Physical and Chemical Properties of Drugs and Calculations

In the realm of drug discovery and development, it is imperative to comprehend the physical and chemical attributes of drugs to refine their pharmacokinetic and pharmacodynamic properties. These features markedly impact the drug's absorption, metabolism, distribution, and elimination inside the body. Through a comprehensive assessment of these properties, pharmaceutical scientists can arrive at informed determinations regarding drug design, formulation, and dosing.

Lipophilicity

Lipophilicity, also called hydrophobicity, is an important parameter in the drug discovery and design process and is closely related to a compound's solubility, membrane permeability, strength of activity, selectivity, and hetero-ubiquity, as well as influencing the compound's pharmacokinetic and pharmacodynamic properties. Appropriate lipid-soluble size, low molecular weight, and polar surface area are the main drivers for a compound to be well absorbed.

The most commonly used parameter to characterize lipid solubility is the Partition Coefficient log P value. Log P is the ratio of the concentration of a nonionized compound (neutral compound) in an aqueous phase to that of an organic solvent phase, typically octanol. Pharmaceutical chemists calculate the log P value based on the structure of the compound, and the fat-soluble log P value of an ideal drug is generally between 1 and 5. The methods used to calculate the log P values of compounds can be broadly classified into two main categories, substructure-based summation modeling methods and property-based methods.

• Substructure-based summation modeling method. The molecule is first partitioned into fragments or individual atoms and then the hydrophobic contributions of these fragments or individual atoms are summed.
• Property-based methods. Based on the physicochemical properties of the whole molecule, such as molecular surface, molecular volume, dipole moment, partial charge, orbital energy, or some topological indices as well as electrostatic indices.

Solubility

Solubility represents a crucial parameter for the characterization of the drug-like qualities of compounds. It stands as one of the most prominently influential factors in drug absorption and bioavailability. To facilitate absorption into the body, a drug must undergo dissolution in water before biofilm penetration can occur. In the early stages of drug development, lipid-soluble structures are frequently introduced to enhance the affinity with target proteins, to boost the activity of compounds. This, in turn, accentuates the issue of compound solubility.

Computational solubility modeling is mainly a statistical approach based on different descriptors to predict solubility by constructing QSAR equations. Solubility is often expressed in its logarithmic form log S. Commonly used methods for solubility prediction include free energy calculation methods based on quantum mechanics and molecular mechanics, which are more computationally demanding, and QSAR methods, which are relatively fast. The latter method is more suitable for the calculation of large-scale compound libraries and is also the most used in drug design.

pKa Value

The pKa value is used to characterize the dissociation constant of a compound and is closely related to the ADME properties of the drug. The distribution and diffusion of a drug are heavily dependent on the ionization state of the drug at physiological pH, with the neutral form of the drug being more lipid-soluble and the ionized form being more polar and water-soluble. Common computational methods can be generally categorized into quantum mechanics-based and QSAR-based methods.

Creative Bioarray Relevant Recommendations

Creative Bioarray provides physicochemical characterization assays to help customers accurately evaluate compounds' physicochemical properties such as solubility and stability, reducing drug development difficulties.

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