Importance of Solubility and Lipophilicity in Drug Development

Solubility and lipophilicity are basic physicochemical properties, but also key parameters that can dictate the success or failure rate of drug discovery and development. In short, their measurement is pivotal for both in vitro and in silico evaluation of drug properties.

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Solubility and its importance

The solubility of a compound is based on its structure and conditions of solution. The structure of the compound can determine other factors associated with it, such as hydrogen bonding, lipophilicity, molecular volume, ionizability, etc.

All the aforementioned factors together determine solubility. The conditions of the solution include pH, co-solvents, additives, ionic strength, and temperature. The poor solubility of a compound can lead to reduced productivity in terms of drug discovery and development.

While the oral route of delivering a drug remains the most convenient and common mode, one of the challenges of this method is the poor bioavailability of oral dosage. This is often due to poor solubility and low level of permeability, as the drug that needs to be absorbed should be in aqueous solution form at the site of absorption. As more than 40% of drugs are currently insoluble in water, this is one of the challenging areas for chemists.

Methods to enhance solubility

Physical modifications

One method to increase solubility is to reduce the size of the particle. Increasing the surface area can allow increased interaction with the solvent, and subsequently, augment the degree of solubility.

Nanosuspension represents a method that is applied to drugs that are poorly soluble in water and oil. It consists of a biphasic system where the nano-sized drug particles are stabilized using surfactant for oral or topical use.

Creating amorphous drug nanostructures that have a high level of porosity at low temperatures is another method to increase the dissolution rate. After processing at low temperatures, dry powder of the drug is obtained using one of the several drying methods - including spray and vacuum freeze-drying.

Chemical modifications

Various chemical methods (such as changing the pH, using buffers, derivatization, etc.) can be used to increase the solubility of the drug. Some of the other methods include using supercritical fluids that have a greater temperature and pressure compared to their critical temperature and critical pressure. This allows scientists to combine the properties of both liquids and gases. Using surfactants to increase the solubility of poorly soluble drugs is another viable strategy.

Lipophilicity and drug discovery

Lipophilicity is an important physicochemical parameter that contributes to absorption, distribution, metabolism, excretion, and toxicity of a drug. This, in turn, affects the solubility and permeability of a drug and contributes to its potency and selectivity.

It is often observed that drugs that are in the early stages of development have high lipophilicity. This often leads to compounds that have a high rate of metabolism, leading to poor solubility, high turn-over, and low absorption. Very high levels of lipophilicity can also lead to toxicity and metabolic clearance. Hence, there is a need to monitor and manage the lipophilic properties of drugs.

Measuring lipophilicity

Lipophilicity is measured as the partition coefficient or distribution coefficient. The distribution coefficient is the ratio of the sum of the concentrations of all the compounds in the two phases. Thus, lipophilicity is the result of all the intermolecular forces present in a solute and the two phases that it partitions.

One of the methods to measure lipophilicity involves dissolving the sample in a mixture of water and octanol, and agitating it until the equilibrium point is reached (so-called shake-flask method); then the two phases of octanol and water can be separated.

Another method is potentiometric titration. Both these methods provide a measure of the lipophilicity, but the shake-flask method is not suitable for degradable compounds, and the titration method is labor-intensive and requires ionization centers.

Bioavailability and lipophilicity

Bioavailability is a parameter that is highly dependent on solubility, permeability, and clearance; moreover, all three parameters, in turn, depend on lipophilicity. Thus, there is a defined role of lipophilicity on bioavailability. Studies report that the optimum range of lipophilicity to achieve good availability is log P (logarithm of the partition coefficient) between zero and three.

Also, parameters, such as rotatable bonds and ionization state are also good predictors of bioavailability as these also have an effect on parameters, including hydrogen bonding, lipophilicity, molecular volume, ionizability. Thus, there has been an increase in the drive to control properties, such as solubility and lipophilicity, in order to improve the quality and likelihood of therapeutic success of drug compounds.

Sources

Further Reading

Last Updated: Aug 26, 2019

Dr. Surat P

Written by

Dr. Surat P

Dr. Surat graduated with a Ph.D. in Cell Biology and Mechanobiology from the Tata Institute of Fundamental Research (Mumbai, India) in 2016. Prior to her Ph.D., Surat studied for a Bachelor of Science (B.Sc.) degree in Zoology, during which she was the recipient of an Indian Academy of Sciences Summer Fellowship to study the proteins involved in AIDs. She produces feature articles on a wide range of topics, such as medical ethics, data manipulation, pseudoscience and superstition, education, and human evolution. She is passionate about science communication and writes articles covering all areas of the life sciences.  

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