Types of Solution Cocrystallization: History
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Solution crystallization has been used in both batch and continuous modes for industrial crystallization for several decades. Solution cocrystallization is often used on a laboratory scale due to its familiarity, simple design, ease of operation, process monitoring, and control. Solvent selection and the mode of supersaturation generation are the two factors that are crucial at the early stages of solution crystallization. For cocrystallization, the solubility of coformers in a given solvent is key factor in solvent selection. Additionally, other operational parameters such as the crystallizer design, mode of agitation, cooling rate/antisolvent addition rate, seeding, or nucleation control can impact final crystal properties such as shape, size, and desired polymorphic.

  • cocrystals
  • solution cocrystallization
  • scale-up
  • cocrystallization kinetics

1. Evaporative Cocrystallization

This method involves the dissolution of the coformers in a suitable solvent, followed by solvent evaporation. As evaporation proceeds, supersaturation is generated, leading to cocrystal nucleation and growth. This is a widely used experimental screening method for possible cocrystal formation due to its simplicity and efficiency in determining the suitable conditions for cocrystal formation. Several authors have successfully used this technique for identifying cocrystals. Some of the cocrystals are carbamazepine-aminobenzoic acid, curcumin-phloroglucinol, curcumin-ascorbic acid, carbamazepine-itaconic acid, and acyclovir-succinic acid [1][2][3][4][5]. Cocrystals of the antiviral drug acyclovir with four dicarboxylic acids have been reported through the solvent evaporation technique. Interestingly, acyclovir did not form cocrystal with malonic acid through the solid-state grinding method [6]. All cocrystals exhibited better solubility and dissolution rate than parent materials. In general, the solvent evaporation method is suitable for low volume screening processes and can be easy to set-up and monitor. However, this method may also lead to the precipitation or crystallization of the pure components or eutectic crystals and undesirable solvate formation. These can be identified by routine analytical techniques such as powder X-ray crystallography or differential scanning calorimetry.
For the cocrystal screening process using solvent evaporation, the solution of coformers can be evaporated quickly using a rotary evaporator or left open in a controlled environment such as an incubator or a fumehood until crystals appear [7][8][9]. Hence, the duration of solvent removal may range from a few minutes to a few weeks. However, the rate of evaporation can significantly affect the formation of crystals. For example, at low evaporation rates, isoniazid forms eutectic crystals with curcumin while they form 2:1 cocrystal at high evaporation rates [10]. Similarly, the evaporation temperature may affect the thermodynamic landscape of the cocrystal in relation to the pure crystals of the coformers. Phase diagrams can be helpful to identify the conditions that will lead to the production of cocrystals or pure coformer crystals [1][11]. In addition to these factors, the presence of external components such as heteronuclei may also affect the selective crystallization of cocrystal forms [12]. Although solvent evaporation is widely used in the screening process, this technique is less likely to be used in an industrial scale production. The significant challenge for scale-up is the longer batch time required for a large amount of solvent and the massive energy demand for the same [13]. Nonetheless, rapid solvent removing equipment such as spray dryers and rotary dryers have been in industrial use for decades. Thereby, these techniques can be used as preferred kinetic methods for the production of cocrystals, especially when they are the metastable solid form. For example, caffeine-dapsone, saccharin-carbamazepine, paracetamol-oxalic acid, and ascorbic acid-isonicotinamide cocrystals have been produced via rapid solvent removal method [14][15].

