Ionization drug solubility

A search [10] of the World Drug Index revealed that 62.5% of marketed drugs are ionizable, which implies that these substances can exist in various charged states depending on the pH of the media. For ionizable drugs, solubility is pH dependent, and it is therefore important to understand the solubility in the context of pH. Ionization of a compound can be defined by the acid dissociation constant, p/C,. For the case of monoprotic compounds, the solubility at a given pH can be described by the following equations ... 

This chapter considered ionizable drug-like molecules. Absorption properties that are influenced by the pKj were explored. The impact of the pKj-absorption relationship on key physicochemical profiling underlying absorption (solubihty, per-meabihty and ionization) was examined in detail and several simpUfying equations were discussed. The various diff relationships considered in the chapter are systematized in Table 3.2. Table 3.3 summarizes the apparent pfQ shift method for detecting aggregates in solubility profiles, when the apparent pff value derived from Henderson-Hasselbalch analysis of log S pH profile does not agree with the... 

Table 6.3 lists a set of reliably determined log So solubility constants for a series of ionizable drugs determined by the pH-metric DTT solubility method. 

Even for experimentally simple systems, a quantitative understanding of the dissolution of ionizable drugs is possible only if drug solubility, drug ionization constant, buffer concentration, buffer species, and buffer pH are known. 

Liposome partitioning of ionizable drugs can be determined by titration, and has been correlated with human absorption [102-104]. A new absorption potential parameter has been suggested, as calculated from liposome distribution data and the solubility-dose ratio, which shows an excellent sigmoidal relationship with human passive intestinal absorption (Eq. 2) [102, 103]. 

Most drugs are ionized in aqueous solution (Table 2.1), and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionization is expressed by the aqueous ionization constant, pKa. As pointed out below, log D is a p Independent term for ionizable drugs. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, permeability through artificial membranes and... 

Mooney et al. [70] investigated the effect of pH on the solubility and dissolution of ionizable drugs based on a film model with total component material balances for reactive species, proposed by Olander. McNamara and Amidon [71] developed a convective diffusion model that included the effects of ionization at the solid-liquid surface and irreversible reaction of the dissolved species in the hydrodynamic boundary layer. Jinno et al. [72], and Kasim et al. [73] investigated the combined effects of pH and surfactants on the dissolution of the ionizable, poorly water-soluble BCS Class II weak acid NSAIDs piroxicam and ketoprofen, respectively. 

On the other hand, the ionized forms, which tend to be less lipid soluble, cannot diffuse across tire lipid phase of the cell membrane. Ionized molecules may also repelled from the cell surface by groups with similar charge, or may be attracted to it and held there by groups with opposite charge. Ionized drug forms are, sometimes, unable to be filtered even through the aqueous pores of the membranes due to their own size or to the size they attain after the attraction of water molecules. 

Knowledge ofthe aqueous ionization constant,pof an ionizable drug candidate is very important because it can be used to predict solubility, lipophilicity, and permeability at different pH therefore, it... 

The effect of various surfactants, the cationics-eetyl trimethyl ammonium bromide (CTAB), and cetyl pyridinium chloride (CPC), the anionic-sodium lauryl sulfate (SLS), and the nonionic-polysorbate 80 (Tween 80), on the solubility and ionization constants of some sparingly soluble weak acids of pharmaceutical interest was studied (Gerakis et al., 1993). Benzoic acid (and its 3-methyl-, 3-nitro-, and 4-tert-butyl-derivatives), acetylsalicylic acid, naproxen, and iopanoic acid were chosen as model drugs. The cationics, CTAB and CPC, were found to considerably increase th< ionization constant of the weak acidS Ka ranged from-0.21 to-3.57), while the anionic, SLS, showed a negligible effect and the nonionic, Tween 80, generally decreased the ionization constants Solubility of the acids increased in aqueous micellar and in acidiLed micellar solutions. 

Transdermal therapeutic systems (TTS) of nitroglycerin (1), isosorbide dinitrate (2), scopolamine (3) or clonidine (4) have been throughly investigated in vitro and in vivo. However, there have been few studies of skin permeation of ionizable water soluble drugs. 

The result of this anatomical characteristic of endothelial cells in the CNS is an increased resistance to water-soluble and ionized drugs entering the brain, and cerebrospinal fluid (CSF), from capillary blood. However, in a few areas of the brain the barrier is absent. These areas include the lateral nuclei of the hypothalamus, the area postrema of the fourth ventricle, the pineal body, and the posterior lobe of the hypophysis. Highly lipophilic compounds can cross the barrier. Tranquilizers such as diazepam and its analogs are known to gain access rapidly to the CSF with a half-life (tm) entry time of less than 1 minute. 

Acidic or basic drugs are less soluble at low or high pH, respectively, because these drugs are not ionized at either pH. Un-ionized drugs are less hydrated in water than ionized ones. Let us now denote S0 for the solubility of the un-ionized species (HA) and S for the total solubility of the un-ionized and ionized species (A-). Then,... 

Using Equation (3.46a), the solubility of the un-ionized and the ionized drug in a mixed solvent system is given by ... 

The solubility of the drug in the solution containing CD increases as the pH, Ka, and the complex constants (i.e., K j1 1 and K 1,) increase. It is common for k k Kj1,. The increase in solubility as a result of adding CD is primarily responsible for the inclusion complex formation of the un-ionized drug at low pH. However, as the pH of the solution increases, the ionized species significantly contributes to the total solubility of the drug. Figure 3.25 presents the solubility of droxicam in the presence of 10% HPpCD at the different pH values. 

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