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.

Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A (RKB-3564D) are described. In the first-generation synthesis, the HfCl(4)-mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone, by using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale preparation. A biomimetic cascade reaction involving oxidation, 6pi-electrocyclization, and then Diels-Alder dimerization is the key reaction in the formation of the complex heptacyclic structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction composed of oxidation, 6pi-electrocyclization, and formal [4 + 4] cycloaddition reactions. A 2H-pyran, generated by oxidation/6pi-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. An azapentacyclic compound is synthesized by a similar cascade reaction composed of the four successive steps: oxidation, imine formation, 6pi-azaelectrocyclization, and Diels-Alder dimerization.

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