Unit 1: Solubility of Drugs

February 25, 2026

Semester 3
BP302T

Introduction to Solubility of Drugs

Solubility is the single most important physicochemical property in drug formulation. A drug must dissolve before it can be absorbed. This unit covers the fundamental mathematics of solutions, the factors influencing how much drug dissolves, and key laws (Raoult’s law, Henry’s law, Distribution law) essential for formulation scientists.
Download PDF

Syllabus & Topics

  • 1Solubility Expressions: Percentage w/v, w/w, v/v; Molarity (M), Molality (m), Mole fraction (X); Pharmacopoeial solubility terms (Very soluble < 1 part, Slightly soluble 100-1000 parts, Practically insoluble > 10,000 parts).
  • 2Mechanisms of Solute-Solvent Interaction: Ion-dipole, Dipole-dipole, Hydrogen bonding, London dispersion forces. ‘Like dissolves like’ principle.
  • 3Ideal Solubility Parameters: Activity coefficient γ = 1 for ideal solutions. Hildebrand solubility parameter (δ).
  • 4Solvation and Association: Solvation (salvation in aqueous media = hydration). Hydrophilic vs hydrophobic drugs.
  • 5Factors influencing solubility (Quantitative approach): Temperature (van’t Hoff equation), pH (Henderson-Hasselbalch for weak acids/bases), particle size (Noyes-Whitney equation), crystalline form (polymorphism), co-solvents.
  • 6Diffusion in Biological Systems: Fick’s First Law: J = -D(dC/dx). Fick’s Second Law. Applications for absorption prediction.
  • 7Solubility of Gases in Liquids: Henry’s Law (p = KH × X). Effect of temperature on gas solubility. Oxygen/CO2 dissolution in blood.
  • 8Binary Solutions and Ideal Solutions: Raoult’s Law for non-volatile solutes: P = P₀X₁ (solvent). Applications to osmometry and cryoscopy.
  • 9Real Solutions: Positive deviations (intermolecular repulsion > attractions) and negative deviations from Raoult’s Law.
  • 10Partially Miscible Liquids: Two-phase systems (e.g., phenol-water at room temperature).
  • 11Critical Solution Temperature (CST): Upper CST (UCST) – above this temp, both liquids mix completely (phenol-water UCST = 65.6°C). Lower CST (LCST). Applications in quality control.
  • 12Distribution Law (Nernst Partition Law): C(org)/C(aq) = K (partition coefficient). Assumptions and limitations.
  • 13Applications of Distribution Law: Extraction (separating drugs), absorption prediction, log P and its importance in Medicinal Chemistry.

Learning Objectives

Solubility Expressions: Convert mg/mL to molarity and vice versa for a given drug.
Raoult’s Law: Calculate vapour pressure of a solution given mole fraction of solute.
Fick’s Law: State Fick’s First Law and define the terms J, D, and dC/dx.
Henry’s Law: Explain why oxygen solubility in blood decreases at high altitude.
Distribution Law: Calculate the partition coefficient given concentrations in two immiscible solvents.

Frequently Asked Questions (FAQs)

Q1. What factors affect solubility of a drug?

Temperature (endothermic dissolution = solubility ↑ with temp), pH (weak acid solubility ↑ with ↑pH; weak base ↑ with ↓pH), Particle size (smaller particles dissolve faster – Noyes-Whitney/Ostwald-Freundlich), Crystal form (amorphous > crystalline solubility), Co-solvents (propylene glycol, ethanol), and Salting-in/Salting-out.

Q2. What is Raoult’s Law?

For an ideal solution, the vapour pressure of a component is proportional to its mole fraction in solution:

P₁ = P₁⁰ × X₁

The total vapour pressure is:

P = P₁⁰X₁ + P₂⁰X₂

Deviations occur when solute–solvent interactions differ from solvent–solvent interactions.

Q3. What is Critical Solution Temperature (CST)?

The UCST (Upper CST) is the temperature above which two partially miscible liquids become completely miscible in all proportions. Below the UCST, two separate liquid phases exist.

Example: Phenol + Water system has a UCST of 65.6°C.
Used in quality control of Phenol Injection.

Q4. What is the Distribution Law (Partition Coefficient)?

At constant temperature, a solute distributes between two immiscible solvents in a constant ratio:

K = Corganic / Caqueous

Limitations: Only applies to same molecular form in both solvents (no ionization, no association/dissociation).

Log P is a pharmaceutical descriptor for lipophilicity.

Q5. What is the significance of Log P in pharmacy?

Log P (Log10 of octanol/water partition coefficient) measures a drug’s lipophilicity.

  • High Log P = lipophilic = good membrane permeability but poor water solubility

  • Low Log P = hydrophilic = poor membrane permeability

Ideal Log P for oral absorption = 1–3
(Lipinski’s Rule of 5: Log P ≤ 5)