Drug Stability & Stability Testing - Part 1 Flashcards
What is quality measured by?
- the CONTENT of the ACTIVE SUBSTANCE in the product
- the PURITY of the active substance in the product (presence of impurities and decomposition products of the active)
- the PHYSICO-CHEMICAL PROPERTIES of the product
- the MICROBIOLOGICAL PROPERTIES of the product
- the ORGANOLEPTIC AND AESTHETIC PROPERTIES of the product
Biological molecule can be..
activated or de-activated
Which Modes of Drug/Product Degradation are frequently closely linked
- chemical
- biological
- physical
- microbiological
Classes of degradation - chemical
Define hydrolysis
Hydrolysis is frequently catalysed by hydrogen ions or hydroxyl ions and by acidic or basic species (buffers).
Can hydrolysis be removed?
Hydrolysis can only be reduced, cannot get rid of it completely
What are the main 4 classes of drugs susceptible to hydrolysis - ‘labile carbonyls’
- esters - e.g. aspirin, cocaine, procaine, tetracaine
- amides - e.g. dibucaine, chloramphenicol
- lactones - e.g. pilocarpine, spironolactone
- lactams - e.g. penicillins, cephalosporins, nitrazepam
Hydrolysis of tetracaine
draw
How do we prevent/reduce hydrolysis?
- Minimise contact/removal of moisture:
solid dosage forms; desiccant (silica gel at high humidity,
molecular sieves (including bentonites, zeolites) at low humidity) - Adjust the pH:
reduce acid-base catalysed hydrolysis - Reduce solubility/less soluble salts/solvents:
if drug is not in solution it can’t be hydrolysed (eg. procaine, penicillin suspensions) - Form complexes:
eg. addition of caffeine to benzocaine, procaine and amethocaine
What does oxidation cause?
Major cause of drug degradation:
morphine, dopamine, adrenaline, some steroids, some
antibiotics
Functional groups subject to oxidation include:
phenols ethers thiols carboxylic acids catechols aldehydes thioethers nitrites
What is chemical oxidation and what are the equations for reversible loss of e-?
Removal of an electropositive atom, radical or electron, or addition of an electronegative atom or electron.
Fe2+ - e- ↔ Fe3+
Fe3+ + e- ↔Fe2+
Red ↔ Oxid + n e-
reversible loss of electrons without the addition of oxygen
What are free radicals?
Chemicals containing at least one unpaired electron.
Highly unstable and highly reactive
What is Auto-oxidation?
many pharmaceutical oxidations are irreversible chain reactions proceeding
slowly under the influence of atmospheric oxygen.
Reactions may occur over several years.
Involves formation of free radicals
Auto-oxidation
What are the steps in the chain reaction
initiation → propagation → termination
What happens at initiation?
free radicals formed by the action of light, heat or trace
metals (such as iron, from where?):
RH → R● + H●
What happens at propagation?
formation of peroxy radical, ROO ●
removal of H from organic molecule to form hydroperoxide ROOH
and a new free radical
R● + O2→ROO●
ROO● + RH → ROOH + R●
What happens at termination?
free radicals combine to form inactive (new) products
ROO● + R●→ ROOR
R● + R●→ RR
How do we prevent / reduce oxidation?
Precautions during manufacturing
! avoid contact of drug with heavy metal ions
! replace oxygen in container with nitrogen (salads…)
! well-filled containers – less room for oxygen…
! store at reduced temperatures (i.e. rate of reaction / solubility of O2 in solvents)
Formulation approaches
! use antioxidants
! primary antioxidants – interfere with propagation step
! synergists – promote activity of primary antioxidants
! reducing agents – have a lower REDOX potential than the drug – more likely to be oxidised than the drug
use chelating agents
! e.g. ethylene diamine tetra-acetic acid (EDTA) ! adjust pH
! decreasing pH often increases REDOX potential (the tendency of a chemical to acquire electrons and thereby be reduced – higher REDOX potential = more likely to be reduced) and increases resistance to oxidation,
! e.g. adrenaline solution – reducing pH from 6 to 4 results in a 2-fold increase in chemical stability
What do antioxidants do?
Interrupt propagation by interaction with free radicals – leads to formation of an antioxidant free radical which Is not sufficiently reactive to maintain the chain reaction – commonly used antioxidants include: • gallic acid • butylated hydroxyanisole • butylated hydroxytoluene • tocopherols
How to prevent/stop initiation?
INHIBIT
! protect from light
! chelate metals
! reduce temperature ! change pH
How to prevent/stop propagation?
INHIBIT
! antioxidants
! reduce/remove free oxygen
Which pharmaceuticals are light sensitive?
- corticosteroids – hydrocortisone; prednisolone;
- phenothiazine tranquillisers – chlorpromazine;
- tetracyclines
- catecholamines – adrenaline
- sulphonamides
- benzodiazepines - diazepam
What happens in Photochemical degradation (photolysis)?
Molecules exposed to electromagnetic radiation → absorb light at CHARACTERISTIC wavelengths (note: UV spectra; IR spectra)
Frequently results in dark-coloured products or fading of colouring agents
! This causes an increase in the energy state of the compound that can lead to
! decomposition
! conversion to heat
! emission of light at a new wavelength (fluorescence)
Photo-degradation depends on..
