Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine, diethylamine and sodium salt forms of diclofenac

Non steroidal anti-inflammatory agents (NSAIDs) such as diclofenac have ver y low aqueous solubilities and consequently salt formation may be used to e nhance solubility and dissolution rate. In this study, we examined the phys icochemical properties of three diclofenac salts, diclofenac sodium (DNa), diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) and diclofenac diethylamine (DDEA), and their different solid state forms to determine the influence o f salt form on solubility, dissolution rate and membrane transport. The equ ilibrium solubility of DDEA at 25 degreesC was determined as 33 mM, lower t han the solubilities of DHEP (273 mM) and DNa (66 mM) previously reported ( Ledwidge and Corrigan, 1998). In addition to the dihydrate form of DHEP pre viously characterised, monohydrate forms of DHEP and DDEA were identified. Intrinsic dissolution rate studies were used to determine the solubility ra tios of the hydrated and anhydrous forms. The monohydrate form of DHEP was found to be 1.8 times less soluble than the anhydrate, whereas DDEA anhydra te was approximately 1.7 times as soluble as the monohydrate form. On inves tigation of the pH-solubility profile (25 degreesC) of DDEA, appreciable su persaturation (76 mM) relative to the theoretical profile, was detected at the pH(max). This contrasts with values of > 800 and 67 mM for DHEP and DNa , respectively. The transport of salt solutions through a porous membrane ( Visking((R))) was investigated. A linear relationship between concentration (mM) and rate of transport (mmol/h) was established for DNa and DHEP solut ions. The mass transfer coefficient determined for DHEP was lower than that for the other two salts. Nevertheless, the maximum transport rate obtained for DHEP is almost six times higher than that obtained for DDEA. (C) 2001 Elsevier Science B.V. All rights reserved.