Abstract
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 R43 (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.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce pain and inflammation
The results reported above mainly focus on two aspects: the indepth study of the crystal packing of structurally related NSAID-PEA diastereomeric salts and of the stability/transformation of their solid forms under different experimental conditions
We have presented the results of a solid-state investigation of the diastereomeric salts of (S)-ibuprofen, (S)naproxen, and (S)-ketoprofen with (R)-(+)- and (S)-(−)-1phenylethylamine by using a combination of experimental and in-silico tools with the aim of extracting suggestions about forces/features which could be exploited in view of the chiral separation of their racemic compounds
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce pain and inflammation. Among the many NSAIDs available, there are ibuprofen ((RS)-2-(4isobutylphenyl)propanoic acid), naproxen ((RS)-2-(6-methoxy-2-naphthyl)propanoic acid), and ketoprofen ((RS)-2(3-benzoylphenyl)propanoic acid), all belonging to the class of arylpropionic acid derivatives (Scheme 1). They are BCS class II drugs[1] (i.e., they are characterized by high permeability and low solubility), and because of their poor aqueous solubility, they are usually formulated as inorganic (e.g., ibuprofen, naproxen, and ketoprofen as sodium salts) as well as organic. Over the last few years, interest in single-enantiomer formulations has increased due to several clinical advantages, including easier/improved pharmacokinetic and pharmacodynamic profiles, lower prescribed amount, and reduced toxicity, just to name a few.[3] The development of a single-enantiomer drug starting from the corresponding chiral one, previously developed as a racemic mixture, is referred to as a “chiral switch”. The change in the status of the drug chirality, i.e., the chiral switch, implies patent issues, e.g., enantiomer patents, a kind of secondary pharmaceutical patent, which claims a single enantiomer of a chiral drug previously claimed as a racemate.[4,5] Ibuprofen was the first NSAID to be switched to the single-enantiomer
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