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A microfluidic approach to seeded crystallization has been demonstrated using abacavir hemisulfate, a nucleoside analog reverse transcriptase inhibitor, in droplet reactors to control polymorphism and produce particles with a low particle size distribution. Two techniques are introduced: (1) the first technique involves an emulsion system consisting of a dispersed phase solvent and a continuous phase, which holds slight solubility of the dispersed phase solvent. The dispersed phase contains both a dissolved active pharmaceutical ingredient (API) and seeds of the desired polymorph. While the continuous phase enables solvent extraction, the negligible solubility of the API allows for growth of seeds inside droplets via extraction and subsequent API saturation. This technique demonstrates the ability to crystallize the API in spherical agglomerates via slow extraction of droplets. (2) The second technique utilizes a combined dispersed phase by joining in-flow a seed suspension stream with a supersaturated active pharmaceutical ingredient (API) stream. The combined dispersed phase is emulsified in a continuous phase for which the dispersed phase solvent and the API are both insoluble - droplets are incubated at temperatures below their saturation limit to induce crystal growth. Decreasing the concentration of seeds in its input stream resulted in a decreased number of crystals per droplet, increase in crystal size, and decrease in PSD. Temperature cycling was utilized as a proof of concept to demonstrate the ability to reduce the number of seeds per droplet where the optimal goal is to obtain a single seed per droplet for all droplets. Utilizing this approach in conjunction with the ability to produce monodispersed droplet reactors allows for enhanced control of particle size distribution (PSD) by precisely controlling the available mass for each individual seed crystal. The development of this technique as a proof-of-concept for crystallization can be expanded to manufacturing scales in a continuous manner using parallelized droplet generators and flow reactors to precisely control the temperature and crystal growth kinetics of individual droplets.

Monodisperse emulsions of solvent saturated with the active pharmaceutical ingredient (API) cabotegravir were generated by microfluidic devices. In contrast to model oil-water emulsions that provide idealized conditions for obtaining highly monodisperse emulsions, APIs impart strict limitations on solvent choice. To provide a suitable environment in which extractive crystallization could occur, and to enhance reproducibility, co-solvents were introduced. Subsequently, the effect of each solvent component on morphology and size was observed. Through the manipulation of solvent composition, particles of both plate-like and spherical multi-crystal agglomerates were obtained, providing the ability to tune the operating conditions to provide particles with desirable characteristics such as size, shape and flowability. Scale-up of the manufacturing process was addressed through the application of existing microfluidic parallelization techniques, resulting in a 100-fold increase in throughput over a single-channel device. Subsequently, the obtained pure, and excipient-bound, API spherical agglomerates, were subjected to batch isolation and washing.

The isolation of component sugars from biomass represents an important step in the bioprocessing of sustainable feedstocks such as sugar beet pulp. Centrifugal partition chromatography (CPC) is used here, as an alternative to multiple resin chromatography steps, to fractionate component monosaccharides from crude hydrolysed sugar beet pulp pectin. CPC separation of samples, prepared in the stationary phase, was carried out using an ethanol: ammonium sulphate (300gL

This article has been made available through the Brunel Open Access Publishing Fund. This paper reports on some of the key outcomes of a 3 year £1.5. m Technology Strategy Board (TSB) funded research programme to develop a small footprint, versatile, counter-current chromatography purification technology and methodology which can be operated at a range of scales in both batch and continuous modes and that can be inserted into existing process plant and systems. Our consortium, integrates technology providers (Dynamic Extractions) and the scientific development team (Brunel) with end user needs (GSK & Pfizer), addressing major production challenges aimed at providing flexible, low capital platform technology driving substantial cost efficiency in both drug development and drug manufacturing processes. The aims of the Technology Strategy Board's high value manufacturing programme are described and how the academic/industry community were challenged to instigate step changes in the manufacturing of high value pharmaceuticals. This paper focusses on one of the themes of the TSB research programme, " Generate a Comprehensive Applications Portfolio" It outlines 15 applications from this portfolio that can be published in the public domain and gives four detailed case studies illustrating the range of application of the technology on the separation of (1) isomers, (2) polar compounds, (3) crude mixtures and (4) on the removal of impurities. Two of these case studies that were scaled up demonstrate between 10 and 20% lower solvent usage and were projected to have significant cost savings compared to conventional solid phase silica gel chromatography at procss scale demonstrating that the latest high performance countercurrent chromatography technology is a competitive platform technolgy for the pharmaceutical industry. © 2013 Elsevier B.V.

This paper addresses the technological readiness of counter-current chromatography (CCC) instruments to become platform technology for the pharmaceutical industry. It charts the development of the prototype technology since its inception in 1966, through conceptual improvements in the 1980s that led to higher speed separations in hours as opposed to days. It then describes the engineering improvements that have led to the development of high performance counter-current chromatography with the potential for scale-up to process scale for manufacturing products in industry with separation times in minutes rather than hours. A new UK Technology Strategy Board high value manufacturing £1.5m research programme to take CCC through to technology readiness level 8 (i.e. as platform technology for continuous 24 × 7 operation by industry) is introduced. Four case studies are given as examples of successes from its expanding applications portfolio, which is mainly confidential. Finally, the hurdles for the uptake of new technology by industry are highlighted and the following potential solutions given: rapid method development, automation, continuous processing and instrument reliability and robustness. The future challenge for the CCC community will be to address these development needs urgently if CCC is to become the platform technology it deserves to be.