Thermal and Structural Characterization of Two Crystalline Polymorphs of Tafamidis Free Acid

Abstract

Tafamidis, chemical formula C14H7Cl2NO3, is a drug used to delay disease progression in adults suffering from transthyretin amyloidosis, and is marketed worldwide under different tradenames as a free acid or in the form of its meglumine salt. The free acid (CAS no. 594839-88-0) is reported to crystallize as distinct (polymorphic) crystal forms, the thermal stability and structural features of which remained thus far undisclosed. In this paper, we present—by selectively isolating highly pure batches of Tafamidis Form 1 and Tafamidis Form 4—the full characterization of these solids, in terms of crystal structures (determined using state-of-the-art structural powder diffraction methods) and spectroscopic and thermal properties. Beyond conventional thermogravimetric and calorimetric analyses, variable-temperature X-ray diffraction was employed to measure the highly anisotropic response of these (poly)crystalline materials to thermal stimuli and enabled the determination of the linear and volumetric thermal expansion coefficients and of the related indicatrix. Both crystal phases are monoclinic and contain substantially flat and π-π stacked Tafamidis molecules, arranged as centrosymmetric dimers by strong O-H···O bonds; weaker C-H···N contacts give rise, in both polymorphs, to infinite ribbons, which guarantee the substantial stiffness of the crystals in the direction of their elongation. Complete knowledge of the structural models will foster the usage of full-pattern quantitative phase analyses of Tafamidis in drug and polymorphic mixtures, an important aspect in both the forensic and the industrial sectors.

Decomposition of Fingerprints on Porous TiO2 Thin Films

“…Artificial fingerprints made of oleic acid, squalene, jojoba oil, and corn oil consist of organic compounds. A carbon compound such as C=O, C=C, and CO bonds was suggested in previous studies [35,36]. In the case of the 2 wt% P25 coating layer, the characteristic peak representing the FT-IR spectrum was reduced after exposure to UV light for 20 min, indicating that CH (2674, 2925, 3006 cm −1 ), C=O (1743 cm −1 ), C=C (1655 cm −1 ), and CO (1170 cm −1 ) bonds decomposed under UV exposure.…”

New Findings on the Crystal Polymorphism of Imepitoin

“…In the pharmaceutical field [11], these difficulties constitute a barrier to the physicochemical and pharmaceutical characterizations essential for the development of the active ingredients from different points of view. In-depth knowledge of the polymorphic behavior of an active ingredient, indeed, is essential for choosing the most suitable crystalline form for the formulation, avoiding unpleasant inconveniences due to the appearance of new crystalline forms in advanced stages of the development of a drug, guaranteeing its maintenance during manufacturing and storage, and defending the patent [12][13][14][15][16][17][18].…”

Microelectron Diffraction Reveals Contamination of Polymorphs by Structure Analysis of Microscale Crystals in a Novel Pharmaceutical Cocrystal

“…Polymorphs are crystal forms composed of the same molecules with different molecular states due to changes in intermolecular interactions, resulting in changes in their physicochemical properties. − Different molecular states among polymorphs can alter the physicochemical properties, which critically impact the in vivo performance of drugs, such as oral bioavailability. − In addition, stability differences are particularly focused on in polymorphs, and metastable forms are often thermodynamically and kinetically transformed to a stable form with convergence to low free energy according to Ostwald’s rule of stages. − Hence, revealing polymorphic forms and investigating their relationships are required for novel drug discovery. In the case of ritonavir, following its removal from the market, it was observed that the generation of a stable form during the manufacturing process reduced the dissolution rate and bioavailability of the drug. , Recent studies have found new polymorphic forms of traditional drugs, including ritonavir. − From this viewpoint, polymorphs are considered regulatory…”