The crystallization of ursodeoxycholic acid drug crystals in gel by reduction of solubility method is the first of its kind to be reported in literature. Monoclinic crystalline form of the structure was confirmed using single crystal X-ray diffraction analysis. This report deals with the kinetic analysis made from the thermogravimetric analysis/differential thermal analysis (TGA/DTA) data using Coats-Redfern (CR) relation. Thermodynamic parameters were also determined. Arrhenius equation for ursodeoxycholic acid was derived as k = 3.10 × 10 10 e −172581/RT mol −1 •s −1.
Pharmaceutical problems like the purity level, qualitative and quantitative analysis of drug formulations and polymorphism are resolved using thermal analysis [
Ursodeoxycholic acid (C24H40O4) [3α, 7β-dihydroxyl-5β-cholan-24-oic acid], (
the thermal decomposition of ursodeoxycholic acid is scarce in literature and was undertaken.
Non-isothermal thermal analysis was carried out on the as grown single crystals of ursodeoxycholic acid crystallized from gel growth method. The grown crystal was subjected to single crystal X-ray diffraction analysis for the structure conformation. Coats-Redfern relation was applied on the thermal data to evaluate the kinetic parameters. Also the thermodynamic parameters were estimated. Arrhenius equation for ursodeoxycholic acid was determined.
Commercial grade ursodeoxycholic acid drug was purchased from Lupin Pharmaceuticals Ltd., India. All other chemicals (AR grade) were purchased from s.d. chemicals Pvt. Ltd., India. Silica gel prepared from sodium metasilicate of specific gravity 1.06 g/cm3 was used as crystal growth medium. Test tubes were used as crystal growth vessels. Crystal growth by single diffusion method was employed for the crystallization. The pH of the gel was set using acetic acid. 5% w/v of UDCA dissolved in methanol was placed over the set gel taken in the test tube. The experiment was carried out at room temperature (≈27˚C).
Enraf-Nonius CAD-4 Diffractometer, with MoKα (λ = 0.71073 Å) radiation was used to obtain the accurate cell parameters of the grown UDCA single crystal at room temperature. Cell parameters were obtained from least-squares refinement of the setting angles of 346 reflections.
Simultaneous thermogravimetric analysis (TGA) and differential thermal analysis (DTA) was carried out for the powdered sample of as grown crystals in the temperature range 40˚C to 350˚C under a constant heating rate of 10˚C/min using Perkin Elmer Diamond thermal analyzer. The crucible used was made of alumina which served as a reference for the sample.
Transparent, rectangular platy crystals of size: 3.5 × 1.5 × 0.5 mm3 were crystallized in a week’s time. The crystals were removed after a growth period of few weeks and photographed (
The unit cell parameters were determined from the collected X-ray data. Lattice parameters of orthorhombic ursodeoxycholic acid form are: a = 26.56(15) Å, b = 13.25(5) Å, c = 12.31(4) Å, and the space group is P212121. These values agree well with the reported values in the literature [
TGA/DTA plot is presented in
The TGA data was analyzed using Origin Lab [
and Redfern relation [
log [ 1 − ( 1 − α ) 1 − n T 2 ( 1 − n ) ] = log [ A R β E ( 1 − 2 R T ¯ E ) ] − [ E 2.303 R T ] (1)
where, α is fraction of original substance decomposed at time t and is calculated from TGA data using Equation (2),
α = m o − m t m o − m f (2)
where mt is the mass at a given time, mo and mf are the initial and final masses of the sample respectively. R denotes gas constant.
To determine the activation energy, frequency factor and order of reaction,
the plot of log [ 1 − ( 1 − α ) 1 − n T 2 ( 1 − n ) ] versus 1/T is drawn for different values of n
(
The Thermodynamic parameters of ursodeoxycholic acid: entropy of activation
(ΔS), enthalpy of activation (ΔH) and Gibbs free energy (ΔG) were calculated using Equations (3)-(5).
A = ( k T / h ) e ( Δ S / R ) (3)
where h and k are Planck’s constant and Boltzmann constant respectively.
Δ H = E – R T (4)
Δ G = Δ H – T Δ S (5)
The values of ∆S, ∆H and ∆G are −50.47 J/Kmol, 167.22 kJ/mol and 199.76 kJ/mol respectively. Positive value of ∆G shows that the decomposition reaction of ursodeoxycholic acid is non-spontaneous.
Single crystals of ursodeoxycholic acid were crystallized by reduction of solubility method in gel for the first time. The crystal structure was confirmed using single crystal X-ray diffraction method. Non-isothermal thermal decomposition showed that the title compound is stable up to the temperature 200.6˚C, also the thermal data was analyzed using CR method and the order of reaction, activation energy and frequency factor were calculated. Arrhenius equation for ursodeoxycholic acid is k = 3.10 × 1010 e−172581/RT mol−1・s−1. Thermodynamic parameter showed that the decomposition reaction of ursodeoxycholic acid is non-spontaneous.
The authors thank the University Grants Commission, Government of India, for providing Major Research Project Dr. K. Ravikumar and Dr. B. Sridhar, Laboratory of X-ray Crystallography, IICT, Hyderabad.
Ramukutty, S., Jeyasudha, R. and Ramachandran, E. (2017) Thermal Decomposition Kinetics of Ursodeoxycholic Acid Drug Crystal. Journal of Crystallization Process and Technology, 7, 85-90. https://doi.org/10.4236/jcpt.2017.74006