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

Abstract

Salt formation is used to optimize pharmaceutical properties for carboxylic acid drugs but selection can often be empirical. An extended series of salts of the anti-hyperlipidaemia carboxylic acid drug gemfibrozil was prepared using related series of amine counterions to gain a molecular insight into the impact of crystal packing arrangements on their physicochemical properties. With only a few exceptions, the salts had similar crystal packing motifs. Although there was no discernible relationship between melting point of the salt form and the aqueous solubility of the salt across the whole dataset, there were trends within structurally-related series of salts relating increasing melting enthalpy with increasing molecular weight of the counter ion.3

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

“…DSC showed GEM to have a melting point of 60.3 °C. This was a sharp narrow peak similar to that published by Ramirez et al (Ramirez et al, 2017) and Aigner et al (Aigner et al, 2005) who reported a melting temperature of 61.2 °C and 59.3 °C respectively. The single endotherm confirmed the thermal stability of GEM and thus the absence of polymorphism within GEM.…”

“…They observed that the increased capacity for hydrogen bond formation had an influence on the crystal structure of the salt and that the increasing hydrophilicity of the counterion was beneficial in solubility enhancement. Ramirez et al characterised the crystal packing, chain conformation and physiochemical properties of crystalline gemfibrozil amine salts (Ramirez et al, 2017). They observed that the cyclic amine counterions increased the melting point, which correlated with an increase in counterion molecular weight whereas the linear amine counterions had a decrease in melting point with an increasing molecular weight and volume.…”

“…The salts were prepared as reported by Ramirez et al (Ramirez et al, 2017). In brief, equimolar ratios of the drug (GEM) and counterion (CPROP, CBUT, CPENT and CHEX) were dissolved in 50 mL of acetonitrile and the resultant precipitated salt filtered under vacuum.…”

“…Poor aqueous solubility, which is now typical of the majority of emerging active pharmaceutical ingredients (API), can be a challenge in pharmaceutical development (Al-Hamidi et al, 2010a;Korn and Balbach, 2014;Ku and Dulin, 2012;Williams et al, 2013). As a result of their crystal structures, APIs can also have undesirable properties which can impact their physicochemical and mechanical properties thus affecting compaction, dissolution, bioavailability, hygroscopicity and stability to name a few (Asare-Addo and Conway, 2017; David et al, 2010;Ramirez et al, 2017).…”

Hot-melt extrusion process impact on polymer choice of glyburide solid dispersions: The effect of wettability and dissolution

“…use of buffers or novel excipients (Asare-Addo et al, 2018;Adebisi et al, 2016;Adebisi et al, 2016;Al-Hamidi et al, 2014, 2010a, 2010bAsare-Addo et al, 2015;Nokhodchi et al, 2017Nokhodchi et al, , 2015Nokhodchi et al, , 2005Rabinow, 2004;Stahl et al, 2008;He at al., 2017;Ramirez et al, 2017;Šupuk et al, 2013).…”