Physical Properties of APIs

Question 1

What is the drug development process?

Answer 1

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]

Question 2

What are the parts of the preclinical stage?

Answer 2

Chemical pharmaceutical development
Nonclinical development - in vitro DMPK, toxicology and safety studies
Clinical development - exploratory phase 0 trial in healthy volunteers

Question 3

What is pre-formulation?

Answer 3

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.

Question 4

How can dosage form affect drug uptake?

Answer 4

Different dosages have different pharmacokinetics, leading to different time of actions. Physicochemical properties are different.

Question 5

What is solubility?

Answer 5

Concentration of solid components in solution at equilibrium between solid and solution.

Question 6

What factors can impact solubility?

Answer 6

Temperature, pressure, presence of other chemicals, pH

Question 7

What determines solubility?

Answer 7

Molecule interactions between solute and solvent, “like dissolves like”, stability of crystal lattice

Question 8

What assumptions does the ideal solution model make?

Answer 8

All molecular interactions are equivalent.

Question 9

How is solubility measured?

Answer 9

Gravimetric method: make a saturated solution, filter and weigh, evaporate solvent and reweigh.
Any analytical technique can be used to identify concentration of solution.

Question 10

What is a solubility curve?

Answer 10

Part of a phase diagram, showing regions of solution and solution and crystals. Along the line is a saturated solution.

Question 11

What is the Schroeder-van Laar equation for an ideal solution?

Answer 11

Ln(xA) = - (ΔHAfus)/R (1/T - 1/(TAfus)), where A is the solute and xA is the mole fraction of A.

Question 12

What does the Schroeder-van Laar equation indicate?

Answer 12

Solubility is independent of the solvent

Question 13

How do we measure fusion data?

Answer 13

Thermal analysis with DSC to give a thermograph. ΔH can be found from kA where k is calorimetric constant and A is peak area.

Question 14

Why is solubility important?

Answer 14

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!

Question 15

What is logP?

Answer 15

Partition coefficient, solubility ratio of unionised species of a compound in a mixture of two immiscible solvents, octanol/water.

Question 16

What does the value of log P tell us?

Answer 16

High values for log P are more soluble in octanol, and low values are more soluble in water.

Question 17

What is the GSE?

Answer 17

general [aqueous] solubility equation
log x(crysAPI) = 0.5 - 0.01(mp - 25) - logP
use for non-ionisable species.

Question 18

What does the solubility of a solid solute in water depend on?

Answer 18

Crystallinity of solute and ability of solute to interact with water

Question 19

What is the Henderson-Hasselbalch equation?

Answer 19

pKa = pH + log [HA}/[A-]
pKa = pH + log [BH+]/[B]

Question 20

What is log D and why might it be used instead of logP?

Answer 20

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.

Question 21

How does the presence of a weak base in a drug affect solubility?

Answer 21

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.

Question 22

How is solubility of amphoteric species considered? How might it change?

Answer 22

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.

Question 23

How does dissolution work?

Answer 23

Step 1: interfacial reaction - release of solute from crystal
Step 2: diffusion of molecule away from boundary layers

Question 24

What is the dissolution rate governed by?

Answer 24

Diffusion generally slower process, so dissolution rates tend to follow Fick’s law.
dC/dt = DA/h (ΔC)

Question 25

What is Fick’s law?

Answer 25

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

Question 26

What factors impact diffusion coefficient?

Answer 26

Size of molecule and viscosity of media. Larger molecules dissolve slower and solutes dissolve slower in more viscous liquids.

Question 27

What factors impact the thickness of the stagnant layer?

Answer 27

= boundary layer
Agitation and media - stirring can get movement in the boundary layers, and could use neutral/reactive solvents to improve stagnation

Question 28

What factors can impact dissolution rates of drugs?

Answer 28

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.