! intensity and wavelength
! shorter the wavelength – higher the energy
What is photo degradation mediated by
free radicals (in similar way to oxidation)
How do we prevent/reduce photochemical degradation?
Storage conditions
! amber bottles
! darkness
! cool temperature
UVabsorbers
! absorb harmful light radiation and dissipate the energy as heat of fuorescence or in a reversible (e.g. keto → enol) chemical reaction
! e.g. benzophenones
Photo degradation of chlorpromazine
draw
What is Isomerisation?
Conversion of a drug to its optical or geometric isomer
Isomers are usually of different…
Isomers are usually of a different activity
– e.g. low activity of adrenaline solutions at low pH
– e.g. tetracycline
– e.g. salbutamol
– Formulated as a racemic mixture of the R- and S-isomers.
– The R-isomer has ca. 150 times greater affinity for the β2-receptor than the S-isomer (and the S-isomer has been associated with toxicity).
– Levalbuterol, the single R-isomer of salbutamol (cost issues).
What is polymerisation?
The process by which two or more identical molecules form a complex – e.g. ampicillin (highly antigenic)
Concomitant self-aminolysis (dimerisation) & hydrolysis of ampicillin
draw
- drug reacting with itself
- the higher the conc of the drug the more likely the reaction is to happen
What are the 3 other chemical decomposition pathways
Dehydration
! breaking of covalent bond to eliminate water molecule
from the structure, e.g. prostaglandin E2; tetracycline
Decarboxylation
! elimination of carbon dioxide from a compound, e.g. when
parenteral solutions of sodium bicarbonate are autoclaved
Chemical incompatibilities
Physical degradation
- Physical properties can change too but are form dependent
Physical degradation
Examples for liquid formulations:
– appearance, colour, odour, pH, clarity (solutions) and freedom from visible particulate contamination, size range of particulate contamination (large volume parenterals), particle size distribution (suspensions), micelle size distribution (micellar solutions), resuspendability (suspensions), viscosity, moisture content (powders for reconstitution), phase separation (emulsions)
Physical degradation
• Examples for tablets and capsules
dissolution rate (or dissolution profiles for sustained-release products), appearance, odour, hardness, friability, moisture content, brittleness
Physical degradation
Examples for ointments and creams
appearance, odour, viscosity, softening range, loss of water, physical and chemical homogeneity, particle size distribution, particle formation, pH
Physical degradation
Examples for transdermal patches
appearance, in vitro release rate, adhesive strength
What are the forms of physical instability
– Those apparent to the user
– Those causing inaccurate dosage
– More subtle changes affecting product performance, i.e. during processing; loss or gain or water? (i.e. lidocaine / Karl Fisher titration)
– Loss of water
– Loss of volatiles, e.g sertraline base, glyceryl trinitrate
– Water absorption, e.g effervescent tablets
– Drug sorption onto / into packaging , e.g. diazepam / PVC bags; peptides, verapamil on / into glass
– Excipient sorption, e.g. preservatives
– Change in product colour
– Change in odour / flavour
– Crystal growth (i.e. suspensions – “ripening”) – Altered particle size distribution
– Polymorphic changes
– Caking of suspensions
– Cracking of emulsions / syneresis
– Ageing of solid dosage forms
– Softening of tablets
– Cracking / splitting of tablet coats
– Release of materials from containers – Packaging changes
How can physical instability be prevented?
– Formulation
– Manufacture
– Packaging
– Storage
Microbiological deterioration
What are microbial flora introduced via and what is the ability of microbes?
Microbial flora introduced via: • raw materials • water • equipment • operators • environment
Ability of microbes to:
• survive manufacturing process
• ingress during storage and use
• adapt to low nutrient requirements
Microbiological deterioration
What are the specific microbial purity and preservation
requirements
- product category, e.g orals; topicals; parenterals
- formulation design
- method of manufacture
- route of administration – i.e. parenterals / aseptic
What are the effects of Microbiological deterioration?
VISUAL/ APPARENT ! Breakdown of emulsion ! Formation of slime, pellicle or sediment ! Surface growth on solids ! Fermentation – formation of gas ! Pigmentation / change in colour ! Cloudiness ! Change in viscosity ! Separation
NON VISUAL
! Growth in fluids (to millions per ml) without opacity
! Growth in creams (to millions per ml) without visible changes
! Formation of endotoxins (≡ pyrogens)
! Formation of foul odours
Microbiological deterioration
Microbiological Quality Assurance
- high levels of GLP and GMP
- special licensed premises
- use of authorised SOPs, raw material and release specifications
- low bioburden prior to sterilisation
- validation of sterility assurance
- monitoring air and water quality
- QP
- stability testing for retention of microbial purity and preservation over shelf life
Some applications – typical changes
• Physical changes..
• Chemical changes..
• Microbial changes..
Physical changes • appearance • meltingpoint • clarityandcolourofsolution • water • crystal modification (polymorphism) • particle size
Chemical changes
• increase in degradation products
• decrease of assay
Microbial changes
• growth of microorganism
