Mathematical modeling and design of layer crystallization in a concentric annulus with and without recirculation

A solution layer crystallization process in a concentric annulus is presented that removes the need for filtration. A dynamic model for layer crystallization with and without a recirculation loop is developed in the form of coupled partial differential equations describing the effects of mass transfer, heat transfer, and crystallization kinetics. The model predicts the variation of the temperature, concentration, and dynamic crystal thickness along the pipe length, and the concentration and temperature along the pipe radius. The model predictions are shown to closely track experimental data that were not used in the model's construction, and also compared to an analytical solution that can be used for quickly obtaining rough estimates when there is no recirculation loop. The model can be used to optimize product yield and crystal layer thickness uniformity, with constraints on the supersaturation to avoid bulk nucleation by adjusting cooling temperatures in the core and jacket. © 2013 American Institute of Chemical Engineers

Mathematical modeling and design of layer crystallization in a concentric annulus with and without recirculation [Abstract]

Mathematical modeling and design of layer crystallization in a concentric annulus with and without recirculation [Abstract

Continuous Crystallization with Impurity Complexation and Nanofiltration Recycle

For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the impurity with an additive can be used to sterically prevent impurity incorporation in the host lattice. A nanofiltration membrane can be used to preferentially reject the higher molecular weight impurity complex in solution, while allowing the lower molecular weight API to permeate through. This permeate stream can be concentrated and recycled to operate the crystallization in a continuous mode with the aim of enhancing both yield and crystal purity simultaneously. In the present work, this strategy was applied to the continuous cooling crystallization of two systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer from their solutions in 50:50 (by volume) water–ethanol mixed solvent. The first system consists of benzamide with 3-nitrobenzoic acid added as an impurity, while the second one is the active pharmaceutical ingredient (API) ketoprofen containing two impurities, ibuprofen and α,4-dimethyl­phenylacetic acid. A working strategy for selecting the complexing agent and nanofiltration membrane was established. For both systems, the membrane-coupled continuous mode with recycle and complexation was found to have a better performance in terms of higher crystallization yield and lower impurity incorporation in crystals compared to both the batch process as well as the continuous process without recycle

Complexation-Assisted Continuous Crystallization of Isomeric Systems with Nanofiltration Recycle

In API-impurity systems consisting of structural isomers, the impurity has a strong affinity to incorporate into the host crystal owing to their identical molecular weight and similar structure. Conventional successive recrystallization turns out to be an unattractive purification strategy in such cases, since it can improve crystal purity only at the cost of yield. As an alternative, selective complexation of the impurity can sterically prevent its incorporation into the host lattice by increasing the apparent molecular weight and dimensions of the impurity. The increase in size of the impurity post complexation can be further exploited using a nanofiltration membrane to preferentially reject the complex in solution, while allowing the smaller molecules of uncrystallized API to permeate through. The crystallization yield can be enhanced by concentrating the permeate stream and recycling it back to the crystallizer. Thus, complexation-assisted nanofiltration recycle presents a strategy to improve both yield and crystal purity simultaneously in a continuous mode. In the present work, the application of this strategy is described for the continuous cooling crystallization of two isomeric systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer. The first system consists of 4-nitrophenol with 3-nitrophenol as an added impurity in an aqueous solvent, while the second one consists of the active pharmaceutical ingredient (API) acetaminophen with its isomer 3-acetamidophenol added as an impurity in a mixed solvent of 50:50 ethanol and water by volume. A working strategy for selecting the complexing agent and nanofiltration membrane is discussed. For both systems, the complexation-assisted continuous mode with nanofiltration recycle performed better than both the batch process as well as the unrecycled MSMPR process in terms of higher crystallization yield and lower impurity incorporation in crystals

Experimental Evaluation of Contact Secondary Nucleation Mechanisms

Contact secondary nucleation has vital importance in industrial crystallizers for reactions and purification, and it recently has been linked to contributing to biological homochirality emerged at an abiotic evolutionary stage. Despite years of studies, the mechanism of contact secondary nucleation has not been resolved whether contact secondary nuclei originate from parent crystals via microattrition or from semiordered solute clusters at the interface of parent crystals. This study takes advantage of the unique thermodynamic and kinetic properties of the glycine system that is capable of differentiating the origin of contact secondary nuclei based on the polymorph of secondary nuclei obtained. It is demonstrated using two different experimental designs that contact secondary nuclei could originate both from the semiordered solute molecules at the interface layer of existing crystals and from parent crystals themselves via the mechanism of microattrition depending on the magnitude of the contact force. When the contact force is relatively small (<2 N for γ-glycine), it is only sufficient to disturb the semiordered solute molecules at the interface layer, which could generate secondary nuclei; when the contact force exceeds a certain threshold (>2 N for γ-glycine), it not only disturbs the interface layer but also causes mechanical damages to the parent crystals

Inhibition of Nucleation Using a Dilute, Weakly Hydrogen-Bonding Molecular Additive

