How Many Parameters Can Affect the Solid Form of Cocrystallization

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How Many Parameters Can Affect the Solid Form of Cocrystallization Products in Mechanochemical Reactions? A Case Study Yue Yuan, Lin Wang, Duanxiu Li, Zongwu Deng, and Hailu Zhang Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 16 Nov 2018 Downloaded from http://pubs.acs.org on November 16, 2018

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Crystal Growth & Design

Cover Page How Many Parameters Can Affect the Solid Form of Cocrystallization Products in Mechanochemical Reactions? A Case Study Yue Yuan,†,‡ Lin Wang,† Duanxiu Li,† Zongwu Deng,† and Hailu Zhang*,† †

Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech

and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China. ‡

School of Pharmacy, Xi'an Jiaotong University, Xi’an 710061, P.R. China.

Abstract: Polymorphism of cocrystals is a fascinating research topic in the field of crystal engineering. For the often employed mechanochemical synthesis approach, the solvent polarity and the stoichiometric ratio of starting materials were previously confirmed as significant variables controlling over the polymorphic outcomes. In this study, the 1:1 (THP-AH11) and 1:2

(THP-AH12)

theophylline-acesulfame

cocrystals

were

obtained

by

using

mechanochemical method with different synthesis parameters. It was found that the solid form of the mechanochemical product can also be altered by grinding energy and forms of starting materials. All these effect factors are understandable from the point of view of energy mechanism, which modified either the energy barrier or the reaction pathway.

*

Corresponding Author

E-mail: [email protected]; Tel: +86-512-62872713; Fax: +86-512-62603079.

ACS Paragon Plus Environment

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How Many Parameters Can Affect the Solid Form of Cocrystallization Products in Mechanochemical Reactions? A Case Study Yue Yuan,†,‡ Lin Wang,† Duanxiu Li,† Zongwu Deng,† and Hailu Zhang*,† †

Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech

and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China. ‡

School of Pharmacy, Xi'an Jiaotong University, Xi’an 710061, P.R. China.

AUTHOR INFORMATION Corresponding Author *E-mail:

[email protected]; Tel: +86-512-62872713; Fax: +86-512-62603079.


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ABSTRACT

Polymorphism of cocrystals is a fascinating research topic in the field of crystal engineering. For the often employed mechanochemical synthesis approach, the solvent polarity and the stoichiometric ratio of starting materials were previously confirmed as significant variables controlling over the polymorphic outcomes. In this study, the 1:1 (THP-AH11) and 1:2 (THPAH12) theophylline-acesulfame cocrystals were obtained by using mechanochemical method with different synthesis parameters. It was found that the solid form of the mechanochemical product can also be altered by grinding energy and forms of starting materials. All these effect factors are understandable from the point of view of energy mechanism, which modified either the energy barrier or the reaction pathway.


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Cocrystals are “solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts”.1 Currently, cocrystal form has become an integral part of the solid form landscape of an active pharmaceutical ingredient (API) for its potential to significantly enhance the physicochemical properties of the pure drug compound.2-4 Similar to monocomponent crystals, cocrystals can also exist in different solid forms and different cocrystal forms may demonstrate diverse physicochemical properties.5-6 In fact, polymorphism of cocrystals is more fascinating than that of single component crystals. For the same pair of API and cocrystal former (coformer), cocrystallization experiments may output cocrystal polymorphs with same stoichiometric ratio, cocrystal forms with stoichiometric variations,7-8 and even crystalline complexes with different ionization states9-10. All these works remind that polymorphism studies should be considered during the cocrystal screening stage.6 Mechanochemical techniques, such as neat grinding and liquid-assisted grinding (LAG), have been widely used as high-efficiency protocols for pharmaceutical cocrystal screening and preparation.11-13 Mechanochemical cocrystallization reactions can be carried out in a ball mill or manually with a mortar and pestle. The latter setup requirement allows the mechanochemical cocrystallization being available in any pharmaceutical crystallography laboratory. For an API and a coformer, using different grinding conditions may produce different cocrystal forms. The polarity of the solvent used in LAG experiments is regarded as a significant variable controlling over the polymorphic outcome.8,14-17 In most cases, each solvent is selective for a specific cocrystal form. Recently, Jones and Halasz noticed that modification of the amount of added liquid may also lead to different cocrystal polymorphs.18-19 For cocrystal forms


