English

• Cocrystal strategy is to construct multi-component crystals by assembling stoichiometric parent molecule and cocrystal co-former (CCF) in the same lattice through non-covalent interactions [1,2]. By manipulating the intermolecular interactions and packing patterns in the crystal, cocrystallization offers an opportunity to optimize the property and performance of functional molecules in an effective, designable and economical manner, which has been widely applied in various fields such as pharmaceutical, agrochemical, explosive and optoelectronic materials [3-8].

  Slurry method is a commonly used approach of cocrystal synthesis, involving suspending the parent molecule and CCF in a solvent and facilitating cocrystal formation via solvent-mediated phase transitions [9]. However, the cocrystallization efficiency is restricted by the isolation of less soluble component due to solubility difference of the two components of cocrystal, and the formation of unwanted solvates. To avoid individual component crystallization, a reaction crystallization method (RCM) was developed in the pharmaceutical field by using saturated solution of CCF to which an amount of active pharmaceutical ingredient (API) exceeding its solubility is added to eliminate the solubility difference between the API and CCF (Fig. 1a) [10,11]. Nevertheless, it also faces the challenge that even slight volatilization of organic solvent during the reaction process can induce substantial precipitation of soluble components, which is especially pronounced in large-scale cocrystal production [12]. Moreover, the issue of solvate formation remains unsolved with RCM [13]. Improper handling of organic solvents also poses risks to public health and environment [14]. Therefore, there is an urgent need to develop an innovate efficient and green cocrystallization approach to ensure the sustainable application of cocrystals.

  Figure 1

  

  Figure 1.  The cocrystal formation by (a) RCM, (b) DSM and (c) DRCM.

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  Deep eutectic solvents (DESs) are room temperature liquids composed of hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA) primarily connected by hydrogen bonds [15]. DESs are new generation of green and sustainable solvents due to unique advantages of biodegradability, reproducible, low cost, non or low toxicity, and low vapor pressure, making them a promising alternative to organic solvents and highly versatile for various industrial applications like organic synthesis, drug delivery, extraction and separation [16-21]. Recently, our group proposed a novel DESs based slurry method (DSM) for green synthesis of cocrystals (Fig. 1b), using DESs as reaction media and the HBD of DESs (such as carboxylic acids, amides and amino acids) as CCFs. The feasibility of DSM has been confirmed in a series of choline chloride DESs, which effectively avoid individual component crystallization and undesirable solvate formation, greatly improving cocrystal synthesis efficiency [22].

  To further verify the universal applicability of DSM, we attempted to use choline (ChOH) DESs as reaction media to synthesize some cocrystals of nicotinamide (NIC), carbamazepine (CBZ) and theophylline (THE). Fifteen DESs were prepared using ChOH as HBA, and a series of CCFs, which have been reported cocrystals with NIC, CBZ and THE, as HBD (Fig. 2) [23-40]. The DESs were characterized by fourier transform infrared spectroscopy (Fig. S1 in Supporting information) and differential scanning calorimetry (Fig. S2 in Supporting information) analyses, respectively, demonstrating the hydrogen bonds formation between HBA and HBD in DESs, and their liquid state at room temperature. Then, DSM experiments were carried out for a library of 33 cocrystal systems. However, NIC, CBZ and THE did not form any cocrystals but instead yielded pure APIs in all experiments (Table 1).

  Figure 2

  

  Figure 2.  The chemical structures of DESs materials and the model drugs.

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  Table 1

  

  Table 1.  The cocrystal synthesis results of NIC, CBZ and THE using DSM and DRCM.

