TB2: Pharmaceutical Preformulation and Solubility

What is pharmaceutical preformulation?

The phase of drug development where the physicochemical properties of a drug are studied to improve formulation and drug delivery.

Why is preformulation important?

It helps in predicting drug stability, solubility, compatibility, and bioavailability, ensuring effective drug formulation.

What are the key objectives of preformulation studies?

To determine drug properties like solubility, stability, polymorphism, partition coefficient, and compatibility with excipients.

Define Solubility in qualitative and quantitative terms

Qualitative: The ability of a solute to dissolve in a given solvent to form a homogenous solution under specific conditions (e.g. Temperature, Pressure, pH)

Quantitative: The maximum concentration of a solute that can dissolve in a solvent at equilibrium (expressed in units mg/L, g/L, or mol/L)

Define Solubilisation and what it does to help

The process of increasing the solubility of a substance (usually a poorly soluble drug) in a solvent by using agents like surfactants, co-solvents, or complexing agents.

Helps a substance dissolve better in a liquid making it easier to absorb or use.

What is the difference between ‘solubility’ and ‘dissolution’?

• Solubility refers to the maximum concentration of a drug that can dissolve in a solvent.

• Dissolution refers to the process by which a drug dissolves in a solvent over time, often a key step in drug absorption.

Why is Solubility important?

• Drugs must dissolve if they are to be absorbed

• Solubility affects rate of release into dissolution medium

• Solubility affects the bioavailability of the drug

Define Saturation and its relations with Solubility

Saturation: Occurs when a solution has dissolved the maximum amount of solute possible at a given temperature and pressure. Any extra solute added will remain undissolved.

• Unsaturated Solution: More solute can dissolve

• Saturated Solution: No more solute can dissolve; excess remains undissolved.

• Supersaturated Solution: More solute is dissolved than normal, often achieved by heating and then cooling the solution.

Name methods used to determine solubility

• Shake Flask Method

• UV-Visible Spectrophotometry

• High-Performance Liquid Chromatography

• Saturation Method

Recall the factors that influence Solubility

• Temperature, increase in temperature → increase in solubility.

• Solvent pH, degree of ionisation depends of the pH.

• Solvent composition

• Physical form of drug

• Solute pKa

• Particle size/shape

Physical Modification Methods to Enhance Solubility

• Particle Size Reduction: Micronisation (decrease particle size → increases surface area) and Nanosuspension (Create ultra-fine particles)

• Drug Dispersions: Drug is dispersed in a water-soluble carrier (e.g. PEG, PVP) to enhance solubility.

• Modifying Crystal Forms: Amorphous forms have higher solubility than crystal forms. Choosing a more polymorphic form improves dissolution.

Chemical Modification Methods to Enhance Solubility

• pH change: Alter the pH of the solution to increase the ionisation and solubility of weak acids or bases.

• Salt formation: Converting a poor soluble drug into a more soluble salt form (e.g. Aspirin vs Sodium Aspirin)

• Complexation: Use cyclodextrins to form inclusion complexes that improve drug solubility.

• Prodrug approach: Modifying the chemical structure to improve solubility, then converting back to the active drug in the body.

What is the thermodynamic condition for solubility?

The Gibbs free energy change (ΔG) must be negative for a substance to dissolve

How does enthalpy (ΔH) affect solubility?

• Endothermic (ΔH>0) → Solubility increases with temperature.

• Exothermic (ΔH<0) → Solubility decreases with temperature.

How does entropy (ΔS) influence solubility?

Higher entropy (ΔS>0) favors dissolution because the system becomes more disordered.

What is the Noyes-Whitney equation?

dC/dt​=DA(Cs​−C)​/h

where:

D = diffusion coefficient

A = surface area

Cs​ = saturation solubility

C = concentration

h = diffusion layer thickness

Which has higher solubility: amorphous or crystalline forms?

Amorphous forms have higher solubility because they lack a rigid crystal lattice

How do hydrates and anhydrates compare in solubility?

Anhydrates are usually more soluble than hydrates because water molecules in hydrates strengthen the crystal lattice.

Why are salt forms of drugs more soluble than free forms?

Salt formation improves ionization and interaction with water, enhancing solubility

What are co-crystals, and how do they affect solubility?

Co-crystals are crystalline structures containing the drug and a co-former, improving solubility.

Why do amorphous drugs dissolve faster than crystalline ones?

They have higher energy and weaker molecular interactions, making dissolution easier.

What happens if a stable polymorph appears in a drug formulation?

Solubility may decrease, affecting drug absorption and effectiveness.