Spectroscopic and thermal approaches to investigate the formation mechanism of piroxicam–saccharin co-crystal induced by liquid-assisted grinding or thermal stress
The use of co-crystal technology applied to pharmaceutical industry has recently attracted considerable interest. It is important to better understand the mechanism of co-crystal formation via specific intermolecular interactions. The objective of the present study was to evaluate a stepwise mechanism of a co-crystal formation between piroxicam (PIR) and saccharin (SAC) after different grinding and thermal treatments by using spectroscopic and thermal analyses. The physical and ground mixtures of PIR–SAC (molar ratio = 1:1) and their preheated mixtures were analyzed using FTIR, DSC and DSC-FTIR techniques. Typical PIR–SAC co-crystal was prepared by solvent evaporation method. Various PIR–SAC ground mixtures after neat grinding process showed the same FTIR spectra as their physical mixtures, but these ground mixtures might be changed to co-crystals after further thermal treatment. By adding two drops of chloroform into PIR–SAC physical mixture, however, the PIR–SAC co-crystal was gradually formed with the increase in grinding time (>57 min) via inter-/intramolecular N–H···O and C–H···O hydrogen bonding between PIR and SAC. By preheating the PIR–SAC physical mixture over 170 °C, it was also gradually transformed into a co-crystal with temperature. The PIR–SAC co-crystal formation might be possibly attributed to a mobile phase formed between PIR and SAC, leading to a co-crystal formation. This mobile phase could be formed by either solution through a lubricating liquid added during grinding process or eutectic melt via thermal stress. A simultaneous DSC-FTIR technique also directly evidenced the PIR–SAC co-crystal formation via a one-step process. The present study concludes that the chloroform-assisted grinding process or thermal stress easily enhanced a PIR–SAC co-crystal formation via gradual induction of inter-/intramolecular hydrogen bonding between PIR and SAC.
KeywordsPiroxicam Saccharin Liquid-assisted grinding Thermal stress DSC-FTIR Co-crystal formation
This work was supported by National Science Council, Taipei, Taiwan, ROC (NSC 100-2320-B-264-001-MY3).
Compliance with ethical standards
Conflict of interest
- 8.FDA. Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals. April, 2013.Google Scholar
- 23.Lipinski CA. Poor aqueous solubility: an industry-wide problem in drug discovery. Am Pharm Rev. 2002;5(1):82–5.Google Scholar
- 24.Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012; Article ID 195727.Google Scholar
- 29.Verma MM, Kumar MT, Balasubramaniam J, Pandit JK. Dissolution, bioavailability and ulcerogenic studies on piroxicam-nicotinamide solid dispersion formulations. Boll Chim Farm. 2003;142:119–24.Google Scholar
- 31.Jug M, Bećirević-Laćan M, Cetina-Cizmek B, Horvat M. Hydroxypropyl methylcellulose microspheres with piroxicam and piroxicam-hydroxypropyl-beta-cyclodextrin inclusion complex. Pharmazie. 2004;59:686–91.Google Scholar
- 54.Trask V, Jones W. Crystal engineering of organic cocrystals by the solid-state grinding approach. Top Curr Chem. 2005;254:41–70.Google Scholar