Introduction

• Solubility is a fundamental concept in pharmacy that significantly impacts drug formulation, bioavailability, and therapeutic effectiveness.
• Understanding solubility and dissolution is essential for optimising drug design and improving patient outcomes, making it a critical area of study for first-year pharmacy students.

What is Solubility?

• Solubility is defined as the maximum amount of a solute that can dissolve in a given quantity of solvent at a specific temperature and pressure, resulting in a homogeneous solution.
• A solute is the substance being dissolved, while the solvent is the medium in which the solute dissolves, typically a liquid.
• A saturated solution occurs when the solvent has dissolved the maximum amount of solute it can hold at a given temperature.
• Miscibility refers to the ability of two liquids to mix in any proportion without separating into two phases.
• Solubility can be described using terms such as “very soluble,” “freely soluble,” and “soluble,” each corresponding to specific solubility ranges (e.g., “soluble” requires 10 to 30 parts of solvent per part of solute).

Factors Influencing Solubility

1. Nature of Solute and Solvent:

   • The rule “like dissolves like” is used to predict solubility.
   • Polar solutes, like salts, dissolve well in polar solvents like water due to strong electrostatic interactions.
   • Non-polar solutes are more soluble in non-polar solvents.

2. Temperature:

   • Solubility of solids in liquids generally increases with temperature as the kinetic energy of the molecules increases, promoting dissolution.
   • Solubility of gases in liquids decreases with rising temperature.

3. Pressure:

   • Primarily affects the solubility of gases; higher pressure increases gas solubility in liquids (Henry’s law).

4. pH:

   • Affects the solubility of ionisable drugs (weak acids and bases).
   • Ionised forms of drugs are generally more soluble in water.

5. Particle Size:

   • Smaller particles have a larger surface area relative to volume, which can increase the rate of dissolution, though it doesn’t directly alter solubility.

Dissolution: From Solid to Solution

• Dissolution is the process by which a solid solute dissolves in a solvent, forming a solution. It is a kinetic process involving the breakdown of the solute into individual molecules or ions that are solvated by the solvent molecules.
• Bioavailability of a drug—its rate and extent of absorption into the systemic circulation—is heavily influenced by the dissolution rate.

Factors Affecting Dissolution Rate

1. Surface Area:

   • Increased surface area (e.g., through particle size reduction) enhances the dissolution rate.

2. Solubility:

   • Higher solubility increases the dissolution rate.

3. Crystal Structure:

   • Different polymorphs (crystalline forms) of a drug can have varying dissolution rates due to differences in lattice energy.

4. Agitation:

   • Stirring or mixing the solution increases the dissolution rate by reducing the thickness of the diffusion layer around the solid.

5. Temperature:

   • Higher temperatures generally increase the dissolution rate.

Noyes-Whitney Equation: Modelling Dissolution

The Noyes-Whitney equation describes the dissolution rate:

dM/dt = (DA(Cs – C))/h

Where:

• dM/dt: Rate of dissolution.
• D: Diffusion coefficient of the solute.
• A: Surface area of the solid.
• Cs: Saturation solubility of the solute.
• C: Concentration of the solute in the bulk solution.
• h: Thickness of the diffusion layer.

Solubility and Drug Development

• Solubility Challenges: Poor aqueous solubility is a common challenge in drug development, often leading to low bioavailability and formulation difficulties.
• Solubility Enhancement Strategies:
  • Salt Formation: Enhances solubility by increasing the drug’s polarity.
  • Prodrugs: Convert inactive derivatives into active drugs after improving solubility.
  • Particle Size Reduction: Increases surface area, enhancing dissolution rates.
  • Solid Dispersions: Dispersing drugs in highly soluble carriers to improve dissolution.
  • Complexation: Using agents like cyclodextrins to form soluble complexes with drugs.
  • Cosolvents: Adding solvents that improve solubility within the formulation.

References

1. University of Utah. (n.d.). Precipitation Reactions. In Introductory Chemistry. Retrieved from University of Utah
2. Ball, D. W., Hill, J. W., & Scott, R. J. (n.d.). The Dissolution Process. In Basics of General, Organic, and Biological Chemistry. LibreTexts. Retrieved from LibreTexts
3. Royal Society of Chemistry. (n.d.). Investigating Solubility. Retrieved from RSC
4. ScienceDirect. (n.d.). Drug Solubility. Retrieved from ScienceDirect
5. McGraw Hill. (n.d.). Solubility and Dissolution. In AccessPharmacy. Retrieved from McGraw Hill