A new crystal form of the NSAID dexketoprofen

Abstract

Dexketoprofen [(2S)‐2‐(3‐benzoylphenyl)propanoic acid], C16H14O3, is the S‐enantiomer of ketoprofen, a nonsteroidal anti‐inflammatory drug (NSAID) that has analgesic, antipyretic and anti‐inflammatory properties, and finds applications for the short‐term treatment of mild to moderate pain. A new crystalline phase of dexketoprofen is reported. Its solid‐state structure was determined by single‐crystal X‐ray diffraction (SCXRD). The molecular structure of the two independent molecules found in the asymmetric unit of this new phase (DXKP‐β) were compared to those of the already known crystal form of dexketoprofen (DXKP‐α) and with the S‐enantiomer of the racemic compound. The three different conformers of dexketoprofen found in DXKP‐α and DXKP‐β were then investigated by computational methods. The optimized structures are very close to the corresponding starting geometries and do not differ significantly in energy. The crystal packing of DXKP‐β was studied by means of Hirshfeld surface (HS) analysis; interaction energies were also calculated. A comparison with DXKP‐α shows close similarities between the two crystal forms, i.e. in both cases, molecules assemble through the catemer O—H…O synthon of the carboxylic acid stabilized by additional C—H…O contacts and, accordingly, the interaction energies, as well as the contributions to the HS area, are very similar. Finally, the thermal behaviour of the two polymorphs of dexketoprofen was assessed by means of XRD (both from single crystal and microcrystalline powder) and differential scanning calorimetry (DSC); both crystal forms are stable under the experimental conditions adopted (air, 300–350 K for DXKP‐α and 300–340 K DXKP‐β) and no solid–solid phase transition occurs between the two crystal forms in the investigated temperature range (from 100 K up to ca 350 K).

Nonsteroidal Anti-Inflammatory Drugs–1-Phenylethylamine Diastereomeric Salts: A Systematic Solid-State Investigation

“…With this in mind, and as part of our ongoing structural study of ( S )-ketoprofen (S-Ket, hereafter), − its DSs with ( R )-(+)- and ( S )-(−)-1-phenylethylamine (α-methylbenzylamine; R-PEA and S-PEA, hereafter, Scheme ) were prepared and investigated. 1-Phenylethylamine was chosen because (1) it is a commonly used resolving agent (it is cheap, and it has the chiral center close to the functional group involved in the recognition event); (2) with carboxylic acids, it forms robust charge-assisted hydrogen-bonded heterosynthons; (3) the structures of both the homochiral and heterochiral DSs with ( S )-ibuprofen (S-Ibu, hereafter) have already been described , as well as that of ( S )-naproxen (S-Nap, hereafter) with R-PEA, thus providing a first set of closely structurally related diastereomeric salts.…”

Solubility Advantage of Amorphous Ketoprofen. Thermodynamic and Kinetic Aspects by Molecular Dynamics and Free Energy Approaches

“…Three crystal KTP forms have been experimentally determined, two of them corresponding to the α and β forms of the S -enantiomer, , which is the only enantiomer displaying anti-inflammatory activity. The third crystal form represents the S - and R -enantiomer racemic mixture .…”

Rationalization of Lattice Thermal Expansion for Beta-Blocker Organic Crystals

“…In the present work, we applied our expertise to study the anisotropic/isotropic expansion of free amine crystalline solid forms. These systems can be simulated using quantum mechanics methods, as demonstrated by several authors in the In the past, we have used both X-ray diffraction data and theoretical chemistry to rationalize solid-state features and related behaviors of APIs, (e.g., isotropic vs. anisotropic thermal expansion, hydration/dehydration processes, polymorphs transformation/stability) [5,7,8,[16][17][18][19], to shed light on the chemical properties of metal complexes (e.g., recognition and sensing, catalysis) [20,21] and of metal coordination in solid state in relation with the supramolecular arrangement [22][23][24][25] as well as the ability of the phosphorus lone pairs in phosphorene to form covalent bonds [26]. In these years, we have learnt that quantum chemistry calculations are more than a simulation tool and they can be fruitfully used for understanding and finding a correlation between the structural change and experimental observations.…”