title: Aqueous solubility of diclofenac diethylamine in the presence of pharmaceutical additives: a comparative study with diclofenac sodium.
abstract: Aqueous solubility of diclofenac diethylamine (DDEA), a nonsteroidal anti-inflammatory drug currently formulated as a topical emulgel, was studied in the presence of pharmaceutical additives and compared with diclofenac sodium (DS). Electrolytes at low concentrations exhibited a salting-in effect on DDEA with peak solubility that was attributed to the association of DDEA into micelles, followed by a salting-out effect at higher concentrations, by which structure formation by DDEA molecules increased and precipitation occurred. For DS, which is not capable of forming micelles, the salting-out effect was dominant due to the common ion effect. Cosolvents displayed significant enhancement in solubility of both salts except glycerol, which showed a slight increase in solubility of DDEA and a decrease in solubility of DS due to transformation into the less soluble hydrate form. Ethanol and polyethylene glycol (PEG) 400 cosolvent systems at all concentrations showed positive deviations from the log-linear solubility equation. In the case of propylene glycol (PG) cosolvent systems, negative deviations were observed at low volume fractions of cosolvent, while positive deviations were observed at high volume fractions of cosolvent for DS and DDEA. The parent drug, being less ionizable and highly nonpolar, showed negative deviations up to 90% PG content. Thus, the positive deviations for DS and DDEA could be attributed to the more ionizable carboxylic group and its higher ability for hydrogen bonding at higher fractions of cosolvent. Polyvinylpyrrolidone (PVP) and PEG4000 or PEG6000 enhanced the solubility of DS and DDEA, with PVP exerting higher solubilizing efficiency and DS showing better solubility than DDEA. Solubilities of DS in Tween 80 (T80) and Pluronic F-127 (PF127) aqueous solutions were almost similar, while the solubility of DDEA in the presence of T80 was higher than the solubility in the presence of PF127. DS appeared to be located more in the polyoxyethylene mantle of the micelles, while DDEA was located more in the core of the micelles.
authors.affiliation: Faculty of Pharmacy, University of Jordan, Amman, Jordan.
authors.forename: E
authors.initials: E
authors.lastname: Khalil
authors.forename: S
authors.initials: S
authors.lastname: Najjar
authors.forename: A
authors.initials: A
authors.lastname: Sallam
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D004573:Electrolytes; D010592:Pharmaceutic Aids; D012995:Solubility; D013501:Surface-Active Agents
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004573:Electrolytes; D010592:Pharmaceutic Aids; D013501:Surface-Active Agents; D004008:Diclofenac