These experimental observations demonstrated how the thermal events were attributed to phase transitions occurring in a binary mixture and clarified the relationship between exothermic peaks and cocrystal formation.

Cocrystallizations of EX and MA improved initial dissolution rates compared to the respective original crystals. The mechanism of dissolution enhancement varied. With cocrystal 1, fine particle formation resulted in enhancement, whereas with cocrystal 2, enhancement was due to the maintenance of the cocrystal form and rapid dissolution before transformation to the original crystal.

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The purpose of the present study was to determine the thermodynamic stability orders of co-crystals by co-crystal former (CCF) exchange reactions. Caffeine (CA) was employed as a model drug. The CCF exchange reaction was performed by liquid-assisted grinding using ethanol. When oxalic acid (OX) was added to CA-citric acid co-crystal (CA-CI), CA-CI converted to CA-OX, suggesting that CA-OX is more stable than CA-CI. The stability orders of other co-crystals were determined in the same manner. The stability order of CA co-crystals was determined as CA-OX≈CA-p-hydroxybenzoic acid (HY)>CA-CI>CA-malonic acid>CA-maleic acid. The stability order correlated with the difference in hydrogen bond energy estimated in silico, except for CA-HY. The π-π stacking in CA-HY was suggested as a reason for this discrepancy. The CCF exchange reaction was demonstrated as a useful method to determine the stability order of co-crystals, which can be used for the validation of in silico parameters to predict co-crystal formation.Key words co-crystal; co-crystal former; exchange reaction; caffeine; hydrogen bond energy Co-crystals have recently received much attention as a means of improving physicochemical properties of active pharmaceutical ingredients.1-10) The number of potential co-crystal formers (CCFs) can reach up to several hundred; therefore, an efficient strategy for CCF screening in drug discovery and development is required. High throughput screening (HTS) technologies have been employed for CCF screening.10-15) However, CCF selection by HTS remains a time-and resource-consuming task. Therefore, an effective pre-screening method for CCF selection would be valuable for drug discovery and development. In the case of salt selection, the difference in pK a values between a drug and a counterion (ΔpK a ) has been used as a criterion for the selection of potential counter-ion candidates.16) Similarly, some in silico physicochemical parameters for CCF selection were proposed by several research groups. [17][18][19][20] For example, the difference in hydrogen bond energy between a co-crystal and each of the sole components (ΔE) was proposed by Musumeci et al., based on the hypothesis that the formation of a co-crystal becomes more probable as ΔE becomes larger.21-23) However, ΔE has not been rigorously validated due to the lack of information about the stability order of co-crystals. The stability order of co-crystals can be determined by CCF exchange reactions. In the literature, there were a few studies on the CCF exchange reactions (a sulfonamide derivative 24) and carbamazepine 25) ). However, in these studies, only a few CCFs were employed so that the data is insufficient for validating in silico models.The purpose of the present study was to determine the stability orders of co-crystals by CCF exchange reaction. Caffeine (CA) was employed as a model drug. The stability order of five CA co-crystals was determined using the CCF exchange reaction. The stability order was then compared with the ΔE estimated in silico.

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