Drug Stability PART 1 Flashcards
Causes of loss of efficacy
Chemical, Physical and Microbial Degradation
Chemical Degradation
- Loss of active drug
- Loss of elegance: colour, taste –> reduced patient compliance
- Production of toxic degradation products
Physical Decomposition
- Irreversible change in crystal form -> reduced bioavailability
- Ageing of dosage form (excipients and vehicles degrade)
- Loss of content potency and uniformity (drug migrate into dosage form)
Microbial Contamination
Loss of efficacy in liquid due to:
- Visibile growth
- Change in colour
- Formation of endotoxins (pyrogens)
Shelf life
Elapsed time after which product does not meet specifications and requirements, due to time dependent changes in the product
Time required to decrease in potency to 90% of initial or labelled potency
Physicochemical factors that affect reaction rates
Temperature Catalysts pH Ionic strength Solvent
Temperature (vs degradation reaction rates)
- Arrhenius equation (2-5 fold increase rates with 10 Celsius increase)
- Kelvin (absolute temperature T - 1-100 deg and range <30 deg)
- Ln(k2/k1)=Ea/R x (1/T2 - 1/T1)
R=1.9872 cal/mol or 8.314 J/mol
Ea J/mol or cal/mol
Deviations from arrhenius behaviour due to:
- Temperature dependence of activation constants
- Change in reaction rate limiting step
- Reaction occurring at surfaces (heterogenous behaviour)
- Denaturation of peptide/ protein reactants
- Denaturation of enzyme reagents
Transition State (temp factor)
- highly reactive intermediate state that forms final product state
- lowest free energy of activation (but still higher than reactant/ products)
Increase temp increases energy of initial state therefore pushes reactant further up in the energy curve (decreases the energy barrier)
Formation of transition state requires
- free energy of activation (energy input)
- Correct orientation of reactants
FAST reaction - small G value
Slow - large G value
Reversible - G=0
Spontaneous and complete = -ve and large
Catalysts (rate factor)
- substance which increase rate of reaction
- not consumed
- doesn’t alter yield
Forms a complex transition state which has lower free energy that uncatalysed transition state
Types of catalytic action in solution
Homogenous - catalyst dissolved in reaction solution (H30)
Heterogenous - Catalyst not dissolved but forms a separate phase (finely divided metal)
Enzymatic - protein with specific characteristics, can be hetero or homogeneous
Maybe irreversibly poisoned by strongly adsorbed retained substances
Catalysis Reactions in solutions (homogeneous)
Specific Acid Catalysis - Hydronium ion (Kw)
Specific Base - Hydroxyl ion (Kw)
General Acid - Proton donor eg acetic acid or protonated base
General Base - Proton acceptor eg carbonate, phosphate anions
Nucleophilic - Electron pair donor eg amines
Electrophilic - Electron pair acceptor eg metal ions
Effects of pH on rate
Specific acid/base - HYDROLYSIS/ oxidation
- acid stability
- steric hindrance
- oral bioavailability
pH rate profiles
- rate of degradation at different pH values
- Overall reaction order for degradation and mechanisms
- pH at which drug is most stable
Marginal stability drug needs to be in solution and need to know pH of max stability - Pseudo-first order
- Varying pH values and other variables constant
- logs of rate constants Vs pH
No ionisable functional groups near degradation reaction centre
Linear: slope -1, 0 or +1
V-shaped: slope -1 intersects slope +1
U-shaped: slope -1 connected by line with slope = 0 to slope +1
Change in state of ionisation of a group in the substrate near to the reaction centre
S-shaped: terminal slopes of 0 with interconnecting region of max slopes +1 and -1
rare
Bell shaped: 2 S-curves joined at the top