2. Cooling Cocrystallization

Cooling cocrystallization relies on the temperature-dependent solubility change to achieve cocrystal formation. Both the coformers are initially dissolved in a solvent, and then supersaturation is achieved by reducing the temperature of the solution. Cooling crystallization has been employed on an industrial level for a large number of organic molecules in the pharmaceutical and allied industries. Hence, extensive research has been done on the effect of various operating parameters, control strategies, and process integration steps for this technique, both in batch and continuous modes [16][17][18]. However, in cooling cocrystallization, the phase diagram of the components at different temperatures is essential for process design [19]. The operating region for producing a specific cocrystal has to be determined based on the relative stability of all the crystal forms and their relative nucleation and growth kinetics. This makes the design and operation of cooling cocrystallization more complex than a single solute cooling crystallization. The purity of the cocrystal would be affected if operated beyond the safe operating conditions. He et al. have reported that the cooling crystallization of caffeine and p-hydroxybenzoic acid can produce single-component crystals or two cocrystals with different stoichiometry based on the relative coformer concentrations [20]. Observations using Pulsed Gradient Spin−Echo Nuclear Magnetic Resonance technique revealed that the variations occur due to the difference in intermolecular interactions between the coformer molecules at various concentration ratios. A similar impact of incongruent coformer solubility and coformer concentrations in cooling cocrystallization has been observed during slow cooling crystallization of carbamazepine and acetamide from acetone and toluene [21]. While carbamazepine dihydrate crystals were formed when the carbamazepine mole fraction was above 0.5, a lower concentration resulted in cocrystals. However, using a 1:1 solvent mixture of acetone-toluene cocrystal was produced at carbamazepine mole fractions in the range of 0.25–0.67. The relative concentration of the coformers is also reported to affect the crystal size distribution of the product cocrystals for the cooling cocrystallization process [22].
Industrial cooling crystallizers are often equipped with agitators or other mechanisms for mixing and flow to keep the crystals suspended during operation. However, fluid flow conditions can affect crystal nucleation [23][24]. In the case of cocrystallization too, the nature of agitation can impact the formation of various crystal forms. For instance, Li et al. reported that in a conventional mixed tank cooling crystallizer nucleation of the metastable 2:1 cocrystal of caffeine-malic acid occurs first, followed by the nucleation of stable 1:1 form. However, a rotating disc crystallizer following a similar cooling regime can directly generate the nuclei of the stable form crystals due to periodic vortex motion [25]. Similarly, induction time, yield, and crystal composition of benzoic acid-sodium benzoate cocrystals in cooling crystallization are affected by the mixing condition [26].
Scale-up for cooling crystallization of carbamazepine-saccharin cocrystal to multi-gram scale has been reported by Hickey et al. in 2007 [27]. Since then, several studies have focused on scaling up cooling cocrystallization of various products to establish the impact of process parameters on product attributes [28][29]. The application of unconventional parameters such as heteronucleants on cooling cocrystallization has also been reported in the literature. Recently, Yu et al. investigated the cooling crystallization of urea-succinic acid cocrystal in the presence of nano-porous glass [30]. It was reported that the stable 2:1 cocrystal formed in the bulk while a mixture of 2:1 and metastable 1:1 cocrystals formed in pores above 100 nm. However, when the pore size was below 60 nm, only 1:1 cocrystals formed.
Cooling crystallizers have been considered as the “workhorse” of industrial crystallization [31]. Hence, it is unsurprising that cooling cocrystallization is a preferred method to produce potential cocrystals from small-scale laboratory manufacturing to commercial-scale production.

3. Antisolvent Cocrystallization

Antisolvent cocrystallization utilizes an antisolvent to reduce the solubility of coformers in the solvent, leading to cocrystal formation. Generally, the solvent and the antisolvent must be miscible, creating a single phase. The most commonly used solvent-antisolvent combination is an organic solvent-water combination. Antisolvent cocrystallization is a suitable alternative to the evaporative and cooling cocrystallization for the cocrystals having lower solubility. Besides, the process can be operated at ambient temperature, consuming less energy than solvent evaporation and cooling. Several studies have explored antisolvent cocrystallization for better control of crystal characteristics with enhanced purity and yield. Selection of the solvent-antisolvent combination suitable for the cocrystallization is the first step in this method. However, with two coformers and a solvent mixture, assessing the solubility of the cocrystal and the component crystals at various solvent ratios becomes a challenging task [32]. Often, such data is nonexistent and has to be determined experimentally or computationally before the suitable solvent-antisolvent combination can be selected. Lange et al. used a combined approach of utilizing thermodynamic model prediction and experimental data to account for the nonideal solubility of the nicotinamide-succinic acid cocrystal system for identifying the solvent-antisolvent combination [33]. Others have also utilized similar approaches for the estimation of ternary phase diagrams of various APIs and coformers in different solvents [34][35]. Such calculations can aid the screening process for the selection of suitable solvent systems for antisolvent crystallization.
The rate of addition of antisolvent is the second major factor that has to be considered in antisolvent cocrystallization. For example, Wang et al. initially reported the formation of carbamazepine-saccharin cocrystal by the addition of water into a methanol solution of the coformers [36]. However, it was later reported that the metastable form II cocrystal was formed when a high rate of antisolvent addition and agitation rate is maintained while similar chemical condition with a low rate of antisolvent addition and agitation rate produces the stable form I crystals [37]. For scale up, an optimized addition rate of the antisolvent would ensure that the composition will remain within the critical operating region where the cocrystal would be the stable form [38]. Additionally, antisolvent cocrystallization may be combined with cooling cocrystallization to achieve a higher yield of cocrystals [39].
Antisolvent cocrystallization has also been used for the production of nano-sized cocrystals. Thakor et al. investigated several solvents, antisolvent, and stabilizers for the production of nano cocrystals of the carbamazepine-nicotinamide system [40]. The impact of the operating parameters such as the concentration of stabilizer, temperature, sonication time, and agitation speed on the cocrystal size was also explored. The study revealed that cocrystal size was affected by the stabilizer concentration and a wide range of nano-cocrystals could be produced from coformers having different solubilities. Based on the results, the authors have suggested a generalized decision tree involving solvent-antisolvent and stabilizer selection process that can be useful in the production of nano cocrystals. With further work on antisolvent cocrystallization, this technique has the potential to provide a bottom-up approach for the production of nano cocrystals. This would enhance the application of cocrystals of poorly water soluble drugs, providing a boost to the dissolution rate and bioavailability [41].

