Nicholas Blagden

Preparation of hydrocortisone nanosuspension through a bottom-up nanoprecipitation technique using microfluidic reactors.

In this work, the possibility of bottom-up creation of a relatively stable aqueous hydrocortisone nanosuspension using microfluidic reactors was examined. The first part of the work involved a study of the parameters of the microfluidic precipitation process that affect the size of generated drug particles. These parameters included flow rates of drug solution and antisolvent, microfluidic channel diameters, microreactors inlet angles and drug concentrations. The experimental results revealed that hydrocortisone nano-sized dispersions in the range of 80-450 nm were obtained and the mean particle size could be changed by modifying the experimental parameters and design of microreactors. The second part of the work studied the possibility of preparing a hydrocortisone nanosuspension using microfluidic reactors. The nano-sized particles generated from a microreactor were rapidly introduced into an aqueous solution of stabilizers stirred at high speed with a propeller mixer. A tangential flow filtration system was then used to concentrate the prepared nanosuspension. The nanosuspension produced was then characterized using photon correlation spectroscopy (PCS), Zeta potential measurement, transmission electron microscopy (TEM), differential scanning calorimetry (DSC) and X-ray analysis. Results showed that a narrow sized nanosuspension composed of amorphous spherical particles with a mean particle size of 500+/-64 nm, a polydispersity index of 0.21+/-0.026 and a zeta potential of -18+/-2.84 mV was obtained. Physical stability studies showed that the hydrocortisone nanosuspension remained homogeneous with slight increase in mean particle size and polydispersity index over a 3-month period.

Hydrocortisone nanosuspensions for ophthalmic delivery: A comparative study between microfluidic nanoprecipitation and wet milling

Recently, drug nanosuspensions have shown a potential for ophthalmic delivery. In this study, a hydrocortisone (HC) nanosuspension (NS) was developed using microfluidic nanoprecipitation as a recent, simple and cost-effective bottom-up technique of drug nanonization. For comparison, a second HC NS was prepared by top-down wet milling procedures. The produced nanosuspensions were characterized for particle size, shape and zeta potential. HC nanosuspensions of approximately 300nm particle size were produced by adjusting experimental conditions of the two processing techniques. Results of X-ray diffraction and differential scanning calorimetry revealed that HC maintained the crystalline structure upon milling, while predominant amorphous particles were generated after precipitation. Ocular bioavailability of HC nanosuspensions was assessed in albino rabbits using HC solution as a control. A sustained drug action was maintained up to 9h for the nanosuspensions compared to 5h for the drug solution. The precipitated and milled NS achieved comparable AUC(0-9h) values of 28.06±4.08 and 30.95±2.2, respectively, that were significantly (P<0.05) higher than that of HC solution (15.86±2.7). After 2 months storage at room temperature, the milled HC NS showed good stability with no discernable changes in particle size, whereas the particle size of the precipitated HC NS increased to 440nm.

Current directions in co-crystal growth

In this feature article we will focus on the issues relating to the crystal growth of co-crystals, with a particular emphasis on drug development. The initial focus of this perspective is on the relevant literature examples that may be able to inform our understanding with regards co-crystal crystallisation and the allied supramolecular concepts. The second part of this perspective contains selected examples from our own work, which add to the literature perspective. Topics include; nucleation templates, in situ synchrotron XRD studies, solid-state synthesis through mixing and screening strategies.

Artificial neural networks modelling the prednisolone nanoprecipitation in microfluidic reactors

This study employs artificial neural networks (ANNs) to create a model to identify relationships between variables affecting drug nanoprecipitation using microfluidic reactors. The input variables examined were saturation levels of prednisolone, solvent and antisolvent flow rates, microreactor inlet angles and internal diameters, while particle size was the single output. ANNs software was used to analyse a set of data obtained by random selection of the variables. The developed model was then assessed using a separate set of validation data and provided good agreement with the observed results. The antisolvent flow rate was found to have the dominant role on determining final particle size.

