Naproxen–Nicotinamide Cocrystals: Racemic and Conglomerate Structures Generated by CO₂ Antisolvent Crystallization

Abstract

Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO 2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to CO 2 antisolvent batch crystallization process. The structure of the molecular complex and the analysis of its intermolecular interactions were investigated by Single Crystal X-ray Diffraction (SCXRD) and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR). The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO 2 feed rate, while very fast introduction of CO 2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis and Temperature Resolved X-Ray Powder Diffraction (TR-XRPD) were used to probe the relationship between the different phases. In addition, all powders produced with CO 2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals. ABSTRACTCocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO 2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to CO 2 antisolvent batch crystallization process. The structure of the molecular complex and the analysis of its intermolecular interactions were investigated by Single Crystal X-ray Diffraction (SCXRD) andAttenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR). The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO 2 feed rate, while very fast introduction of CO 2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis and Temperature Resolved X-Ray Powder Diffraction (TR-XRPD) were used to probe the relationship between the different phases. In addition, all powders produced with CO 2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals.

Metastable Chiral Azobenzenes Stabilized in a Double Racemate

“…[14,15] Ac rystalline supramolecular assembly with two or more distinct molecules connected by various non-covalent interactions,t hat is,acocrystal, holds tremendous potential for novel functionalities that ensue from the synergy of its components.Racemic A + /A À molecular units in the presence of additional chiral or achiral (B + /B) agents have ag eneral tendency to retain the inherent chiral/achiral nature of the added co-formers while assembling either into the same crystal system (diastereomeric,S cheme 1a,f-i)o rs eparate as different crystalline units (Scheme 1b,e). [16][17][18][20][21][22][23][24] In another case,t he introduction of ar acemic co-former to ar acemic host solution has been observed to result in adouble-racemic cocrystal, where each entity retains their own symmetry in the same crystal system (Scheme 1d). Yet, at wisted doubleracemic co-crystalline motif originating from ar acemic host through chiral induction in achiral guests has received less attention (Scheme 1f-ii).…”

“…Furthermore, Scheme 1. Representative outcomes of the crystallization of aracemic mixture (A + A À )with chiral (B + ), racemic (B + B À ), and achiral (B) guests resulting in aa), b) diastereomeric, [16,17] c) kryptoracemate, [18,19] d) double racemic, [18,20] e) conglomerate, [21,22] f-i)racemic cocrystal, [22] and fii)double racemic cocrystal. Motif (a) is unknown.…”

Ionic Co‐Crystal Formation as a Path Towards Chiral Resolution in the Solid State

“…[6] To the best of these authors'k nowledge, these are the only studies describing conglomerate formation via co-crystallization in all-organic systems. [10] Recently,t he possibility of inducing conglomerate formation by using inorganic salts in the formation of ionic co-crystals (ICCs) with chiral organic molecules has been investigated. [11] An ionic co-crystal (ICC) has been defined as am ulticomponent crystal system constituted of an inorganic salt and of an organic molecule in ad efined stoichiometricr atio.…”

Gas Antisolvent Approach for the Precipitation of α-Methoxyphenylacetic Acid – (R)-1-Cyclohexylethylamine Diateromeric Salt

“…Supercritical fluid extraction (SFE) with carbon dioxide (CO 2 ) has been successfully used in resolutions of various compounds. [8][9][10][11] In some cases, diastereomeric salt formation using a modified version of the PopePeachy method showed high dependence on changes in pressure and temperature, thus affecting the enantiomeric excess (ee) of the products. [12][13][14] α-Methoxyphenylacetic acid (MPAA) is widely used as a resolving agent and building block in various organic syntheses.…”