The Effect of lonic Strength on Liposome–Buffer and 1-Octanol–Buffer Distribution Coefficients

Abstract

The distribution of salmeterol and proxicromil between unilamellar vesicles of dioleoylphosphatidylcholine (DOPC) and aqueous buffer at pH 7.4 has been studied, using an ultrafiltration method, as a function of compound concentration, DOPC concentration, and buffer ionic strength. The binding of these ionized lipophilic compounds to neutral DOPC vesicles induces a surface charge, which causes the observed membrane distribution coefficient D(mem)obs to vary significantly with bound compound to DOPC ratio and with ionic strength. This variability is shown to be well-described with use of the Gouy-Chapman theory of the ionic double layer and is contrasted with the ideal behavior shown by the neutral compound clofibrate. Increasing ionic strength is also shown to increase the observed 1-octanol-buffer distribution coefficients D(o/w)obs of proxicromil but through a very different mechanism involving the extraction of ion pairs. This study highlights the experimental difficulty in determining concentration-independent liposome distribution coefficients of ionized lipophilic compounds and describes when deviations will be significant and how observed values may be corrected for such effects. The general effect of ionic strength on membrane-buffer distribution and 1-octanol-buffer distribution is discussed with particular reference to the very different propensity for ion pair formation shown by the two systems, and the most suitable experimental conditions that should be used with each system.

Chemical Speciation of Organics and of Metals at Biological Interphases

“…Ion pairing was also excluded because the apparent D mw varied at fixed ionic strength with the concentration of drug. The ion pair formation accounted for no more than 5 % of the overall partitioning of the anionic drug proxicromil [132].…”

“…The ion pair of pentachlorophenoxide (PCP À ) with Li þ partitions about half a log-unit preferentially into octanol than the ion pair with Na þ or K þ , both of which form about equally strong ion pairs [129]. Moreover, the acidic drug proxicromil exhibited ion pair partitioning that was threefold higher with Li þ than with Na þ [132]. Experiments of ion pair formation of PCP À with divalent counter-ions Mg 2þ and Ca 2þ suggest that a 2:1 complex of PCP À and M 2þ is formed, most likely in the form of MPCP þ with PCP À as a counter-ion [129].…”

“…Austin et al [132] measured the ionic strength dependence of the liposomewater distribution of several acidic and basic drugs and modelled the data with a combination of electrostatic and ion pair models. They concluded that the increased apparent D mw values at higher ionic strength were due primarily to the reduction in surface potential and not to ion pairing.…”

Ion-paired Drug Delivery: An Avenue for Bioavailability Improvement

“…They concluded that the 'propranolol-sodium lauryl sulfate complex' provided promising sustained drug delivery and were feasible to be encapsulated in microparticles for a more sustained drug release effect. Austin et al (1998) studied the distribution of salmeterol and proxicromil between unilamellar vesicles of dioleoylphosphatidylcholine (DOPC) and aqueous buffer at pH 7.4, using an ultrafiltration method, as a function of compound concentration, DOPC concentration, and buffer ionic strength. The binding of these ionized lipophilic compounds to neutral DOPC vesicles induces a surface charge, which causes the observed membrane distribution coefficient D (mem)obs to vary significantly with bound compound to DOPC ratio and with ionic strength.…”

Aplicação do conceito do par iônico e seus efeitos sobre a lipofilicidade de brometos de amônio quaternários estruturalmente análogos a procaína, com atividade de bloqueio da transmissão neuromuscular, para estudos de <i>(Q)SAR</i>

“…Na partição de compostos contendo grupos ionizáveis ou permanentemente carregados, encontram-se trabalhos explorando outros aspectos importantes para a partição, como os efeitos das variações da concentração do composto, dos volumes das fases (Dearden & Bresnen, 1988;Andrés et al, 2015), da temperatura (Brooke et al, 1986), da força iônica (Austin et al, 1998;Wenlock et al, 2011), de mudanças nos valores de pH utilizando tampões (Avdeef, 2001;Malvezzi & Amaral, 2010) e verificando as possibilidades de formação de par iônico (Takacs-Novak & Szasz, 1999;Koufopoulou et al, 2006;Darwish et al, 2015). Este último aspecto é de grande importância, por exemplo, nos casos em que é observado um aumento da lipofilicidade devido à possível formação do par iônico.…”