Poorly Water Soluble Drugs Flashcards
WHY does low water solubility reduce oral bioavailability?
Because absorption for poorly water soluble drugs is dissolution rate limited. The solid drug must first undergo dissolution to become a drug in solution before it can permeate the intestinal membranes.
What are the TWO main problems for delivery of poorly water soluble compounds?
1) Low bioavailability
2) Variable plasma profiles
What TWO main variables of the dissolution formula can be manipulated to increase dissolution (and therefore absoroption)
- *S** = Solubility
- *Cs **= Surface Area (concentration)
You can’t change h because you can’t ‘stir’ and mix the intestines to decrease the diffusion layer thickness
You can’t change D (diffusion co-efficient) because it’s the molecular property, especially if it is of a small molecular weight.
What THREE things must a drug do to be able to go into solution in water?
- Break apart solute (drug) molecules in the solid state.
(energy needed to break solute-solute bonds; melting point) - Create a ‘cavity’ in the solvent
(break bonds b/w solvent molecules: easier than solute molecules) - Insert solute molecule (drug) into cavity in solvent.
(favourable solute-solvent interactions, eg. polarity & ionisation)
Name SIX methods can be used to enhance oral bioavailability.
- Isolation of salts
- Alteration to crystal structure (Polymorphs)
- Particle size reduction
- Solid dispersions
- Use of surfactants
- Lipid based formulations
WHY does isolation of WEAK acids and bases as a salt increase solubility?
It stabilises the drug as an ionised salt form to increase it’s ability to interact with a polar solvent (e.g. water), thus making this ionised drug more soluble.
HOW can a WEAK acid or base be isolated as a more water soluble salt?
For example, to form the Sodium (Na) salt of Para Aminosalicyclic acid (PAS):
- Free acid of PAS (**acid) dissolved in organic solution
- Sodium Hydroxide (base) added
- Sodium salt (Na PAS) precipitates and is isolated
- Sodium salt (Na PAS) is then dissolved back into water
- Ionised acid (PAS-) (more soluble) and base reformed.
[The pH of the saturated solution of Na PAS will be basic] - Enhanced solute-solvent interaction
What is the rationale behind altering crystal structure to change solubility? And what is the downside of increasing solubility via this method?
Reducing the strength of the intermolecular solute-solute interactions increases solubility.
It reduces the melting point, leading to to ‘high energy’ crystal forms (Polymorphs, Amorphous forms, Solvates). BUT it has the potential for instability on storage because of being thermodynamically unstable.
Can reducing the particle size generally increase solubility?
No. Reducing the particle size can only increase the rate of dissolution by increasing the surface area available to be in contact with the solvent.
It doesn’t change the intermolecular (solid state) properties since it is still going to interact in the solution the same way.
But, it will get the particles in contact with the solution faster, so will only allow it to reach its highest solubility point faster. Therefore, it’s useless for drugs with low solubility.
What is a solid dispersion and how is it usually formed?
It is a solid dose form where the drug is present in a molecularly dispersed form of a drug in carrier (often in the amorphous state).
It is produced via:
- Mixing a drug with a water soluble carrier (e.g. polymer) in the liquid state (molten or in a solvent)
- Rapidly solidified via cooling or solvent evaporation
What are THREE advantages to solid dispersions
- Stabilise high energry crystal forms (e.g. amorphous) that have higher aqueous solubility
(polymer prevents 2 drug molecules from aggregating to a crystal) - Super-saturated solutions
- High dissolution rate, despite precipitation.
Name two polymers as carriers that can be utilised to produce solid dispersions, and list their advantages.
-
Polyethylene glycol (PEG)
(i) Wide range of molecular weights (1K - 20K)
(ii) Stabilised metastable forms due to increase in viscosity of solid
(iii) Increase solubility by re-arranging water structure around itself to increase rate of dissolution -
Polyvinylpyrollidine (PVP)
(i) High melting point >275oC
(ii) Wide range of molecular weights (10k - 700k)
(iii) Stops recrystillisation by H bond interactions with drug
Can you use the ‘melting technology’ for Polyvinylpyrollidine (PVP)?
No. PVP has a melting point > 275oC. Most drugs would degrade to match that melting point.
Therefore, you’d use the solvent method, where you end up with a drug and polymer contained in a liquid state. Then, rapidly solidified to create an amorphous form.
List THREE possible effects of surfactants.
- Increase Wetting
- Decrease Aggregation
- Increase solubilisation in surfactant micelles (at conc > CMC [Critical Micelle Concentratio])
“The addition of surfactants to solid dose forms is primarily used for its wetting effects. Not to increase solubilisation of surfactant micelles” True or False. Explain.
True.
The amount of surfactant used isn’t sufficient enough to generate a concentration in GIT to be > CMC (Critical Micelle Concentratio).
Therefore, the wetting effects are most important to change the interfacial tensions between the solid & water to allow it to go into solution. Also, to decrease aggregation.
