Effect of Impeller Design on Homogeneity, Size and Strength of Pharmaceutical Granules produced by High Shear Wet Granulation

Small mixer impeller design is not tailored for granulation because impellers are intended for a wide range of processes. The aim of this research was to evaluate the performances of several impellers to provide guidance on the selection and design for the purposes of granulation. Lactose granules were produced using wet granulation with water as a binder. A Kenwood KM070 mixer was used as a standard apparatus and five impeller designs with different shapes and surface areas were used. The efficacy of granulate formation was measured by adding an optically sensitive tracer to determine variations in active ingredient content across random samples of granules from the same size classes. It was found that impeller design influenced the homogeneity of the granules and therefore can affect final product performance. The variation in active ingredient content across granules of differing size was also investigated. The results show that small granules were more potent than larger granules.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Slow Release Drug Dissolution Profile Prediction in Pharmaceutical Manufacturing: a Multivariate and Machine Learning Approach

Slow release drugs must be manufactured to meet target specifications with respect to dissolution curve profiles. In this paper we consider the problem of identifying the drivers of dissolution curve variability of a drug from historical manufacturing data. Several data sources are considered: raw material parameters, coating data, loss on drying and pellet size statistics. The methodology employed is to develop predictive models using LASSO, a powerful machine learning algorithm for regression with high-dimensional datasets. LASSO provides sparse solutions facilitating the identification of the most important causes of variability in the drug fabrication process. The proposed methodology is illustrated using manufacturing data for a slow release drug.

Hydrogel antimicrobial capture coatings for endotracheal tubes; a pharmaceutical strategy designed to prevent ventilator-associated pneumonia.

This paper presents a novel strategy for the prevention of ventilator-associatedpneumonia that involves coating poly(vinyl chloride, PVC) endotracheal tubes (ET) withhydrogels that may be subsequently used to entrap nebulized antimicrobial solutions. Candidatehydrogels were prepared containing a range of ratios of hydroxyethyl methacrylate (HEMA) andmethacrylic acid (MAA) from 100:0 to 70:30 using free radical polymerization and, whenrequired, simultaneous attachment to PVC was performed. The mechanical properties, glasstransition temperatures, swelling kinetics, uptake of gentamicin from an aqueous medium, andgentamicin release were characterized. Increasing the MAA content of the hydrogels significantlydecreased the ultimate tensile strength, % elongation at break, Young’s modulus, and increasedthe glass transition temperature, the swelling ratio, and gentamicin uptake. Microbial(Staphylococcus aureus and Pseudomonas aeruginosa) adherence to control (drug-free) hydrogelswas observed; however, while adherence to gentamicin-containing p(HEMA) occurred, noadherence occurred to gentamicin-containing HEMA:MAA copolymers. Antimicrobialpersistence of gentamicin-containing hydrogels was examined by determining the zone ofinhibition against each microorganism on successive days. Hydrogel composition affected the observed antimicrobial persistence,with the hydrogel composed of 70:30 HEMA:MAA exhibiting >20 days persistence against S. aureus and P. aeruginosa,respectively. To simulate clinical use, the hydrogels (coated onto PVC) were first exposed to a nebulized solution of gentamicin(4 mL, 80 mg for 20 min), and then to nebulized bacteria (4 mL ca. 1 × 109 colony forming units mL−1, 30 min). Viable bacteriawere not observed on the gentamicin-treated p(HEMA: MAA) copolymers, whereas growth was observed on gentamicin-treatedp(HEMA). In light of the excellent antimicrobial activity and physicochemical properties, p(HEMA: MAA) copolymerscomposed of ratios of 80:20 or 70:30 HEMA: MAA were identified as potentially useful coatings of endotracheal tubes to be usedin conjunction with the clinical nebulization of gentamicin and designed for the prevention of ventilator-associated pneumonia

Characterisation and modelling of the thermorheological properties of pharmaceutical polymers and their blends using capillary rheometry: Implications for hot melt processing of dosage forms.

Given the growing interest in thermal processing methods, this study describes the use of an advanced rheological technique, capillary rheometry, to accurately determine the thermorheological properties of two pharmaceutical polymers, Eudragit E100 (E100) and hydroxypropylcellulose JF (HPC) and their blends, both in the presence and absence of a model therapeutic agent (quinine, as the base and hydrochloride salt). Furthermore, the glass transition temperatures (Tg) of the cooled extrudates produced using capillary rheometry were characterised using Dynamic Mechanical Thermal Analysis (DMTA) thereby enabling correlations to be drawn between the information derived from capillary rheometry and the glass transition properties of the extrudates. The shear viscosities of E100 and HPC (and their blends) decreased as functions of increasing temperature and shear rates, with the shear viscosity of E100 being significantly greater than that of HPC at all temperatures and shear rates. All platforms were readily processed at shear rates relevant to extrusion (approximately 200–300 s−1) and injection moulding (approximately 900 s−1). Quinine base was observed to lower the shear viscosities of E100 and E100/HPC blends during processing and the Tg of extrudates, indicative of plasticisation at processing temperatures and when cooled (i.e. in the solid state). Quinine hydrochloride (20% w/w) increased the shear viscosities of E100 and HPC and their blends during processing and did not affect the Tg of the parent polymer. However, the shear viscosities of these systems were not prohibitive to processing at shear rates relevant to extrusion and injection moulding. As the ratio of E100:HPC increased within the polymer blends the effects of quinine base on the lowering of both shear viscosity and Tg of the polymer blends increased, reflecting the greater solubility of quinine within E100. In conclusion, this study has highlighted the importance of capillary rheometry in identifying processing conditions, polymer miscibility and plasticisation phenomena.