4. Slurry Cocrystallization

Slurry cocrystallization is an alternative approach for producing cocrystals whose coformers have incongruent solubilities. The process starts with a suspension of either or both of the coformer crystals in a small amount of solvent, creating a slurry. As the stable cocrystal nucleates and grows, the single component crystals dissolve, akin to the solution-mediated polymorphic transformation process. Slurry cocrystallization was first proposed as an effective cocrystal screening technique by Zhang et al. [42]. Once established, this approach is easy to operate and involves crystallization of pure cocrystal utilizing small quantities of solvents. However, this method can be chosen for cocrystal production only when the required cocrystal is the most stable thermodynamic form in comparison to other crystal forms. Hence, the technique may also be used to screen for the most stable form of the crystals [43]. Further, slurry cocrystallization could also be used to establish the ternary phase diagram, which is an essential component for the process design during scale-up. Hong et al. utilized the method to determine the phase solubility diagram of four cocrystals of myricetin, which was subsequently verified with conventional techniques [44]. The major advantage of the method is that the cocrystals can be generated even without the knowledge of the required stoichiometric ratio of the cocrystal.
Recently, Ahuja et al. reported three new cocrystals (sulfamethazine–nicotinamide, sulfamerazine–salicylamide, and sulfamerazine–anthranilic acid) using the slurry cocrystallization technique. The authors reported that the rate of cocrystal formation was higher when microwave was used as the heating source [45]. Similar enhancement on slurry cocrystallization of caffeine-maleic acid cocrystal has also been reported with the use of high power ultrasound [46][47]. The temperature of the slurry during crystal transformation plays a crucial role in determining both the thermodynamic and kinetic parameters of the process. Soares and Carneiro reported that carbamazepine-nicotinamide cocrystals formed only when the slurry temperature was above 60 °C [48]. While the complete conversion occurred when the slurry temperature was 80 °C, cocrystal nucleation was optimal at 60 °C, inferred from the large number of small cocrystals produced. Furthermore, unconventional phase transitions may also occur during slurry cocrystallization. Qu et al. reported that the formation of pyraclostrobin-thiophanate methyl cocrystal through slurry cocrystallization undergoes a gelation and hardening phase before the suspension of cocrystal is formed [49].
Slurry cocrystallization is a screening as well as a production technique for cocrystals. However, the batch time of the technique is limited by the solution-mediated conversion kinetics. Hence, the production of pure cocrystals would require conditions that ensure complete conversion of other crystal forms within the batch time. Subsequently, while the method is beneficial for batch operation due to low solvent requirement, continuous single-stage operation could produce a mixture of crystal forms.

