Isothermal Suspension Conversion as a Route to Cocrystal Production

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Isothermal Suspension Conversion as a route to cocrystal production: One pot scalable synthesis Denise Croker, and Ake Rasmuson Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500145a • Publication Date (Web): 09 Jul 2014 Downloaded from http://pubs.acs.org on July 15, 2014

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Organic Process Research & Development

Isothermal Suspension Conversion as a route to cocrystal production: One pot scalable synthesis Denise M. Croker, Åke C. Rasmuson Materials & Surface Science Institute, Chemical & Environmental Science Department & Synthesis & Solid State Pharmaceutical Centre (SSPC), University of Limerick, Ireland

Abstract

Isothermal suspension conversion is presented as a suitable method for the manufacture of pure cocrystal products once the ternary phase diagram (TPD) for the cocrystal system in the desired solvent is available. 1:1 and 3:2 cocrystals of p-toluenesulphonamide/triphenylphosphine oxide were produced in acetonitrile and dichloromethane using this method. 8 individual batches of product were prepared with complete conversion to pure product achieved in 7 batches. Product recovery (77 - 99%), reaction conversion (17 - 89%), and volumetric productivity (0.03 – 0.63 g/cm3) were calculated for each product batch. These parameters are essentially determined by the batch operating mass fraction composition selected from the TPD, allowing for tailoring of processing conditions to suit process requirements and capabilities by careful selection of the optimum operating mass fraction composition.

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Introduction The definition of a cocrystal has been debated in the scientific community 1-3 but today there is a general consensus that a cocrystal is a multi-component crystal comprising two or more compounds that are solids under ambient conditions, present in a stoichiometric ratio and interact by noncovalent interactions such as hydrogen bonding. Examples of binary cocrystals, consisting of a target molecule and a coformer molecule are common in existing literature4-6. Pharmaceutical cocrystals are further defined as having an active pharmaceutical ingredient (API) as the target molecule 7. Cocrystals are of interest to the pharmaceutical world as they have the potential to alter the physical properties of API molecules such as solubility, dissolution rate and bioavailability8-14. This in turn is attractive as it offers a means of improving physical properties of drug products, reviving opportunities for products shelved due to unfavorable physical property characteristics, and potentially providing patent extensions for existing products through intellectual property generation. Cocrystallization has also been demonstrated as an aid in the purification of solutions17,

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pharmaceutical products15,

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, and resolution of racemic

. While attractive, cocrystallization has yet to be realized at commercial scale,

partly due to complexities in designing processes to robustly manufacture cocrystals in pure and stable forms (additional complexity arises with respect to the regulatory approval process for cocrystal drug products3,

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). In a standard crystallization, the process is controlled by the

supersaturation of the crystallizing phase. Knowledge of the solubility of the crystallizing phase allows for the calculation of supersaturation and control of the crystallization. In a cocrystallization, the process is further complicated by the presence of the cocrystal co-former. Identification of operating spaces where the desired cocrystal product can be isolated requires knowledge of the thermodynamics of the system, and identification of cocrystal stability relative to that of the starting materials. Determination of relevant solubility data and representation in a


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suitable format – most usually a ternary phase diagram (TPD)20, 21, is key to understanding and designing cocrystallization. The TPD also rationalizes the dissolution of a cocrystal in a given solvent. Congruent and incongruent dissolution pathways are possible in cocrystal systems, and the reader is referred to references for additional information4, 22. On a small scale, bespoke synthesis of cocrystals by somewhat trial and error methodologies has become quite a norm, with the focus on characterization of the final product rather than rationalization of the formation mechanism or design of the manufacturing route. Dry grinding2325

