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

Abstract

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 ...

A Systematic Approach to the Development of Cilostazol Nanosuspension by Liquid Antisolvent Precipitation (LASP) and Its Combination with Ultrasound

“…Detailed literature discussion is presented in Appendix A. The LASP process of cilostazol from 10% DMSO or 5% DMF without stabilizers did not change its polymorphic form A [32] and did not generate solvates (data not shown), in agreement with the literature [26,27].…”

“…Baek et al reprecipitated cilostazol directly into an adsorbing carrier, which does not qualify as nanocrystals [25]. A typical LASP as a sole technique for cilostazol processing has been described by Sai Gouthami et al [26] and Tari et al [27]; however, these works aimed to modify cilostazol crystal habit instead of reducing the particles to nanosize, and consequently the reported particles are larger.…”

Impact of Crystal Habit on the Dissolution Rate and In Vivo Pharmacokinetics of Sorafenib Tosylate

“…Besides this, crystal habit, which is described as the external appearance of a crystalline solid, is also attracting attention in the pharmaceutical industry [ 16 , 17 ]. Crystal habit impacts the physicochemical properties and behaviors of a drug due to the anisotropic surface chemistry of different facets in crystalline material [ 18 , 19 ]. For example, the higher dissolution rate and oral bioavailability of celecoxib crystals in plate-shaped crystals than that in acicular crystals was attributed to their different hydrophilic surfaces [ 20 ].…”

Particle Size and Crystal Habit Modification of Active Pharmaceutical Ingredient Using Cooling Sonocrystallization: A Case Study of Probenecid

“…Production of microparticle with narrow size distribution and regular habit, which provides better dissolution characteristics and flowability, is beneficial in downstream process. [ 32‐34 ] To screen the appropriate solvent system in cooling sonocrystallization experiments, solubility data of probenecid in various organic solvent were either acquired from literatures or experimentally determined in this study. In addition to demonstrate the feasibility of crystal quality improvement of probenecid, the effect of operating parameters in cooling sonocrystallization was also studied.…”