Drug Solubilisation I Flashcards
What is a solution?
A system in which molecules of a solute (drug/ protein/ crystal etc.) are dissolved in a solvent vehicle.
Stages of solubilisation
- Solute or drug molecule removed from its crystal
- Cavity for the molecule created in the solvent
- Solute molecule inserted into this cavity
Factors effecting solubility of drugs in
formulation
1. Nature of solvent/s • Aqueous • Organic 2. Size/shape drug molecule 3. Molecular weight 4. Temperature
Nature of solvent
• Polarity
- Like dissolves in like
- Non-polar drugs in non-polar solvents
- Polar drugs in polar solvents
- Size/shape of drug
•In order to be solvated within a given solvent, its
molecules must first be able to be accommodated within
the cavities between the solvent molecules
• Therefore decreasing particle size will increase solubility
Noyes-Witney Equation: The rate of solution of solids
dw/dy = k(cs - c) where k = DA/o
dw/dt - rate of dissolution of solid
A – surface area of solid
c – concentration in bulk of medium
cs – saturation solubility of the dissolution layer
k – rate constant of dissolution
D – diffusion coefficient of dissolved solute
σ - thickness of diffusion layer
What would happen if you reduced the particle size (A)?
As A↑ then k ↑
resulting in dw/dt ↑
•If dissolution was rate limiting step in bioavailability then change in A (or cs) will result in change in bioavailability
Partition coefficient
- In solution drugs can partition between two immiscible solvents relative to their concentration and affinity for each phase.
- Partition coefficient (P)– measure of hydrophobicity of molecule
𝑃= Co/Cw
CO – concentration in oily (non-aqueous phase)
CW – concentration in aqueous phase
- Useful for estimating distribution of drugs within the body
- Higher value P, the greater the lipid solubility of the solute.
- Often referred to in log form (logP)
Traditional excipients for drug solubilisation
- Surfactants
- Cosolvents
- Microemulsions
- Surfactants
- Low molecular weight amphiphilic compounds
- Hydrophobic regions usually consists of saturated or unsaturated hydrocarbon chains, heterocyclic or aromatic ring systems
- Classified according to their hydrophilic group
Surfactant micelles
In aqueous environments surfactants spontaneously aggregate to form micelles. Type of intermolecular aggregation.
Critical micellar concentration
• Concentration above which micelles will be formed in solutions is known as the critical micellar concentration (CMC)
↓ CMC = ↑ micellar stability
• Factors effecting CMC:
- Structure and nature of hydrophobic group
- Addition of electrolytes
- Temperature
- pH
Examples of commonly used surfactants
- Tweens e.g. Tween 80
- Spans E.g. Span 80
- Cremophor EL
- Sodium docecyl sulphate (SDS)
Disadvantages of surfactants
- Possess relatively high CMC values – unstable upon dilution resulting in premature drug loss
- High excipient/drug ratio - low efficiency
- High levels needed can cause safety concerns and can lead to unnecessary side effects
- Oily/viscous solutions cause great patient discomfort upon administration
- Cosolvents
- Where drug solubility in one solvent is limited, the presence of two solvents employed
- Two miscible solvents mixed, one is water and one is a solvent the drug dissolves readily in.
- E.g. polypropylene glycol, glycerine or ethanol mixed with water.
- This method not preferred as residual organic solvents remain in formulation may be toxic to patient
- Microemulsions
- Microemulsions are liquid mixtures of oil, water and surfactants (or cosurfactants)
- They are usually clear and are thermodynamically stable
- Microemulsions are essentially swollen micellar systems
- It is difficult to make clear a distinction between emulsification and solubilisation as there is a very gradual transition from one process to the other
- At the transition to swollen micelles (also known as microemulsions) occur
- The microdroplet size formed is usually less than 100 µm.
Disadvantages microemulsions
- High excipient:drug ratios
- Costly
- Viscous
- Side effects
- Low efficiency
- Relatively low stability
Advanced technologies for hydrophobic drug solubilisation
• Liposomes
Amphiphilic polymers • Block copolymer • Graft polymers • Star shaped polymers • Dendrimers
• Cyclodextrins
Advantages of nano sized drug delivery systems
- At such a small size, particles have the capability of showing a wide range of unique physical and chemical properties.
- The exaggerated surface: volume ratio of nanoparticles makes them ideal for functionalization and specialization.
- Nanoparticles can be fabricated through controlled synthesis enabling their physical properties such as size, shape, composition and other properties, to be tailor made.
- The surface reactivity of nanoparticles can be modified by using a variety of functional groups giving them ‘intelligent properties’.
- Nanoparticles injected systemically, can accumulate in the leaky microvasculature of tumour cells due the phenomenon known as the enhanced permeability and retention effect (EPR)
What are liposomes?
• Liposomes are closed spherical vesicles consisting of an aqueous core surrounded by one or more concentrically arranged bilayer membranes.
• Membranes can be composed of natural or
synthetic lipid molecules
• Usually phospholipids are used to formulate liposomes, however a range of other polar lipids can be used.
Liposomal structure
- Liposome vesicles are composed of unilamellar or multilamellar lipid bilayers which have alternative aqueous layers sandwiched between the bilayers
- Upon aggregation multilayered liposomes are formed however, these are easily converted to unilamellar entities by sonication
Liposome Formation
- To prepare liposomes energy has to be added to the system (forming lamellar and not micellar structures)
- Driving force is interaction of aqueous regions and segregation of lipid regions from aqueous phase.
Liposome formation dependant on:
- Temperature
- Lipid concentration
- Electrostatic interactions of polar lipids with solvent and solute molecules