, solvent grinding11, 26, and slow evaporation22, 27-30 are typically reported for the manufacture of

cocrystals, but none of these technologies are immediately transferrable to an industrial process. Solution based cocrystallization methods13, 20, 31-35 have most potential for scale-up and transfer to industry. Sheikh et al described manufacture of the carbamazepine:nicatinamide I co-crystals at a 1L scale using a seeded cooling crystallization from a solution where the coformer concentration was maintained in strong excess36. Reaction yield of 90% were achieved using this method. Earlier this year, Kudo et al reported on a cocrystal production method suitable to industrial production37. Two-solution mixing based on the ternary phase diagram was successfully used to manufacture carbamazepine/saccharin cocrystals, and a basis for supersaturation calculation and process design outlined. The objective of this work is to introduce a methodology for cocrystal manufacture which is potentially transferrable to industry and realizable on an commercial scale. Isothermal Suspension Conversion (ISC) simply involves equilibrating the cocrystal coformers in a solvent of choice at fixed temperature for a defined equilibration time. The method uses the ternary phase diagram to identify the necessary solution composition to ensure cocrystal formation & stability. Here, the method is presented on a laboratory scale using the p-toluene


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sulphonamide/triphenylphosphine oxide as a case study. This system is capable of forming 2 cocrystals – a 1:1 stoichiometry and a 3:2 stoichiometry (Figure 1), and the ternary phase diagram for the system has been previously published22. (a)

(b)

(c)

(d)

Figure 1: Chemical structure of (a) p-toluenesulphonamide, (b) triphenylphosphine oxide and the crystal structure of (c) the 3:2 cocrystal and (d) the 1:1 cocrystal, formed between these 2 solids.

Methodology Experiments were completed on a 5 g scale, using sealed glass tubes as reaction vessels in a water bath (Grant GR150 with 38L bath) equipped with a serial magnetic stirrer plate. The (predetermined22) ternary phase diagram in acetonitrile at 20oC was used to identify a total mass fraction composition where the 3:2 cocrystal is the thermodynamically stable solid phase in acetonitrile, M1, Figure 2. For clarity, the term total mass fraction composition is defined as the relative mass fraction of TSA, TPPO and solvent at a given point in the TPD, the sum of which


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is always 1. For example M1 (Table 1) has a total mass fraction composition of 0.16 TSA:0.04 TPPO:0.80 Acetonitrile. For simplicity total mass fraction composition will be abbreviated as MF from this point forward. A batch suspension corresponding to this MF was prepared by combining the appropriate mass of TSA, Ph3PO and solvent in a glass vial, as per Table 1. A small magnetic stirrer was inserted into the vial and the vial was sealed and placed in the water bath at 20 oC to stir at 200rpm for 24 hours. An equilibration time of 24 hours was selected to correspond with the equilibration times used in construction of the TPD. In reality there is scope to reduce this time, but this was not considered for this particular work. This process was repeated for a second MF, with higher solids loading, relating to the 3:2 cocrystal,M2, and 2 MF relating to the 1:1 cocrystal, M3 and M4 (Figure 1, Table 1). 4 MF were also tested in dichloromethane using the ternary phase diagram for that system at 20 oC, Figure 3, Table 1.


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Table 1. Mass of TSA, Ph3PO and solvent used in the isothermal suspension conversion experiments, the corresponding mass fractions (MF) on a total mass fraction composition basis, and the respective cocrystal region in the TPD.

Experiment TSA/g Ph3PO/g Solvent/g MFTSA MFPh3PO MFSOL

Cocrystal Region

Predicted Yield/g

TSA-Ph3PO-MeCN System M1

0.8024 0.2088

4.02

0.16

0.04

0.80

3:2 CC

0.22

M2

1.8522 1.3511

2.3585

0.33

0.24

0.42

3:2 CC

2.62

M3

0.4016 0.6045

4.0348

0.08

0.12

0.80

1:1 CC

0.59

M4

1.1564 1.853

2.006

0.23

0.37

0.40

1:1 CC

2.80

TSA-Ph3PO-CH2Cl2 System C1

0.658

1.1073

3.23

0.13

0.22

0.65

3:2 CC

1.09

C2

1.3073 1.6518

2.17

0.25

0.32

0.42

3:2 CC

2.60

C3

0.256

3.26

0.05

0.30

0.65

1:1 CC

0.34

C4

0.8477 2.1602

1.9944

0.17

0.43

0.40

1:1 CC

2.01

1.5058


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Figure 2. Ternary phase diagram for the TSA-Ph3PO-MeCN system at 20 oC, expressed as mass fraction. Experimental mass compositions, M1 – M4, are denoted in the regions where the 3:2 cocrystal (blue area) and the 1:1 cocrystal (red area) are the only stable solid phases.


