Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation

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.


COMPLEMENTARY FIGURES AND TABLES
. Geometric parameters of the principal H-bonds in the DTIC crystal forms.

Figure
Figure S11. 1 H NMR (600 MHz) spectrum of dacarbazine hydrogen citrate salt-cocrystal (DTIC-HCIT) in DMSO-d 6 .* Represents the signals of DMSO and H 2 O (solvents) as well as the signal of crystallization water molecules (crystal structure).

Table S1 .
Results of linearity, accuracy, precision, and limits of quantitation and detection obtained during analytical method validation for DTIC.

Table S2 .
Results of linearity, accuracy, precision, and limits of quantitation and detection obtained during analytical method validation for 2-AZA.

Table S3 .
Composition of the solutions and standard buffer solutions used in the solubility and dissolution experiments.

Table S4 .
Calculated ΔpKa between DTIC and the salt formers.

Table S7 .
Main thermal data from the DSC and TG curves of DTIC samples.

Table S8 .
pH measured in different dissolution media before and after solubility studies.
* Under acidic conditions, neutral DTIC is readily protonated, raising the pH.