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The ΔpKa rule is commonly applied by chemists and crystal engineers as a guideline for the rational design of molecular salts and co-crystals. For multi-component crystals containing acid and base constituents, empirical evidence has shown that ΔpKa > 4 almost always leads to salts, ΔpKa < −1 almost always leads to co-crystals and ΔpKa between −1 and 4 can be either. This paper reviews the theoretical background of the ΔpKa rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base. New data on the frequency of the occurrence of co-crystals and salts in multi-component crystal structures containing acid and base constituents show that the relationship between ΔpKa and the frequency of salt/co-crystal formation is influenced by the composition of the crystal. For unsolvated co-crystals/salts, containing only the principal acid and base components, the point of 50% probability for salt/co-crystal formation occurs at ΔpKa ≈ 1.4, while for hydrates of co-crystals and salts, this point is shifted to ΔpKa ≈ −0.5. For acid–base crystals with the possibility for two proton transfers, the overall frequency of occurrence of any salt (monovalent or divalent) versus a co-crystal is comparable to that of the whole data set, but the point of 50% probability for observing a monovalent salt vs. a divalent salt lies at ΔpKa,II ≈ −4.5. Hence, where two proton transfers are possible, the balance is between co-crystals and divalent salts, with monovalent salts being far less common. Finally, the overall role played by the “crystal” solvation is illustrated by the fact that acid–base complexes in the intermediate region of ΔpKa tip towards salt formation if ancillary hydrogen bonds can exist. Thus, the solvation strength of the lattice plays a key role in the stabilisation of the ions.

Approximately 80% of active pharmaceutical ingredients (APIs) studied as lead candidates in drug development exhibit low aqueous solubility, which typically results in such APIs being poorly absorbed and exhibiting low bioavailability. Salts of ionizable APIs and, more recently, pharmaceutical cocrystals can address low solubility and other relevant physicochemical proper?ties. Pharmaceutical cocrystals are amenable to design through crystal engineering because supramolecular synthons, especially those sustained by hydrogen bonds, can be anticipated through computational modeling or Cambridge Structural Database (CSD) mining. In this contribution, we report a combined experimental and CSD study on a class of cocrystals that, although present in approved drug substances, remains understudied from a crystal engineering perspective: ionic cocrystals composed of dihydrogen phosphate (DHP) salts and phosphoric acid (PA). Ten novel DHP:PA ionic cocrystals were prepared from nine organic bases (4,4′-bipyridine, 5-aminoquinoline, 4,4′-azopyridine, 1,4-diazabicyclo[2.2.2]octane, piperazine, 1,2-bis(4-pyridyl)ethane, 1,2-bis(4-pyridyl)xylene, 1,2-di(4-pyridyl)-1,2-ethanediol, and isoquinoline-5-carboxylic acid) and one anticonvulsant API, lamotrigine. From the resulting crystal structures and a CSD search of previously reported DHP:PA ionic cocrystals, 46 distinct hydrogen bonding motifs (HBMs) have been identified between DHP anions, PA molecules, and, in some cases, water molecules. Our results indicate that although DHP:PA ionic cocrystals are a challenge from a crystal engineering perspective, they are formed reliably and, given that phosphoric acid is a pharmaceutically acceptable coformer, this makes them relevant to pharmaceutical science.

We report the anion-recognition properties and anion-mediated templation of Metal-Organic knots and links in aqueous solutions., Two synthetic approaches—temperature variation and anion templation—allowed for the selective formation of a [2]catenane ([2]C4+) or a trefoil knot (TK6+), or for the enhanced formation of a Solomon link (SL8+), all from a simple set of starting materials (Zn(ii) acetate, diformylpyridine (DFP) and a diamino-2,2′-bipyridine (DAB)) in mixed aqueous solutions. The catenane formed exclusively at 90 °C in a 1 : 1 mixed solvent of D2O and MeOD. In the presence of bromide ion as template, TK6+ formed exclusively at 50 °C in the same solvent. In the solid state, TK6+ hosts two bromide ions in its central cavity by forming six Csp2–H hydrogen bonds. In D2O, TK6+, which was originally prepared as a trifluoroacetate (TFA) salt, was found to exchange two TFA counterions for two monovalent anions of different sizes and shapes, which lodged within the knot's central cavity. In contrast to bromide, the larger triflate anion (CF3SO3 –) promoted the formation of SL8+, which was characterized by 1H NMR spectroscopy and mass spectrometry. Two dimensional heteronuclear 19F-1H-HOSEY NMR experiments detected CH···F interactions inside the cavity of SL8+. Thus, the product distribution of this dynamic link forming system is sensitive to temperature and the size and shape of the anion template, and one of the products, TK6+, is capable of binding a variety of monovalent anions in D2O with high affinity (with log β 2 values of 4 to 6 being typical).