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Figure 3. Ternary phase diagram for the TSA-Ph3PO-CH2Cl2 system at 20 oC. Experimental mass compositions are denoted in the regions where the 3:2cocrystal (blue area) and the 1:1 cocrystal (red area) are the only stable solid phases.

At the end of the equilibration time, solids were isolated from the product suspension using filtration across a 0.45m PTFE filter. The solids were washed with a minimal amount of the parent solvent and placed in a vacuum oven at 50 oC to dry overnight. Once dry, the solids were weighed to record a product mass. The dry solids were ground lightly in a mortar and pestle


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before being analyzed for phase composition with powder X-ray diffraction (Philips PanAnalytical X’Pert MPD Pro with PW3064 sample spinner, reflectance mode). Reference PXRD patterns for the 3:2 and 1:1 co-crystal were generated from their respective crystallographic information files (CIF) using Mercury 2.4. In an effort to quantify the performance and efficiency of the ISC, reaction conversion (1), product recovery (2), and volumetric productivity (3) were calculated for each experiment as defined below.

Results In all experiments, solids were recovered from the product suspensions after 24 hours PXRD patterns of the solids recovered from acetonitrile are presented in Figure 4, along with a reference PXRD pattern for each cocrystal. A slight drift is apparent in the experimental patterns relative to the reference patterns due to temperature effects; the reference patterns were recorded at low temperatures. In all experiments, a pure cocrystal product was achieved as dictated by the TPD. MF taken from the 1:1 cocrystal zone of the TPD yielded 1:1 cocrystal product, with an


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equivalent result achieved for the 3:2 cocrystal experiment. No remaining starting materials could be detected using PXRD. A similar result was achieved in dichloromethane (Figure 5) with one exception. Slight traces of the TSA starting material were present in the product from sample C2. It is thought that this was due to incomplete mixing in this sample during the equilibration time. All samples were left overnight with agitation for equilibration. At some point during the night, agitation in vial C2 stopped resulting in settling of solids to the bottom of the vial. It is thought that this mixing inefficiency resulted in stagnant zones and limited mass transport and it is speculated that as a result the starting TSA did not fully dissolve to react, or became isolated in its own dead zone. In total, 7 of the 8 experiments were successful in producing a pure product with no traces of co-former impurity.


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M4 M3

Relative Intensity

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1:1 Ref.

M2

M1

3:2 Ref 5

10

15

20

25

2q Figure 4. PXRD patterns of solids isolated following isothermal suspension conversion in acetonitrile at 20 oC and reference patterns for the pure 3:2 and 1:1 co-crystal. Labels refer to experimental compositions outlined in Table 1.


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C4 C3

Relative Intensity

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1:1 Ref.

C2

C1

3:2 Ref. 5

10

15

20

25

2q Figure 5. PXRD patterns of solids isolated following isothermal suspension conversion in dichloromethane at 20 oC and reference patterns for the pure 3:2 and 1:1 co-crystal. Labels refer to experimental compositions outlined in Table 1. With regard to the mechanism of cocrystal formation, a number of options are possible. It is reasonable to assume the cocrystals products form from some dissolution-reprecipitation mechanism involving nucleation and growth of the cocrystal phase. One possible mechanism is demonstrated schematically in Figure 6 for a simple stoichiometric conversion. In stage 1, the dissolution of TSA and TPPO feed the solvent and increase the concentration in solution. At some point, termed stage 2, the solution concentration reaches a critical level where nucleation of the cocrystal is possible. Subsequent growth of the cocrystal consumes TSA and TPPO from the


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solution, providing a driving force for further dissolution of the solid TSA and TPPO. Here, solution concentration is balanced by the dissolution/growth events (stage 3). When all the solid TSA and TPPO have been consumed, cocrystal growth continues until the solution concentration reaches the solubility level of the cocrystal, and thermodynamic equilibrium is attained (stage 4). It is also possible that the solution concentration could plateau before stage 2 with a metastable equilibrium established prior to nucleation of the cocrystal phase (black line, Figure 6). Tracking the reaction with an in-situ measurement technique – IR, Raman, would provide conclusive evidence for the exact mechanism, and this is planned as future work.

