chemical stability Flashcards
temperature
- all chemical mechanisms are effected by temperature
-greater free energy Leeds to faster degration
-generally a 10 degree increase lead to to a 2-5 times increase in decay - Arrhenius equation allows rate of decay at a given temperature to be calculated
most common cause of drug instability
-this is hydrolysis
-bonds are broken by nucleophilic attack
eg: ester being broken down into an alcohol and carboxylic acid
what is hydrolysis catalysed by
-presence of OH- and H+, heat and light
-certain bonds are more susceptible to hydrolysis than others
Influence of pH
-pH influences hydrolysis
-may drugs are weak acids and weak basis
pronated form is a base which means there is a low pH, low water solubility and high stability
Ionised form is acidic, high pH, highly water soluble and has a low stability
how to use pH to controls stability
-use buffer to control pH
Unionized form: For many drugs, the unionized form (the form without a charge) is typically more stable and easier to absorb in the body because it can pass through cell membranes more easily.
However, it’s not always the easiest to dissolve in water.
Ionized form: On the other hand, the ionized form (charged form) tends to be less stable but can be more soluble in water, making it easier to dissolve in a solution.
use pH to acquire right balance
define cosolvent
A cosolvent is an additional solvent used in a mixture to help dissolve a substance that doesn’t dissolve well in the main solvent.
how does cosolvent improve stability
Cosolvent environment: When you add a cosolvent like ethanol to a solution, it makes the environment less polar than water. Cosolvents are more “organic” (like ethanol), compared to water, which is very polar.
Stabilizing the drug: If a drug starts to break down (degrade) and produces products that don’t dissolve well in the cosolvent, the cosolvent can help stabilize the original drug. This happens because the breakdown products are less soluble in the cosolvent, so the breakdown reaction is less likely to happen.
cosolvent aspirin example
When aspirin degrades, it breaks down into salicylic acid and acetic acid. If these breakdown products don’t dissolve well in the cosolvent, the cosolvent helps keep the aspirin stable by making it harder for the degradation to continue.
the unionised from is more soluble in the cosolvent so it stays in that form rather than degraded to the ionised form which is less soluble
other ways to reduce hydrolysis
-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)
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
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)
oxidation
loss of electrons by a molecule (or hydrogen organic)
Can involve addition of oxygen but oxidation doesn’t necessarily involve oxygen!
Can occur in anaerobic environment
what can catalyse oxidation
-light
-trace metals
-oxygen
-oxidising agents
-temp
types of oxidation
-reversible loss of electrons can occur in anaerobic conditions
-can involve atmospheric oxygen and occur very slowly overtime
whats the feature that makes molecules more susceptible to degration
carbon- carbon double bonds as they are electron rich or lone pair of electrons
autoxidation
oxidation done by atmospheric oxygen
how do prevent oxidation 1
antioxidants, function be providing more electrons and are oxidised more easily than the drug so they terminate the chain reaction be making free radicals neutralised
how do prevent oxidation 2
-Reducing agents: more readily oxidised than the drugs, reverses oxidation by donating electrons back
-To prevent oxidation in formulations, the air in the container is often replaced with an inert gas like Nitrogen (N₂) or Carbon Dioxide (CO₂).
photolysis
-light catalyses the degradation of many pharmaceutical compounds and products
-exposure to light of certain wavelengths results in the absorption of light and increase in energy state (excited)
-can be converted to heat
-can be retained or transferred (stay excited or excite another molecule)
-this can result in the emission of light
-this causes decompositions (photolysis) and the generation of free radicals
trace metal catalysis
-trace metal ions can catalyse oxidation and other forms f degradation
-to prevent this we can formulate with chelating agents, they are capable of forming complex salts with metal ions by donation of lone electron pairs this staples them effectively trapping the ion
isomerization
- Process of conversion of a molecule (drug/excipient) into its optical or geometric isomer
-Important to understand as different isomers often have different biological activities
e.g. Loss of activity in adrenaline solutions (low pH) due to racemisation
-Conversion of the therapeutically active form to the racemic mixture which is inactive
How to avoid/prevent isomerization
Difficult!
Knowledge of conditions in which the isomerization processes occur e.g. extremes of pH, oxidising conditions
Try to formulate in conditions where these occur slowly
Freeze Drying
-to preserve integrity
because : even at very low temperatures
presence of water leads to degradation
freeze drying positives and negatives
Advantages
Low temperatures and vacuum conditions inhibit hydrolysis and oxidation
The porous solid produced is more readily soluble
Disadvantages
The porosity, solubility and dryness of the solid make it very hygroscopic (rapidly adsorbs moisture if exposed to the air)
Can be slow, complicated and expensive
Relatively difficult for solutions containing non-aqueous solvents
