Characterization of solvatomorphs of methotrexate using thermoanalytical and other techniques

Abstract

Investigation of polymorphism and solvatomorphism in drug molecules is an important step in any pre-formulation program from both biopharmaceutical and technological point of view (1, 2). It is well known that polymorphs are different crystalline forms of the same compound whereas the inclusion of a solvent in a crystal lattice gives rise to pseudopolymorphs or solvatomorphs (2). One of the most relevant features among polymorphic modifications is the difference in their solubility and dissolution rate that affect their bioavailability (3-5).In crystal hydrates/solvates, the combination of intermolecular forces (hydrogen bonding) and crystal packing can produce very strong solvent-solid interactions leading to completely new properties in the solid state (6, 7). Some stable solvatomorphs require vigorous conditions for desolvation before melting, while others lose the solvent of crys- Identification and characterization of different forms of methotrexate were carried out by crystallization from different solvents. Five different forms of the drug were obtained. Appearance of a desolvation endotherm in the DSC accompanied by mass loss in TGA for forms I, II, IV and V showed these forms to be acetonitrile solvate hydrate (form I), trihydrate (forms II and IV) and dimethylformamide solvate (form V), respectively. However, the desolvation peak was absent in form III (obtained from methanol) indicating the absence of any solvent of crystallization. This form was found to be partially crystalline by its XRPD pattern. Solution calorimetry was further used to differentiate between the forms as they differ in lattice energy, resulting in different enthalpies of solution. The dissolution and solubility profiles were correlated with the enthalpy of solution and subsequently with crystallinity of all the forms; the least endothermic form (form III) had the highest dissolution rate.

Physicochemical aspects involved in methotrexate release kinetics from biodegradable spray-dried chitosan microparticles

“…4 shows XRD analysis for different samples. Unprocessed methotrexate occurred in a crystalline state, which was attributed to well-defined diffraction peaks at 2θ of 7.6 and 9.2, characteristic of its trihydrate form [10,19]. In accordance with some reported studies, in the XRD of chitosan diffraction peaks were observed at 10°or 20°corresponding to hydrated and anhydrous crystals respectively [20,21].…”

Efficacy of methotrexate-loaded poly(ε-caprolactone) implants in Ehrlich solid tumor-bearing mice

“…Further, a broad peak at 240-270 C was also verified due to the decomposition of the MTX, which overlapped the melting endotherm of the drug. The obtained results corroborated with those previously described (Chan & Gonda, 1991;Chadha et al, 2009). For the MTX PCL implants (Figure 3d), the DSC thermogram showed all endothermic events corresponding to the PCL and the drug.…”

Molecular structure, vibrational spectra and DFT molecular orbital calculations (TD-DFT and NMR) of the antiproliferative drug Methotrexate

“…Changqun et al studied and analyzed how the Methotrexate molecule interacts with nucleic acids by multi-spectroscopic method [9]. Recently, identification and characterization of different forms of Methotrexate were carried out by crystallization from different solvents by Chadha et al [10]. The crystal and molecular structure of Methotrexate were reported by Hambley et al [11] and Mastrapolo et al [12].…”