A Combined Crystallographic and Computational Study on Dexketoprofen Trometamol Dihydrate Salt

Rossi, Patrizia; Paoli, Paola; Milazzo, Stella; Chelazzi, L.; Giovannoni, Maria Paola; Guerrini, Gabriella; Ienco, Andrea; Valleri, Maurizio; Conti, Luca

doi:10.3390/cryst10080659

Cited by 8 publications

(4 citation statements)

References 40 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Rossi

Ceccarelli

Milazzo

et al. 2021

Crystal Growth & Design

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The solid-state investigation of the diastereomeric salts (S)-ibuprofen (S-Ibu), (S)-naproxen, (S-Nap), and (S)-ketoprofen (S-Ket) with (R)-(+)- and (S)-(−)-1-phenylethylamine, R-PEA, and S-PEA respectively, has been carried out by using a combination of experimental and in-silico tools. The focus was on their crystal packing and on the stability/transformation of their solid forms under different experimental conditions with the final aim of extracting useful information on the forces/features which could be exploited for the chiral separation of the corresponding racemic compounds. All the salts are 21-column crystals, each column consisting of API and 1-phenylethylamine ions assembled via the 1-phenylethylammonium-carboxylate supramolecular heterosynthon which originates a R 4 3 (10) pattern, the intercolumns contacts being definitely weaker. In spite of an overall similarity in the crystal packing forces and motifs of the anhydrous salts, the temperature stability range suggests that the homochiral species are the most stable. The fact that the homochiral salt of S-Ket (S-Ket_S-PEA) is stable toward the hydration, at variance with the heterochiral one (S-Ket_R-PEA), further confirms this hypothesis. On the other hand, preliminary sorption tests show that S-Ket and S-Ibu preferentially capture the homochiral PEA (S-Nap is not selective). This behavior has been correlated to the almost planar boundary surfaces which characterize and differentiate the 21 sheets in S-Ket_S-PEA and S-Ibu_S-PEA salts with respect to the corresponding heterochiral ones.

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Section: Introductionmentioning

confidence: 99%

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

Rossi

Ceccarelli

Milazzo

et al. 2021

Crystal Growth & Design

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“…In the case of the dexketoprofen-tromethamine salt crystal, the dihydrate phase was identified, where water molecules were incorporated into the interlayer [36], implying that molecular solvation interactions with water molecules are expected in a water solution. In order to examine the solvation effects on dissolution, hydration energies (E hy ) were estimated by calculating DFT with the solvent model SM5.4 (Table 3).…”

Section: Hirshfeld Surfaces and Hydration Energy Calculationmentioning

confidence: 99%

Improved Solubility and Dissolution Rate of Ketoprofen by the Formation of Multicomponent Crystals with Tromethamine

Fitriani

Firdaus

Sidadang³

et al. 2022

Crystals

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This study aims to improve the dissolution rate of ketoprofen by preparing multicomponent crystals with tromethamine. The multicomponent crystals (equimolar ratio) of ketoprofen and tromethamine were prepared by the solvent co-evaporation method. The solid-state properties of the resulting powder were characterized by powder X-ray diffraction, DSC thermal analysis, FT–IR spectroscopy, solubility, and in vitro dissolution rate. The crystal structure of the multicomponent crystal was determined by single-crystal X-ray diffraction analysis. The results showed that the powder X-ray diffraction pattern of the ketoprofen–tromethamine binary system was different from that of the starting materials. This difference indicates the formation of a new crystalline phase between ketoprofen and tromethamine (equimolar ratio). The DSC thermogram of the ketoprofen–tromethamine binary system exhibited a single and sharp endothermic peak at 128.67 °C, attributed to the melting point of a multicomponent crystal of ketoprofen–tromethamine. A single-crystal X-ray analysis revealed that ketoprofen–tromethamine formed a layered structure, salt-type multicomponent crystal. The solubility and dissolution rate of the multicomponent crystal were notably enhanced compared to the intact ketoprofen. The ketoprofen–tromethamine binary system forms salt-type multicomponent crystals, which can significantly increase the solubility and dissolution rate.

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“…As part of our ongoing structural investigations of non-steroidal anti-inflammatory drug (NSAID) solid forms, − we have recently reported on the diastereomeric salts of naproxen (Nap), ibuprofen (Ibu), and ketoprofen (Ket) (Scheme ) with ( R )-(+)- and ( S )-(−)-1-phenylethylamine (PEA) . Nap, Ibu, and Ket are 2-arylpropionic acid derivatives containing a stereocenter in the α-position, commonly used for the treatment of pain and inflammatory conditions (e.g., rheumatoid arthritis, postoperative surgical conditions, and menstrual cramps). − According to our study, S-Ket and S-Ibu preferentially capture the homochiral PEA (whereas S-Nap is not selective).…”

Section: Introductionmentioning

confidence: 99%

The Same but Not the Same: The Case of (S)-Naproxen/cis-1-Amino-2-indanol Chiral Resolution via Diastereomeric Salt Formation

Lippi,

Rossi,

Ceccarelli

et al. 2024

Crystal Growth & Design

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The solid state of four novel S-(+)-Naproxen (S-Nap) diastereomeric salts with cis-1-amino-2-indanol (SR-AI and RS-AI enantiomers) is reported. The anhydrous SR-AI_S-Nap_A is the only obtained phase in all the experimental conditions used, while the kinetically preferred diastereomeric salt RS-AI_S-Nap_A1 forms only in certain conditions and undergoes an irreversible phase transition to RS-AI_S-Nap_A2 after melting; this second phase was obtained even by dehydration of the monohydrate salt RS-AI_S-Nap_W. The preferred crystallization of SR-AI_S-Nap_A was observed when S-Nap was introduced in a solution containing equimolar quantity of the racemic cis-1-amino-2-indanol, in spite of the strict similarity of the crystal packings of SR-AI_S-Nap_A and RS-AI_S-Nap_A1. With the aim of trying to explain the preference of S-Nap for the SR-AI enantiomer, an in-depth analysis and comparison of the diastereomeric salt crystal structures were carried out.

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A Combined Crystallographic and Computational Study on Dexketoprofen Trometamol Dihydrate Salt

Cited by 8 publications

References 40 publications

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

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

Improved Solubility and Dissolution Rate of Ketoprofen by the Formation of Multicomponent Crystals with Tromethamine

The Same but Not the Same: The Case of (S)-Naproxen/cis-1-Amino-2-indanol Chiral Resolution via Diastereomeric Salt Formation

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