THEOPHYLLINE–NA–SACHARRINE SINGLE CRYSTAL ISOLATION FOR ITS STRUCTURE DETERMINATION
Keywords:Co-crystal, Single-crystal, Slow evaporation, Theophylline anhydrous, Sodium saccharin dihydrate
Objective: Co-crystal is a crystal form which consists of two or more components in a specific stoichiometric ratio. Theophylline has been reported to form a co-crystal with sodium saccharin, but its single-crystal has not been isolated, so its structure also has not been known yet. This research aimed to isolate the theophylline-sodium saccharin co-crystal with several solvent, studied its single-crystal structure, and observed the stability of the co-crystal formed in a high humidity.
Methods: Theophylline anhydrous powder (TA), sodium saccharin dihydrate (NSD), and the physical mixtures of TA-NSD were characterized using a polarizing microscope, Fourier-Transform Infrared Spectroscopy (FTIR), Powder X-ray Diffractometer (PXRD), and Karl Fischer Titration (KFT); respectively. The single TA-NSD co-crystal formation was done by slow evaporation at ambient temperature (25 °C) and 12 °C, using four types of solvent mixtures, such as: water-isopropanol; water-acetone; ethanol-dichloromethane; and ethanol. The rate formations of co-crystals were observed and characterized using polarizing microscopy, FTIR, PXRD. The isolated co-crystal was analyzed using a Single-crystal X-Ray Diffractometer (SC-XRD). Finally; stability test was applied to TA-NSD co-crystal at an RH 95% chamber.
Results: Single-crystals at most formed in water-isopropanol (1:7), with the size of 0.6 to 1.2 cm (at ambient temperature) and 0.6 to 1 cm (at 12 °C) and solvent of water-acetone 1: 9 with a size of 0.5 to 1.1 cm (at ambient temperature/25 °C). Meanwhile from the other solvents, co-crystal just was produced in the crystalline form; and thin crystals with a size of ≤ 5 mm both in ambient temperature and 12 °C. Visual observations that were supported by polarizing microscope magnification showed TA-NSD co-crystal has rod-shaped and translucent color. FTIR spectra analysis results showed N-H stretching of the co-crystal shift from a wavenumber 3124.12 to 3129.7-3131.83 cm-1. The diffractogram from PXRD analysis indicated that TA-NSD co-crystal has sharp peaks on 2Ɵ = 5.58, 12.32, 17.48, 22.40, 26.86, 27.4, 28.84, and 34.1 °. The SC-XRD result showed the TA-NSD co-crystal has monoclinic crystal system, which has not been reported previously. The stability test in high humidity proved that the co-crystal shows unchanged shift N-H strain, which means that TA-NSD co-crystal is stable.
Conclusion: Based on all data, it is concluded that TA-NSD co-crystal has rod-shaped with translucent color, and has a monoclinic crystal system with volume 1583.9 (7) Å3. The single-crystals yielded from the water-isopropanol solvent system at ambient temperature and 12 °C; while from water-acetone 1: 9 was formed at 12 °C. The stability test in an RH 95% chamber showed that TA-NSD co-crystal is stable against the moisture.
Trask AV, Motherwell WD, Sam W, Jones W. Physical stability enhancement of theophylline via co-crystallization. Int J Pharm 2006;320:114-23.
Ronco MPF, Kluge J, Mazzotti M. High-pressure homogenization as a novel approach for the preparation of co-crystals. Cryst Growth Des 2013;13:2013-24.
Amjad A. Theophylline co-crystals prepared by spray drying: physicochemical properties and aerosolization performance. AAPS Pharm Sci Tech 2013;41:265â€“76.
Banerjee R, Bhatt PM, Ravindra NV, Desiraju GR. Saccharin salts of active pharmaceutical ingredients their crystal structures and increased water solubilities. Cryst Growth Des 2005;5:2298-09.
Nugrahani I, Bahari MU. The dynamic study of co-crystal formation between anhydrous and monohydrate theophylline with sodium saccharine dihydrate by FTIR. J Chem Biochem 2014;2:117-37.
Syahbani MM, Nugrahani I. Determination stoichiometry of theophylline and sodium saccharine co-crystal and hygroscopicity test. Undergraduate Thesis. School of Pharmacy-ITB, Bandung; 2014.
Khanam J. Crystallization. Jadavpur University. Kolkatta; 2007. p. 8-11.
Trask AV, Jones W. Crystal engineering of organic co-crystal by the solid state grinding approach. Top Curr Chem 2005;254:41-70.
Salih AI. Effect of carbon wt % on the iron X-ray diffraction pattern and the volume of iron unit cell. Sci Studies 2010;6:155-65.
Zhishen MB, Hao Y, Dan-Ni Z. The degree of crystallinity of multicomponent Polymers by WAXD. Chin J Polym Sci 1994;12:296-301.
Chung FH, Scott RW. A new approach to the determination of crystallinity of polymers by X-ray diffraction. J Appl Cryst 1973;6:225-30.