The relative

concentrations of TSA/TPPO in solution determine the composition of the solid phase at the end of the conversion. Operating in the pure cocrystal region of the TPD ensures a pure cocrystal product.

1

2

3

TSA/Ph3PO Solids Consumed

4

[TSA] [Ph3PO] [TSA] - alternative

Figure 6. Schematic illustration of the proposed mechanism for cocrystal formation as visualized through solution concentration changes during the conversion.


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The mass of product recovered from each batch is presented in Table 2. In general, as in any crystallization, the further the distance of the experimental point from the solubility curve, the greater the mass of product formed. Recovery was calculated against the predicted yield (Table 1, Supporting Information) and an average of 90% recovery achieved across all experiments. The low recovery achieved in experiment C1 is in part due to a small loss of the product suspension during transfer to filtration. Reaction conversion was calculated as the mass of product recovered per mass of the reagents (TSA + TPPO) charged to the experiment. This parameter varied significantly across all experiments and was highest for the experimental points that contained a low solvent mass fraction. This is intuitive as a certain amount of the reagents will stay in solution due to solubility. Reaction conversion of greater than 85 % was achieved in experiments M4 and C2. Volumetric productivity was calculated as the mass of product recovered per 1ml of solution. A wide spread was again observed across the 8 batches with volumetric productivity varying from 0.03 g/ml (M1) to 0.6 g/ml (C2). In general, this parameter increases with decreasing solvent mass fraction, as greater product is formed from less solvent. All calculations for sample C2 are slightly inaccurate due to the TSA contamination in this sample. As the amount of TSA was very low (as indicated by PXRD, see supporting information), this inaccuracy is considered to be negligible. Overall, all calculated parameters were higher in dichloromethane, but a direct comparison is not possible due to the different shape of the TPD in dichloromethane relative to acetonitrile. The solvent fractions that can be used are dependent on the shape of the TPD and specific to each solvent system.


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Table 2: Mass of product recovered, yield, TSA conversion and productivity for each experiment Experiment Ref

Product Recovered (g)

Solid Form

Recovery (%)

Conversion (%)

Volumetric Productivity (g.cm-3)

M1 M2 M3 M4 C1 C2

0.17 2.40 0.55 2.67 0.97

3:2 CC 3:2 CC 1:1 CC 1:1 CC 3:2 CC 3:2 CC +TSA 1:1 CC 1:1 CC

77 92 92 95 88

17 75 54 89 55

0.03 0.43 0.09 0.53 0.25

99 85 86

87 16 58

0.63 0.07 0.44

C3 C4

2.56 0.29 1.74

It is apparent that recovery, conversion and throughput varied widely across all the batches. Reaction performance is strongly dependent on the operating MF. Selection of an appropriate operating MF should provide for an efficient conversion where a desirable product yield is achieved in the least amount of solvent. Suspension density must also be considered in selection of this appropriate operating MF. Use of lower solvent mass fractions in the operating MF will increase yield and throughput but will result in product slurries that are difficult to agitate, for example batch C2 above, or on a large scale, transferred and isolated. Yield and productivity cannot be maximized at the loss of operating practicalities. Acknowledging this, the benefit of having process parameters tied to MF is that the desired parameters can essentially be dialed up by considered selection of the optimum operating MF. For example, if a conversion of 80 % at 0.5g/ml volumetric productivity is required, the operating MF can be tailored to achieve this (M4 above). This allows a wide range of operating windows for the manufacture of cocrystals using isothermal suspension conversion. The potential exists to maximize the yield further after the 24 hour equilibration time by adding a cooling or anti-solvent step. The additional is an anti-solvent step would only be


