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Willemsz T.A.,University of Groningen | Nguyen T.T.,University of Groningen | Hooijmaijers R.,Pharmaceutical science and Clinical Supplies | Van Der Voort Maarschalk K.,University of Groningen
Pharmaceutisch Weekblad | Year: 2015

OBJECTIVE: To identify the basic mechanisms of agglomerate breakage during powder blending. Presence of drug agglomerates in a blend poses a potential safety risk in e.g. pharmaceutical applications. Therefore, agglomerates need to be removed. DESIGN AND METHODS: This study assessed the critical process parameters and rules that must be observed when scaling up a mixing process. RESULTS: Experiments using so-called brittle calibrated test particles provided evidence that agglomerates reduce in size via an abrasion mechanism. The abrasion rate is not only influenced by the (mechanical) properties of agglomerates and process conditions, but also by the particle size distribution of the filler. A novel method to measure powder velocities enabled the development of a quantitative model that describes the relationships between powder motion during blending and agglomerate abrasion. A Stokes number (Stabr) defined as the ratio between the kinetic energy density of the bed and the work of fracture of agglomerates predicts the rate of agglomerate abrasion very well. CONCLUSION: Particle velocity critically affects agglomerate abrasion and mixing time. Therefore mixing of a powder blend containing a cohesive material should be approached as a particle size reduction problem rather than a distribution issue.


Williams H.D.,University of Nottingham | Williams H.D.,Monash Institute of Pharmaceutical Sciences | Nott K.P.,Oxford Instruments | Barrett D.A.,University of Nottingham | And 3 more authors.
Journal of Pharmaceutical Sciences | Year: 2011

"Biorelevant" media for the fed stomach, including fat emulsions, are routinely used during in vitro testing of solid dosage forms. However, their complexity undoubtedly creates difficulties in identifying factors which affect drug release. Here, we show fats can directly influence drug release from hydroxypropyl methylcellulose (HPMC; Methocel K4M) matrices which are often subjected to biorelevant testing. Model fat systems included milk (0.1%-3.5% fat) and the parenteral emulsion Intralipid® (20%-30% fat). The matrix showed good extended-release properties for at least 12h in these media (USP-1/USP-4), but at the highest fat concentration, release was retarded and shifted towards zero-order release. Confocal imaging studies using a water-soluble (fluorescein) and fat-soluble (Nile red) fluorophore provided evidence of phase separation of Intralipid® at the surface of the emerging gel. Combined magnetic resonance imaging-USP-4 drug release testing provided further evidence for deposition of fat on the tablets. We propose that the aqueous portion of the emulsion is removed by the hydrating matrix, causing coalescence and deposition of a fat layer at the surface, and these deposits cause slower drug release by reducing the matrix surface area available for release. Therefore, there is a risk of a direct interaction between fat emulsions and HPMC tablets, with resultant effects on drug release in vitro. © 2011 Wiley-Liss, Inc.


Batchelor H.K.,University of Birmingham | Kendall R.,Pharmaceutical science and Clinical Supplies | Desset-Brethes S.,Novartis | Alex R.,Roche Holding AG | Ernest T.B.,Glaxosmithkline
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

Biopharmaceutics is routinely used in the design and development of medicines to generate science based evidence to predict in vivo performance; the application of this knowledge specifically to paediatric medicines development is yet to be explored. The aim of this review is to present the current status of available biopharmaceutical tools and tests including solubility, permeability and dissolution that may be appropriate for use in the development of immediate release oral paediatric medicines. The existing tools used in adults are discussed together with any limitations for their use within paediatric populations. The results of this review highlight several knowledge gaps in current methodologies in paediatric biopharmaceutics. The authors provide recommendations based on existing knowledge to adapt tests to better represent paediatric patient populations and also provide suggestions for future research that may lead to better tools to evaluate paediatric medicines. © 2013 Elsevier B.V. All rights reserved.


Besseling R.,Pharmaceutical science and Clinical Supplies | Damen M.,Pharmaceutical science and Clinical Supplies | Tran T.,University of Cambridge | Nguyen T.,Pharmaceutical science and Clinical Supplies | And 5 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

Dry powder mixing is a wide spread Unit Operation in the Pharmaceutical industry. With the advent of in-line Near Infrared (NIR) Spectroscopy and Quality by Design principles, application of Process Analytical Technology to monitor Blend Uniformity (BU) is taking a more prominent role. Yet routine use of NIR for monitoring, let alone control of blending processes is not common in the industry, despite the improved process understanding and (cost) efficiency that it may offer. Method maintenance, robustness and translation to regulatory requirements have been important barriers to implement the method. This paper presents a qualitative NIR-BU method offering a convenient and compliant approach to apply BU control for routine operation and process understanding, without extensive calibration and method maintenance requirements. The method employs a moving F-test to detect the steady state of measured spectral variances and the endpoint of mixing. The fundamentals and performance characteristics of the method are first presented, followed by a description of the link to regulatory BU criteria, the method sensitivity and practical considerations. Applications in upscaling, tech transfer and commercial production are described, along with evaluation of the method performance by comparison with results from quantitative calibration models. A full application, in which end-point detection via the F-test controls the blending process of a low dose product, was successfully filed in Europe and Australia, implemented in commercial production and routinely used for about five years and more than 100 batches. © 2015 Elsevier B.V.


PubMed | Abbott Laboratories, Pharmaceutical science and Clinical Supplies, Patheon and University of Cambridge
Type: | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2015

Dry powder mixing is a wide spread Unit Operation in the Pharmaceutical industry. With the advent of in-line Near Infrared (NIR) Spectroscopy and Quality by Design principles, application of Process Analytical Technology to monitor Blend Uniformity (BU) is taking a more prominent role. Yet routine use of NIR for monitoring, let alone control of blending processes is not common in the industry, despite the improved process understanding and (cost) efficiency that it may offer. Method maintenance, robustness and translation to regulatory requirements have been important barriers to implement the method. This paper presents a qualitative NIR-BU method offering a convenient and compliant approach to apply BU control for routine operation and process understanding, without extensive calibration and method maintenance requirements. The method employs a moving F-test to detect the steady state of measured spectral variances and the endpoint of mixing. The fundamentals and performance characteristics of the method are first presented, followed by a description of the link to regulatory BU criteria, the method sensitivity and practical considerations. Applications in upscaling, tech transfer and commercial production are described, along with evaluation of the method performance by comparison with results from quantitative calibration models. A full application, in which end-point detection via the F-test controls the blending process of a low dose product, was successfully filed in Europe and Australia, implemented in commercial production and routinely used for about five years and more than 100 batches.

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