Solid-State Properties and Dehydration Behavior of the Active Pharmaceutical Ingredient Potassium Guaiacol-4-sulfonate

Abstract

Potassium guaiacolsulfonate is an active pharmaceutical ingredient that has been in use for more than a century, and it is still widely used in cough syrups. Nonetheless, no crystal structure has ever been determined to facilitate quality control. This is all the more surprising because two isomers are known to exist. A commercial sample has been studied by X-ray diffraction and thermogravimetric methods. It consists of potassium guaiacol-4-sulfonate, and it crystallizes in the monoclinic space group C2/c as a hemihydrate. The crystals exhibit uniaxial negative thermal expansion, and the electrostatic forces between the ions appear to be the major driving force of the observed displacements. Dehydration of the hemihydrate was observed above 380 K. The anhydrate has a structure similar to the hemihydrate with almost the same unit cell parameters. The dehydration kinetics points to a displacive mechanism; water molecules are located in channels, through which they leave the crystal. The structural readjustments that occur to accommodate the loss of water are driven by electrostatic interactions between the ions similar to the displacements observed for thermal expansion. Under ambient conditions (and humidity), the anhydrate is not stable and transforms into the hemihydrate.

Improved pharmacokinetics of mercaptopurine afforded by a thermally robust hemihydrate

“…Moreover, this new form has a dehydration temperature of 240 1C, which is, to our knowledge, the highest seen of any single component hydrate in the literature. [13][14][15][16][17] This combination of solubility and stability may be useful from a pharmaceutical standpoint to increase the bioavailability of this API.…”

Role of Anomalous Water Constraints in the Efficacy of Pharmaceuticals Probed by 1H Solid‐State NMR

“…The monohydrate has a dehydration temperature of 150 °C, whereas the hemihydrate form shows an exceptionally high dehydration temperature of 240 °C. This value is the highest observed for any non‐salt hydrate in the literature, and a staggering 90 °C higher than the monohydrate form. Consequentially, an ideal balance of stability and solubility is found in the hemihydrate form that is responsible for its increased efficacy.…”

Does the trihydrate of atorvastatin calcium possess a melting point?

“…Solid-state NMR results in the literature indicate that two water molecules bridge two divalent calcium ions (Holmes et al, 2019), which most likely explains the high temperature at which these two molecules leave the crystal. The water loss peak below 100 °C is most likely related to the loss of the water molecule bound to a single calcium ion (Holmes et al, 2019;Mahe et al, 2013;Wang et al, 2012).…”