Ionizable molecules, aqueous solubility

Thus, for the modeling of skin penetration, it is usually considered preferable to use descriptors that may be related to the capability of a molecule to cross the stratum comeum. This typically relates to hydrophobic and steric properties of a molecule, but other commonly utilized descriptors include those for hydrogen bonding, ionization, and aqueous solubility. Such properties may be related directly to capability of a molecule to cross a membrane such as the skin (Moss et al., 2002). 

Two sensibly priced commercial databases for solubility exist [366,507], An article in the journal Analytical Profiles of Drug Substances carries solubility data [496]. Abraham and Le [508] published a list of intrinsic aqueous solubilities of 665 compounds, with many ionizable molecules. It is difficult to tell from published lists what the quality of the data for ionizable molecules is. Sometimes, it is not clear what the listed number stands for. For example, Sw, water solubility, can mean several different things either intrinsic value, or value determined at a particular pH (using buffers), or value measured by saturating distilled water with excess compound. In the most critical applications using ionizable molecules, it may be necessary to scour the original publications in order to be confident of the quality of reported values. 

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... 

When the soluble salt sodium formate (NaHCOO) is added to a formic acid solution, the salt undergoes complete dissociation in water to produce the common ion, HCOO-. The original equilibrium involving the weak acid shifts to the left. As a result, the fraction of HCOOH molecules that undergo ionization in aqueous solution will be less. 

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. 

Aqueous solubility of ionizable molecules at different pH values is an important characteristic because it indicates the potential substance behavior in the stomach and intestinal tract and its potential impact on bioavailability. Moreover, it also provides important information for formulation scientists to define the class of a drug substance in the Biopharmaceutics Classification System (BCS), a regulatory guidance for bioequivalence studies. The BCS is a scientific framework proposed by the FDA to classify drug substances based on their aqueous solubility and intestinal permeability and defines important parameters in the selection of drug candidates into development. According to the BCS, drug substances are classified as shown in Table 12-4. 

Identification of pharmaceutically acceptable vehicles that afford sufficient solubilization while maximizing physiological compatibility for preclinical pharmacokinetic evaluation is critical. The most frequently used solubilization techniques include pH manipulation for ionizable compounds use of cosolvents such as PEG 400, ethanol, DMSO, and propylene glycol micellar solubilization with surfactants such as Tween 80 or SLS complexation with cylodextrins [40]. By using the solubilization techniques, the enhancement in solubility of poor water-soluble compounds can be significant compared to aqueous solubility and can facilitate the absorption of drug molecules in the gastrointestinal tract when delivered in solution form. 

Molecules that are weak acids or bases cross membranes more readily when they are in the non-ionized form. However, aqueous solubility is favored for the ionized form. In order to be available to cross any membrane, a drug must be in solution. This paradoxical requirement of both aqueous and lipid solubility is of particular concern in the area of drug absorption and presents a constant challenge in pharmaceutical formulation. 

Notice that the assumption used in equation (9.9) is not valid in general. First, water dissolves in octanol, and thus charged compounds will partition in it too. Second, as in the case of aqueous solubility, the ionization of molecules depends on other parameters than just pH, such as the concentration and nature of the counter-ions [63]. 

Changing the pK of an acidic or basic group in a molecule so that more of the compound exists in the ionized form at physiological pH lowers log D (at about pH 7) and, in general, should improve aqueous solubility. The improvement in solubility is limited, however, if the solubility of the neutral form of the compound (the inherent solubility) is very low. The situation is worsened if the starting pK is far from 7. We find this to be a particular problem with weak bases. Weakly basic pyridines, quinolines, quinazo-lines and thiazoles seem to be frequent members of combinatorial libraries. Understanding the ionization behavior of drugs and how this property relates to oral absorption is extremely complex and likely beyond the capability (and interest) of many medicinal chemists. The reader is referred to an excellent recent review in this complex area. ... 

The terminal hydroxyl group is sufficiently hydrophylic to givx surface activity but does not convey polarity to the molecule, so that there is no ionization in aqueous solution. Many of them tend to become less soluble at temperatures approaching the boil, and are most effective cold or at the lower temperature ranges. It is probable that the formation of hydrogen bonds of the type R.O.CH,.CH, - with the solvent help to keep them in... 

Experimental measurements of solubility are influenced by many different factors, including the purity of the solute and solvent, presence of cosolvents, presence of salts, temperature, physical form of the undissolved solute, ionization state, and solution pH [18]. Consequently many different definitions of solubility are in common use in the published literature. Here we discuss the intrinsic aqueous solubility, Sg, which is defined as the concentration of the neutral form of the molecule in saturated aqueous solution at thermodynamic equilibrium at a given tanperature [18-20]. Intrinsic aqueous solubility is used to calculate dissolution rate and pH-dependent solubility in models such as the Noyes-Whimey equation [21] and the Henderson-Hasselbalch equation [22, 23], respectively. Prediction of the intrinsic aqueous solubility of bioactive molecules is of great importance in the biochemical sciences because it is a key determinant in the bioavailability of novel pharmaceuticals [1, 3, 24-26] and the environmental fate of potential pollutants [27, 28],... 

Many drugs and metabolites are acidic, basic, or amphoteric and can be protonated or deprotonated depending on their pH and pKg values. An ionization center can produce a chained species and thus a water-soluble ion. Conversely, neutral molecules are soluble in organic solvents such as methylene chloride. Control and manipulation of the pH of an aqueous phase is exploited in LLEs and in solid-phase extractions (SPEs), to maximize separation efficiency. 

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