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

• Published in: International journal of pharmaceutics 2001-07, Vol.222 (2), p.281-293
• Main Authors: O'Connor, Karen M., Corrigan, Owen I.
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Biological and medical sciences; Biological Transport; Bones, joints and connective tissue. Antiinflammatory agents; Diclofenac - analogs & derivatives; Diclofenac - chemistry; Diclofenac - pharmacokinetics; Diclofenac salts; Diethylamine; Dissolution; General pharmacology; Hydrogen-Ion Concentration; Medical sciences; Membrane transport; N-(2-hydroxyethyl)pyrrolidine; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Sodium; Solubility; X-Ray Diffraction
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/S0378-5173(01)00717-7

Non steroidal anti-inflammatory agents (NSAIDs) such as diclofenac have very low aqueous solubilities and consequently salt formation may be used to enhance solubility and dissolution rate. In this study, we examined the physicochemical 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 of salt form on solubility, dissolution rate and membrane transport. The equilibrium solubility of DDEA at 25 °C was determined as 33 mM, lower than the solubilities of DHEP (273 mM) and DNa (66 mM) previously reported ( Ledwidge and Corrigan, 1998). In addition to the dihydrate form of DHEP previously characterised, monohydrate forms of DHEP and DDEA were identified. Intrinsic dissolution rate studies were used to determine the solubility ratios 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 anhydrate was approximately 1.7 times as soluble as the monohydrate form. On investigation of the pH-solubility profile (25 °C) of DDEA, appreciable supersaturation (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®) was investigated. A linear relationship between concentration (mM) and rate of transport (mmol/h) was established for DNa and DHEP solutions. 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.