ABSTRACT

Background: Ethyl diclofenac was reported can increase the effect of diclofenac acid due to its lower plasma binding, but ester form has a low melting point which make it unstable in the high temperature. A novel cocrystal from ethyl diclofenac (ED) wit diclofenac acid (DA) has been isolated and determined using Single Crystal Xray Diffractometer (SCXRD). However, the yielded cocrystal was still not pure and homogenous.  Objective: This research aimed to find the better method to obtain the pure ED-DA cocrsytal. Next, the stability tests were performed by heating and high humidity storage on the ED-DA cocrystal.  Methods: ED-DA cocrystal production was optimized by a combination of some methods: solvent drop grinding (SDG), microwave (MW), and recrystallization with the organic solvents. Besides, cocrystallization was carried out by the new innovation method, namely “simultanoeus-reflux esterification-cocrsytallization”. Solid analysis characterized ED-DA cocrystal by thermal analysis (electrothermal and DSC), vibration spectrophotometry (FTIR), and PXRD. The stability test was conducted by using microwave and high humidity chamber. Results: The results showed that recrystallization with acetone and ethanol can yield the targeted cocrystal, with the specific new diffraction peaks at 2θ = 16.42^o, 21.26^o, and 33.20^o through PXRD analysis. However, there were still several peaks of origine compound which indicate that the result was not pure. Furthermore, the reflux method with ethanol 96% produced ED-DA cocrystal that was pure with only one endothermic peak on the thermogram and without the existance of the starting materials in the diffractogram. Moreover, the data showed that DA-ED cocrystal produced by the reflux method was stable under the experiment conditions, which was not separated to the physical mixture.Besides, it was more resistant to water adsorption. Conclusion: ED-AD form a novel cocrystal which can be made purely by the simultaneous esterification-reflux method, which is stable against heating  and high humidity.

Keyword: ethyl diclofenac, diclofenac acid, cocrystal, simultaneous esterification method, stability.