Solution Properties

Dissociation constant (K_d ) is the rate constant of dissociation at equilibrium, defined as the ratio of the rate constant of dissociation of the drug from the receptor (K_off ) and the rate constant of association of the drug to the receptor (K_on ). Association constant (K_a) is the opposite of K_d. When K_a is high (or K_d is low), the drug has a high affinity for the receptor. The determination of the dissociation constant (K_d) is essential during drug development, which help us design drugs that can be targeted and selectively combined with the target. We use a variety of analysis method to test dissociation constant (K_d), such as ELISA, SPR, spectral analysis, equilibrium dialysis.

Complexation constants (formation constants, or binding constants) are defined as an equilibrium constant for the formation of complexes in solution. Complexation constants can provide the information used to calculate the concentration of a complex in solution. It is widely used in chemical, biological and pharmaceutical fields. The capillary electrophoresis (CE) methods have been developed for the determination of complexation constants.

The vast majority of drug substances are weak bases and weak acids, and their aqueous solubility are pH-dependent. The solubility is a function of both the pK_a of the compound and the pH of the formulation. That is, the solubility of acidic compounds increases as the pH of the solution is increased (above the pK_a) and the solubility of basic compounds increases as the pH is lowered below the pK_a. The appropriate pH value for the drug solution can help optimize the solubility of therapeutic agent. We adjust of the pH value of solution by using a buffer that does not adversely affect the solubility of the therapeutic agent.

Solubility is defined as maximum amount of solute that can be dissolved in a given amount of solvent, it fundamentally depends on the solvent used as well as on temperature and pressure. There are some factors related solvent properties influencing solubility of drug, including polarity, pH of the medium and volume of solvent employed. Good selection of a solvent may also be critical for solution solubility. Water or vegetable oils are commonly used as solvents for solutions in pharmaceutical industry. Poorly water-soluble drugs are normally dissolved in non-aqueous vehicles. Usually solubility can be improved by incorporating co-solvent.

Partition coefficients are defined as a particular ratio of the concentrations of a solute between the two solvents. The partition coefficients describe how hydrophilic ("water-loving") or hydrophobic ("water-fearing") a drug substance is. Partition coefficients are useful in estimating the distribution of drugs within the body. Partition coefficients can be experimentally determined using various techniques, including the shake-flask, reverse phase HPLC, and pH-metric techniques.

Stability refers to the capacity of the pharmaceutical dosage form to remain specifications established to ensure its identity, quality and purity during the time of storage and usage by the patient. Three drug stabilities should be considered: physical stability, chemical stability and microbiological stability. The stability tests are key assurance of quality of pharmaceuticals. On one hand, it provides evidence on how the drug substance or product quality varies with time under environmental conditions during distribution; on the other hand, it helps to recommend storage conditions. Drugs formulated as solution almost always have chemical and physical stability challenges. The factors affecting stability include temperature, pH, concentration and oxygen. Generally, stability of the pharmaceutical solution is measured by monitoring the change in the content of the active substance over time.

Pharmaceutical thermodynamics is the chemical thermodynamic study of drug action. Thermodynamics plays a role in pharmaceutical sciences. The partitioning of solutes between immiscible solvents, the solubility of drugs, micellisation and drug-receptor interaction can all be treated as thermodynamic terms. The thermodynamic properties of pharmaceutical are important for rational design and optimizing separations such as crystallization. Several computational thermodynamic models now have been used for solvent selection in the pharmaceutical industry.