A new polymorph and two pseudopolymorphs of pyrimethamine

Area of Science:

• Crystallography and Materials Science
• Medicinal Chemistry and Drug Discovery

Background:

• The antimalarial drug pyrimethamine, with its donor-acceptor-donor site, is a candidate for supramolecular synthon applications.
• Understanding the crystalline behavior of pyrimethamine is crucial for its potential use in advanced materials and drug formulations.

Purpose of the Study:

• To investigate new crystalline forms of pyrimethamine through cocrystallization.
• To characterize the structural differences and hydrogen bonding patterns in novel polymorphs and solvates.
• To explore potential reactivity of pyrimethamine with common organic solvents.

Main Methods:

• Cocrystallization screening to obtain new solid forms of pyrimethamine.
• Single-crystal X-ray diffraction to determine the structures of obtained polymorphs and solvates.
• Database analysis to compare molecular conformations and hydrogen bonding of pyrimethamine.

Main Results:

• Three new crystalline forms of pyrimethamine were obtained: one new solvent-free polymorph (I) and two pseudopolymorphs (Ia, Ib) with dimethyl sulfoxide and N-methylpyrrolidin-2-one.
• All forms exhibit similar pyrimethamine conformations forming R(2)(2)(8) dimers, but display distinct packing arrangements and hydrogen bonding networks.
• An unexpected reaction between pyrimethamine and N-methylpyrrolidin-2-one yielded a new derivative, C(22)H(27)ClN(6)O(2) (II), also characterized by X-ray diffraction.

Conclusions:

• Pyrimethamine exhibits diverse crystalline packing behaviors, influenced by solvent interactions and hydrogen bonding.
• The study highlights the potential for unexpected chemical reactions during cocrystallization experiments.
• Detailed structural analysis provides insights into the supramolecular chemistry of pyrimethamine.