Open Access Article. Published on 20 June 2018. Downloaded on 4/12/2024 9:56:07 AM. (PIER) aici is consdunders Creve Commons Atbtion-NoxCoamerial 30 Vopr Lice CrystEngComm COMMUNICATION chock tor updates (exe his: CysténgCom, 2018, 20 se Receved 2a May 2018, ‘Accepted 2th Jae 2018 'BOF: 101039/¢8ce008594 rselVerystengeomm Liquid assisted grinding using imidazolium-based tonic liquids GWL-AG) was found to be effective in isolation of cocrystals and ‘cocrystal polymorphs. Isolation of specific polymorphs of caffeine. citic acid (CAF-CA) and caffeine-glutaric acid (CAF-GLU) cocrystals highlights the tunabilty of Ls in polymorphic control ‘The study of coerystals has become an attractive area of ‘eystallization science in general and erystal engineering in particular because of their fundamental and practical importance." From a fundamental perspective, crystallization,” iainly used as a purification technique, is prone to produce single component crystals and therefore design of eocrystals, ‘which are essentially multicomponent, enhances the understanding of the relative importance of various interactions that are involved in the crystallization process.” ‘This aspect of coetystal synthesis has been explored recently by adopting the concept of structural landscape.* Sometimes, ‘eocrystals. may also serve as an alternative to molecular symthesis."® Both these aspects have garnered significant ‘attention from solid-state chemists in recent times and ‘cocrystals with increasing structural complexity and diverse applications have been synthesized.” “This growing interest in cocrystal synthesis calls for adop- tion of variegated experimental techniques. Although ‘cocrystals are traditionally synthesized by slow solvent evapo- ration, this suffers from environmental hazards due to exces: sive solvent evaporation and from the lack of quantitative smative to this, mechanochemical approaches "While these approaches can be broadly di- vided into two sub-categories, such as neat grinding (NG) and liquid assisted grinding (LAG), the later has attracted a Tot of attention recently due to its ability to produce “ novate MIT Cente for Continuous Manefecuring and Department of Chemical Pngnering Masachsets Ite of Teoogy, 77 Masaru Avenue, Cambridge, Massechuses 02199, USA mal mperonibmi edu "625 Soon, Ine, 7.0. Box 2205, Tuscaloosa, A 3543, USK ‘electronic supplementary information (ES) avaible See DO 101039) “Ts jounas © The Royal Socety of Chemisty 2018 ROYAL SOCETY SeehenisTey Nee ed Cocrystal formation by ionic liquid-assisted grinding: case study with cocrystals of caffeine} Arijit Mukherjee, ®° Robin D. Rogers ®@” and A. S. Myerson @** ‘cocrystals that are othenwise difficult to synthesize."® Despite its great success in obtaining new cocrystals, LAG has some- times suffered undesired outcomes." In this regard, Jones ‘and coworkers have recently adopted a polymer based grind- ing approach (POLAG) which provides an alternative to tradi tional solvent based grinding."*"” This approach was inspired by polymer-induced nucleation studies of organic molecules in the past'® and has shown that by changing the polarity of the ethylene glycol (EG) derivatives, the ‘cocrystallization outcome can be controlled. More intrigu- ingly, it was noted that the chemical nature of the micto- ‘environment of the EG derivatives is likely to influence the nucleation and growth stages of eoorystal formation. Tonic liquids (tts) exhibit short and long range interac- tions between the positively and negatively charged ionic ‘components and therefore are very different from traditional solvents.” Although these types of interactions are complex in nature, recently we have shown that the effect of certain Is can be studied with respect to crystallization and poly- morphism.” In analogy with the POLAG approach as men- tioned above, we hypothesized that changing the structural variables of suitable 1Ls by changing either of the compo- nents may give us access to desirable coerystals. While the chain length of the EG derivatives could be only variable in POLAG, the structural variables of 1Ls can be controlled ei- ther by individual tuning of the components or in a dual ‘manner, inereasing the number of variables in the grinding process. To cheek the viability of our approach we have eho- sen «wo coerystal systems: (i) eaffeine-citrie acid (CAF-CA), ‘where coerystals (Form 1) can only be obtained by the LAG technique, illustrating the importance of the grinding liquid, ‘and (i) eaffeine-glutarie acid (CAF-GLU) where the polymor- phic outcome can be controlled by tuning the structural vari- ables of the grinding solvents. Tnorganie ionic salts have been