Understanding Hygroscopicity of Theophyllineviaa Novel Cocrystal Polymorph: A Charge Density Study

Abstract

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.

An experimental and theoretical charge density study of theophylline and malonic acid cocrystallization

“…In turn, the new lattice energy for the Triclinic THEO:MA is À231.7 kJ mol À1 , suggesting a decrease in the stability compared to THEO of 21.1 kJ mol À1 , and it is less stable compared to (1) by 35.9 kJ mol À1 . 31 These results may suggest the Triclinic polymorph is a metastable intermediate of (1), which has been seen previously for methylxanthines in the case of CAF:GLU. 11,12,64 Another method to review stability is comparing molecular dipole moments (MDMs).…”

“…However, [O(01)–C(01)–C(02)–C(03)], the opposite direction torsion angle of MA's carbon chain is −167.47° in the triclinic form, compared −122.91° in (1) and −91.86° in MA, respectively. 31 It is known that minor torsion angle differences can effect packing density by reducing the potential for weak hydrogen bond formation. 7 This suggest that in (1) combining THEO and MA caused limited geometrical differences and limits the change in overall packing from THEO.…”

“…12,43 For the THE-O:GLU system; The overall change is +22.7 kJ mol À1 . 31 From this it can be presumed that THEO:GLU should not have improved stability from THEO, and it should have failed the humidity testing at a point in time prior to THEO. However, the energetic difference for THEO:GLU compared to THEO is less than (1), suggesting THEO:GLU is more stable than (1).…”

Co-Crystallization Approach to Enhance the Stability of Moisture-Sensitive Drugs

“…The aromatic donor-acceptor interactions also influence the atomic charge on the atoms of the molecule that are not involved in any bonding interactions [ 78 ]. Stanton et al [ 28 ] carried out a charge density distribution study to understand the atomic interactions responsible for reducing the hygroscopicity of the triclinic malonic acid-theophylline co-crystals. They studied various parameters, such as the orientation of the co-former and API molecules, lattice energies, and molecular interactions in different crystalline forms of the same co-crystal, i.e., monoclinic and triclinic forms.…”

“…The co-crystals are formed by an API and co-formers with the action of non-covalent bonds. Co-crystals provide an effective approach to enhancing the stability of APIs in multiple ways; this is discussed in detail in a later section of this review article [ 28 ]. The use of substances from the USFDA list of generally recognized as safe (GRAS) nutraceuticals as co-formers makes the co-crystals devoid of any toxicity due to the use of co-formers [ 29 ].…”