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possible where it has been shown not to interfere with the stability of the cocrystal solid phase or cause a phase transformation. Additionally, it is likely that the equilibration time could be reduced by monitoring the approach to full conversion. The system most likely does not require the full 24 hours for complete conversion. This will be investigated by use of in-situ monitoring of reaction progression in future work. In theory, this method could be adapted to industrial manufacture as it is carried out in a typical batch reactor vessel, and requires only charging of solvent and solid fractions and agitation at the necessary operating conditions. It is fully acknowledged that additional challenges may need to be addressed in scale-up. Careful consideration of the selection of the mass fraction composition is needed, to maximize yield and productivity, but also produce product suspension which can be handled and transferred. A margin of error would be needed around the mass fraction composition to accommodate small fluctuations in process charges. In an industrial setting it is likely that the API molecule may already be supplied in mother liquor from the synthesis step. This would require some additional design considerations but there is no reason the solid coformer could not be added to such a solution and the cocrystal formed in-situ. For final step API manufacture this method may be limited by the requirements to have filtration on all incoming reactants in order to eliminate mechanical impurities. In this case coformer could be dissolved in the required solvent prior to addition to the pure vessel allowing for in-line filtration during charging. Careful consideration of total operating mass fraction would be required to ensure the required solid phase is formed.


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Conclusion This work demonstrated isothermal suspension conversion as a simple, robust route to cocrystal manufacture. A pure cocrystal product was produced in 7 out of 8 batch experiments, with a reasonable route to failure identified for the 8th batch. Product recovery, reaction conversion and volumetric productivity for each batch were varied, dictated by the operating total mass fraction compositions within the ternary phase diagram for that batch. The concept was demonstrated in 2 solvents indicating that the method is not solvent specific and will operate in any solvent where the cocrystals have a reasonable degree of stability. The ternary phase diagram is necessary to identify suitable operating mass fractions for this method. The methodology used is scalable; as long as the appropriate mass fraction is maintained, the cocrystal product will form.

AUTHOR INFORMATION Corresponding Author *[email protected] Funding Sources Funding from Science Foundation Ireland (07/SRC/B1158) is gratefully acknowledged. Supporting Information Available: A method of predicting the yield using the ternary phase diagram and PXRD patterns of batch C2 with TSA and 3:2 cocrystal references is provided. This information is available free of charge via the Internet at http://pubs.acs.org/.


