Famciclovir–fumaric acid: an all-in-one multicomponent system with salt, cocrystal and salt–cocrystal continuum

Abstract

The design and development of multicomponent systems in the salt–cocrystal continuum zone (ΔpK_a = −1 to 4) are considered advantageous since they can crystallize as a salt, cocrystal, or combination of both and create opportunities to select the right crystal form with desirable properties for product development. Herein, the choice of solvent, temperature, pH, and crystal environment significantly influenced the ionization state in the crystal; however, the structural features that stabilize the neutral or ionic molecular pairs were not clear, and thus further studies are necessary from a crystal engineering point of view. A new multicomponent system was envisaged between the antiviral drug famciclovir and its coformer fumaric acid (FAM–FUM), which falls in the salt–cocrystal continuum zone (with ΔpK_a value of 0.81) and possesses complementary functional groups to form robust supramolecular synthons, such as acid–pyrimidine and acid–imidazole for co-crystallization. Three novel crystalline forms of famciclovir–fumaric acid were identified in our crystallization trials, including a cocrystal (FAM–FUM 2 : 2 form I), a salt (FAM–FUM 2 : 2 form II) and a salt–cocrystal continuum (FAM–FUM 1 : 0.5). The first two forms are actually polymorphs having the same drug-to-coformer stoichiometry, while the third is a different stoichiometry structure. These crystal forms were well characterized by different solid-state techniques (SCXRD, PXRD, DSC, TGA, HSM, FT-IR spectroscopy, and SS-NMR). All three structures are sustained by a similar two-point acid–pyrimidine heterosynthon but differ in their ionization state. The synthon is neutral in 2 : 2 form I, ionic in 2 : 2 form II, and adopts an intermediate state in the 1 : 0.5 crystal. Interestingly, these three forms were concomitantly crystallized in the same solvent medium, which suggests that the crystal environment/solid-state structure may play a dominant role in the ionization state of the complex rather than the experimental variables. The crystal structure analysis provided important clues on why the different structures adopted different ionization states. An auxiliary hydrogen bond was seen to stabilize the ionic synthon in FAM–FUM 2 : 2 form II, while it was absent in the neutral synthon of the FAM–FUM 2 : 2 form I. The intermediate state or partially ionic state in FAM–FUM 1 : 0.5 was stabilized by shorter hydrogen bonds compared to the neutral synthon.