The effect of a weakly interacting dilute complexing agent on the nucleation rates of a small-molecule solute was explored using the model system of 3-nitrophenol as the inhibited molecule in a toluene solution with a 3-aminobenzoic acid inhibitor. Induction times were measured experimentally using the probability distribution of the solute crystals nucleation events as a function of time. Experimental results demonstrated that a small concentration of inhibitor (0.25% molar with respect to solute) led to a 230% increase in induction times with respect to noninhibited controls at identical supersaturation. Product crystal growth rates, polymorphism, and purity were found to be unaffected by the complexing agent, confirming that the change in nucleation rate was only due to nucleation inhibition. The nucleation rate kinetics of the solute were studied as a function of supersaturation, with and without the inhibitor. Data indicated that upon the addition of the inhibitor, there is a sharp decrease in the pre-exponential factor for the nucleation rate correlation, while there is minimal change on the activation energy. The experimental data were rationalized using a nucleation kinetics model based on the two-step nucleation theory. Analysis of the parameters defined in the nucleation rate equation for the two-step model indicated that the change in rates came from suppression of the ordering kinetic constant for the transition from a prenucleation cluster to a nucleus. A mechanism for the inhibition was proposed in which the formation of intermolecular complexes between solute and additive disrupts the ordering step by hindering the rearrangement of molecules within clusters

Continuous Spherical Crystallization of Albuterol Sulfate with Solvent Recycle System

Spherical crystallization enables the direct preparation of crystal agglomerates of active pharmaceutical ingredients (APIs) with improved crystal handling properties. The continuous spherical crystallization of albuterol sulfate as a model API was developed using a mixed-suspension, mixed-product removal (MSMPR) crystallizer. The application of a solvent recycling system for reuse of the antisolvent in the single-stage MSMPR crystallizer was also demonstrated. Spherical agglomerates of albuterol sulfate were obtained via antisolvent crystallization using the MSMPR crystallizer with water as the solvent and an ethyl acetate/emulsifier (Pluronic L-121) mixture as the antisolvent. Steady-state continuous spherical crystallization was rapidly achieved after 30 min, and a yield of >95% was obtained. The influence of process parameters such as the solvent/antisolvent ratio, emulsifier concentration, residence time, and reactor scale on the properties of the agglomerates formed during the crystallization process was examined. In the MSMPR crystallizer, the desired solvent to antisolvent ratio was maintained by controlling the flow rates of the feed, antisolvent, and recycle stream, and 90% of the mother liquor was recycled during the continuous spherical crystallization of albuterol sulfate by optimizing the rate of each stream

Polymorph Control of Micro/Nano-Sized Mefenamic Acid Crystals on Patterned Self-Assembled Monolayer Islands

The nucleation of organic molecular compounds is a stochastic process and is difficult to control. The problem becomes even more complex when the compound has two or more polymorphic forms that can concomitantly nucleate. In this work, patterned self-assembled monolayers (SAMs) are employed, on which a large number of identical experiments can be conducted. SAMs can be an effective way to induce heterogeneous nucleation and were used in this work to generate the desired polymorphic form based on the chemical interactions. Seven different self-assembled monolayers were employed to study the nucleation behavior of the nonsteroidal anti-inflammatory drug mefenamic acid [MA, <i>N</i>-(2,3-xylyl)­anthranilic acid]. The results show that SAMs forming a strong interaction with the −COOH group of MA molecules preferably produced form II. The effects of temperature, solvent, droplet size, and concentration on the nucleation kinetics of MA were also explored. The ability to prepare crystalline MA as small as ∼300 nm while controlling the polymorphic form was demonstrated

Multistage Continuous Mixed-Suspension, Mixed-Product Removal (MSMPR) Crystallization with Solids Recycle

Continuous crystallization process has potential advantages such as lower cost and improved flexibility in pharmaceutical production when compared to batch crystallization. A good continuous crystallization process should achieve a high product yield and purity comparable to current batch crystallization processes. For compounds that have low growth rates, a high yield is difficult to achieve without long residence times. Solids recycle is a potential solution for this problem as it can increase the surface area of crystals in the crystallizer thus increasing the mass deposition rate. In this study, solids recycle was used in a two-stage continuous mixed-suspension, mixed-product removal (MSMPR) cooling crystallization. Manual solids recycle and the use of a designed column for automatic slurry concentration were employed. The crystallization of cyclosporine, which has very low growth rate (about 0.1 μm/min) at low temperatures in acetone, showed only 65.0% yield in a two-stage MSMPR without solids recycle. With solids recycle to the second stage and both stages, 75.3% and 79.8% in yield were achieved, respectively. The product purity remained the same, while the yield was enhanced. A population balance model was developed to estimate the final yield of continuous process with solids recycle. The simulation results showed that optimization in stage number, stage temperatures, and solids recycle ratios could improve the yield to 83.9% in four-stage MSMPR crystallization with solids recycle. This yield was close to the batch yield at equilibrium, i.e., 86.0%

Geometric Design of Heterogeneous Nucleation Sites on Biocompatible Surfaces

Biocompatible polymer surfaces imprinted with nanopores of various geometries were utilized as heteronucleants during crystallizations of mefenamic acid (MA). MA, a nonsteroidal anti-inflammatory drug (NSAID) that possesses two structurally characterized polymorphs, is utilized as a model compound. By combining geometric nanoconfinement and favorable surface–solute interactions, it was possible to influence the nucleation kinetics of this system and harvest the metastable form of MA, MA form II, on the square nanopores. An exploration of the relationship between the preferred orientation found by powder X-ray diffraction (PXRD) and the angular matching based on the intrinsic angles, determined by the predicted morphology, was used to provide insights into the mechanism for the observed nucleation enhancement and polymorph selection. The results presented here might lead to a rational design strategy of surfaces to control nucleation and, therefore, polymorphism