Emily Krantz
Chem 367
Article Summary
Diclofenac Soluility: Independent Determination of the Intrinsic Solubility of Three
Crystal Forms
Introduction:
There are many different types and definitions of solubility and it is hard to measure
them accurately thus there are many measurements on solubility in literature that
differ dramatically.
Results and Discussion:
Diclofenac solubility in water was investigated using precisely controlled
experimental procedures using 3 forms: anhydrous sodium salt, 4.75 hydrate
sodium salt and the anhyfrous free acid.
An intrinsic solubility determination was used based on ‘potentio-metric acid-base
titration’, which is a process carried out by dissolving a material in water and
partially re-precipitating it. Cheqsol program was used taking the data and
displaying it on a screen. The solution is changed from sub-saturated to
supersaturated until the value for the transition shows itself in the data. The
experiment was repeated 10 times.
Sigma-Aldrich (2-[(2,6-dichlorophenyl)amino]- phenylacetic acid)) was dissolved in ethanol left in
a room for a week until crystal appeared. The difference from pentahydrate is in the
arrangement of sodium ion and water molecules. X ray diffraction showed the
crystal was a hydrate with 4 diclofenac anions, 4 sodium cations and nineteen water
molecules. The water molecules became ordered suggesting a new crystal form with
5 % less water and a higher R factor.
X-ray powder experiments distinguished between re-crystallized diclofenac and the
commercial sample. Thermogravimetric analysis showed the commercial sample
had a melting point of 284.3 and the re-crystallized had a melting point of 263.38.
Titrations were performed at difference concentrations of the cosolvent and
extrapolation to zero of the co-solvent at .15M ionic strength and 25C.
The results showed agreement between the transition point from supersaturation
to sub-saturation. If the crossing points lie close to eachother the system is in
equilibrium, if they are far apart they need more time to evolve toward the steady
state.
Neutral diclofenac was isolated after 8 experiments at pH of 6.5. Differential
scanning calorimetry, thermogravimetric analysis and powder x-ray diffraction
chaterorgized the sample to a structure of SIKL10H01 with a melting point of 180.5.
The results of the experiment that was carried out 10 times and showed an
agreement between the different forms of diclofenac and shows that intrinsic
solubility is independent of the original form of the experiment.
Reporting aqueous solubility without pH is confusing because carbonate-saturated
water could affect the pH and the solubility.
Aqueous solubility is concentratin of compound when excess solid is presend in a
solution that is saturated of pure warer. An equation gives the monoprotic acid
aqueous solubility.
Using the mean solubility at a pH of 7 the solubility in water was found to be 857.7
ug mL^-1.
Consistent conditions for repeating the runs were used. The kinetic solubilities, a
measure of the ability of the compound to form supersaturated solutions, were
much laeer than intrinsic solubilities. The kinetic values were distint with variances
in the mean values much larger than the standard deviations.
Experimental Section
GLpKa titrator and D=Pas spectrometer were used with Cheqsol software in a .15 M
KCl solution in a Ni atmosphere using .5M KCl and .5M KOH.
Metler Toledo DSC 821 differential scanning caloimeter was used with 5-10 mg of
each sample sealed in an pan with a hold pierced in the lid that was made out of
aluminum.
Metler MT5 was used for thermogravimetric analysis using STAR software.
A sample with .7mm diameter borosilicate capillary was used in a stoe- stadi =diffractometer operating in debye-scherrer geometry at 290 K and counting over a
24 hour period.
Perfluoropolyether oil was used to immerse the single crystals mounted on glass
fibers and placed in a low temperature N stream. Nonius Kappa CCD diffractometer
was used to exame the crystals using a thin slice K and omega scans at 150K
utilizing Mo and Ka radiation. SORTA V was used to correct the data and SHELXTL
software was used to solve directly.
http://pubs.acs.org/doi/abs/10.1021/jm0612970