Ionization pKa

The dogma based on the pH-partition theory that only neutral species cross a membrane has been challenged [11]. Using cyclic voltammetry, it was shown that compounds in their ionized form pass into organic phases and might well cross membranes in this ionized form [32]. Various ways that an ion may cross a membrane have been described [33], including transport as an ion (trans- and/or para- 

The importance of drug ionization in the in vitro prediction of in vivo absorption has been discussed [34], When the apical pH used in Caco-2 studies was lowered from 7.4 to 6.0, a better correlation was obtained with in vivo data, demonstrating that careful selection of experimental conditions in vitro is crucial to have a reliable model. Studies with Caco-2 monolayers also suggested that the ionic species may contribute considerably to overall drug transport [35], 

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Up to now we have focused on measurement of permeability and membrane retention at pH 7.4. Since the GIT covers a range of pH values, with pH 5-8 characterizing the small intestine, it is necessary to address the pH dependence of the transport of drug molecules. Even nonionizable molecules may be affected by pH dependence, since several biological membrane components themselves are ionizable (pKa values listed in Fig. 7.4). For example, with PS, PA, and DA (free fatty acid) undergoing changes in charge state in the pH 5-8 interval. In this section, we examine the consequences of pH dependence. 

The lipid solubility, degree of ionization, pKa of the drug, pH of the drug solution, presence of saliva and the membrane characteristics, molecular weight and size of the drug, various physicochemical properties of the formulation, and the presence or absence of permeation enhancers, all affect the absorption and the permeation of drugs through the oral mucosa. 

To account for the good oral activity of enalapril, attention was drawn to the fact that enalaprilat is an anionic zwitterion at physiological pH (pffa s 2.8, 3.5 and 7.6), whereas only the carboxyl of enalapril is ionized (pKa s 3.0 and 5.4) (118,120). The possibility was considered that enalapril is absorbed from the intestine, as are bile acids and other carboxyl-containing compounds including the nonsteroid anti-inflammatory drugs. Later, Amidon and colleagues published data supporting peptide transport in the oral absorption of enalapril (126,127). 

Ionization, pKa, and Aqueous Solubility Most drugs are weak acids or bases. It is important to note the relationship between the pKa of the compound and the absorptive environment. Delivery systems that are dependent on diffusion or dissolution will likewise be dependent on the solubility of drug in the aqueous media. Since drugs must be in solution before they can be absorbed, compounds with very low aqueous solubility usually have the oral bioavailability problems because of limited GI transit time of the undissolved drug particles and they are limited at the absorption site. Unfortunately, for many of the drugs and bioactive compounds, the site of maximum absorption occurs at the site where solubility of these compounds is least. 

Hilal, S.H., Karichoff, S.W. and Carreira, L.A. (1995). A Rigorous Test for SPARC s Chemical Reactivity Models Estimation of More Than 4300 Ionization pKas. Quant.Struct.-Act.Relat., 14, 348-355. 

One simple point to note about Eq. 19 is the 50% dissociation (or ionization), pKa = pH. It should also be noted that, usually, pK values are preferred for bases instead of the pfCb values (pK = pKa + p b)-... 

Hilal SH, El-Shabrawy Y, Carreira LA, Karickhoff SW, Toubar SS, Rizk M. Estimation of the ionization pKa of pharmaceutical substances using the computer program SPARC. Talanta 1996 43 607-619. 

This increase in pH also changes the physical behavior of the fatty acids they become partly ionized (pKa for long-chain fatty acids is approximately 6.4-6.6), migrate to the interface of the emulsified lipid particles, and mediate— together with bile salts, phospholipids, and cholesterol—lipid solubilization. However, in exocrine pancreatic insufficiency, a shortage of pancreatic bicarbonate secretion impairs this neutralization of pH. As a result, the postprandial... 

In phenol ionization, pKa values (water, 25 °C) for some p-X, o-X pairs are as follows CN, 7.95,6.90 F, 9.91,8.71 Cl 9.42,8.53 Br, 9.36,8.44 NO2,7.15,7.23. (Various different values may be found in the literature for some of these substituted phenols. As far as possible the individual values quoted for the members of each pair have been determined by the same authors.) Here the pattern for CN is similar to those for F, Cl and Br, but different from that shown by NO2, for which the isomeric phenols differ little in acidity. The increase in acidity when an electron-attracting group is moved from para- to nr /zn-position in phenol is doubtless due to an increased transmission of the inductive effect to the reaction centre, which more than outweighs any unfavourable effect of change in orientation. The anomalously low acidity of n-nitrophenol is usually attributed to stabilization of the undissociated form by hydrogen-bonding between OH and ONO. 

Dissolution of the compound also depends on its physicochemical properties notably, its aqueous solubility, ionizability (pKa), and lipophilicity (partition coefficient log Pfor neutral species or log P74 for partially ionized compounds). In addition to its effect on solubility, log Pis a crucial factor that governs passive membrane partitioning. However, while an increase in log P enhances permeability, it indicates a reduced solubility and... 

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