Cocrystallization modeling: a review

Rafael Siqueira Colombo, André Bernardo, Caliane Bastos Borba Costa

Rio de Janeiro, May 22nd, 2019

Cocrystal

• Cocrystals are solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds held by non-covalent interactions in a stoichiometric ratio which are neither solvates nor simple salts.

Diagram of ethenzamine (2-ethoxybenzamide)-saccharin cocrystal structure Source: Tong et al. (2016) 2

Applications

• Pharmaceuticals cocrystal can improve some physical and chemical properties (e.g., stability, solubility in water, dissolution rate, bioavailability) of active pharmaceutical ingredient (API), without compromising its action. • API + conformer (Basavoju et al., 2008; Padrela et al., 2009, Sheikh et al.,

2009) • API + API (drug-drug)

• Cocrystallization process can be used to accomplish difficult separations, e.g.: • Racemic mixtures (Ghazali et al., 2006) • Recuperation of vanillin (1:2 co-crystals of phenazine-vanillin, Lee et al., 2012)

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How can cocrystals be produced?

• Grinding: solid state as well as liquid-assisted (solvent-drop)

• Slow evaporation

• Cooling crystallization

• Antisolvent crystallization

• Using supercritical fluid / compressed fluid • Solvent (cocrystallization with supercritical solvent, CSS)

• Antisolvent (supercritical antisolvent, SAS; gaseous antisolvent, GAS)

• Atomizer enhancer and antisolvent (AAS)

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As a crystallization process…

• Solute leaves solution to be incorporated into crystalline lattice

• Thermodynamics and kinetics: • SLE data

• Rate of crystallization mechanisms expressed mainly as functions of supersaturation (driving force)

• Mechanisms for supersaturation generation

• Other equilibrium data

• Implications of heat and mass transfer during scale-up on kinetic processes

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Equilibrium

6 Source: Holaň et al. (2014)

Narrow range for pure cocrystal production!

Equilibrium

7 Source: Yu et al. (2010)

Risk of crystallizing single component phase!

Crystallization Mechanisms

• Primary nucleation – calculated by classical crystallization theory

• Secondary nucleation

• Growth (size dependent?)

• Agglomeration

• Breakage

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Other aspects

• Polymorphism (process parameters are important to avoid it)

• Crystal size distribution

• Crystal morphology

• Seeding

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Crystallization modeling (first-principles)

• Population balance (mainly unidimensional) • Crystallization kinetics • Solubility model

• Mass balance • Energy balance

Coupling of PDE, ODEs and algebraic equations. Different degrees of sophistication of the modeling (considerations). CFD evaluating effects of micro and macro-mixing.

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Literature on cocrystallization

• Many experimental studies reports (Sheikh et al., 2009): • Classification of potential coformers

• Development of cocrystal screening methods

• Selection of solvent (influence on purity, size, shape, polymorphism, yield)

• Characterization and evaluation of physical properties in comparison to original API

• Development of scalable techniques to deliver large amounts of cocrystals

• PSE tools are still scarce in cocrystallization literature, although they are very common on literature of crystallization of monocompounds. • Many well-established techniques and procedures commonly used in single

component crystallization to manipulate and control the process for desired process performance and product attributes has potential to be employed to cocrystallization

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Literature on cocrystallization modeling • Yu et al. (2014) modeled the batch cooling crystallization of caffeine-glutaric acid using acetonitrile as

solvent: • Well-mixed crystallizer and constant volume assumptions; also only cocrystals were supposed to be produced

• 1D Population balance model (only size-independent G) solved with method of moments.

• Kinetic parameters (only data from solution)

• Proposal of aging period after seeding in order to avoid high supersaturaion (and avoidance of undesired polymorph).

• Erriguible et al. (2015) modeled the GAS antisolvent process for naproxen + nicotinamide cocrystal production aiming to estimate kinetic crystallization mechanisms parameters: • Well-mixed reactor assumption; also only cocrystals were supposed to be produced

• LVE model for solvent (acetone) and antisolvent (CO2) and effects on API and conformer equilibrium concentrations on liquid phase (Peng Robinson and experimental data)

• 1D Population balance model (PN with interfacial tension as a function of composition of liquid phase + SN + size-independent G) solved with method of moments and ode15s subroutine

• Levenberg-Marquardt method for estimating kinetic parameters

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Literature on cocrystallization modeling • Holaň et al. (2015) modeled the batch cooling crystallization of aglomelatine-citric acid using MEK as

solvent: • Well-mixed crystallizer and constant volume assumptions; also only cocrystals were supposed to be produced

• 1D Population balance model (PN + SN + size-independent G) solved with finite difference method and integrated with Euler method.

• Kinetic parameters estimated

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Literature on cocrystallization control/data analysis • Yu et al. (2011) proposed a feedback controller for a caffeine- glutaric acid cocrystallization process.

