L18 - Drug Solubility And Dissolution Rate 3 Flashcards
What are many pharmaceutical counterions?
- hydrochloride (43%), sulphate (7.5%) mesylate phosphate, maleate, salicylate, tartrate, lactate, citrate, succinate, acetate
- sodium (62%), potassium (11%), calcium (10%), lithium (14%), magnesium, diethanolamine, zinc, choline, aluminium
What is the regulatory point of view?
- new entity (toxicity testing) -> preformulation -> selection of the most suitable salt
What happens to a WB in the GI tract? (2)
- high dissolution rate in the stomach
- dissolution rate falls as the pH of the GI tract rises
What happens to a WA in the GI tract? (2)
- minimal dissolution rate in the stomach
- dissolution increases down the gut
What will the dissolution rate of a salt form be like in the GI tract?
Will be usually greater than that of the free form
What does the use of the salt form modify?
The pH of the diffusion layer
What does the salt of a WA do to the pH of the diffusion layer?
Increases the pH
What does the salt of a WB do to the pH of the diffusion layer?
Decreases the pH
The pH of the diffusion layer will be:
- that of the bulk solution if we use the free acid
- that of the salt (or ~) if we use the salt form
In conclusion, the use of the salt form results in:
Controlled pH of the diffusion layer independently of the position of the GI tract
What does a controlled pH of the diffusion layer improve?
The dissolution rate
When is the controlled of pH of the diffusion layer an important tool?
when developing slow-release or controlled-release products
When at a given pH of solution, what does the drug in ionic form behave like?
Behaves as a solution of strong electrolyte
What happens when the pH is adjusted to produce mostly unionised molecules exceeding solubility of this form?
Precipitation occurs
How is the solubility of weak electrolytes or non-polar compounds in water can often be improved by?
The addition of water-miscible solvent in which the compound is soluble
What are co-solvents?
Vehicles used in combination with water to increase the solubility of a drug
What is the solubility like in mixed systems compared to individual solvents?
Tends to be greater
What is cosolvency?
Frequently a solute is more soluble in a mixture of solvents than in one alone
What is the purpose of cosolvency? (3)
- obtain aq-based system which the drug solubility is higher than the aq solubility
- higher conc of the drug
- improves stability
What do cosolvents have to be? (3)
- organic compounds
- miscible with water
- better solvents than water for the drug
How are solvent better than water for the drug? (3)
- no single unique structural feature
(H bond donor/acceptor groups, small CHO regions) - most cosolvents are liquid (ethanol, glycerol, propylene glycol)
- some are solids that are highly soluble in water (PEG, PVP, urea)
What do cosolvents decrease?
The hydrogen bond density of aq systems
What does the reduction of H bond density of aq systems reduce?
The cohesive interactions of water
What does the reduction of cohesive interactions of water reduce?
The polarity of the solution
What does the reduction of H bond density, cohesive interactions of water and polarity lead to?
Solution is less effective than water in squeezing out nonpolar solutes
What is sigma in the model for solubilisation by cosolvency?
Solubilisation slope
- effectiveness of a cosolvent as a solubiliser for a particular solute
What is fc in the model for solubilisation by cosolvency?
Volume fraction of the cosolvent
What is the equation for the model for solubilisation by cosolvency?
LogSmixture = logSwater + sigmafc
What does the solubilisation slope tend to do?
Increase with decreasing polarity of the solvent
What does the addition of a cosolvent increase?
The solubility of a nonpolar and semipolar solute in water
What happens to cosolvency as the solute becomes more polar?
Cosolvency becomes less efficient
What does reduces cosolvency do?
It will decrease the solubility of a poalr solute in water
