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BME 621 0 Small Molecule Stability -
Formulation Test With Solution
Experimental formats are used to... - ANSWER Determine drug stability. A perfect world would want... - ANSWER 5 year expiration, "shelf life".
"Shelf-life" is defined by the FDA in two ways: - ANSWER 1. Product at least 90% potent from the manufacturing date.
- Product must look and act as the day it was manufactured.
How to measure drug potency and stability? - ANSWER By adding stressors to the formulation.
Different examples of stressors: - ANSWER 1. Temperature - Rate of reaction increases with increasing temperature.
- Humidity - Rate of reaction increases with increasing humidity.
- Physical stress - Products tend to be crystals with different lattice energies.
Most common degradation reactions: - ANSWER 1. Hydrolysis - Adding water across a bond.
- Oxidation
- Photolysis - Light
Zero Order Reactions: - ANSWER A ---(k0)---> B
-d[A]/dt = k0 for a zero order reaction - ANSWER [A] = [A]0 - k0t
Graph with a straight line for zero order reactions... - ANSWER [A] versus t
The slope of a zero order reaction is... - ANSWER k
t50 for a zero order reaction is... - ANSWER t50 = (0.5[A]0) / k
We care about t90 (90% potency) which is... - ANSWER t90 = (0.1[A]0) / k
Example of a pseudo-zero order: - ANSWER Drug suspensions
- Solid, very slow degradation
- Not in equilibrium, the solid state amount will change
- Will plateau once all the solids dissolve
- Molecule that degrades is replaced by a non-degraded one
- Take dissolved ones out by degradation
Arrhenius Equation: - ANSWER lnk = ln[A] - Ea/RT A -> Constant Ea -> Activation energy R -> Gas constant T -> Temperature in Kelvins
Plot lnk vs 1/T (linear in a perfect world) - ANSWER Predict k at 20 degrees Celsius, get lnk to get t
Non-linear Arrhenius plots: - ANSWER 1. Concave up
- Concave down
Example of a concave up Arrhenius: - ANSWER Pilocarpine
- Two degradation mechanisms
- Indicative of change in dominating degradation mechanism
- lnK vs 1/T is the left half of a parabola.
- Plot of Gibbs versus reaction progress at low and high temperatures
- At low T, isomerization higher energy than hydrolysis, so hydrolysis dominates
- At high T, hydrolysis requires more energy, so isomerization dominates
Example of a concave down Arrhenius: - ANSWER A -> B -> C
- Change in rate limiting step
- More than one linear degradation process
- High lnk low 1/T to low lnk high 1/T
Experiments for pH effects: - ANSWER 1. Concentration (t) at different pHs
- Measure k(obs)
- ln[C] vs. t
pH and Kobs table: - ANSWER Ex.
- More acidic, faster, increases in K lead to increases in H+, k(obs) vs [H+] is a straight-increasing line
- More basic, increase in K leads to increases in OH-, k(obs) vs [OH-] is a strain-increasing line
- All together pH-rate curve is slightly v-shaped
- Minimum of the graph is the minimum pH
-d[C]/dt = k(obs) * [C] [H2O] - ANSWER H2O -> constant
pH Rate Curve Signoidal: - ANSWER - log(kobs) vs pH
- Tertiary amine pKa = 9.1, 50% one ionized species and 50% the counterpart
- (+) in acidic regime, wants electrons, gets them from the oxygen
- Neutral at equilibrium, reacts slower
- 2 pH away from pKa start to deprotonate, and rate constant slows
Other formulation components (buffers): - ANSWER Control pH, keep it stable
Buffer experimentation: - ANSWER 1. Keep pH stable
- Change [C] of the buffer
- No change in rate
With a changing rate, find new buffer
Kind of buffer you want: - ANSWER No change to reaction rate, multiple ln[C] versus t experiments give you the same straight line
