(469f) Integrated Continuous Crystallization and Spray Drying of Insulin

Insulin injection is commonly used for the treatment of diabetes. Pulmonary delivery through inhalation of dry insulin powders is commercially also available and offers a more convenient route compared to injection.¹The manufacture of such powders is challenged by the need to produce crystalline particles with an aerodynamic diameter in the narrow range of 1 – 5 μm. Particles outside the optimal size range will not deposit well into the lungs. Amorphous particles produced from spray drying an insulin solution are limited by their fast dissolution,² whichleads to a therapeutic effect of only several hours. Furthermore, in general, crystalline particles have a better stability and aerosolization performance and different drug release characteristics compared to amorphous particles.^3,4 Therefore, the manufacture of a dry powder with insulin crystals is of interest to potentially improve pulmonary delivery of insulin. The crystallization of insulin has been studied in various crystallizers.^5–7 However, those processes generally do not deliver crystals in the optimal size range for pulmonary delivery. Therefore, there is a need for novel crystallization processes that can produce insulin crystals with tailored size for the application of dry powder inhalation more efficiently.

The objective of this work is to develop and characterize a novel continuous crystallization process for insulin that is tailored for dry powder inhalation by integrating a segmented-flow crystallizer with spray drying for rapid solvent removal. Continuous crystallization has received growing interest in the fine-chemical and pharmaceutical industries due to typical advantages such as easier process control and a more consistent product quality compared to batch crystallization.⁸ The benefits of integrating continuous crystallization with spray drying for the manufacture of dry powders for inhalation has been demonstrated by earlier work from our group for different small-molecule active pharmaceutical ingredients.⁹ The present work is, to the best of our knowledge, the first demonstration of such process for a therapeutic protein.

The process consisted of a tubular crystallizer and a spray dryer. A calibrated two-channel peristaltic pump was used to introduce the feed and the precipitant solution into the crystallizer at the same flow rate through a T-mixer. A gas flow controller was used to introduce nitrogen with controlled flow rate via another T-mixer to create a segmented flow, which offers the benefit of a narrow residence time distribution.^10,11 The supersaturation was generated by both cooling and a change in pH. The tubular crystallizer, which consisted of two connected pieces of tubing of 14m long each, was immersed in a thermostatic bath to allow temperature control. At the outlet of the crystallizer, a buffer vessel was used for separation of nitrogen and to provide a steady flow to the spray dryer using another peristaltic pump. Finally, the dry powder was collected in a powder collector located below a cyclone. Initially, the crystallizer was operated stand-alone to identify optimal crystallization conditions. Subsequently, optimal crystallization conditions were applied for the integrated process. The morphology of the particles and their approximate size were characterized with optical microscopy and scanning electron microscopy (SEM). The mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) fraction was measured with a Next Generation Impactor (NGI).

The recovery of insulin from stand-alone crystallization experiments was in excess of 90% when using a combined flow rate of 1.2 ml/min and an insulin concentration of 2.4 mg/ml. A lower recovery was obtained at higher combined flow rates, and thus shorter residence times, in the range of 1.8 ml/min to 2.4 ml/min. A constant recovery could be approached in a short period of about 10 to 15 minutes when running at a high initial concentration in the range of 2.0 mg/ml to 2.4 mg/ml. Such fast start-up time is consistent with plug-flow conditions, which is an inherent benefit of a segmented-flow crystallizer compared to a mixed-suspension mixed-product-removal crystallizer. The produced particles appeared crystalline from SEM and were close to the desired size range for pulmonary drug delivery. The particles produced with the integrated process under optimal conditions were characterized by a MMAD in the range of 2 μm to 6 μm and an FPF of 20 - 40%, which indicated a good potential for pulmonary drug delivery. In conclusion, the demonstrated benefits of the novel process include a short total residence time, high recovery from crystallization, and suitable product quality attributes for pulmonary drug delivery of insulin without any added excipients.

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