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with stoichiometric variations, the stoichiometric ratio of starting materials shows pronounced effect on the final product.7,8 Additionally, some cocrystal polymorphs exist as intermediates in mechanochemical reactions. Thus, using in-situ or ex-situ monitoring protocols may direct the discovery and isolation of these forms.7,8,16,20,21 Inspired by these pioneered reports, one question we want to know is whether there are other factors can affect the polymorphic outcome in a mechanochemical cocrystallization reaction. The model cocrystal system used in this contribution is theophylline-acesulfame (THP-AH). There are two cocrystal forms of THP-AH. The 1:2 pharmaceutical cocrystal of THP-AH (THP-AH12) was reported by our group via LAG method manually prepared in a mortar.22 The crystal structure of THP-AH12 was solved via powder XRD refinement. In each asymmetric unit, one THP (Scheme 1a) molecule interacts with one enol form AH (Scheme 1b) via O—H···N, and interacts with one keto form AH (Scheme 1c) via an (9) hetero-synthon (Fig. 1a), respectively.22 This is the first report of the existence of keto form AH in the crystalline complexes. To confirm the structure, solvent crystallization method was employed to prepare a single crystal sample using different ratios of starting materials and different solvents. In this process, an unanticipated single crystal sample of 1:1 THP-AH cocrystal (THP-AH11, CCDC No.: 1028553) was accidentally picked out from the evaporated products (mixture of THP-AH11 and THP form II23) of 1:1 toluene solution. THP-AH11 crystallizes in the triclinic P space group with two asymmetric units in a unit cell, and each asymmetric unit (Fig. 1b) contains two THP molecules and two AH molecules (Z = 4, Z’ = 2). Unlike the structure of THPAH12, in which keto and enol form AH molecules coexist, THP-AH11 contains the simplex enol form of AH. THP and AH are connected via O—H···N bonds, and dimeric


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supramolecular interactions (

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(10) synthon) are formed between two non-equivalent

THP molecules. O H3C

O

O

N

N N

N H

O H3C

S

O

O

NH

O O

S

O N

H3C

OH

CH3

(a) THP

(b) AH keto

(c) AH enol

Scheme 1 Chemical structures of THP (a), AH in keto form (b), and AH in enol form (c).

Figure 1 The asymmetric units of THP-AH12 (a) and THP-AH11 (b). Seven solvents with different polarities were used in LAG experiments in our previous study. THP form II and AH form I24 were employed as the starting materials for these solid forms are relatively easy to obtain. Their structural information can be found in Ref. 23 and 24, respectively. THP-AH12 can be consistently formed regardless of the solvent used.22 In fact, THP-AH12 can also be built by neat grinding manually (Fig. S1). With the discovery of THP-AH11, we want to know whether this form can also be prepared via mechanochemical approach. The stoichiometric ratio of THP (form II) and AH (Form I) was first adjusted to 1:1. Again, THP-AH12 was consistently produced


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(with the excess THP) in the mortar by either neat grinding or LAG (line 3, Table 1). Typical XRD pattern of the product (THP-AH12+THP form II) is shown in Fig. S2.


