Development Laboratories

Eindhoven, Netherlands

Development Laboratories

Eindhoven, Netherlands
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Avalle P.,Development Laboratories | Pygall S.R.,Development Laboratories | Pritchard J.,Imperial College London | Jastrzemska A.,Development Laboratories
European Journal of Pharmaceutical Sciences | Year: 2013

The present work explores the application of in situ near infrared (NIR) imaging to determine the drug release mechanisms from hydrophilic matrices containing a low solubility model drug (Compound A, with aqueous solubility at 37 °C ∼0.05 mg/mL). Correlation maps generated from the NIR data determined the extent drug and HPMC co-localisation. Judicious thresholding facilitated band separation of low drug/HPMC ratio and high drug/HPMC ratio. A pseudo-image time-series confirmed the dominant erosion release mechanisms. The gel layer region showed low drug concentration with progressive dissolution. However, large drug aggregates remained unchanged even when fully "immersed" within the gel layer. From the correlation maps, further discrimination was possible for the pure drug signal, generating a highly contrasted image that enabled individual particle tracking. These contrasted images also revealed the evolution of single or clusters of drug particles. Initially, an aggregative process involving the drug particles occurred, with a subsequent migration process of such particles. This second process dominated the subsequent 90 min before significant erosion. In summary, this study has provided tentative confirmation that NIR imaging has the potential to afford insights into drug liberation phenomena where erosion is the predominant release mechanism. © 2012 Elsevier B.V. All rights reserved.


Phillips D.J.,University of Warwick | Pygall S.R.,Development Laboratories | Cooper V.B.,Development Laboratories | Mann J.C.,Development Laboratories
Journal of Pharmacy and Pharmacology | Year: 2012

Objectives The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly-soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly-soluble species, will also be discussed. Key findings The biphasic dissolution model utilizes media comprising immiscible aqueous and organic layers whereby the drug, following initial aqueous dissolution, partitions into the organic layer. This step, which acts to remove all dissolved species from the aqueous layer, enables further aqueous dissolution to occur and hence the dissolution-partition cycle continues. Crucially, the aqueous layer does not saturate allowing sink conditions to be maintained and hence the experiment will, in theory, yield complete dissolution. Summary This review highlights important concepts regarding solubility/sink limitation and intends to provoke debate among analytical and formulation scientists as to the potential advantages, long-term development and widespread implementation of a biphasic dissolution system in drug development. © 2012 Royal Pharmaceutical Society.


Avalle P.,Development Laboratories | Pygall S.R.,Development Laboratories | Gower N.,Development Laboratories | Midwinter A.,Development Laboratories
European Journal of Pharmaceutical Sciences | Year: 2011

In this study, near infrared (NIR) spectroscopy has been used to track the spatial and temporal movement of a model drug (Compound A) while monitoring in situ the gel layer development in hydrophilic matrices based on hydroxypropyl methylcellulose (HPMC). To validate the NIR experimental set-up, Compound A was formulated in "slow" and "fast" drug releasing formulations with high (56% w/w) and low (18% w/w) levels of HPMC K100M, respectively. NIR microscopy was used to (i) define the extent of HPMC pseudo-gel swelling, (ii) elucidate the movement of the polymer swelling front and (iii) track movement of the drug through the gel layer. Dissolution testing (USP I) allowed correlation of mechanistic details ascertained using NIR with the rate and extent of drug release. Several critical differences were observable between "fast" and "slow" formulations. In the "fast" formulation, HPMC swelling front movement occurred at a slower rate and to a lesser extent compared to drug release, suggestive of inadequate gel layer formation and a partial loss of extended release characteristics. In contrast, the "slow" formulation exhibited a similar rate of HPMC swelling front movement compared to drug release, suggesting a release mechanism predominately controlled by polymer erosion, supported by an apparent zero order drug dissolution curve in USP I. In conclusion, the study suggests the potential future value of using NIR in situ to elucidate mechanistic insights in drug release rate from pharmaceutical formulations. © 2011 Elsevier B.V. All rights reserved.


Phillips D.J.,University of Warwick | Pygall S.R.,Development Laboratories | Brett Cooper V.,Development Laboratories | Mann J.C.,Development Laboratories
Dissolution Technologies | Year: 2012

The potential of a biphasic dissolution system to assist with the analysis of controlled-release (CR), Biopharmaceutics Classification System (BCS) Class II pharmaceutical products has been investigated. Use of a biphasic dissolution medium (aqueous/octanol) provided sink conditions and afforded complete dissolution of nifedipine formulated in a CR matrix tablet while maintaining the dosage form in an aqueous environment. This was not possible in a monophasic (aqueousonly) dissolution medium. Consequently, the biphasic model allowed the discrimination of three formulations containing different HPMC loadings while the monophasic medium did not. The performance of the formulations in conventional dissolution media incorporating the inorganic salt dibasic sodium phosphate, the surfactant sodium dodecyl sulfate (SDS), and ethanol as solubility modifiers was assessed. The addition of the salt and surfactant failed to produce complete discrimination in a predictive manner. The use of a hydroalcoholic medium comprising water and ethanol enabled the statistical discrimination of the three formulations but not as effectively as the biphasic medium.


