The salt–cocrystal spectrum in salicylic acid–adenine: the influence of crystal structure on proton-transfer balance

Abstract

At one extreme of the proton-transfer spectrum in cocrystals, proton transfer is absent, whilst at the opposite extreme, in salts, the proton-transfer process is complete. However, for acid-base pairs with a small ÁpK a (pK a of base À pK a of acid), prediction of the extent of proton transfer is not possible as there is a continuum between the salt and cocrystal ends. In this context, we attempt to illustrate that in these systems, in addition to ÁpK a , the crystalline environment could change the extent of proton transfer. To this end, two compounds of salicylic acid (SaH) and adenine (Ad) have been prepared. Despite the same small ÁpK a value (%1.2), different ionization states are found. Both crystals, namely adeninium salicylate monohydrate, C 5 H 6 N 5 + ÁC 7 H 5 O 3 À ÁH 2 O, I, and adeninium salicylate-adenine-salicylic acid-water (1/2/1/2), C 5 H 6 N 5 + ÁC 7 H 5 O 3 À Á-2C 5 H 5 N 5 ÁC 7 H 6 O 3 Á2H 2 O, II, have been characterized by single-crystal X-ray diffraction, IR spectroscopy and elemental analysis (C, H and N) techniques. In addition, the intermolecular hydrogen-bonding interactions of compounds I and II have been investigated and quantified in detail on the basis of Hirshfeld surface analysis and fingerprint plots. Throughout the study, we use crystal engineering, which is based on modifications of the intermolecular interactions, thus offering a more comprehensive screening of the salt-cocrystal continuum in comparison with pure pK a analysis.

Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates

“…The fundamental question in connection to the tenofovir alafenamide fumarate derivatives' structure that remained to be answered was related to the continuum between the salt and co-crystal states. Indeed, the combination of tenofovir, which possesses an adenine heterocyclic core that contains nitrogen atoms (pK a1 = 4.2, pK a2 = 9.8) [103][104][105][106], and fumaric acid (pK a1 = 3.0, pK a2 = 4.4) [107] might result in complexes with no proton transfer, due to a small ∆pK a (pK a of base -pK a of acid) value of ca. 1.2.…”

“…Recently, we disclosed the preparation of two novel tenofovir alafenamide monofumarate forms II and III: TA MF2 and TA MF3 [102] (Figure 1). Due to the molecular structure of tenofovir alafenamide, which contains an adenine heterocyclic core with several nitrogen atoms (pKa1 = 4.2, pKa2 = 9.8) [103][104][105][106] and the acidity of fumaric acid (pKa1 Due to the molecular structure of tenofovir alafenamide, which contains an adenine heterocyclic core with several nitrogen atoms (pK a1 = 4.2, pK a2 = 9.8) [103][104][105][106] and the acidity of fumaric acid (pK a1 = 3.0, pK a2 = 4.4) [107], this acid-base pair has a small ∆pK a (pK a of base -pK a of acid) value of ca. 1.2.…”

Co-crystals, Salts, and Ionic Co-crystals of Ethanol and Ammonia

“…The equilibria for these two reactions are predicted to be at +4.46 and −0.30 GPa, respectively. These results highlight the likely importance of the stoichiometry and local chemical environment over simple rules based on p K a differences between the acidic and basic components. − …”

“…These results highlight the likely importance of the stoichiometry and the local chemical environment over simple rules based on pKa differences between the acidic and basic components. [72][73][74][75] I and others have predicted the occurrence of similar complete and partial proton transfer reactions in ammonia hydrates, [76][77][78] including the transformation of ammonia monohydrate (AMH)…”

Strategy for Efficient Discovery of Cocrystals via a Network-Based Recommendation Model

“…57 However, unpredictability remained when proton transfer occurred when the pK a values of API and cofomers are comparable. 58 Therefore, it is understandable that cocrystals or salts are likely to form among these components, 59 although the network used was established on the basis of existing cocrystals. In addition, APA-DDA crystals were suitable for single-crystal X-ray diffraction.…”