approach using artificial intelligence techniques to control the critical quality attributes of ramipril tablets manufactured by wet granulation.

Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.