Naslov
The polymorphism of 2-amino-4-methylpyridine salicylate: a thermodynamic study of stability

Autori
Golenić, Neven ; Ilić, Ivan ; Piteša, Tomislav ; Stilinović, Vladimir ; Cinčić, Dominik

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
24th Croatian – Slovenian Crystallographic Meeting - Book of abstracts / - , 2016, N/A-N/A

Skup
24th Croatian – Slovenian Crystallographic Meeting

Mjesto i datum
Bol, Hrvatska, 22.09.2016. - 24.09.2016

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
polymorphism ; thermodynamic study

Sažetak
Effective supramolecular control of polymorphism in various pharmaceutical compounds is of considerable interest in drug design, being that different polymorphs can significantly differ in their physical properties including solubility, bioavailability, and stability. However, controlling the conditions necessary to obtain phase-pure polymorphs has proven to be quite a challenge due to the many effects governing polymorph formation. Most notably, the effects of temperature and solvent evaporation rate were the main subject of this study. To describe their influence on crystallization outcomes, we present a detailed structural and thermodynamic characterization of 2-amino-4- methylpiridine salicylate as a model system exhibiting at least four polymorphic forms: I (P-1, previously reported by Hemamalini, 2010.), II (P21/c), III (P21/c), and IV (P21). Form II was crystalized from a methanol solution of salicylic acid and 2-amino-4- methylpiridine at room temperature and structurally characterized by single-crystal X- ray diffraction (SC-XD). Mechanochemical synthesis and ageing of the mixture of reactants under normal laboratory conditions for 2 days also yielded form II. Differential scanning calorimetry (DSC) measurements were preformed to investigate the thermochemical properties of the system and a phase transition of form II to form III was discovered in the temperature range of 144 – 154 °C. By slow heating a single crystal of form II from 25 to 148 °C and subsequent quenching to 25 °C we obtained a single-crystal of the high- temperature form III. Form III was also prepared by slow cooling of solution of reactants in 1-octanol (ϑb =195 °C) previously seeded with crystals of form III. Form III was found to be metastable and would interconvert back to form II at room temperature over ~ 2 days. Form IV was prepared by rapid air-venting the methanol solution of reactants at ~ 7 °C until complete solvent evaporation. A single-crystal of form IV was prepared by seeding a methanol solution of the reactants and characterized by SC-XD. DSC measurements of form IV indicated a phase transition of form IV to form II in the temperature range of 114 – 128 °C. Form IV was also found to interconvert to form II at room temperature (in solution, even at –15 °C) after ~ 8 days. In order to obtain exact temperatures of phase equilibria between respective forms and further elucidate their thermodynamic stability, solubility measurements were conducted in o-xylene (ϑb = 144 °C) on a wide temperature range (–15 – 135 °C). Form II was found to change into form III at TII->III = 100.7 °C. Relatively large overheating of form II which was necessary for its interconversion into form III was likely due to the extensive hydrogen bonding between the constituent molecules which is present in all four polymorphs.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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