Formation of Isomorphic Desolvates: Creating a Molecular Vacuum

Abstract

The objective of this work was to investigate a common but poorly understood category of crystalline organic substances: isomorphic desolvates. When solvent is lost from a crystal lattice but the lattice retains its three-dimensional order, a lattice is created which is in a high-energy state relative to the original solvate structure. The desolvated lattice can reduce its internal energy by either resorbing solvent or by relaxation processes which increase the packing efficiency of the solid by reducing the unit cell volume. In the following paper, solid-state properties of isomorphic desolvates of cephalexin, cefaclor, erythromycin A, and spirapril hydrochloride hydrates are investigated. The hygroscopicity of the compounds are evaluated using a vacuum moisture balance, and structural relaxation is measured using a combination of X-ray powder diffraction and isothermal microcalorimetry. The study results are explained in terms of Kitaigorodski's close packing principle.

Cephalexin: a channel hydrate

“…There is some¯exibility in the amide backbone, with the OÐCÐCÐN(H 3 ) torsion angles ranging from 27.3 (6) to 44.5 (6) . The geometry of the related species cefadroxil (Shin & Cho, 1992) has a similar conformation, ®tting within the range found here for CEX, as does CEX complexed with -napthol (Kemperman et al, 1999), although here the amide backbone is more eclipsed (equivalent angle = 16.2 ).That the stochiometrically exact dihydrate is not found is unsurprising, given the steep gradient observed by Stephenson et al (1998) in the moisture adsorption isotherms of CEX. Only above 70% relative humidity does CEX begin to approach a genuine dihydrate.…”

“…That the stochiometrically exact dihydrate is not found is unsurprising, given the steep gradient observed by Stephenson et al (1998) in the moisture adsorption isotherms of CEX. Only above 70% relative humidity does CEX begin to approach a genuine dihydrate.…”

“…The characterization of the solid-state properties of CEX has, however, been hampered by uncertainty over the exact nature of its hydration behaviour. CEX can form a range of hydrates in the solid state, all with essentially identical unit cells, and has thus been identi®ed as part of the class of compounds known as isomorphic desolvates (Stephenson et al, 1998). Indeed, CEX is known to go further and reversibly replaces water with other small, polar, solvent molecules (Pfeiffer et al, 1970).…”

Influence of Bio-Isosteric Replacement on the Formation of Templating Methanol and Acetonitrile Solvates in Lophines

“…This shows the significance of using solvate formation during crystal form discovery, as has been frequently shown for organic compounds. 17,20,47,49 I-TPI results in the same crystal form independent from the solvent/solvate, which again points towards one energetically favoured modification.…”

Prediction of Hydrate and Solvate Formation Using Statistical Models

“…There are many examples of drugs that are formulated as a hydrate form, such as cephalexin, cefaclor, ampicillin and theophylline. [4][5] Hydrates (water solvates) are of special concern, because they occur more frequently than other solvates. Another factor that makes hydrates particularly important is the fact that water is a non-toxic solvent.…”