Effect of jet velocity on crystal size distribution from antisolvent and cooling crystallizations in a dual impinging jet mixer

Jiang, Mo; Li, Yao-En David; Tung, Hsien‐Hsin; Braatz, Richard D.

doi:10.1016/j.cep.2015.09.005

Cited by 39 publications

(27 citation statements)

References 13 publications

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“…Continuous crystallization has received increasing attention in pharmaceutical manufacturing due to its high process efficiency and flexibility . Millifluidic tubular crystallizers with practical production capacity is of recent interest , but obtaining real‐time information on the crystals inside such crystallizers has been limited by available techniques.…”

Section: Introductionmentioning

confidence: 99%

“…The inline videos and offline images use 2D visualizations with the main optical path connected to a camera, which is the same kind of visualization as the compound microscopes commonly taken for crystal imaging , , , but with a larger depth of field and much lower complexity and cost . The large depth of field in a stereomicroscope allows the direct imaging of particles as they move under flow in tubes with transparent walls.…”

Section: Introductionmentioning

confidence: 99%

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Low‐Cost Noninvasive Real‐Time Imaging for Tubular Continuous‐Flow Crystallization

Jiang

Braatz

2017

Chem Eng & Technol

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A key design limitation to the effective monitoring and control of continuous crystallization processes is the ability to characterize crystals in real time. A lowcost system composed of a basic stereomicroscope and video camera for the in situ imaging of sub-millimeter crystals through curved walls of millifluidic tubular crystallizers is described. Real-time videos taken for millimeter-size slurry slugs are used to guide the experimental design for a recently developed multiphaseflow crystallization process, including the improvement of the slug aspect ratio, visualization of crystal shapes, and observation of the extent of aggregation. Design considerations are also discussed for the use of multiple stereomicroscopes in other continuous-flow tubular experiments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low‐Cost Noninvasive Real‐Time Imaging for Tubular Continuous‐Flow Crystallization

Jiang

Braatz

2017

Chem Eng & Technol

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“…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 generation of high-intensity micromixing of fluids to achieve high and continual supersaturation before the onset of nucleation at the impinging point [25,26]. Some recent literature developed the impinging jet method with different processes, such as combined with the use of additives to improve the crystal roundness of the products [27] or supplemented with cooling crystallization to narrow crystal size distribution [28].In the case of poorly water-soluble drugs, which belong to Biopharmaceutics Classification System (BCS) Classes II or IV, the crystal habit is particularly important [29,30]. The small particle size of the final crystallized product can increase dissolution rate and quantity from dosage forms, improve the bioavailability of the drug products, as well as enhance the stability and the uniformity of the API incorporated in tablets [31,32].…”

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confidence: 99%

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confidence: 99%

Comparative Study of Different Crystallization Methods in the Case of Cilostazol Crystal Habit Optimization

2019

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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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“…At the impinging point, where the mixing of small volumes of the two solutions occurs, high supersaturation evolves before the onset of nucleation, which produces a monodisperse population of small crystals with a high surface area [7,8]. The PSD can be adjusted by modifying the crystallization parameters, including the linear velocity of the fluid flow, the temperature of the liquids, or the post-mixing time [9]. On the other hand, modifying the crystal shape is hardly feasible because of the momentary and extremely rapid nature of the crystallization process.…”

Section: Introductionmentioning

confidence: 99%

Optimizing the Crystal Habit of Glycine by Using an Additive for Impinging Jet Crystallization

et al. 2017

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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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Effect of jet velocity on crystal size distribution from antisolvent and cooling crystallizations in a dual impinging jet mixer

Cited by 39 publications

References 13 publications

Low‐Cost Noninvasive Real‐Time Imaging for Tubular Continuous‐Flow Crystallization

Low‐Cost Noninvasive Real‐Time Imaging for Tubular Continuous‐Flow Crystallization

Comparative Study of Different Crystallization Methods in the Case of Cilostazol Crystal Habit Optimization

Optimizing the Crystal Habit of Glycine by Using an Additive for Impinging Jet Crystallization

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