Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Understanding hygroscopicity of theophylline via a novel cocrystal polymorph: a charge density study

Stanton, Stephen A., Du, Jonathan J., Lai, Felcia, Stanton, Gyte, Hawkins, Bryson A., Ong, Jennifer A., Groundwater, Paul W., Platts, James A. and Hibbs, David E. 2021. Understanding hygroscopicity of theophylline via a novel cocrystal polymorph: a charge density study. The Journal of Physical Chemistry A 125 (45) , 9736–9756. 10.1021/acs.jpca.0c09536
Item availability restricted.

[thumbnail of Theophylline Malonic Acid Manuscript FINAL (002).pdf] PDF - Accepted Post-Print Version
Restricted to Repository staff only until 3 November 2022 due to copyright restrictions.

Download (3MB)


The charge density distribution in a novel cocrystal (1) complex of 1,3-dimethylxanthine (theophylline) and propanedioic acid (malonic acid) has been determined. The molecules crystallize in the triclinic, centrosymmetric space group P1̅, with four independent molecules (Z = 4) in the asymmetric unit (two molecules each of theophylline and malonic acid). Theophylline has a notably high hygroscopic nature, and numerous cocrystals have shown a significant improvement in stability to humidity. A charge density study of the novel polymorph has identified interesting theoretical results correlating the stability enhancement of theophylline via cocrystallization. Topological analysis of the electron density highlighted key differences (up to 17.8) in Laplacian (∇2ρ) between the experimental (EXP) and single-point (SP) models, mainly around intermolecular-bonded carbonyls. Further investigation via molecular electrostatic potential maps reaffirmed that the charge redistribution enhanced intramolecular hydrogen bonding, predominantly for N(2′) and N(2) (61.2 and 61.8 kJ mol–1, respectively). An overall weaker lattice energy of the triclinic form (−126.1 kJ mol–1) compared to that of the monoclinic form (−133.8 kJ mol–1) suggests a lower energy threshold to overcome to initiate dissociation. Future work via physical testing of the novel cocrystal in both dissolution and solubility will further solidify the correlation between theoretical and experimental results.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: American Chemical Society
ISSN: 1089-5639
Date of First Compliant Deposit: 24 January 2022
Date of Acceptance: 3 November 2021
Last Modified: 28 Jan 2022 18:35

Citation Data

Cited 1 time in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics