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.

Highlights

  • Niflumic acid (NIF, 2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinecarboxylic acid, Scheme 1) is a widely prescribed non-steroidal anti-inflammatory drug (NSAID)

  • The development of multicomponent pharmaceutical solids is a novel strategy addressed by the pharmaceutical industry to enhance drug performance [3]

  • The successful isolation of novel cocrystals of an enhancement the solubility properties of the novel pharmaceutical solid compared niflumic acid withofcaffeine has already been reported in a Russian patent, which claims an to the parent of Thereproperties existofrelevant examples of NIF cocrystals with to other enhancement the[17]

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Summary

Introduction

Niflumic acid (NIF, 2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinecarboxylic acid, Scheme 1) is a widely prescribed non-steroidal anti-inflammatory drug (NSAID). The development of multicomponent pharmaceutical solids is a novel strategy addressed by the pharmaceutical industry to enhance drug performance [3] This is achieved through crystal engineering of the intimate structure of pharmaceutical solids on which the physicochemical properties rely, without modifying the chemical identity of those active pharmaceutical ingredients (APIs) involved in the formulation [4]. Among all kinds proach to efficiently modulate the pharmaceutical properties of APIs already existing of in multicomponent pharmaceutical cocrystals have emergedprofile, as a promising approach the market at a relatively low cost,solids, such as solubility, dissolution and stability [5,6]. The successful isolation of novel cocrystals of an enhancement the solubility properties of the novel pharmaceutical solid compared niflumic acid withofcaffeine has already been reported in a Russian patent, which claims an to the parent of API.

General Procedure for Synthesis of Cocrystal Polymorphs
Preparation of Single Crystals
Computational Studies
FT-IR Analysis
Thermal Analysis
Stability Test
2.10. Powder Dissolution Profile
Preparation of Cocrystal Polymorphs
Quantification was undertaken by Rietveld analysis on the obtained X-ray
Crystal
Peaks each new phaseofare highlighted in blue
Microphotograph
Stability
Powder
The the parent
Conclusions
Figure S12
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