employed earlier to dem- “onstrate improved synthesis of metal organic frameworks. In ‘order to prepare [Zn4{ta)(dabeo)), required amounts of zine ‘oxide was mixed with terephthalic acid (ta) and 1,¢- CCoystengComn, 2018, 20, 5817-5821 | 3817ed on 20 June 2018. Downloaded on 4/12/2024 9:56:07 AM. rnsed under a Creative Commoas Atribution-NonCommercal 3.0 Unported Licence, Communication diazabicyelof2.2.2}octane (dabeo) and ground in presence of some inorganic salts (such as potassium nitrate) with di- ‘methyl formamide as a grinding solvent. This approach was termed as ion and liquid assisted grinding (ILAG).” However, this isthe first time, to the best of our knowledge, where li Lid salts (Is) are employed in liquid-assisted grinding to form coerystals of organie compounds. In order to different- ate with the previous approach (ILAG), we term it as ionic liquid-assised grinding (WAG). Our objectives were to determine whether ILs have any role as grinding solvent when used in catalytic amount in ‘mechanochemical grinding, and if they have a role, to deter ‘mine how they affect the erystallization outcome. ‘The first cocrystal system we studied was caffeine-citrc acid (CAP- ‘CA). This cocrystal system has two polymorphic forms (CSD Refcodes: KIGKER, KIGKERO1). While sereened through techniques based on organic solvents, cocrystals of Form 1 ‘were obtained only by LAG™ while the Form it was obtained from a chloroform/methanol solution.” However, no coerys- tals were obtained by NG." Later, POLAG was shown to be effective in isolating the Form I cocrysta."* As Form 1 of this coerystal system can only be obtained either by LAG or by POLAG, it demonstrates the importance of the grinding liquid in obtaining the Form 1 (Scheme 1). We chose imidazolium-based 1Ls with relatively inert anions as grinding liquids because of their utility in crys tallization of small molecules in previous studies."” While previous studies employed different solvents or polymers of varying chain lengths, the focus of our strategy involved tuning the Mts either by modifying the substitution on the imidazolium cation or by changing the anions. ‘The Ls studied, included 1-ethyls- methyl imidazolium bis(trifuoromethylsulfonylimide) (Cmim]JNT), -butyh3- methyl imidazolium bis(tf_uoromethylsulfonylimide) (CamimJNTe), —t-methyts-octyl imidazolium bis (Crifuoromethyisulfonylimide) ([CamimJNth), t-dodeeyk: methyl imidazolium bis(tf_uoromethylsulfonylimide) (CiamimJNTh), thydroyethyts-methykimidazolium bis (Csifuoromethyisulfonylimide) ((OHCamimJNTE), —t-ethyl S-methylimidazolium — tetrafluoroborate —_((Camim|[BF) ‘hydroxyethy-3-methybimidazolium tetrafluoroborate (OHCamim|[BFy) (For chemical diagrams of the ths, please see ESI). These ILs are diverse with respect to important key parameters. [Camim]JNTf} and (CamimJH"4] differ in hydro- phobicity ([Camim][Ntf] being hydrophobie and [Camim} Scheme 1 The cocrystal systems used in this study BIB | Cystengcomm, 2018, 20, se17-3821, CCrystEngComm [BF4] being hydrophilic).°°** Hydroxy ILs [OHCsmimIINT%] ‘and ((OHC,mim][BFy) ean sustain enhanced hydrogen bond- ing ability compared to [Camim][NTf) oF (CamimIBF4] (¢s, [OHG;mimNTH;] possesses unusual hyper polarity”). ‘The Ils, were stored in a protected environment (in a slovebox and under vacuum) and were shown to have mit ‘mal water content (for details see ESIt) prior to use. CAP-CA coerystal formation was monitored mainly through the low 20 peaks (See ESI for the full range diffractograms). Form 1 of the coerystals is identified by peaks around 24 = 10.5%, 12.5° and 13° (blue bands, Fig. 1). Peaks at ca. 20 = 12° indi cated the presence of unreacted CAF (grey band) and at ca 14° unreacted CA (red band, Fig. 1. During the grinding ex: periment, two coformers were taken in 1:1 molar ratio and placed in a mortar. Approximately, 40 i of IL, was added thereafter and the mixture was ground with a pestle for 15 ‘minutes approximately ‘We first tried to grind the neat powders (NG) of CAF and. ‘CA and confirmed previous studies that NG (Fig. 1) does not produce cocrystals."" Nest, we carried out the grinding with [CsmimI[Ntf], and the powler obtained alter grinding shows ‘dominant presence of Form 1. Along with, a significant ‘amount of unreacted CAF and a slight amount of CA was also present in the grinding mixture. Formation of Form 1 ‘cocrystals was also observed when the grinding liquid was ‘changed to [Camimi[BF,] or [OHCamim]N,] keeping similar ‘grinding conditions. However, the decreased relative intensity ‘of the CAF peak suggests towards higher rate of coerystal for- mation in these 1s. Although employing [OHC:mim]Bt4] as ‘grinding liquid also generated