Peters H.J.,Technical University of Delft | Peters H.J.,Development Laboratories | Goosen J.F.L.,Technical University of Delft | Van Keulen F.,Technical University of Delft
International Journal of Micro Air Vehicles | Year: 2015

Energy-effective hovering and active flight control are of paramount importance for the usefulness of Flapping Wing Micro Air Vehicles (FWMAVs). Recent studies have focused on separate parts (e.g., wing planform design, wing kinematics, or flight control) rather than on the complete system. This work presents a combined approach to find an optimal wing design (i.e., wing planform and pitching kinematics) for energy-effective hovering and roll control. Relatively simple mathematical descriptions are used for the kinematics, the aerodynamics and the roll motion to allow its use in optimization techniques. Results show that the wing design depends significantly on the relative importance of either energy-effective hovering or effective roll control during the optimization. The roll control effectiveness increases if the wing area around the wingtip is increased to push the center of lift outwards. Additionally, we show that the most effective control variable, to enforce the required body moment for the roll motion, depends strongly on the wing design. In conclusion, flapping wing design requires, in general, a combined approach to guarantee both energy-effective hovering and effective roll control. © 2015, Multi-Science Publishing Co. Ltd. All rights reserved.


Peters H.J.,Technical University of Delft | Peters H.J.,Development Laboratories | Tiso P.,Technical University of Delft | Goosen J.F.L.,Technical University of Delft | Van Keulen F.,Technical University of Delft
Journal of Sound and Vibration | Year: 2015

Structural resonance can be exploited to obtain a specific motion at low input power. This paper presents an approach to determine the locations, number, and dimensions of local structural changes to temporary obtain different resonance configurations while consuming minimal control power. The starting point is a non-dissipative resonance mode. Eigensolu-tion sensitivities are used to approximate the effect of the local structural changes on a given resonance mode. In order to increase insight and intuitive understanding, these sensitivities are expressed in terms of the modal basis. A projection is proposed to focus on the modifications at specific regions of interest, thus leaving the remaining portions of the mode unspecified. By expressing this projection in terms of the modal basis, the number of significant modes in the analysis decreases drastically, and the computational effort is largely reduced. Closely spaced eigenfrequencies appear to be attractive for effective resonance mode modifications. A plate example demonstrates the approach. © 2014 Elsevier Ltd. All rights reserved.


Kostewicz E.S.,Goethe University Frankfurt | Abrahamsson B.,Astrazeneca | Brewster M.,Drug Product Development | Brouwers J.,Catholic University of Leuven | And 15 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation...) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract. © 2013 Elsevier B.V. All rights reserved.


Peters H.J.,Technical University of Delft | Peters H.J.,Development Laboratories | Goosen J.F.L.,Technical University of Delft | Keulen F.V.,Technical University of Delft
Smart Materials and Structures | Year: 2016

Lightweight vibrating structures (such as flapping wing micro air vehicle (FWMAV) designs) often require some form of control. To achieve controllability, local structural property changes (e.g., damping and stiffness changes) might be induced in an active manner. The stroke-averaged lift force production of a FWMAV wing can be modified by changing the structural properties of that wing at carefully selected places (e.g., changing the properties of the elastic hinge at the wing root as studied in this work). To actively change the structural properties, we investigate three different methods which are based on: (1) piezoelectric polymers, (2) electrorheological fluids, and (3) electrostatic softening. This work aims to gain simple yet insightful ways to determine the potential of these methods without focusing on the precise modeling. Analytical models of FWMAV wing designs that include control approaches based on these three methods are used to calculate the achievable lift force modifications after activating these methods. The lift force production as a result of a wing flapping motion is determined using a quasi-steady aerodynamic model. Both piezoelectric polymers and electrostatic softening are found to be promising in changing the structural properties and, hence, the lift force production of FWMAV wings. For the control of lightweight FWMAV designs, numerical simulations reveal a promising roll maneuverability due to the induced lift force difference between a pair of opposite wings. Although applied to a specific FWMAV design, this work is relevant for control of small, lightweight, possible compliant, vibrating structures in general. © 2016 IOP Publishing Ltd.


Lalloo A.K.,Merck And Co. | McConnell E.L.,Development Laboratories | Jin L.,Merck And Co. | Elkes R.,Development Laboratories | And 2 more authors.
International Journal of Pharmaceutics | Year: 2012

Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations. © 2012 Elsevier B.V. All rights reserved.


PubMed | Development Laboratories
Type: Journal Article | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2013

The present work explores the application of in situ near infrared (NIR) imaging to determine the drug release mechanisms from hydrophilic matrices containing a low solubility model drug (Compound A, with aqueous solubility at 37C 0.05 mg/mL). Correlation maps generated from the NIR data determined the extent drug and HPMC co-localisation. Judicious thresholding facilitated band separation of low drug/HPMC ratio and high drug/HPMC ratio. A pseudo-image time-series confirmed the dominant erosion release mechanisms. The gel layer region showed low drug concentration with progressive dissolution. However, large drug aggregates remained unchanged even when fully immersed within the gel layer. From the correlation maps, further discrimination was possible for the pure drug signal, generating a highly contrasted image that enabled individual particle tracking. These contrasted images also revealed the evolution of single or clusters of drug particles. Initially, an aggregative process involving the drug particles occurred, with a subsequent migration process of such particles. This second process dominated the subsequent 90 min before significant erosion. In summary, this study has provided tentative confirmation that NIR imaging has the potential to afford insights into drug liberation phenomena where erosion is the predominant release mechanism.

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