Crystengcomm Accepted Manuscript

Crystengcomm Accepted Manuscript

CrystEngComm Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/crystengcomm Page 1 of 12 PleaseCrystEngComm do not adjust margins CrystEngComm ARTICLE Isoniazid cocrystallisation with dicarboxylic acids: vapochemical, mechanochemical and thermal methods Received 00th January 20xx, a† a a Accepted 00th January 20xx I. Sarceviča, A. Kons and L. Orola DOI: 10.1039/x0xx00000x Cocrystallisation with a series of related compounds allows for the exploration of trends and limitations set by structural differences between these compounds. In this work, we investigate how the length of a dicarboxylic acid influences the www.rsc.org/ outcome of cocrystallisation with isoniazid. We have performed a systematic study on the mechanochemical, thermal and solvent vapour-assisted cocrystallisation of aliphatic dicarboxylic acids (C 3–C10 ) with isoniazid. Our results demonstrate that the rate of mechanochemical and vapour-assisted cocrystallisation depends on acid chain length and shows alternation between odd- and even- chain acids. The results of thermal cocrystallisation showed that eutectic melting temperatures of isoniazid–dicarboxylic acid mixtures follow the same trend as do the melting points of dicarboxylic acids. 13,22 formation of a cocrystal . The thermal method is a fast Manuscript Introduction method compared to crystallisation from solution. Alongside mechanochemistry, thermal cocrystallisation also usually gives As a way to improve the characteristics of materials, cocrystal 11,14 1–4 good results in cocrystal screening and can be efficiently form has recently became of a large interest . The possibility used to identify systems that can form cocrystals. to tune the properties of compounds via cocrystallisation has 23 2,3,5 Spontaneous cocrystallisation is also possible and is usually been shown and has been used to develop new materials 24,25 6,7 8 facilitated by moisture . Although the promotional effect of for non-linear optics , semiconductors and pharmaceutical 24,25 26,27 1–3 the vapour of water or organic solvent on applications . Various methods based on crystallisation from solution 9–12 or from melt (thermal cocrystallisation) 11,13,14 , cocrystallisation is known and has been investigated by several 15–18 groups, little practical advantage of this knowledge has been mechanical treatment etc. are used for cocrystal Accepted preparation. From these, the mechanochemical gained until now. Perhaps the lack of appreciation for solvent cocrystallisation is typically recognised to give the best vapour-assisted cocrystallisation as a cocrystal screening results 11 , moreover, liquid-assisted grinding is more efficient method stems from the difficulty in predicting whether it will compared to neat grinding (no solvent used). In screening be useful in the system of interest. Consequently, this method experiments that employ and compare different mostly has been neglected in systematic screenings and only cocrystallisation methods, solvent–drop grinding has been individual cases of vapour-assisted cocrystallisation have been shown to produce the largest number of cocrystals 11 . In reported. Our results, however, imply that vapochemistry addition, mechanochemistry allows inter-conversion between could be beneficial for cocrystallisation of small molecules. In cocrystals 19 of different stoichiometry and polymorphism order to evaluate the usability of the vapochemical approach control 20,21 . Further benefits of the mechanochemical method in each system, it is important to understand the limitations include minimal use of solvent, high yields and easiness to set by the molecular parameters of cocrystal ingredients and perform 17 . by solvent properties. One of the possible limitations could be The thermal cocrystallisation method is based on the size of molecules, as the movement of large molecules understanding that cocrystals can form from the eutectic melt. would be hampered. The presence of thermal effects (in the thermal analysis data) There are several explanations available for the promotional effect of water vapour on cocrystal formation. In some cases, corresponding to eutectic melting and crystallisation implies CrystEngComm the adsorbed water has been shown to partially dissolve cocrystal ingredients, allowing cocrystallisation from a saturated solution 24,25 . In other examples water serves as a plasticizer and therefore promotes cocrystallisation 28 . Various solvents are expected to influence cocrystallisation differently in accordance with their properties. Therefore, solvent vapour- assisted cocrystallisation is also expected to offer polymorph control, similar to crystallization from different solvents 29 . This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins PleaseCrystEngComm do not adjust margins Page 2 of 12 ARTICLE Journal Name A commonly used set of cocrystal formers is the series of stoichiometry, although malonic acid is an odd-chain aliphatic dicarboxylic acids 30–33 . The choice of these dicarboxylic acid. In our mechanochemical, thermochemical dicarboxylic acids as cocrystal formers is advantageous in and vapochemical cocrystallisation experiments, we used many aspects. They easily form cocrystals with hydrogen these known stoichiometries. acceptor compounds; their crystal structures 34 and physicochemical properties 35–39 are described in the literature. Mechanochemical cocrystallisation In addition, dicarboxylic acids offer a set of related compounds To investigate the effect of molecule size on the rate of with similar molecular structures, and therefore render the mechanochemical cocrystal formation, milling experiments interpretation of results easier. Most physicochemical were performed for isoniazid and dicarboxylic acid (C 3−C10 ) properties of dicarboxylic acids follow an interesting trend of mixtures. The conversion (relative amount of cocrystal in a alternation between odd- and even-chain acids. For example, sample) was acquired by Rietveld analysis of the diffraction the solubility 35,36 and saturated vapour pressure 37,38,40 of odd- patterns of milling products. Inspection of PXRD patterns of chain acids are higher than for even-chain acids. The melting milling products showed that they contain cocrystal phases points 34 and vaporisation enthalpies 40 of odd-chain acids are with the known crystal structures 41 of isoniazid–dicarboxylic lower, compared with those of even-chain acids. These trends acid cocrystals, and these structures were used in Rietveld are commonly explained by the twisted conformations of odd- refinement. It should be noted that some peak broadening and chain acids in their crystal structures 34,37 , leading to lower minor background changes were observed in the powder X-ray stability of these structures compared with crystal structures diffraction (PXRD) patterns of milling products, implying a of even-chain acids. Interestingly, the cocrystals of dicarboxylic possible presence of amorphous phase. Results of the acids also often show the odd-even alternation effect in their quantitative analysis should therefore not be seen as absolute physicochemical properties 30–33 . values, but rather as an indication of the extent of Here we report a series of experiments that demonstrate the cocrystallisation (the amount of the cocrystal relative to the Manuscript vapour-assisted, thermal and mechanochemical amounts of crystalline isoniazid and acid). Examples of PXRD cocrystallisation of an anti-tubercular drug isoniazid with patterns of milling products are available in Figures S1–S8 in aliphatic dicarboxylic acids (C 3–C10 ) as cocrystal formers ESI. (Scheme 1). Isoniazid was chosen as a model compound for Figure 1 presents cocrystallisation results for isoniazid and our experiments as it is known to form cocrystals with all C 3–C8 dicarboxylic acid milling experiments performed for 5 and 15 dicarboxylic acids 41,42 and many other acidic compounds 41,43–53 . minutes under the same conditions. A comparison of the Organometallic complexes 54–58 and salts 59,60 with inorganic results shows that longer mechanical treatment returned a anions of isoniazid are also known. Our experiments reveal higher amount of cocrystal. In the case of isoniazid–glutaric how the length of the acid and its physicochemical properties acid sample, however, the conversion difference was small due determine trends in cocrystal formation with isoniazid. to partial amorphisation and formation of an unidentified Accepted phase. Cocrystallisation of isoniazid and malonic

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