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Table 1. Grinding products of THP (form II or IV) and AH (form I) using 1:1 stoichiometric ratio.* water

ethanol

acetonitrile ethyl acetate DCM manually with a mortar and pestle ▼II ∆+▼H ∆+▼II ∆+▼II ∆+▼II ∆+▼II ▼IV ∆+▼H ∆+▼IV ∆+▼IV ∆+▼IV ∆+▼IV using a ball mill** ▼II O O O O O ▼IV O O O O O Symbols: ▼II: THP form II; ▼IV: THP form IV; ▼H: THP monohydrate; ∆: THP-AH12; O: THP-AH11. *: volume of solvent/sample weight = 0.15 μL/mg; **: frequency = 40 Hz, reaction time = 20 min. DCM: dichloromethane.

n-hexane

neat grinding

∆+▼II ∆+▼IV

∆+▼II ∆+▼IV

O ∆+▼IV

∆+▼II ∆+▼IV


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The amazing thing is that THP-AH11 can be obtained in all LAG experiments once a ball mill is employed (line 6, Table 1). The typical powder XRD pattern of THP-AH11 is provided in Fig. 2. Compared with grinding by hand, ball mill can provide much higher stress energy for the reactants. It’s previously confirmed that the higher stress energy can accelerate the product conversion.25,26 In this contribution, its influence on the solid form of the product was observed. It’s hypothesized that the formation of THP-AH11 needs to step over a much higher activation energy barrier than that of THP-AH12 during the solid-state cocrystallization. Also, the presence of solvents is helpful for getting over the energy barrier (line 6, Table 1). Manual grinding is one commonly used method for cocrystal screening and preparation. It is generally regarded as a mild synthesis method. While, it’s not easy to control or describe the relative mechanochemical energy. To confirm our speculation, cogrinding THP (form II) and AH (form I) in a ball mill at lower grinding frequency (30 Hz) was performed with the assistance of polar solvent (water or ethanol). THP-AH12 was synthesized rather than THP-AH11. The results are repeatable and further confirm the importance of the grinding energy.


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(d)

(c)

(b)

(a) 5

10

15

20

25

30

35

40

2Theta (degree)

Figure 2. Powder XRD patterns of THP-AH11 (a) and THP-AH12 (c). Simulated patterns of these two forms are also provided (b and d). Some experiments were conducted to realize the solid state transition of THP-AH11 and THP-AH12 (Scheme 2). Co-grinding (in mortar or ball mill, 1:1 ratio) THP-AH12 and THP (form II) with the assistance of ethanol cannot produce THP-AH11 (line 1, Scheme 2). According to this result, we may suppose THP-AH12 should not be an intermediate for the THP-AH11 formation. While the ex-situ observation for the ethanolassisted grinding of THP II and AH I (1:1 ratio) in the ball mill demonstrated that THPAH12 can be detected in the process and finally converted to THP-AH11 (Fig. S3). It’s not surprised by the presence of THP-AH12 due to the lower energy barrier. The conversion of THP-AH12 to THP-AH11 then must depend on the presence of THP-AH11 as crystal seed. Such seeding experiment (THP-AH12:THP II:THP-AH11 = 1:1:1) was performed in the ball mill by ethanol-assisted grinding, and pure THP-AH11 was obtained (line 2 of Scheme 2, Fig. S4).


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Scheme 2. Solid state transition of THP-AH11 and THP-AH12. (∆: THP-AH12; O: THPAH11; ▼II: THP form II; ▲I: AH form I.) Pure THP-AH12 can be achieved (line 3 of Scheme 2) via the ethanol-assisted grinding (in mortar or ball mill, 1:1 ratio) of THP-AH11 and AH (form I), indicating THP-AH12 should locate at the lower energy level than the physical mixture of THPAH11 and AH (form I). We must point out that the formation of THP-AH12 from 1:2 THP (form II) and AH (form I) does not need THP-AH11 as an intermediate for the lower energy barrier and the stoichiometric ratio (1:2) can confirm the direct conversion (Fig. S5). It’s very clear that the selective formation of THP-AH11 or THP-AH12 in grinding experiment is an energy-related process. Since polymorphs of the same compound often hold different thermodynamics stability, we wonder whether using different crystalline forms of starting materials will lead to different outcomes. Form II is the crystal phase of commercial THP, which was used in all above experiments. Form IV, the most thermodynamically stable anhydrous polymorph of THP, can be easily prepared in the laboratory.27 When THP form IV was used in mechanochemical reactions with AH form I (line 4&7, Table 1), one different experimental result was observed. THP-AH12, rather than THP-AH11, was formed in the n-hexane-assisted ball grinding reaction. Such


