Estimation of Distribution Coefficients from the Partition Coefficient and p K a

tion in the assessment of relative lipophilicity and hydrophilicity of a compound. Recent advances in computational chemistry have enabled scientists to estimate partition coefficients for neutral species very easily. For ionizable species, the distribution coefficient is a more relevant parameter; however, less effort has been applied to its assessment. Knowledge of the distribution coefficient and pKa is important for the basic characterization of a compound (1), particularly when assessing the compound’s potential to penetrate biological or lipid barriers (2). In addition, the majority of compounds are passively absorbed and a large number of new chemical entities fail in the development stages because of related pharmacokinetic reasons (3). Assessing a compound’s relative lipophilicity dictates a formulation strategy that will ensure absorption or tissue penetration, which ultimately will lead to delivery of the drug to the site of action. In recognition of the value of knowing the extent of a drug’s gastrointestinal permeation along with other necessary parameters, FDA has issued guidance for a waiver of in vivo bioavailability and bioequivalence testing for immediate-release solid oral dosage forms. This guidance is based on the Biopharmaceutics Classification System, which ranks drugs according to aqueous solubility, intestinal permeability, and drug product dissolution (4). Although distribution coefficients are not entirely representative of permeability through gastrointestinal tissue, skin, or other tissues, they are related—the distribution coefficient is a key factor in determining the permeability of drugs through lipid barriers. Methods of estimating the distribution coefficient vary from simple approaches to those that are highly complex and can be measured or calculated (5–10). A few methods consider the partitioning of the ionized species in the oil phase. For example, ACD/LogD Suite (Advanced Chemistry Development, Inc., Toronto, Canada) is a computational chemistry software package that includes the presence of the ionized species in the oil phase. In most cases, it may seem unreasonable that the ionized species can exist at any appreciable amount in the oil phase (octanol); however, this can be explained by the fact that octanol, when it comes into contact with water such as during the