Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation

Abstract

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and ¹H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

Keywords: cocrystal; cocrystallization; dacarbazine; salt; solubility; stability.

Scheme 1. Molecular Structure of Dacarbazine (DTIC) and the Coformers: Oxalic, Maleic, Fumaric, Succinic, and Citric Acids

Figure 1

2D sheet motifs from the chain assemblies and layered crystalline packings for (a) DTIC-HOXA, (b) DTIC-H₂FUM, and (c) DTIC-H₂SUC.

Figure 2

2D sheet arrangements of chains and layered crystalline assemblies for (a) DTIC-HMAL and (b) DTIC-HCIT.

Figure 3

Experimental (exp) and calculated (calcd) diffractograms of DTIC and its new multicomponent crystals.

Figure 4

DSC curves (red solid line) and TG thermograms (black dashed line) for the DTIC solid forms.

Figure 5

Equilibrium solubility plot of DTIC and its salt and cocrystal forms in different dissolution media.

Figure 6

Intrinsic dissolution profile of DTIC and its salt/cocrystal forms in phosphate buffer, pH 6.8.

Figure 7

(a) Conversion of DTIC (1) to 2-AZA (2) under light. (b) Chromatogram highlighting the DTIC and 2-AZA separation. Kinetics of (c) DTIC photodegradation and (d) 2-AZA photogeneration from API solutions prepared with each DTIC crystal form.

Figure 8

Mass spectrum of (a) 2-AZA and (b) DTIC, showing the main product ions found in fragmentation. (c) Chromatogram of a freshly prepared DTIC sample (blue) compared to the chromatogram of a fully photodegraded DTIC sample (in red).