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phenomenon is understandable for higher polarity solvents are required to overcome the increased activation energy barrier for the formation of THP-AH11. AH can also exist in different anhydrous forms, form I and form II.24 Bulk sample of AH form II was successfully prepared via a melting-grinding procedure (Fig. S6). Since form II, relative to form I, is metastable, THP-AH11 should be more easily formed in LAG reactions when AH form II is used as starting reagent. However, the co-grinding product of 1:1 THP form II and AH form II after ethanol-assisted grinding in the ball mill is a mixture of THP-AH12 and THP form II. This illogical result is finally explained by the ex-situ observation (Fig. S7). It was found that AH form II and THP form II are more prone to transform into amorphous state as intermediates in this reaction, which consumes too much energy to leap over the high energy barrier towards THP-AH11. In summary, one novel 1:1 THP-AH cocrystal, THP-AH11, was obtained, and its crystal structure was solved. Both this form and previously reported THP-AH12 cocrystal can be successfully prepared via mechanochemical synthesis. The formation of THPAH11 needs more stress energy than that of THP-AH12 to get over the activation energy barrier. Thus, using different grinding methods may produce different THP-AH forms. It’s previously mentioned that polarity of the solvent, stoichiometry of starting materials, grinding time, and using seed crystal may have pronounced effect on the final solid form, which was validated again in this contribution. Additionally, different solid forms of starting materials can also modify the mechanochemical outcomes. Mechanochemical synthesis is a very efficient method for cocrystal screening and preparation. While for cocrystals with polymorphism and stoichiometric variations, many factors should be


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considered to obtain different forms as much as possible. Thus, one new question is how to learn whether an API and a coformer can form different cocrystals. Though several factors have been noticed, the above posed question is still asked. Whether there are other factors (e.g., ambient temperature, other additive) can affect the polymorphic outcomes in a mechanochemical cocrystallization reaction? ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/xxxxxxx. Experimental details and powder XRD patterns. (PDF) Accession Codes CCDC 1028553 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. AUTHOR INFORMATION Corresponding Author *Email:

[email protected]

ORCID Hailu Zhang: 0000-0001-6936-9197 Notes The authors declare no competing financial interests.


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ACKNOWLEDGMENT We are grateful for financial support from the National Natural Science Foundation of China (No. 21874148, 21673279), the Youth Innovation Promotion Association of CAS (No. 2012242), and the China Postdoctoral Science Foundation and the CAS jointly funded outstanding postdoctoral project (No. 2017LH045). REFERENCES (1) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. Q. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Thaper, R. K.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Polymorphs, Salts, and Cocrystals: What’s in a Name? Cryst. Growth Des., 2012, 12, 2147-2152. (2) Duggirala, N. K.; Perry, M. L.; Almarsson, Ö.; Zaworotko, M. J. Pharmaceutical Cocrystals: Along the Path to Improved Medicines. Chem. Commun., 2016, 52, 640-655. (3) Cherukuvada, S.; Kaur, R.; Row, T. N. G. Co-crystallization and Small Molecule Crystal Form Diversity: From Pharmaceutical to Materials Applications. CrystEngComm, 2016, 18, 8528-8555. (4) Panzade, P. S.; Shendarkar, G. R. Pharmaceutical Cocrystal: An Antique and Multifaceted Approach. Curr. Drug Deliv., 2017, 14, 1097-1105.


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For Table of Contents Use Only How Many Parameters Can Affect the Solid Form of Cocrystallization Products in Mechanochemical Reactions? A Case Study Yue Yuan, Lin Wang, Duanxiu Li, Zongwu Deng, and Hailu Zhang

For mechanochemical cocrystallization, the solid form of product may be alerted by grinding energy, forms of starting materials, as well as other synthesis factors.


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How Many Parameters Can Affect the Solid Form of Cocrystallization

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