D10. Chemical stability part 1 Flashcards
what should you aim self life to be?
-typically 3 years
-tablets can up to 5 years
-aqueous based medicines less than 3 years
What does stability mean?
-Ensures that medicine retains, within specified limits, and throughout its shelf life, the same properties and characteristics that it possessed at the time of its manufacture
-The ‘specified limits’ ensure quality, safety & efficacy of a medicine e.g drug identity, strength, purity
How does instability or degradation occur?
it is thermodynamic in nature (affected by temp) and occur in the following mechanisms:
-chemical (hydrolysis, oxidation, photolysis, trace metal catalysis…)
-microbiological (microbial contamination)
-physical (Vaporization, water loss/gain, cracked emulsions….)
NB - Mechanisms of degradation usually complex for medicines & may involve many processes in series or parallel
Describe how temperature affects chemical mechanisms of degradation
-all chemical mechanisms affected by temperature
-greater free energy usually leads to more rapid degradation
-generally a 10°C rise 2 to 5 times increase in decay
-Arrhenius eq. allows rate of decay at a given temperature to be calculated ONE NOTE
What is the arrhenius equation
k=Ae to the power of Ea/RT
Where, k = reaction rate constant, A = frequency factor (a constant!), Ea = activation energy, R=gas constant, T=temperature
Describe hydrolysis
-most likely cause of drug instability
-bonds hydrolyse via nucleophilic attack by water
-Also may get solvolysis e.g where solvent is not water ONE NOTE
How does hydrolysis occur
Catalyzed by OH-, H+, presence of ions, heat and light
Certain bonds are more susceptible to hydrolysis than others e.g lactam > ester > amide > imide
ONE NOTE
Describe the influence of pH on stability
-Many drugs are weak acids/bases
-Tend to be most water soluble when ionized, but this in when they are most unstable!
-Hydrolysis is catalyzed by extremes of pH (e.g. very basic/acidic conditions)
-Acid -> basic pH (ionised form) –most unstable
-Base -> acidic pH (ionised form) – most unstable
ONE NOTE
How can we use pH to control stability?
Determine pH at which drug most stable (kinetic studies) and formulate at that pH
If needed use buffer to control pH
Why add water miscible solvent to formulation (to form a cosolvent)?
-Include solvents such as ethanol, glycerol or propylene glycol
-Favours solubility of the more stable ‘unionized form’ of the weak acid/base
-can reduce pH extreme required for solubility
-More of the stable form unionised in solution
Describe the cosolvent and environment
-Environment of cosolvent is less polar than water (solvent more ‘organic’ in nature e.g ethanol )
-If a degradation reaction produces products that are less soluble in the cosolvent than the non-degraded starting product(s), the co-solvent environment will stabilize (e.g. forward reaction becomes unfavourable) For example, aspirin degradation to salicylic and acetic acid
ONE NOTE
What are other methods to reduce hydrolysis (not cosolvent)?
-Make the drug less soluble by adding excipients to make suspensions(citrates, dextrose or sorbitol) or chemically modifying the drug
-Solubilize or ‘hide’ the drug away from the aqueous environment: Formulate as a micellar formulation (using surfactants), or as an inclusion complex (e.g. with cyclic saccharides called cyclodextrins)
ONE NOTE
Describe micellar solubilization
-Non-polar compounds solubilized in the oily interior of micelle protected from hydrolysis (and other degradative processes)
-e.g. hydrolysis of benzocaine decreased
-For more polar compounds (situated nearer the surface of the micelle) surface charges of micelle repel/capture hydrolysing anions, and thus still stabilize
Describe cyclodextrin Inclusion Complexes
-Many reports that cyclodextrins protect from degradation
-But…..hydroxyl groups within cyclodextrin structure can also catalyse hydrolysis, and increase degradation
e.g. increased rate of decomposition of hydrocortisone and betamethasone - 17 - valerate (in basic solution)