  DownLoad: CSV

  No.	HBD (CCF)	NIC: CCF	DSM	DRCM	CBZ: CCF	DSM	DRCM	THE: CCF	DSM	DRCM
  1	OA	1:1	×	√	1:1	×	√	2:1	×	√
  2	MA	2:1	×	√	2:1	×	√	1:1	×	√
  3	SA	2:1	×	√	2:1	×	√	/	/	/
  4	GA	1:1	×	√	1:1	×	√	1:1	×	√
  5	AA	1:1	×	√	2:1	×	√	2:1	×	√
  6	PA	1:1	×	√	/	/	/	/	/	/
  7	SuA	1:1	×	√	/	/	/	/	/	/
  8	BA	1:1	×	√	1:1	×	√	1:1	×	√
  9	4HBA	1:1	×	√	1:1	×	√	1:1	×	√
  10	SaA	1:1	×	√	1:1	×	√	1:1	×	√
  11	4AA	/	/	/	/	/	/	1:1	×	√
  12	CA	1:1	×	√	1:1	×	√	1:1	×	√
  13	MaA	1:1	×	√	/	/	/	/	/	/
  14	24DHBA	1:1	×	√	/	/	/	1:1	×	√
  15	26DHBA	1:1	×	√	/	/	/	/	/	/
  √ cocrystal formation, × no cocrystal formation, / no reported cocrystal.

  Previous study has shown that the cocrystal formation in DESs depends on the competitive hydrogen bonding interactions between the API, HBA and HBD molecules, and the dominant hydrogen bonds between the API and HBD could promote their cocrystal formation [22]. To explain why cocrystals of NIC, CBZ and THE cannot be obtained by DSM in ChOH DESs, molecular electrostatic potential surface (MEPS) analysis was conducted to analyze nucleophilic and electrophilic points [41,42], and predict non-covalent interactions between ChOH/API and HBD. ChOH exhibits much lower Ep_min value (−63.42 kcal/mol) than CBZ (−53.22 kcal/mol), NIC (−42.52 kcal/mol), and THE (−39.83 kcal/mol), showing stronger competitiveness in forming non-covalent interactions with HBD (Fig. S3 in Supporting information). Artificial Bee Colony (ABC) algorithm was then employed to search for the low-energy stable molecular clusters in three representative THE-DESs systems, which can be approximated as the precursors of cocrystals [43]. As shown in Fig. S4 (Supporting information), no hydrogen bonded supra-molecular synthons between HBD and THE were observed in the first five stable clusters of each system. Combined the MEP analysis and ABC algorithm, it can be inferred that the presence of ChOH prevents mutual recognition of APIs and HBDs, making it difficult for the systems to generate ordered hetero supramolecular structures. This may be one reason for the experimental results of DSM.

  Inspired by conventional RCM in organic solvents, we envision that for compounds that cannot produce cocrystals by DSM, whether we can obtain cocrystals by stirring stoichiometric API and CCF using DESs which were saturated with the reactants in advance (Fig. 1c). It is essentially a DESs based reaction crystallization method (DRCM). The library of 33 cocrystal systems were also treated by DRCM. For each cocrystal system, a stoichiometric ratio mixture of API and HBD (as CCF) was added to 1 mL of DES. The obtained slurries were then stirred at 600 rpm under ambient conditions for 24 h. The solid phases were isolated and examined by powder X-ray diffraction (PXRD) and compared to the reported or simulated PXRD patterns. For those solids that the PXRD patterns are not consistent with the reported or simulated ones, the formation of the cocrystals was confirmed by single crystal structure determination. The outcome of all DRCM experiments is presented in Table 1. As we can see, all reported cocrystals that failed by DSM were successfully synthesized by DRCM, with the PXRD patterns well matched the simulated patterns (Fig. S5 in Supporting information). Additionally, a new cocrystal of THE with adipic acid (THE/AA) was discovered. The single crystal was obtained by volatilization method in acetonitrile and determined by single crystal X-ray diffraction analysis (Tables S1 and S2 in Supporting information), demonstrating it is a 2:1 cocrystal containing THE and adipic acid. Such results confirmed the feasibility of preparing cocrystal of the API and HBD by DRCM. The cocrystal formation process of DRCM is similar to traditional RCM, where supersaturated reactants in DESs increase the reaction activity and reduce the solubility of cocrystal, ultimately promoting the formation of cocrystals.

