Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 1. Cooling Crystallization

Rimez, Bart; Debuysschère, Robin; Conté, Jennifer; Lecomte-Norrant, Edith; Gourdon, Christophe; Cognet, Patrick; Scheid, Benoît

doi:10.1021/acs.cgd.8b00928

Cited by 27 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

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

2019

View full text Add to dashboard Cite

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 ...

show abstract

mentioning

confidence: 99%

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

2019

View full text Add to dashboard Cite

show abstract

“…Tests performed in Couette flow conditions by Forsyth and coworkers show an increased nucleation rate as a function of average shear rate inside a tubular reactor [24]. We demonstrated recently that the application of specific flow structures by using capillary tubing and high flow velocities result in high nucleation rates while a solution is cooled down to the supersaturated state [21]. These experimental data to reach enhanced nucleation rates were obtained for the Active Pharmaceutical Ingredient Brivaracetam and demanded generalization using other molecules.…”

Section: Introductionmentioning

confidence: 76%

“…This takes typically a maximum of 30 min after sampling, depending on the tested conditions. The slurries are then filtered and dried at room temperature during 24 h. Note that the chosen flow rate remains unchanged throughout the paper to reduce the amount of variables; for a true optimization of the end-product after crystallization, the influence of flow rate on the nucleation rate should be investigated; 30 mL.min −1 is however regarded as a good starting point as it resulted in high nucleation rates for Brivaracetam [21]. Average nucleation rates J for samples that are set to crystallize to the saturation conditions can be calculated using the following relation:…”

Section: Methodsmentioning

confidence: 99%

“…The main reason is the lack of control of the suitable conditions, so that nucleation gets out of hand resulting in retrieved cakes inside the reactors [20]. The use of milli-and micro-metric tubular reactors to perform crystal nucleation may overcome this drawback as residence times at nucleating conditions are drastically reduced; despite the reached high supersaturation values that ensure high nucleation rates [21,22].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The creation and testing of a fully continuous tubular crystallization device suited for incorporation into flow chemistry setups

et al. 2019

Self Cite

View full text Add to dashboard Cite

The study presents the use of a continuous crystallization device that can be directly incorporated into flow chemistry setups. Inside this device spontaneous nucleation and growth of organic molecules are controlled and maintained, using Aspirin as model molecule. The identification of the optimal crystallization scenario is discussed in view of the chemical stability of Aspirin and based on the determination of the solubility and the metastable zone width corresponding to the presented experimental setups. Physicochemical analyses combined with heat transfer modeling of the solution whilst flowing through a capillary placed inside a thermostated water bath provide the desired cooling profile and hence the degree of supersaturation along the system. The crystalline quality and stability of the crystalline output is evidenced for two different pump setups having distinguished flow patterns to show the independence on the flow stability, an important parameter for the success rate of the complete reaction scheme and in the perspective of operation scale-up. Reproducible output of material with narrow size distributions is obtained throughout all experiments.

show abstract

“…It is in fact, if more than one phase is thermodynamically possible, the resulting phase is not just the one that is thermodynamically most likely. Instead, the resulting crystals are determined by the relative rates of crystal nucleation and growth of the metastable and stable forms, which usually depends on the process conditions, e.g., supersaturation, crystallization temperature, and the solvent type [4,[45][46][47].…”

Section: Theorymentioning

confidence: 99%

Modelling of the Polymorph Nucleation Based on Classical Nucleation Theory

Shiau

2019

Crystals

View full text Add to dashboard Cite

To elucidate the relative nucleation rates of different polymorphs, a competitive kinetic model is developed based on classical nucleation theory to describe the time evolution of two different polymorphic cluster size distributions controlled by the association and dissociation of the solute molecules during polymorph nucleation. Although there is only one type of the solute molecules, the agglomerated solute clusters are divided into two types-A form and B form, which resemble the structures and morphologies of the different mature polymorphs and eventually lead to the formation of two polymorphic crystals. A dissociation kernel is incorporated into the proposed model to account for gradual dissolution of the solute clusters smaller than a critical nucleus size due to the thermodynamic instability. By fitting the experimental induction period data and the final measured weight fractions of eflucimibe polymorphs with the proposed model, the association and dissociation rate constants for two polymorphs are determined. The developed model is satisfactory to explain the competitive mechanism of polymorph nucleation for eflucimibe that B form dominates at higher supersaturation while A form dominates at lower supersaturation. The results also indicate that A form is more stable than B form with a transition energy of 3.1 kJ/mole at 35 • C.

show abstract

Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 1. Cooling Crystallization

Cited by 27 publications

References 34 publications

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

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

The creation and testing of a fully continuous tubular crystallization device suited for incorporation into flow chemistry setups

Modelling of the Polymorph Nucleation Based on Classical Nucleation Theory

Contact Info

Product

Resources

About