Third polymorph and salt complexes of teriflunomide-A multiple sclerosis drug

Abstract

Teriflunomide (TEF) is a BCS class II molecule used to treat multiple sclerosis. A third polymorph of TEF (FIII) was accidentally formed when an attempt was made to crystallize with palmatine co-former. Seven salt complexes were developed with the following co-formers viz., 4,4 bipyridine(4,4 BPY), 1,2-Bis(4-dipyridyl)ethane (Bipyeta), trans-1,2-Bis(4-dipyridyl)ethylene (Bipyete), trimethoprim (TMP), olanzapine (OZP), and lamotrigine (LAM). Out of these, TEF-TMP existed in two polymorphic forms (FI & FII). Single-crystal X-ray diffraction (SC-XRD) and hot-stage microscopy (HSM) were employed for TEF FIII and the TEF-LAM systems due to a lack of phase-pure bulk material. The TEF-Bipyeta and TEF-Bipyete crystal structures have a 1:0.5 ratio, while all other structures have a 1:1 ratio in their asymmetric units. Powder X-ray diffraction (PXRD), infrared spectroscopy (IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solubility, dissolution, and stability studies were also performed. The TEF FIII has a lower melting temperature than the other two polymorphs. The DSC data reveal that all salts exhibit endothermic peaks between drugs and co-formers except TEF-TMP polymorphs. They exhibit lower melting point peaks compared to both TEF and TMP. The TGA data showed that all the salt forms are anhydrous. IR analysis showed the absence of OH stretching frequency and the presence of NH stretching frequency, confirming the salt formation. The stability studies revealed that all the salt systems remained unchanged over 30 days, except for the TEF-4 4 BPY system, which partially converted to the parent TEF from the 7^th day onwards. The TEF-4 4 BPY salt exhibited the highest improvement in solubility and dissolution across all media, while other salts like TEF-Bipyeta and TEF-Bipyete showed moderate enhancement. Dissolution and residue PXRD analysis confirmed that most salts remained stable in water and pH 6.8, but partially or fully converted to TEF under acidic conditions, indicating reduced stability at low pH. The polymorph TEF (FIII) exhibits cis orientation, whereas TEF salt structures have trans orientation. This conformation difference led to the formation of intramolecular O-H···O hydrogen bonds in TEF polymorphs, while in the TEF salt structures, it formed intramolecular N-H···O hydrogen bonds.