Form 1 as one of the prod- ucts, the lowest 20 peak is split, suggesting the presence of ‘other products. Taking all the results into account, it can be said that the formation of Form 1 of CAF-CA eocrystals were not affected only by the hydrophobicity/hydrophilicity of the Ms, instead the hydrogen bonding ability of the TL cations may also have a key role Relative Intensity a.) Fig. 1 Simulated pattem of the coerystal CAF-CA, Form 1 (Pi) (a) and CAF-CA Form Il 2c) (the ground powder as obtained fom [Caries (2) [Cail (3), YOHCaimlINT fe), [OHCraBF) (0, experimental pattern of the powder midure of CAF and CA ‘obtained from neat grinding (gl, and CA (h) and CAF () used in the grinding experiments This journal's © The Royal Society of Chemisty 2018ed on 20 June 2018. Downloaded on 4/12/2024 9:56:07 AM. rnsed under a Creative Commoas Atribution-NonCommercal 3.0 Unported Licence, CCrystEngComm Having successfully demonstrated the uly of HAG tech- nique for the CAF-CA system, we proceeded to investigate the coerystal system of caffeine and glutaric acid (CAF-GLU). In this system, there are two forms: Form 1 is metastable and converts to Form Ml under certain conditions (CSD refeodes: EXUQU) and EXUQUJOI)” Both the forms can be prepared through solution crystallization, as well as mech- anochemical techniques.” While NG of the two coformers results in the formation of Form 1, LAG gives acess to both the forms: Form 1 is obtained when ground with non-polar liquids (eg, hexane or heptane) whereas Form Mis prepared by grinding with polar sohents (eg, acetonitrile or dichloromethane). The POLAG approach employed polymers of varying BG chains and it was observed that by increasing the non polar EG units with respect to terminal polar -OHt ups lead to increased formation of Form 1" The observ tions both from LAG and POLAG were rationalized earlier based on the presence of a non-polar stip plane (200) in Form 1 (and absence of such in Form I) which interacts favorably ‘with non-polar liquids: In our study of this system with LL-AG, we wanted to deter- rine (i) if itis possible to employ hydrophobie and non- polar ILs to stabilize the non-polar slip plane (200) leading to caxclusive observation of Form 1, and (i) what happens when the alkyl chain lengths are systematically varied on an imidazolium cation? We thus, first investigated the series of Ms [Cymim[NTE] (n = 2, 4, 8, 12). The experimental proce- dures used were the same as deseribed above for our studies of CAF-CA. ‘We monitored the CAF-GLU system again using PXRD. Form 1 cocrystals (blue band) are identified with peaks at ca. 20 = 7 and 10.5%, while Form tt (red band, Fig. 3) ean be monitored by peaks at ea. 241 = 8° and 15°. The presence of peaks at ea. 20/= 12° indicates the presence of unreacted CAF (grey band). Employing catalytic amount of all these hydro- phobie ths lead to Form 1, however, inereasing the alkyl chai length on the imidazolium cation leads to a decrease in the rate of coenstal formation during mechanochemical grind- ing. Although, itis dificult to quantify the exact extent of cocnstallization in these studies, the amount of unreacted ‘CAF inereased with increasing alkyl ehain length as ean be seen in Fig 2 Next, three additional ths with varying polarity ouCamim]pstf,), [Comim[oe,), and [OHCymim|Bry] were studied. AS mentioned above, the grinding experiment with hydrophobic [CymimJINT] resulted in che exclusive forma- tion of Form I with taces of CAF present in the mixture Sim: ilar outcomes were also observed with the employment of ouC:mimJPNTf;] and [Cymiml[or, as grinding liquid. How- ever, while ground with [OHCymim|INTEy, the absence of rep: resentative peaks of CAF probably indicated better conversion to the coorystals. When the grinding IL was changed from (OHC:mimJNTH,] to [OHCamimifBRA, the cocrystals formed ‘were predominantly Form Il with traces of Form I present. As the polymorphic preference changes from Form I to Form Mt with the change of anions and overall hydrophobic-hydro: This journals © The Royal Socety of Chemis 2018, ‘Communication Relative intensity (2.1) 5 0 18 2007, CuK Fig. 2 Simulated pattern of CAFGLU Form 1 (monoctinic) (a Simulated pattem of CAF-GLU Form ll (vctnic) (b, the ground Powder of CAF-GLU as obtained from [CzmimlNTs} (e). (Cami) INTE (4, (CgmielINTE fe}, (CrailINTE) (9, CAF (G) and GLU 1h) Used in the grinding experiments philic nature of the IL, these results indicate towards the role ‘of anions in the cocrystal formation (Fig 3). ‘The observations in CAF-GLU system illustrate a vital point that the changes in erystallization outcome could often be accomplished by modifying only one fon, while keeping