Immunological determination of the pharmaceutical diclofenac in environmental and biological samples

A highly sensitive and specific competitive ELISA on 96-microwell plates was developed for the analysis of the nonsteroidal anti-inflammatory drug diclofenac. Within the water cycle in Europe, this is one of the most frequently detected pharmaceutically active compounds. The LOD at a signal-tonoise ratio (S/N) of 3, and the IC ₅₀, were found to be 6 ng/L and 60 ng/L respectively in tap water. In a comparative study using ELISA and GC-MS, diclofenac levels in wastewater from 21 sewage treatment plants were determined and a good correlation between these methods was found (ELISA vs. GCMS: r = 0.70, slope = 0,90, intercept = 0.37, n = 24). An average degradation rate of -25% can be calculated. Labscale-experiments on the elimination of diclofenac in continuous pilot sewage plants revealed a removal rate of only 5% over a period of 13 weeks. In a further study, the ELISA was applied to a number of extracts of various animal tissues from a range of species, and again a very good relationship between ELISA and LC-ESI/MS data sets was obtained (r = 0.90, p<0.0001; n = 117). The ELISA has proven to be a simple, rapid, reliable and affordable alternative to otherwise costly and advanced techniques for the detection of diclofenac in matrix diverse water samples and tissue extracts after only relatively simple sample preparation. © 2007 American Chemical Society.

Effect of poly ethylene glycol on the mechanical and thermal properties of bioactive Poly (ε–caprolactone) melt extrudates for pharmaceutical applications

This paper investigates the effects of polyethylene glycol (PEG), on the mechanical and thermal properties of nalidixic acid/ploy ε-caprolactone (NA)/PCL blends prepared by hot melt extrusion. The blends were characterized by tensile and flexural analysis, dynamic mechanical analysis, differential scanning calorimetry, thermogravimetric analysis and X-ray diffraction. Experimental data indicated that the addition of NA caused loss of the tensile strength and toughness of PCL. Thermal analysis of the PCL showed that on addition of the thermally unstable NA, thermal degradation occurred early and was autocatalytic. However, the NA did benefit from the heat shielding provided by the PCL matrix resulting in more thermally stable NA particles. Results show that loading PEG in the PCL had a detrimental effect on the tensile strength and toughness of the blends, reducing them by 20-40%. The partial miscibility of the PCL-PEG system, causes an increase in Tg. While increases in the crystallinity is attributed to the plasticisation effect of PEG and the nucleation effect of NA. The average crystal size increased by 8% upon PEG addition.

Curricular training report: pharmaceutical industry & spin-off company

O presente relatório expõe as atividades desenvolvidas durante o estágio curricular, frequentado na Bluepharma - Indústria Farmacêutica S.A. e na TREAT U, Lda. uma Spin-off da Universidade de Coimbra, no âmbito do Mestrado em Biomedicina Farmacêutica da Universidade de Aveiro. Esta foi uma experiência de 6 meses que teve duas componentes, uma multidisciplinar e outra monodisciplinar, as quais me permitiram desenvolver os conhecimentos e aptidões adquiridas ao longo do curso de mestrado e de as aplicar ao mundo real. Para além do desenvolvimento de competências profissionais, esta experiência possibilitou também a aquisição e desenvolvimento de várias aptidões, quer a nível pessoal como social. Nos primeiros dois meses desta minha experiência adquiri um conhecimento essencialmente teórico em várias áreas da indústria farmacêutica (financeira, desenvolvimento de negócio, assuntos regulamentares, investigação e desenvolvimento de medicamentos, garantia da qualidade, etc.) através da minha passagem pela Bluepharma. De seguida, na minha experiência de quatro meses na TREAT U, foi-me dada a oportunidade de realizar de forma mais independente, as funções inerentes ao cargo de assistente da gerência, com especial enfoque para atividades de gestão de projeto (incluindo assuntos regulamentares), tais como, apoio na preparação do plano de desenvolvimento não clínico e na preparação do pedido de aconselhamento científico. Este relatório começa assim por descrever os objectivos do estágio e uma breve descrição das instituições que me acolheram para a sua realização. De seguida, os conhecimentos adquiridos na vertente multidisciplinar do estágio e depois as atividades desenvolvidas no âmbito monodisciplinar. Por fim, apresenta uma análise das dificuldades e desafios encontrados bem como os esforços realizados para os ultrapassar.