Spontaneous crystal growth of co-crystals: the contribution of particle size reduction and convection mixing of the co-formers

Previously reported methods for co-crystal synthesis have employed a variety of strategies and these include co-grinding, co-precipitation, growth from the solution, melt and slurry (M. Zaworotko, Polymorphism in Co-crystals and Pharmaceutical Co-crystals, XX Congress of the International Union of Crystallography, Florence, 2005) and spontaneous co-crystal formation without pre-milling activation (C. Maheshwari, J. Jayasankar, N. A. Khan, G. E. Amidon and N. Rodriguez-Hornedo, CrystEngComm, 2009, 11, 493–500). In this contribution the impact of particle size and pre-milling of the components on spontaneous co-crystal formation is described. This report builds on concepts outlined in a perspective by the authors on future developments in co-crystal formation (N. Blagden, D. J. Berry, A. Parkin, H. Javed, A. Ibrahim, P. T. Gavan, L. L. Dematos and C. C. Seaton, New. J. Chem., 2008, 32, 1659–1672) in this area. In particular, the opportunity for spontaneous co-crystal formation utilizing a solid component mixing process with a separate pre-milling step to activate the process is presented. Previously reported systems known to form co-crystals were examined, namely caffeine and urea as the model drug, and malonic acid and 2-methoxybenzamide (2-MB) as well-documented molecular complex formers. The synthesis approach adopted for this study involves pre-milling of the solid components to a particular particle size range and subsequent tracking of any co-crystal formation in a physical mixture during a solid-state convection mixing of the components. For both systems, three different size fractions (20–45 µm), (75–125 µm), and (180–250 µm) were examined. An assessment of transformation from component phase to molecular complex indicated that, typically, the co-crystals started to form after 30 min, as reflected in the evolution of co-crystal powder X-ray diffraction peaks with time. Notably, the rate of co-crystal formation rapidly increased for the smallest size fraction (20–45 µm). No buried eutectic or extensive amorphous intermediate phase was identified and this outcome suggests that the propensity for crystallization was associated with inter-particle contact and that this is linked to an increase in contact areas with decreasing particle size.

Development of a novel liquid crystal based cell traction force transducer system.

Keratinocyte traction forces play a crucial role in wound healing. The aim of this study was to develop a novel cell traction force (CTF) transducer system based on cholesteryl ester liquid crystals (LC). Keratinocytes cultured on LC induced linear and isolated deformation lines in the LC surface. As suggested by the fluorescence staining, the deformation lines appeared to correlate with the forces generated by the contraction of circumferential actin filaments which were transmitted to the LC surface via the focal adhesions. Due to the linear viscoelastic behavior of the LC, Hookes equation was used to quantify the CTFs by associating Youngs modulus of LC to the cell induced stresses and biaxial strain in forming the LC deformation. Youngs modulus of the LC was profiled by using spherical indentation and determined at approximately 87.1±17.2kPa. A new technique involving cytochalasin-B treatment was used to disrupt the intracellular force generating actin fibers, and consequently the biaxial strain in the LC induced by the cells was determined. Due to the improved sensitivity and spatial resolution (∼1μm) of the LC based CTF transducer, a wide range of CTFs was determined (10-120nN). These were found to be linearly proportional to the length of the deformations. The linear relationship of CTF-deformations was then applied in a bespoke CTF mapping software to estimate CTFs and to map CTF fields. The generated CTF map highlighted distinct distributions and different magnitude of CTFs were revealed for polarized and non-polarized keratinocytes.

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.

Formation of a hybrid coordination-molecular complex

The synthesis and crystal structure of the lithium hydrate salt of the charge transfer complex between 3,5-dinitrobenzoic acid and 4-(dimethylamino) benzoic acid is reported. It is the first crystal structure reported for such a class of hybrid inorganic/organic material. The design principles may have utility in the future creation of new ternary and higher complexes.

A Hydrocortisone Nanoparticle Dosage Form

Purpose: To model and interpret drug distribution in the dermis and underlying tissues after topical application which is relevant to the treatment of local conditions. Methods: We created a new physiological pharmacokinetic model to describe the effect of blood flow, blood protein binding and dermal binding on the rate and depth of penetration of topical drugs into the underlying skin. We used this model to interpret literature in vivo human biopsy data on dermal drug concentration at various depths in the dermis after topical application of 6 substances. This interpretation was facilitated by our in vitro human dermal penetration studies in which dermal diffusion coefficient and binding were estimated. Results: The model shows that dermal diffusion alone cannot explain the in vivo data and blood and/or lymphatic transport to deep tissues must be present for almost all of the drugs tested. Conclusion: Topical drug delivery systems for deeper tissue delivery should recognise that blood/ lymphatic transport may dominate over dermal diffusion for certain compounds.