Supramolecular Synthon Promiscuity in Phosphoric Acid–Dihydrogen Phosphate Ionic Cocrystals

Abstract

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 properties. 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(4pyridyl)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.

Conformational Trimorphism in an Ionic Cocrystal of Hesperetin

“…71,72 HES belongs to the group of natural products known as flavonoids and contains multiple phenolic groups. Phenols are classified as medium strength H-bond donors 38 and have been established as being able to form supramolecular heterosynthons with Hbond acceptors such as chloride anions, 39 carboxylate moieties, 40 and aromatic nitrogen bases. 41 Recently, we reported a crystal engineering study on ICCs of phenol and substituted phenol derivatives with their conjugate bases, which indicated that the phenol…”

“…Whereas cocrystals have long been known, their amenability to design through crystal engineering approaches was not well recognized until the early 2000s when four papers detailed the design of pharmaceutical cocrystals. − Successful crystal engineering approaches to cocrystal design are generally based on a knowledge of possible H-bonded supramolecular synthons . In this context, H-bonded supramolecular heterosynthons between coformers are key to understanding and designing cocrystals since their hierarchies − can be used to project whether a cocrystal is amenable to being readily isolated . Pharmaceutical cocrystals can significantly diversify the number of crystal forms available for a given API, thereby improving the likelihood that a crystalline form suitable for use in a drug product will be identified.…”

“…In this contribution, we focus upon the nutraceutical hesperetin, HES (Scheme ), which exhibits potentially useful biological properties such as antioxidant, anti-inflammatory, and antitumor activities, , but offers relatively low solubility of 1.35 mg·L –1 and low bioavailability. , HES belongs to the group of natural products known as flavonoids and contains multiple phenolic groups. Phenols are classified as medium strength H-bond donors and have been established as being able to form supramolecular heterosynthons with H-bond acceptors such as chloride anions, carboxylate moieties, and aromatic nitrogen bases . Recently, we reported a crystal engineering study on ICCs of phenol and substituted phenol derivatives with their conjugate bases, which indicated that the phenol···phenolate (PhOH···PhO – ) supramolecular heterosynthon is robust and can be relied upon to form cocrystals .…”

Polymorphs, ionic cocrystal and inclusion complex of N-amino-1,8-naphthalimide

“…The information on self-assemblies with enhanced composition becomes important on applications in materials, or for recovery from solution where they may remain as vulnerable contaminants. 31 Appropriately functionalized acid or base derivatives form salts or ionic cocrystals [32][33][34][35][36][37] or stabilize zwitterion forms. 38 The stacking effect and the concomitant hydrogen bond donor/acceptor behavior of naphthalimide derivatives make them attractive to generate polymorphs.…”

Crystal engineering and structural diversity of 2-aminopyridinium hypodiphosphates obtained by crystallization and dehydration

“…17,18 By introducing three different components (rather than two as in salts), ionic co-crystals increase diversity and create new sets of materials and properties to explore, like it was recently reported for phosphoric acid–dihydrogen phosphate co-crystals. 19…”