The therapeutic usage of cilostazol is limited owing to its poor aqueous solubility and oral bioavailability. Our aim was to produce cilostazol crystals with small average particle size; besides suitable roundness, narrow particle size distribution and stable polymorphic form to increase its dissolution rate and improve processability. Different conventional crystallization methods with or without sonication were compared with impinging jet crystallization combined with cooling, and the optimization of the various parameters was also implemented. The effects of post-mixing time and temperature difference were studied by means of a full factorial design. The physical properties of powder particles were characterized by, i.a., XRPD, DSC and SEM. The dissolution rate and the contact angle of solid surfaces were also determined to elucidate the relationship between wettability and dissolution. It was observed that impinging jet crystallization combined with cooling is a very effective and reproducible method for reducing the particle size of cilostazol. This method resulted in significantly smaller particle size (d(0.5) = 3-5 µm) and more uniform crystals compared to the original ground material (d(0.5) = 24 µm) or the conventional methods (d(0.5) = 8-14 µm), and it also resulted in a stable polymorphic form and enhanced the dissolution rate.Crystals 2019, 9, 295 2 of 15 temperature, cooling rate, solvent-antisolvent ratio and quality, active pharmaceutical ingredient (API) concentration, mixing factors, etc., can influence the physicochemical properties of the product [12][13][14]. However, the conventional route can reduce particle size only within certain limits. Therefore, several alternative processes have been developed for the control and modification of the solid-state properties of APIs. For example, laminar-flow tubular crystallizer was used to produce selectively the desired polymorphic form of brivaracetam [15], multi-inlet vortex mixer was redesigned to facilitate formulation screening in small-scale experiments with biologics [16], or continuous plug flow crystallization was applied to generate particles with controlled characteristics [17]. Based on the literature, ultrasound application in crystallization is suitable for modifying the quality of the crystals. It can reduce the metastable zone width, and generate rapid, uniform mixing, which reduces the agglomeration of particles [18,19]. Higher sonication intensity and longer sonication time favour the formation of smaller crystals with narrow PSD [20][21][22].Impinging jet crystallization is a relatively new field for the researchers in pharmaceutical manufacturing and industrial crystallization [23]. However, it is proved that this method effectively reduces particle size, as well as it has the potential advantage to produce reproducible products with small average particle size and narrow PSD [24]. The rich solution of the API and the antisolvent flow through two jet nozzles, which are arranged diametrically opposite each other, and it enables the ...

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The parameters of crystallization processes determine the habit and particle size distribution of the products. A narrow particle size distribution and a small average particle size are crucial for the bioavailability of poorly water-soluble pharmacons. Thus, particle size reduction is often required during crystallization processes. Impinging jet crystallization is a method that results in a product with a reduced particle size due to the homogeneous and high degree of supersaturation at the impingement point. In this work, the applicability of the impinging jet technique as a new approach in crystallization was investigated for the antisolvent crystallization of glycine. A factorial design was applied to choose the relevant crystallization factors. The results were analysed by means of a statistical program. The particle size distribution of the crystallized products was investigated with a laser diffraction particle size analyser. The roundness and morphology were determined with the use of a light microscopic image analysis system and a scanning electron microscope. Polymorphism was characterized by differential scanning calorimetry and powder X-ray diffraction. Headspace gas chromatography was utilized to determine the residual solvent content. Impinging jet crystallization proved to reduce the particle size of glycine. The particle size distribution was appropriate, and the average particle size was an order of magnitude smaller (d(0.5)=8-35 μm) than that achieved with conventional crystallization (d(0.5)=82-680 μm). The polymorphic forms of the products were influenced by the solvent ratio. The quantity of residual solvent in the crystallized products was in compliance with the requirements of the International Conference on Harmonization.

Additives selectively inhibit or enhance the growth of crystal faces and effectively change the crystal morphology. For the first time, potassium chloride was used as additive during impinging jet crystallization of glycine. The structure of the powder particles was evaluated by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy with energy dispersive X-ray spectroscopy, headspace gas chromatography, and flame atomic absorption spectrometry. Even a minor amount of KCl had a significant effect on the crystal roundness and reduced the particle size significantly, despite of the extremely rapid nature of the crystallization process. This method resulted in the a-polymorph of glycine with an appropriate low residual additive content and a minimal residual organic solvent content. The arrangement and the optimal concentration of the additive were determined.

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