Synthesis and Pharmacokinetic Study of Three Gemfibrozil Salts: An Exploration of the Structure–Property Relationship

Abstract

Three salts, [H3N­(CH2)2NH3)]­[gem]2 (1), [H3N­(CH2)3NH3)]­[gem]2·2H2O (2), and [H3N­(CH2)4NH3)]­[gem]2­·2H2O (3) of the minimally soluble drug gmfibrozil (Hgem), used for the treatment of hyperlipidemia have been synthesized by using a series of diamine with different carbon chain lengths and characterized by single crystal/powder X-ray diffraction, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance. In the three salts, two protons of two gmfibrozil molecules transfer to one diamine, and the resulting organic diammonium cation and gmfibrozil anion are assembled by hydrogen bond interactions into a two-dimensional layer. Although the apparent solubility of salts 1–3 is obviously improved compared to that of the original gemfibrozil, pharmacokinetic studies in rats indicate the enhancement of absorption is limited with the relative bioavailability of 104% for 1, 154% for 2, and 108% for 3. It is notable that the rapid dissolution behavior of salt 1–3 leads to the increase of maximal plasma concentration (C max) and the dramatic shortening of the time required to reach the C max. The investigation of the structure–property relationship shows that there is little correlation of solubility with the carbon chain length of cation which is different from previous observations, and we speculate that both electrostatic attraction and hydrogen bond interaction contribute to the solubility order (2 > 1 > 3) .

Crystal Packing Arrangement, Chain Conformation, and Physicochemical Properties of Gemfibrozil Amine Salts

“…The effect on crystal packing of systematically varying the length of the alkyl chain in diamine salts (of the form H2N(CH2)nNH2, where n = 3, 4 or 5) of gemfibrozil has also been described previously 14 , where each ammonium group is associated with a gemfibrozil carboxylate anion, with some similar observations to the monoamine salts reported here. When n = 3, these groups form the familiar ladders of (10) rings along the b axis, connected to adjacent ladders via (18) rings, thereby creating a supramolecular sheet.…”

Influence of Annealing in the Close Vicinity of Tg on the Reorganization within Dimers and Its Impact on the Crystallization Kinetics of Gemfibrozil

“…It should be noted that the values of the melting temperature determined for both GEM and dGEM were close to each other ( T m = 334 and 333.4 K, respectively). Moreover, the T m of neat API stayed in a good agreement with those reported in the literature (332.25–337.4 K). − Next, the molten samples of GEM and dGEM were cooled to T = 223 K and heated again at the rate of 10 K/min. Upon lowering the temperature, there was no trace of exothermic peaks, suggesting the undergoing crystallization in the examined systems.…”

Direct imaging of the dissolution of salt forms of a carboxylic acid drug

“…Thermal analysis showed an increase in melting point with the use of the counterion. The three salts showed an increased dissolution rate compared to that of the free acid (Yang et al, 2016).…”