the other ion the same. As the hydrophobicity is controlled ‘mainly by the anions in the given set of Its, the modification ‘of the cation with respect to differing ally chain lengths con- tributed in the different rate of formation of Form 1 CAF GLU cocrystals whereas a change in the nature of the anions (c.g, while going from [OHC,mim]NTH) to [OHC3mim] 2.) lead to the change in the overall polymorphic outcome. This type of subtle adjustment of the overall environment of the Ils by modifying only one component offers fine tuning of the crystallization outcome. “To investigate the generality ofthese observations further, we tried to investigate the previously published crystal struc ture of CAR-CA" in detail using the coordinates taken from Rela tensity (a8) 5 ry 200, 60K Fig. 5 Simulated pattern of CAFGLU Form | (monoclinic) (a simulated pattem of CAF-GLU Form Il (trctnic) (B, the ground Powder of CAF-GLU as obtained trom ICzimlINTT] (2 (CmimlBFa) (@), [OH CamimlINTE) (@) [OH CzmimilBFa (9, experimental powder pattern of GLU (a) and CAF (h} used inthe grinding experiments Ccysttngcomm 2018 20, 817-3821 | 3819ed on 20 June 2018. Downloaded on 4/12/2024 9:56:07 AM. rnsed under a Creative Commoas Atribution-NonCommercal 3.0 Unported Licence, Communication the CSD.” Form I of CAF-CA shares a striking similarity in primary and secondary synthon patterns (Fig. 4) with CAR-GLU Form I and a non-polar slip plane along (200) is present in the stricture of CAF-CA as shown in Fig. 4 ‘Therefore, succesful isolation of Form 1 CAP-CA.cocrystal with the employment of the relatively hydrophobic Its may share the same origin as the formation of Form I of CAF- GLU. Although ILs differ from either organi solvents or the G based polymer derivatives in terms of interactions, the simitarty of the observations in both the cases in the importance of relatively non-polar and hydrophobic Is in stabilizing the (200) sip plane and may be indicative of the importance of IL microenvironment to affect the nucle ation and growth stages, hence in determining. the polymor phic outcome. In summary, we have employed ILs ina mechanochemical srinding approach to sce how the nature of ILs affect the cnytalization outcome. For the fist system, CAP-CA, the im- portance of IL as grinding liquid was illustrated whereas for the second system, CAR-GLU, the polymorphic outcome of the cocrsta systems were investigated systematically with re spect to IL structural variables such asthe all chain lengths on imidazolium cations and by changing the anions and hydrogen bonding abiliy ofthe IL components. At the end, polymorphic preferences of CAP-GLU and CAF-CA systems tay be controled by the interactions of the respective ILs ‘with the slip planes resent in these ystems. onic liquidassisted grinding represents @_ promising approach in mechanochemisty. AS many properties of ILs can be tuned systematically, either by individual tuning of the individual ionie components or in a dual manner, this approach provides a beter platform with wider tuning range a5 compared to either the organic solvents or the polymer 1m this work, we have shown that changing ether of the com- ponents in a systematic way contribute to different aspects of Iechanochemical synthesis. A slight modifieation of the allyl part on the imidazolium cation mainly contributes towards subtle control of rate of coenstal formation while change in the aveall hydrophobiciy-hydrophilicty by chang: Fig. 4 Synthon patterns and packing dagram of CAF-CA and CAF- GLU (Form 1) to to bottom). Note the simlarity between primary and secondary synton structures in all three structures. Also note thatthe slip planes exist along (200) in CAF-CA and CAF-GLU (Form 3820 | CostngConn, 2018 20, 3617-3821 CCrystEngComm ing the anions of the hydroxylated ILs contributed to a dras- tic change in the overall polymorphic outcome. ‘This aspect of ILAG may allow rational coerystal design in future, as well, as provide access to some otherwise inaccessible cocrystal polymorphs. This approach adds to the diversity in liquid assisted grinding techniques and provides more variables in terms of systematic tuning of the properties of grinding liquid. Hence, it carries importance to various fields includ- ing crystal engineering, Its, and mechanochemisty. ‘We thank Novartis for their financial support. Conflicts of interest There are no conflicts to dectare. Notes and references 1 S.Aitipamula, e al, Cryst. Growth Des., 2012, 12, 2147-2152. 2A. Myerson, Handbook of industrial cryseallization, ‘Butterworth-Heinemann, 2002, 3 G.R.Desiraju, Angew: Chem, Int. Bi, 2007, 46, 8342-8356, 4A. 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