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(16) Lee, T.; Chen, R. H.; 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 2012, 12, (5897-5907). (17) Springuel, G.; Leyssens, T., Innovative Chiral Resolution Using Enantiospecific CoCrystallization in Solution. Crystal Growth & Design 2012, 12, (7), 3374-3378. (18) Farina, A.; Meille, S. V.; Messina, M. T.; Metrangolo, P.; Resnati, G.; Vecchio, G., Resolution of Racemic 1,2-Dibromohexafluoropropane through Halogen-Bonded Supramolecular Helices. Angewandte Chemie International Edition 1999, 38, (16), 2433-2436. (19) The United States FDA Guidance for Industry: Regulatory Classification of Phamaceutical Co-crystals; 2013. (20) Chadwick, K.; Davey, R. J.; Sadiq, G.; Cross, W.; Pritchard, R., The utility of a ternary phase diagram in the discovery of new co-crystal forms. CrystEngComm 2009, 11, 412-414. (21) Chiarella, R. A.; Davey, R. J.; Peterson, M. L., Making co-crystals - the utility of the ternary phase diagram. Crystal Growth & Design 2007, 7, (7), 1223-1226. (22) Croker, D. M.; Foreman, M. E.; Hogan, B. N.; Maguire, N. M.; Elcoate, C. J.; Hodnett, B. K.; Maguire, A. R.; Rasmuson, Å. C.; Lawrence, S. E., Understanding the pToluenesulfonamide/Triphenylphosphine Oxide Crystal Chemistry: A New 1:1 Cocrystal and Ternary Phase Diagram. Crystal Growth & Design 2011, 12, (2), 869-875. (23) Deutsch, Z.; Bernstein, J., Cocrystal of Urea and Imidazolidone: Formation of an Unexpected 1-D Substructure in a Plausibly Predictable Cocrystal. Crystal Growth & Design 2008, 8, (10), 3537-3542. (24) Hu, Y.; Gniado, K.; Erxleben, A.; McArdle, P., Mechanochemical Reaction of Sulfathiazole with Carboxylic Acids: Formation of a Cocrystal, a Salt, and Coamorphous Solids. Crystal Growth & Design 2013, 14, (2), 803-813. (25) Leyssens, T.; Springuel, G.; Montis, R.; Candoni, N.; Veesler, S., Importance of Solvent Selection for Stoichiometrically Diverse Cocrystal Systems: Caffeine/Maleic Acid 1:1 and 2:1 Cocrystals. Crystal Growth & Design 2012, 12, (3), 1520-1530. (26) Bian, L.; Zhao, H.; Hao, H.; Yin, Q.; Wu, S.; Gong, J.; Dong, W., Novel Glutaric Acid Cocrystal Formation via Cogrinding and Solution Crystallization. Chemical Engineering & Technology 2013, 36, (8), 1292-1299. (27) Caira, M. R., Sulfa Drugs as Model Cocrystal Formers. Molecular Pharmaceutics 2007, 4, (3), 310-316. (28) Lu, J.; Rohani, S., Preparation and Characterization of Theophylline−Nicotinamide Cocrystal. Organic Process Research & Development 2009, 13, (6), 1269-1275. (29) Rager, T.; Hilfiker, R., Cocrystal Formation from Solvent Mixtures. Crystal Growth & Design 2010, 10, (7), 3237-3241. (30) Takata, N.; Shiraki, K.; Takano, R.; Hayashi, Y.; Terada, K., Cocrystal Screening of Stanolone and Mestanolone Using Slurry Crystallization. Crystal Growth & Design 2008, 8, (8), 3032-3037. (31) Chadwick, K.; Davey, R. J.; Dent, G.; Pritchard, R. G.; Hunter, C. A.; Musumeci, D., Cocrytsallisation: A solution chemistry perspective and the case of benzophenone and diphenylamine. Crystal Growth & Design 2009, 9, (4), 1990-1999. (32) Gagniere, E.; Mangin, D.; Puel, F.; Bebon, C.; Klein, J.-P.; Monnier, O.; Garcia, E., Cocrystal formation in solution: in-situ solution monitoring of the two componets and kinetic pathways. Crystal Growth & Design 2009, 9, (8), 3376-3383.


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(33) Yu, Z. Q.; Chow, P. S.; Tan, R. B. H., Operating regions in cooling crystallization of caffeine and glutaric acid in acetonitrile. Crystal Growth & Design 2010, 10, 2382-2387. (34) Gagniere, E.; Mangin, D.; Puel, F.; Valour, J.-P.; Klein, J.-P.; Monnier, O., Cocrystal formation in solution:Inducing phase transition by manipulating the amount of cocrystallizing agent. Journal of Crystal Growth 2011, 316, 118-125. (35) Croker, D. M.; Davey, R. J.; Rasmuson, Å. C.; Seaton, C. C., Nucleation in the pToluenesulfonamide/Triphenylphosphine Oxide Co-crystal System. Crystal Growth & Design 2013, 13, (8), 3754-3762. (36) Sheikh, A. Y.; Rahim, S. A.; Hammond, R. B.; Roberts, K. J., Scalable solution cocrystallization: case of carbamazepine-nicotinamide I. CrystEngComm 2009, 11, (3), 501-509. (37) Kudo, S.; Takiyama, H., Production method of carbamazepine/saccharin cocrystal particles by using two solution mixing based on the ternary phase diagram. Journal of Crystal Growth 2014, 392, 87-91. Table of Contents Graphic Isothermal Suspension Conversion Solid API - MF Solid Coformer - MF

Solvent - MF

Cocrystal Product

Summary: Isothermal suspension conversion is presented as a simple scalable solution based method of producing cocrystal solids.


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Isothermal Suspension Conversion as a Route to Cocrystal Production

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