5. Ultrasound-Assisted Cocrystallization

Solution cocrystallization has been explored along with sonication as process intensification in cocrystal formation. The sonication induces the formation of cavity bubbles inside the solution, which acts as sites for nucleation and leads to nucleation events at lower superstations. The sonication can enhance nucleation rate and reduce induction time and agglomeration of cocrystals [50]. Apshingekar et al. used ultrasound in slurry cocrystallization of caffeine-maleic acid cocrystal using water as a solvent [46]. The authors emphasized the impact of sonication on the ternary phase diagram of the cocrystal. It was reported that the aqueous solubility of both the coformers increased significantly on sonication. Consequently, the stable region of pure cocrystal on the phase diagram decreased, resulting in the solvent-mediated transformation to pure coformer crystals. Similar to other solution cocrystallization techniques, the molar ratio of the coformers is an essential parameter in producing pure cocrystals. Ultrasound can be applied as a process intensification parameter along with cooling or slurry cocrystallization to produce pure cocrystals under conditions that might result in crystal mixtures in conventional processes [47]. Nonetheless, Rodrigues et al. have utilized ultrasound-assisted cocrystallization for high-throughput screening of cocrystals of hydrochlorothiazide [51]. Out of the six coformers tested, the screening was able to identify nicotinamide and p-aminobenzoic acid as coformers that produced cocrystal with the solute.
Sonication can be a process intensification tool that can increase nucleation rate and alter the phase diagram. However, industrial scale-up of the process would be difficult due to the requirement of high sonication power, which could enhance the operating cost of cocrystal formation.

6. Supercritical Fluid Cocrystallization

Supercritical fluid cocrystallization has been tested in recent years as a green approach to produce high purity cocrystals. The supercritical fluid can be used as an antisolvent, solvent, or cosolvent. The process often used is analogous to the antisolvent cocrystallization process, where the supercritical fluid is the antisolvent. In this technology, a fluid (most commonly—carbon dioxide (CO2)) is pressurized and heated above its critical point, thereby creating a supercritical phase. Beyond the critical point, fluid has the diffusivity of gas and the solvating property of liquid. The supercritical fluid is then added to the solution, containing a solvent in which the supercritical fluid is miscible. This addition causes a reduction in solubility and crystal nucleation. The low solubility of many solutes in supercritical CO2 and the low critical conditions of CO2 make it an excellent choice for the supercritical crystallization process [52]. Solvent selection, CO2 addition rate, contact time, temperature, pressure, agitation rate, and coformer concentration are process parameters that can be utilized for achieving required product attributes. Wichianphong and Charoenchaitrakool used Box–Behnken design approach to optimize operating temperature, coformer concentration ratio, and drug saturation for the production of mefenamic acid–nicotinamide cocrystals with a high dissolution rate [53]. Similarly, cocrystal of the resveratrol-nicotinamide system with high dissolution rate has been produced by using supercritical CO2 as an antisolvent for organic solvents [54].
However, the supercritical fluid may also be used as the single solvent or the favored solvent in the solvent-antisolvent process. Ribas et al. investigated the production of curcumin-nicotinamide cocrystal by using CO2 as the supercritical solvent [55]. The cocrystals exhibited a significant increase in the dissolution rate in comparison to pure curcumin crystals. Additionally, it was found that utilizing acetone as a cosolvent in the supercritical process produced smaller crystals with a weaker crystalline structure, thereby increasing the dissolution rate of the cocrystals. Padrela et al. used supercritical CO2 as a green solvent for the cocrystallization of six APIs (theophylline, indomethacin, sulfamethazine, caffeine, acetylsalicylic acid, and carbamazepine) with saccharin [56]. They reported the formation of pure cocrystals for theophylline, indomethacin, and carbamazepine. The investigation revealed that stirring played an important role in determining the rate of cocrystallization. Without stirring, the cocrystallization was significantly limited. Further, the cocrystallization rate was higher when the dissolution rate and the solubility of the coformers were high. In this study too, the addition of ethanol as a cosolvent resulted in the formation of new cocrystals that were not produced otherwise.
Supercritical cocrystallization can be a potential candidate for screening as well as production of cocrystals. This technique is a single-step scalable method and allows to control morphology and size of cocrystal [57]. Supercritical fluids can also be used for cocrystallization of heat-sensitive products and is an eco-friendly method, reducing the use of hazardous solvents. However, there are several challenges that need to be overcome. For example, estimation of coformer and cocrystal solubility in a supercritical fluid is more complex than for a simple fluid. Several different experimental and computational approaches have been reported in the literature towards this [58]. In-line measurement tools for monitoring product quality need to be developed specifically for the operating conditions that require high pressure. Moreover, the contact time required for the production of pure cocrystals is typically in the range of a few hours, with additional time required for pressurizing and depressurizing the system. The process is typically conducted batch-wise, challenging continuous product removal from the pressurized crystallizer vessel. The continuous operation would require further adaptation of techniques such as modified atomization or spray drying processes that utilize supercritical fluid [59]. Furthermore, setting up an industrial-scale operation for supercritical crystallization requires heavy capital investment for handling and recovery of the supercritical fluid.

This entry is adapted from the peer-reviewed paper 10.3390/cryst11030303


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