Physical Properties of APIs Flashcards
What is the drug development process?
Preclinical (phase 0) - is the drug candidate safe and bioavailable?
Early development with clinical phases 1-2 (1 = healthy patients, 2 = patients with disease) [exploratory]
Late development with clinical phases 2-4 (scaling up of clinical testing) [confirmatory]
What are the parts of the preclinical stage?
Chemical pharmaceutical development
Nonclinical development - in vitro DMPK, toxicology and safety studies
Clinical development - exploratory phase 0 trial in healthy volunteers
What is pre-formulation?
Stage in drug and dosage form development before formulation proper - aims to optimise process of turning a drug candidate into a product.
Physicochemical properties of drug candidates are determined.
How can dosage form affect drug uptake?
Different dosages have different pharmacokinetics, leading to different time of actions. Physicochemical properties are different.
What is solubility?
Concentration of solid components in solution at equilibrium between solid and solution.
What factors can impact solubility?
Temperature, pressure, presence of other chemicals, pH
What determines solubility?
Molecule interactions between solute and solvent, “like dissolves like”, stability of crystal lattice
What assumptions does the ideal solution model make?
All molecular interactions are equivalent.
How is solubility measured?
Gravimetric method: make a saturated solution, filter and weigh, evaporate solvent and reweigh.
Any analytical technique can be used to identify concentration of solution.
What is a solubility curve?
Part of a phase diagram, showing regions of solution and solution and crystals. Along the line is a saturated solution.
What is the Schroeder-van Laar equation for an ideal solution?
Ln(xA) = - (ΔHAfus)/R (1/T - 1/(TAfus)), where A is the solute and xA is the mole fraction of A.
What does the Schroeder-van Laar equation indicate?
Solubility is independent of the solvent
How do we measure fusion data?
Thermal analysis with DSC to give a thermograph. ΔH can be found from kA where k is calorimetric constant and A is peak area.
Why is solubility important?
For drug absorption, must be present in solution at absorption site. Generally this is water, and drugs have to balance being able to move through lipid bilayers to enter cells and solubility in water!
What is logP?
Partition coefficient, solubility ratio of unionised species of a compound in a mixture of two immiscible solvents, octanol/water.
What does the value of log P tell us?
High values for log P are more soluble in octanol, and low values are more soluble in water.
What is the GSE?
general [aqueous] solubility equation
log x(crysAPI) = 0.5 - 0.01(mp - 25) - logP
use for non-ionisable species.
What does the solubility of a solid solute in water depend on?
Crystallinity of solute and ability of solute to interact with water
What is the Henderson-Hasselbalch equation?
pKa = pH + log [HA}/[A-]
pKa = pH + log [BH+]/[B]
What is log D and why might it be used instead of logP?
log D is solubility ratio of all species of a compound in a mixture of two immiscible solvents, and is used to include speciation effects in solubility.
How does the presence of a weak base in a drug affect solubility?
log D value will be lower than log P as positive charge improves solubility of drug in water. at low pH, base will be protonated, and so solubility higher.
How is solubility of amphoteric species considered? How might it change?
Need to consider different states of ionisation across pH range to get a full picture of drug solubility. Intrinsic solubilities of charged species in water will be much higher.
How does dissolution work?
Step 1: interfacial reaction - release of solute from crystal
Step 2: diffusion of molecule away from boundary layers
What is the dissolution rate governed by?
Diffusion generally slower process, so dissolution rates tend to follow Fick’s law.
dC/dt = DA/h (ΔC)
What is Fick’s law?
dC/dt = DA/h (ΔC)
where ΔC is difference in concentration between two sides of diffusion layer, D = diffusion coefficient, A = surface area of dissolving particle, h = thickness of boundary layer
What factors impact diffusion coefficient?
Size of molecule and viscosity of media. Larger molecules dissolve slower and solutes dissolve slower in more viscous liquids.
What factors impact the thickness of the stagnant layer?
= boundary layer
Agitation and media - stirring can get movement in the boundary layers, and could use neutral/reactive solvents to improve stagnation
What factors can impact dissolution rates of drugs?
Dosage form, tableting method, binders/excipients/coatings. Tableting - tightly packed, may need to break into pieces to improve dissolution rates. Coatings - need to get through coating before in solution.