Sequestration of CO2, either from gas mixtures or directly from air (direct air capture), is a technological goal important to large-scale industrial processes such as gas purification and the mitigation of carbon emissions. Previously, we investigated five porous materials, three porous metal-organic materials (MOMs), a benchmark inorganic material, Zeolite 13X and a chemisorbent, TEPA-SBA-15, for their ability to adsorb CO2 directly from air and from simulated flue gas. In this contribution, a further 10 physisorbent materials that exhibit strong interactions with CO2 have been evaluated by temperature-programmed desorption for their potential utility in carbon capture applications: four hybrid ultramicroporous materials, SIFSIX-3-Cu, DICRO-3-Ni-i, SIFSIX-2-Cu-i and MOOFOUR-1-Ni; five microporous MOMs, DMOF-1, ZIF-8, MIL-101, UiO-66 and UiO-66-NH2; an ultramicroporous MOM, Ni-4-PyC. The performance of these MOMs was found to be negatively impacted by moisture. Overall, we demonstrate that the incorporation of strong electrostatics from inorganic moieties combined with ultramicropores offers improved CO2 capture performance from even moist gas mixtures but not enough to compete with chemisorbents.

Sequestration of CO2, either from gas mixtures or directly from air (direct air capture), is a technological goal important to large-scale industrial processes such as gas purification and the mitigation of carbon emissions. Previously, we investigated five porous materials, three porous metal-organic materials (MOMs), a benchmark inorganic material, Zeolite 13X and a chemisorbent, TEPA-SBA-15, for their ability to adsorb CO2 directly from air and from simulated flue gas. In this contribution, a further 10 physisorbent materials that exhibit strong interactions with CO2 have been evaluated by temperature-programmed desorption for their potential utility in carbon capture applications: four hybrid ultramicroporous materials, SIFSIX-3-Cu, DICRO-3-Ni-i, SIFSIX-2-Cu-i and MOOFOUR-1-Ni; five microporous MOMs, DMOF-1, ZIF-8, MIL-101, UiO-66 and UiO-66-NH2; an ultramicroporous MOM, Ni-4-PyC. The performance of these MOMs was found to be negatively impacted by moisture. Overall, we demonstrate that the incorporation of strong electrostatics from inorganic moieties combined with ultramicropores offers improved CO2 capture performance from even moist gas mixtures but not enough to compete with chemisorbents.

peer-reviewed Solid solutions enable the fine tuning of crystalline materials’ properties by adjusting the composition of their components. They can be applied to several classes of materials with a wide range of applications but are difficult to prepare. A general guidelines for the preparation of solid solutions were summarised by Hume-Rothery (1926) and Kitaigorodsky (1973, 1984). As the use of solid solution in the pharmaceutical field is still understudied, the present work describes several research themes which consist in the formation of novel solid solutions of APIs. They are lithium in salts and in coordination polymers, organic compound (steroids), and metal complexes. One of the aims of the present work is to verify the aforementioned guidelines of solid solution formations. From this perspective, they are chosen compounds that present challenges in their structure to be made as solid solution, according to the conventional rules. From the pharmaceutical aspect, solid solutions can aid in the preparation of pharmaceutical materials with desirable properties, by varying the ratios of components in continuum or at least to a certain extent. The successful syntheses of Li/Na mixed salts, Li coordination polymers, and steroid solid solutions demonstrate that solid solutions can form amongst non-isostructural molecules and pseudo-isomorphous pairs. It is also observed that the existence of more stable forms may hinder solid solution formation despite the isomorphous nature of the parent structures.

Vinpocetine is a poorly water soluble weakly basic drug (pKa = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test). Pharmacokinetic performance was also tested in a human pilot study. This pharmaceutical ionic cocrystal exhibits superior solubilization kinetics and modulates important pharmacokinetic values such as maximum concentration in plasma (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve (AUC) of the poorly soluble vinpocetine and it therefore offers an innovative approach to improve its bioavailability.