Tetramorphs of the Antibiotic Drug Trimethoprim: Characterization and Stability

Trimethoprim (TMP) is a well-known
antifolate drug and one of the
most widely used broad-spectrum antibiotics. TMP was first approved
by the United States FDA in combination with sulfamethoxazole (SMZ)
in 1973, and three polymorphs of TMP (named Form I, II, and III) and
a hydrate form were reported in 1978. However, a complete characterization
and molecular level analysis of polymorphic structures are not available.
We report herein four polymorphs (Forms 1–4) of TMP and a hemihydrate
form with complete structural and thermal characterization. The polymorphs
were isolated in the pure state by different techniques such as antisolvent
method, freeze-drying, and spray drying. Polymorphs 1 and 2 of our
study match with Forms I and II reported, and polymorphs 3 and 4 are
novel. The X-ray crystal structure of a novel TMP Form 2 is now reported
nearly four decades after the first crystal structure of Form 1 was
determined by neutron diffraction (J. Am. Chem. Soc. 1976, 98, 2074−2078). The
crystal structure of Form 1 has two types of R22(8) motifs, and Form 2 has a third
type R22(8)
and R32(8) motif
of N–H···Narom hydrogen bonds. The
polymorphs were characterized by FT-IR and Raman spectroscopy, differential
scanning calorimetry (DSC), 15N ss-NMR, field emission
scanning electron microscopy, powder X-ray diffraction, and also dynamic
vapor sorption. Thermodynamic stability, phase transformations, and
Hirshfeld surfaces are also discussed. The polymorphs were tested
under accelerated International Conference on Harmonization (ICH) conditions of
40 °C and 75% RH for stability, and found that all the solid
forms were stable for three months except TMP Form 3, which converted
to Form 2. Slurry grinding and thermal experiments suggest that TMP
Form 1 is the most stable modification among TMP crystal forms.