Use of Wet Milling Combined with Temperature Cycling to Minimize Crystal Agglomeration in a Sequential Antisolvent-Cooling Crystallization.

The objective of the research was to improve the process design of a combined antisolvent-cooling crystallization to reduce the degree of agglomeration of a real active pharmaceutical ingredient product, which was manufactured using a crystallization stage employing a methanol/water solvent system. Knowledge was gained from the use of process analytical technology (PAT) tools to monitor the process variables, allowing particle size, degree of agglomeration, solute concentration, and supersaturation to be tracked throughout the process. Based on knowledge of the solubility behavior and interpretation of the PAT histories, changes were made to the sequences of antisolvent addition and cooling within the crystallization process to reduce agglomeration in the final product. Different seed loadings and seeding addition points were also investigated to maintain operation within lower supersaturation regions of the phase diagram to limit agglomeration and avoid an undesired polymorphic transformation to an unstable form. The improved sequences of operations and seeding conditions did not provide sufficient improvement in the product quality and so were augmented by applying wet milling for further deagglomeration followed by temperature cycling to remove fine particles generated during milling. Open-loop heating and cooling cycles produced some limited improvements, whereas closed-loop direct nucleation control methods using FBRM as a feedback sensor for particle counts per second were much more successful at producing high-quality crystals of the desired polymorphic form. The work shows that understanding the trajectory of the process through the phase diagram to follow appropriate supersaturation profiles gives improved control of the various kinetic mechanisms and can be used to improve the quality of the final product.

Microneedle-assisted microparticle delivery by gene guns: experiments and modeling on the effects of particle characteristics.

Microneedles (MNs) have been shown to enhance the penetration depths of microparticles delivered by gene gun. This study aims to investigate the penetration of model microparticle materials, namely, tungsten (<1 µm diameter) and stainless steel (18 and 30 µm diameters) into a skin mimicking agarose gel to determine the effects of particle characteristics (mainly particle size). A number of experiments have been processed to analyze the passage percentage and the penetration depth of these microparticles in relation to the operating pressures and MN lengths. A comparison between the stainless steel and tungsten microparticles has been discussed, e.g. passage percentage, penetration depth. The passage percentage of tungsten microparticles is found to be less than the stainless steel. It is worth mentioning that the tungsten microparticles present unfavourable results which show that they cannot penetrate into the skin mimicking agarose gel without the help of MN due to insufficient momentum due to the smaller particle size. This condition does not occur for stainless steel microparticles. In order to further understand the penetration of the microparticles, a mathematical model has been built based on the experimental set up. The penetration depth of the microparticles is analyzed in relation to the size, operating pressure and MN length for conditions that cannot be obtained in the experiments. In addition, the penetration depth difference between stainless steel and tungsten microparticles is studied using the developed model to further understand the effect of an increased particle density and size on the penetration depth.

Microneedle assisted micro-particle delivery from gene guns: experiments using skin-mimicking agarose gel.

A set of laboratory experiments has been carried out to determine if micro-needles (MNs) can enhance penetration depths of high-speed micro-particles delivered by a type of gene gun. The micro-particles were fired into a model target material, agarose gel, which was prepared to mimic the viscoelastic properties of porcine skin. The agarose gel was chosen as a model target as it can be prepared as a homogeneous and transparent medium with controllable and reproducible properties allowing accurate determination of penetration depths. Insertions of various MNs into gels have been analysed to show that the length of the holes increases with an increase in the agarose concentration. The penetration depths of micro-particle were analysed in relation to a number of variables, namely the operating pressure, the particle size, the size of a mesh used for particle separation and the MN dimensions. The results suggest that the penetration depths increase with an increase of the mesh pore size, because of the passage of large agglomerates. As these particles seem to damage the target surface, then smaller mesh sizes are recommended; here, a mesh with a pore size of 178 µm was used for the majority of the experiments. The operating pressure provides a positive effect on the penetration depth, that is it increases as pressure is increased. Further, as expected, an application of MNs maximises the micro-particle penetration depth. The maximum penetration depth is found to increase as the lengths of the MNs increase, for example it is found to be 1272 ± 42, 1009 ± 49 and 656 ± 85 µm at 4.5 bar pressure for spherical micro-particles of 18 ± 7 µm diameter when we used MNs of 1500, 1200 and 750 µm length, respectively.

