Novel Polymorphic Cocrystals of the Non-Steroidal Anti-Inflammatory Drug Niflumic Acid: Expanding the Pharmaceutical Landscape

Abstract

Any time the pharmaceutical industry develops a new drug, potential polymorphic events must be thoroughly described, because in a crystalline pharmaceutical solid, different arrangements of the same active pharmaceutical ingredient can yield to very different physicochemical properties that might be crucial for its efficacy, such as dissolution, solubility, or stability. Polymorphism in cocrystal formulation cannot be neglected, either. In this work, two different cocrystal polymorphs of the non-steroidal anti-inflammatory drug niflumic acid and caffeine are reported. They have been synthesized by mechanochemical methods and thoroughly characterized in solid-state by powder and single crystal X-ray diffraction respectively, as well as other techniques such as thermal analyses, infrared spectroscopy and computational methods. Both theoretical and experimental results are in agreement, confirming a conformational polymorphism. The polymorph NIF–CAF Form I exhibits improved solubility and dissolution rate compared to NIF–CAF Form II, although Form II is significantly more stable than Form I. The conditions needed to obtain these polymorphs and their transition have been carefully characterized, revealing an intricate system.

Polymorphism in cocrystals of metronidazole benzoate

“…The dissolution profiles of both polymorphic pairs show that the ratio of their concentration maxima is very close to one, indicating that there is no clear benefit in selecting one polymorph over the other. The same behavior has been reported in several polymorphic cocrystals of APIs such as melatonin, 50 ethenzamide, 51 carbamazepine, 52 hesperetin, 53 niflumic, 54 and barbituric acid, 55 among others. Nevertheless, this assumption cannot be generalized because in some cases an actual improvement on the apparent solubility or dissolution rates have also been reported, as for example for phloretin 56 and dapsone.…”

New cocrystals of heterocyclic drugs: structural, antileishmanial, larvicidal and urease inhibition studies

“…2400.0 cm À 1 and overlaps with C-H absorptions. The carbonyl stretching frequencies appeared to be red-shifted in the cocrystal at 1667.2 cm À 1 and therefore, supported the hydrogen bonding(Acebedo-Martı ´nez et al, 2021). Cocrystal CBZ:5-SA (4) further showed a blue shift in the asymmetric stretching frequency of the amine group at 3495.0 cm À 1 , while the symmetric stretching frequency remain the same, indicating that only one amide H atom (N2-H1A� � �O2) is involved in cocrystal formation.…”

Polymorphism of amantadinium niflumate

“…In the Cambridge Structural Database (CSD, Version 5.43, 2023) 4 there are only a few reports of the crystal structures of organic co-crystals and salts of niflumic acid with bioactive ingredients such as: nicotinamide, 5 sulfamethazine, 6,7 l -proline, 8 caffeine, 9 maleic acid, 10 tyramine, 11 and morniflumate. 12 Moreover, complexes of niflumic acid with caprolactam, pyridin-2(1 H )-one 11 and 4,4′-bipyridine 13 are reported.…”