  To further examine the effect of slurry duration time and slurry speed on outcome and yield of cocrystals, THE cocrystal systems were selected as the research model and DRCM experiments in ten ChOH DESs were further performed at 600 rpm for 6, 12 h and at 300 and 900 rpm for 6 h. The results are compared with those of experiments performed at 600 rpm for 24 h and shown in Table 2 and Fig. S6 (Supporting information). When slurry at 600 rpm for 6 h, only OA, CA and 24DHBA completely converted to the respective cocrystals, while other systems exhibited no or incomplete conversion. By 12 and 24 h, all systems had achieved cocrystal formation. To verify whether different slurry speed could affect our DRCM experiments, we have also conducted 6 h slurry experiments of THE cocrystal systems at 300 and 900 rpm. The results reveal that the conversion to the cocrystals is complete at 900 rpm for all systems except for THE/GA system, while all cocrystal systems at 300 rpm exhibited no conversion except for THE/OA and THE/CA systems. The yields of all cocrystals are between 70%−85%, and extending the slurry duration time did not result in an increase in yield. In a word, slurry duration time affected the outcome of DRCM experiments and slurry speed affected the reaction rate.

  Table 2

  

  Table 2.  The cocrystal synthesis results of THE using DRCM with different slurry duration time and slurry speed.

  DownLoad: CSV

  No.	Cocrystal	Slurry duration time (h) and slurry speed (rpm)*
  		6 h, 300 rpm	6 h, 600 rpm	6 h, 900 rpm	12 h, 600 rpm	24 h, 600 rpm
  1	THE/OA	cocrystal	cocrystal	cocrystal	cocrystal	cocrystal
  		78.6%	77.9%	80.8%	81.2%	79.3%
  2	THE/MA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				82.3%	81.8%	83.1%
  3	THE/GA	THE and CCF	THE and CCF	THE and CCF	cocrystal	cocrystal
  					80.1%	77.8%
  4	THE/AA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				78.3%	76.3%	73.2%
  5	THE/BA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				79.4%	79.4%	80.5%
  6	THE/4HBA	THE and CCF	THE, CCF and cocrystal	cocrystal	cocrystal	cocrystal
  				79.4%	77.8%	74.2%
  7	THE/SaA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				74.5%	70.5%	72.8%
  8	THE/4AA	THE and CCF	THE, CCF and cocrystal	cocrystal	cocrystal	cocrystal
  				85.2%	84.2%	83.0%
  9	THE/CA	cocrystal	cocrystal	cocrystal	cocrystal	cocrystal
  		83.7%	81.5%	85.5%	85.4%	84.1%
  10	THE/24DHBA	THE and CCF	cocrystal	cocrystal	cocrystal	cocrystal
  			81.4%	79.0%	78.9%	80.8%
  * Percentage values indicate the yields of cocrystals.

  Conventional RCM experiments for ten THE cocrystal systems using organic solvents, such as methanol, acetonitrile, ethyl acetate and acetone, were also conducted for 24 h to compare with DRCM. As shown in Table S3 (Supporting information), for the 40 RCM experiments in organic solvents saturated with THE and CCF, only 40% experiments generate high-purity cocrystals of THE, while 50% experiments produce cocrystal mixed with CCF due to organic solvent volatilization. Non-reaction and incomplete reaction were observed for THE/GA and THE/4AA cocrystal systems, which may be due to inappropriate solvent polarity or insufficient reaction time (Fig. S7 in Supporting information). By comparison, DRCM process produced pure cocrystal in all systems without soluble component precipitation attributed to the low volatility of DESs, indicating it is a more effective cocrystal synthesis method than traditional RCM in these systems.

  In this work, fifteen ChOH DESs were synthesized to further verify the universal applicability of DSM for cocrystal synthesis of NIC, CBZ and THE. However, due to the strong competitiveness of ChOH in forming non-covalent interactions with HBD, the desired API-HBD cocrystals cannot be obtained. In this situation, DRCM should be a viable alternative manner, which produce cocrystals of APIs and HBDs by increasing the reaction activity and reducing the solubility of cocrystals in DESs that were saturated with APIs and HBDs. DRCM not only inherits the advantages of DSM such as being green and safe, avoiding unwanted solvate formation and individual component crystallization events, but also avoids the defect of precipitation of soluble components during traditional RCM process caused by organic solvent volatilization. Undeniably, the DRCM also faces challenges such as high viscosity and solvent residue that need more in-depth and extensive research. But overall, the DRCM we proposed combines the advantages of DSM and RCM, providing a novel, green and economical approach for efficient and high-quality synthesis of cocrystals.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Xia-Lin Dai: Writing – original draft. Yu-Hang Yao: Data curation. Jian-Feng Zhen: Investigation. Wei Gao: Methodology. Jia-Mei Chen: Funding acquisition. Tong-Bu Lu: Visualization, Supervision.