Potential of microneedle-assisted micro-particle delivery by gene guns: a review.

CONTEXT: Gene guns have been used to deliver deoxyribonucleic acid (DNA) loaded micro-particle and breach the muscle tissue to target cells of interest to achieve gene transfection. OBJECTIVE: This article aims to discuss the potential of microneedle (MN) assisted micro-particle delivery from gene guns, with a view to reducing tissue damage. METHODS: Using a range of sources, the main gene guns for micro-particle delivery are reviewed along with the primary features of their technology, e.g. their design configurations, the material selection of the micro-particle, the driving gas type and pressure. Depending on the gene gun system, the achieved penetration depths in the skin are discussed as a function of the gas pressure, the type of the gene gun system and particle size, velocity and density. The concept of MN-assisted micro-particles delivery which consists of three stages (namely, acceleration, separation and decoration stage) is discussed. In this method, solid MNs are inserted into the skin to penetrate the epidermis/dermis layer and create holes for particle injection. Several designs of MN array are discussed and the insertion mechanism is explored, as it determines the feasibility of the MN-based system for particle transfer. RESULTS: This review suggests that one of the problems of gene guns is that they need high operating pressures, which may result in direct or indirect tissue/cells damage. MNs seem to be a promising method which if combined with the gene guns may reduce the operating pressures for these devices and reduce tissue/cell damages. CONCLUSIONS: There is sufficient potential for MN-assisted particle delivery systems.

An experimental study of microneedle-assisted microparticle delivery.

A set of well-defined experiments has been carried out to explore whether microneedles (MNs) can enhance the penetration depths of microparticles moving at high velocity such as those expected in gene guns for delivery of gene-loaded microparticles into target tissues. These experiments are based on applying solid MNs that are used to reduce the effect of mechanical barrier function of the target so as to allow delivery of microparticles at less imposed pressure as compared with most typical gene guns. Further, a low-cost material, namely, biomedical-grade stainless steel microparticle with size ranging between 1 and 20 µm, has been used in this study. The microparticles are compressed and bound in the form of a cylindrical pellet and mounted on a ground slide, which are then accelerated together by compressed air through a barrel. When the ground slide reaches the end of the barrel, the pellet is separated from the ground slide and is broken down into particle form by a mesh that is placed at the end of the barrel. Subsequently, these particles penetrate into the target. This paper investigates the implications of velocity of the pellet along with various other important factors that affect the particle delivery into the target. Our results suggest that the particle passage increases with an increase in pressure, mesh pore size, and decreases with increase in polyvinylpyrrolidone concentration. Most importantly, it is shown that MNs increase the penetration depths of the particles.

Investigation of the riddle of sulfathiazole polymorphism.

Since the discovery of sulfathiazole as an antimicrobial agent in 1939, numerous works in the screening for its different polymorphic forms, which is an essential part of drug development, have been conducted and published. These works consequently result in the availability of various methods for generating a particular polymorph. By following these methods, however, one cannot be guaranteed to obtain the intended pure polymorph because most of the methods do not clearly and adequately describe the crystallisation conditions, such as cooling rates and initial solute concentrations. In this paper, the available methods for generating all the known polymorphs of sulfathiazole are reviewed and selected methods for generating certain polymorphs, performed with their processes monitored using process analytical technology tools, i.e. focussed beam reflectance measurement and attenuated total reflectance ultraviolet spectroscopy, are presented. The properties of the obtained crystals, examined using various characterisation methods, are also presented and whenever possible, are compared with those of other workers.