Pharmaceutical science and Clinical Supplies

West Point, Pennsylvania, United States

Pharmaceutical science and Clinical Supplies

West Point, Pennsylvania, United States
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Mann A.K.P.,Pharmaceutical science and Clinical Supplies | Rumondor A.C.F.,Merck Animal Health | Jin X.,Merck Animal Health | Marota M.,Formulation science | Dalton C.,Pharmaceutical science and Clinical Supplies
Journal of Pharmaceutical Sciences | Year: 2017

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and Cmax. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics. © 2017 American Pharmacists Association®.


Capen R.,Nonclinical and Pharmaceutical science Statistics | Capen R.,Merck And Co. | Christopher D.,Nonclinical and Pharmaceutical science Statistics | Forenzo P.,Novartis | And 10 more authors.
AAPS PharmSciTech | Year: 2012

This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of product on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf lifea Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute. © 2012 American Association of Pharmaceutical Scientists.


Willemsz T.A.,University of Groningen | Nguyen T.T.,University of Groningen | Hooijmaijers R.,Pharmaceutical science and Clinical Supplies | Frijlink H.W.,University of Groningen | And 3 more authors.
AAPS PharmSciTech | Year: 2013

Removal of microcrystalline cellulose agglomerates in a dry-mixing system (lactose, 100 M) predominantly occurs via abrasion. The agglomerate abrasion rate potential is estimated by the Stokes abrasion (StAbr) number of the system. The StAbr number equals the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. Basically, the StAbr number concept describes the blending condition of the dry-mixing system. The concept has been applied to investigate the relevance of process parameters on agglomerate abrasion in tumbling blenders. Here, process parameters such as blender rotational speed and relative fill volumes were investigated. In this study, the StAbr approach revealed a transition point between abrasion rate behaviors. Below this transition point, a blending condition exists where agglomerate abrasion is dominated by the kinetic energy density of the powder blend. Above this transition point, a blending condition exists where agglomerates show (undesirable) slow abrasion rates. In this situation, the blending condition is mainly determined by the high fill volume of the filler. © 2012 American Association of Pharmaceutical Scientists.


Willemsz T.A.,University of Groningen | Hooijmaijers R.,Pharmaceutical science and Clinical Supplies | Rubingh C.M.,TNO | Tran T.N.,Center for Mathematical science Europe | And 5 more authors.
European Journal of Pharmaceutical Sciences | Year: 2012

Problems related to the blending of a cohesive powder with a free flowing bulk powder are frequently encountered in the pharmaceutical industry. The cohesive powder often forms lumps or agglomerates which are not dispersed during the mixing process and are therefore detrimental to blend uniformity. Achieving sufficient blend uniformity requires that the blending conditions are able to break up agglomerates, which is often an abrasion process. This study was based on the assumption that the abrasion rate of agglomerates determines the required blending time. It is shown that the kinetic energy density of the moving powder bed is a relevant parameter which correlates with the abrasion rate of agglomerates. However, aspects related to the strength of agglomerates should also be considered. For this reason the Stokes abrasion number (St Abr) has been defined. This parameter describes the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. The St Abr number is shown to predict the abrasion potential of agglomerates in the dry-mixing process. It appeared possible to include effects of filler particle size and impeller rotational rate into this concept. A clear relationship between abrasion rate of agglomerates and the value of St Abr was demonstrated. © 2011 Elsevier B.V. All rights reserved.


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.


Batchelor H.K.,University of Birmingham | Kendall R.,Pharmaceutical science and Clinical Supplies | Desset-Brethes S.,Novartis | Alex R.,Hoffmann-La Roche | 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.


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.


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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