Supersaturation was controlled (based on in situ concentration and temperature measurements) manipulating water circulation through the jacket in order to avoid nucleation of metastable polymorphic form. Seeding with stable polymorphic form was also a policy used and resulted in alrger average particle size.

• In 2015, Lee et al. showed the importance of process parameters, such as the rate of addition of antisolvent or the change in the speed of agitation, to determine which polymorphic form would be obtained for polymorphic cocrystals of carbamazepine-saccharin in water-methanol antisolvent crystallization process. They used PCA to assist the analysis.

• In 2017, Silva et al. compared the statistical control of the batch cocrystallization (with solvent – methanol – evaporation) process of hydrochlorothiazide - p-aminobenzoic acid by the methods of orthogonal partial least squares (OPLS) regression with partial least squares regression (PLS). The process was monitored by near infrared spectroscopy (FT-NIR) and imposed disturbances were used to test methods ability to detect abnormal situations and OPLC performed better.

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Conclusions

• Application of PSE tools to cocrystallization processes are still scarce in the literature.

• Experimental works on cocrystallization along with the solid framework of first-principles models of monocomponent crystallization may open a new range of research for this type of crystallization, addressing areas not still deeply explored: • Process modeling

• Process optimization

• Process control

• Efforts in this direction could be key actors in the establishment of production policies that avoid the appearance of unwanted crystals, such as polymorphs or mixture of cocrystals and pure crystals of one of the solutes.

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References

• Basavoju, S.; Boström, D.; Velaga, S. P. Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization. Pharmaceutical Research, 25 (2008) 530-541.

• Erriguible, A.; Neurohr, C.; Revelli, A.-L.; Laugier, S.; Fevotte, G.; Subra-Paternault, P. Cocrystallization induced by compressed CO2 as antisolvent: simulation of a batch process for the estimation of nucleation and growth parameters. The Journal of Supercritical Fluids, 98 (2015) 194-203.

• Ghazali, N. F.; Ferreira, F. C.; White, A. J. P.; Livingston, A. G. Enantiomer separation by enantioselective inclusion complexation-organic solvent nanofiltration. Tetrahedron: Asymmetry, 17 (2006) 1846-1852.

• Holaň, J.; Štěpánek, F.; Billot, P.; Ridvan, L. The construction, prediction and measurement of co-crystal ternary phase diagrams as a tool for solvent selection. European Journal of Pharmaceutical Sciences, 63 (2014) 124-131.

• Holaň, J.; Ridvan, L.; Billot, P.; Štěpánek, F. Design of co-crystallization processes with regard to particle size distribution. Chemical Engineering Science, 128 (2015) 36-43.

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References

• Lee, T.; Chen, H. R.; Lin, H. Y.; Lee, H. L. Continuous co-crystallization as a separation technology: the study of 1:2 co-crystals of phenazine-vanillin. Crystal Growth & Design, 12 (2012) 5897-5907.

• Lee, M.-J.; Wang, I.-C.; Kim, P.; Song, K.-H.; Chun, N.-H.; Park, H.-G.; Choi, G. J. Controlling the polymorphism of carbamazepine-saccharin cocrystals formed during antisolvent cocrystallization using kinetic parameters. Korean Journal of Chemical Engineering, 32 (2015) 1910-1917.

• Padrela, L.; Rodrigues, M. A.; Velaga, S. P.; Matos, H. A.; Azevedo, E. G. Formation of indomethacin-saccharin cocrystals using supercritical fluid technology. European Journal of Pharmaceutical Sciences, 38 (2009) 9-17.

• Sheikh, A.; Rahim, S. A.; Hammond, R. B.; Roberts, K. J. Scalable solution cocrystallization: case of carbamazepine-nicotinamide I. Crystal Engineering Communication, 11 (2009) 501-509.

• Silva, A. F. T.; Sarraguça, M. C.; Ribeiro, P. R.; Santos, A. O.; de Beer, T.; Lopes, J. A. Statistical process control of cocrystallization processes: a comparison between OPLS and PLS. International Journal of Pharmaceutics, 520 (2017) 29-38.

• Tong, Y.; Wang, Z.; Dang, L.; Wei, H. Solid-liquid phase equilibrium and ternary phase diagrams of ethenzamide-saccharin cocrystals in different solventes. Fluid Phase Equilibria, 419 (2016) 24-30.

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References

• Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Operating regions in cooling crystallization of caffeine and glutaric acid in acetonitrile. Crystal Growth and Design, 10 (2010) 2382-2387.

• Yu, Z. Q.; Chow, P. S.; Tan, R. B. H; Ang, W. H. Supersaturation control in cooling polymorphic co-crystallization of caffeine and glutaric acid. Crystal Growth and Design, 11 (2011) 4525-4532.

• Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Design space for polymorphic co-crystallization: incorporating process model uncertainty and operational variability. Crystal Growth & Design, 14 (2014) 3949-3957.

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Thank you!

cbbcosta@uem.br

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