  Acknowledgments

  This work was financially supported by National Natural Science Foundation of China (Nos. 22101204 and 22271220). We also gratefully acknowledge the project grant from the Innovation and Strengthening Project of Guangdong Pharmaceutical University-Special Project of the Guangdong Education Commission (No. 2020KZDZX1128), the Research Projects of the Chinese Medicine Council of Guangdong Province (No. 20231209), and the Key Laboratory of Tropical Medicinal Resource Chemistry of the Ministry of Education at Hainan Normal University (No. RDZH2023001).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110413.

  
  
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• 

  Figure 1  The cocrystal formation by (a) RCM, (b) DSM and (c) DRCM.

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  Figure 2  The chemical structures of DESs materials and the model drugs.

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  Table 1.  The cocrystal synthesis results of NIC, CBZ and THE using DSM and DRCM.

  No.	HBD (CCF)	NIC: CCF	DSM	DRCM	CBZ: CCF	DSM	DRCM	THE: CCF	DSM	DRCM
  1	OA	1:1	×	√	1:1	×	√	2:1	×	√
  2	MA	2:1	×	√	2:1	×	√	1:1	×	√
  3	SA	2:1	×	√	2:1	×	√	/	/	/
  4	GA	1:1	×	√	1:1	×	√	1:1	×	√
  5	AA	1:1	×	√	2:1	×	√	2:1	×	√
  6	PA	1:1	×	√	/	/	/	/	/	/
  7	SuA	1:1	×	√	/	/	/	/	/	/
  8	BA	1:1	×	√	1:1	×	√	1:1	×	√
  9	4HBA	1:1	×	√	1:1	×	√	1:1	×	√
  10	SaA	1:1	×	√	1:1	×	√	1:1	×	√
  11	4AA	/	/	/	/	/	/	1:1	×	√
  12	CA	1:1	×	√	1:1	×	√	1:1	×	√
  13	MaA	1:1	×	√	/	/	/	/	/	/
  14	24DHBA	1:1	×	√	/	/	/	1:1	×	√
  15	26DHBA	1:1	×	√	/	/	/	/	/	/
  √ cocrystal formation, × no cocrystal formation, / no reported cocrystal.

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  Table 2.  The cocrystal synthesis results of THE using DRCM with different slurry duration time and slurry speed.

  No.	Cocrystal	Slurry duration time (h) and slurry speed (rpm)*
  		6 h, 300 rpm	6 h, 600 rpm	6 h, 900 rpm	12 h, 600 rpm	24 h, 600 rpm
  1	THE/OA	cocrystal	cocrystal	cocrystal	cocrystal	cocrystal
  		78.6%	77.9%	80.8%	81.2%	79.3%
  2	THE/MA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				82.3%	81.8%	83.1%
  3	THE/GA	THE and CCF	THE and CCF	THE and CCF	cocrystal	cocrystal
  					80.1%	77.8%
  4	THE/AA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				78.3%	76.3%	73.2%
  5	THE/BA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				79.4%	79.4%	80.5%
  6	THE/4HBA	THE and CCF	THE, CCF and cocrystal	cocrystal	cocrystal	cocrystal
  				79.4%	77.8%	74.2%
  7	THE/SaA	THE and CCF	THE and CCF	cocrystal	cocrystal	cocrystal
  				74.5%	70.5%	72.8%
  8	THE/4AA	THE and CCF	THE, CCF and cocrystal	cocrystal	cocrystal	cocrystal
  				85.2%	84.2%	83.0%
  9	THE/CA	cocrystal	cocrystal	cocrystal	cocrystal	cocrystal
  		83.7%	81.5%	85.5%	85.4%	84.1%
  10	THE/24DHBA	THE and CCF	cocrystal	cocrystal	cocrystal	cocrystal
  			81.4%	79.0%	78.9%	80.8%
  * Percentage values indicate the yields of cocrystals.

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•