Lipophilicity Study

Drugs must have appropriate solubility in water and fat to be absorbed through biofilms. Oil-water partition coefficient is a critical parameter used to predict the transmembrane transport of drugs. It is the ratio of the concentration of drugs when they reach dissolution equilibrium in the oil phase and the water phase. Oil-water partition coefficient is an important index of physicochemical properties of drugs, which can predict the solubility of drugs in water or mixed solutions and other physicochemical activities of drugs. The distribution coefficient of a compound is determined by its lipophilicity, which is a tendency for a compound to preferentially allocate in a non-polar lipid medium rather than in the aqueous phase.

Lipophilism is a physicochemical property that can have a great influence on the absorption, distribution, metabolism, toxicity and pharmacological activity of drugs. Lipophilism is associated with many other properties, such as solubility, permeability, metabolism, toxicity, protein binding and distribution.

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RLD lipophilicity should be measured in the phase of pre-prescription studies. It can not only provide basic data for the process of drugs, but also provide reference for the structure-activity relationship, absorption and metabolism of compounds.

Our company is a professional one-stop generic drug consistency evaluation service company. We have helped a number of pharmaceutical companies around the world complete the reverse analysis of RLD and the entire generic drug research process. We use advanced equipment and technology to help customers conduct a full range of RLD analyses, including lipophilicity determination.

The oil-water partition coefficient is determined to simulate the distribution of drugs between buffered aqueous (polar) and fat-soluble (non-polar) phases in living organisms. Since the structure and physicochemical properties of n-octanol are more similar to the biological phase, it is generally considered that a n-octanol-buffered aqueous solution system is an optimal model for studying drug distribution in cuticle-water, and is widely used.

LogP and LogD

Lipophilicity has two forms, logP and logD. LogP is the logarithm of the compound in the ratio of n-octanol to water. The larger the logP, the better the lipophilicity of the drug, and the smaller the logP, the better the hydrophilicity of the drug. The higher the lipophilicity, the more likely the drug is to cross the biological cell membrane increases. But too high fat solubility will have the problem of low solubility. Low lipophilicity (too high hydrophilicity) can also make drugs more difficult to penetrate into biofilms. Therefore, the optimal balance between lipophilicity and hydrophilicity is ideal for drug dissolution and absorption.

LogD is the logarithm of the ratio of octanol to different pH buffers. LogD should be investigated when partial or total solute ionization is caused by pH. Since logD is pH dependent, the pH of the aqueous phase should always be fixed when a logD value is determined. LogD is most commonly measured at the physiological pH of the vasculature (pH 7.4). In simple terms, log P is a constant, and logD has a corresponding pH value.

Our Lipophilicity Study Methods

• Shake-flask

Our company can test the lipophilicity of RLD using the classic shake-flask method. The distribution of the compound in the fat soluble phase (n-octanol) and the water phase reached equilibrium through continuous shaking for a certain time. The distribution coefficient can be determined by measuring the concentration of the compound in the two phases when equilibrium is reached by UV or HPLC.

Fig. 1. shake-flask procedures for the determination of partition coefficients (log D). (Axel Andrés.; et al., 2015)

• Potentiometric titration

The compound is titrated over a certain pH range to obtain the titration curve of the compound in an aqueous solution, as well as in the presence of n-octanol. Lipophilicity is calculated by the displacement of the titration curve due to the allocation of the compound to n-octanol.