Term
|
Definition
is rate at which processes/changes occur
may be physical (drug across a boundary)
chemical (drug decomposition) |
|
|
Term
|
Definition
| the mechanism of such a chemical reaction, aims to describe product formation over a period of time |
|
|
Term
|
Definition
| reaction rate that id independent of the conc of reactants =k (M/sec) |
|
|
Term
|
Definition
reaction rate proportional to conc of the reactant =k[reactant] k in sec
common in pharmaceuticals (decomposition during storage and passage of drugs from 1 body compartment to another) |
|
|
Term
|
Definition
| reaction rate proportional to conc of the square of a single reactant or the product of the 2 reactants = k[A]2 or B in M-1 or sec-1 |
|
|
Term
|
Definition
| reaction rate RR is fractional or not a zero, 1st or 2nd order |
|
|
Term
|
Definition
sometimes the order of a reaction can be a fractional value (not a whole number)
eg 2A+B=C, RR-k[A]2[B]1 |
|
|
Term
|
Definition
zero order: seen in thermal chemical decomposition (antibiotics in suspensions)
1st order seen in drugs in solution
2nd order reaction has 2 conc terms and also seen in some drug decomposition processes |
|
|
Term
| degradation pathways (DP) mixed order |
|
Definition
| when the order of reaction changes during the various steps of the reaction (like change in pH) |
|
|
Term
|
Definition
normal solutions
determined by 1 molar conc
conc decreases exponentially linear with time
K=equilibrium constant k= rate constant |
|
|
Term
|
Definition
is independent of initial conc A0
rate is dependent on conc and proportional to amount present at any time |
|
|
Term
|
Definition
time for the conc to fall to 90%
1st order half life: t90=0.105/k1
this is also independent of A0 |
|
|
Term
|
Definition
zero order: conc vs time
1st order: log conc vs time
2nd order: 1/conc vs time
need the right kinetic order for each drug formulation |
|
|
Term
|
Definition
|
|
Term
|
Definition
| suspensions: drug in bulk suspension-dissolution-drug in solution (this undergoes reaction) |
|
|
Term
|
Definition
dimerization of amoxicillin in an alkaline solution
plot line goes up not down like zero and 1st order |
|
|
Term
|
Definition
conc of 1 reactant B is held constant compared to A eg large amount of B added
constant achieved by reactant in excess or adding a buffer
thus k2 incorporates k1 and reactant |
|
|
Term
| competency standards for pharmacists knowledge of stability |
|
Definition
choosing packages for safety
applying labelling for storage
apply research findings to workplace
knowledge on formulations that will effect stability
ID info needed for safety of medicine
potential for physiochemical incompatibilities, oxidation, hydrolysis and colour change
ID when formulations need adjusting
ID effects of moisture, heat, microbes, o2
ID factors affecting storage |
|
|
Term
| degradation product limitations |
|
Definition
epi-anhydrotetracycline causing fanconi syndrome due to high temp
pyridine from ceftazidime: shelf life consider pyridine levels
aspirin & salicyclic acid |
|
|
Term
| temperature and stability equation |
|
Definition
Arrhenius
dependence of the k of chemical degradation on the temp and activation energy |
|
|
Term
|
Definition
k=number of collisons that result in reaction (per time)
A= total number of collision
R= gas constant
T= temo
Ea= activation energy
shelf life: reciprocal relation to k |
|
|
Term
|
Definition
| adjust shelf life for improper storage |
|
|
Term
|
Definition
energy required to lift molecules from ground state to activated state (collision is this state undergo reaction)
higher the Ea the more influence temp have on shelf life |
|
|
Term
|
Definition
| forms before product forms |
|
|
Term
|
Definition
t90
max 5 years
degradation product limitation |
|
|
Term
|
Definition
<30
<25
2-8 refrigerate don't freeze
<8 refrigerate
< -5 freeze
< -18 deep freeze |
|
|
Term
| additional storage requirements |
|
Definition
changes: webster packing
freshly prepared <24hrs
recently prepared: within 1 week
extemporaneously: 28 days |
|
|
Term
|
Definition
GTN tablets: once out of glass container loss of activity rapidly
thyroxine: 4 weeks out of fridge |
|
|
Term
| shelf life based upon degredants |
|
Definition
allowable level of impurity t90
likelihood of toxicity
based upon daily intake levels |
|
|
Term
|
Definition
reporting: a certain level must be reported. <1g, 0.1% TDI (total daily intake)
ID: chemical ID. <1g, 1% of TDI
qualification: ensure safety <10mg, 1&% TDI |
|
|
Term
|
Definition
| MKT calculated at <25 or between 15-30, uses average temp over 52 weeks |
|
|
Term
|
Definition
zones 1 and 2: 25C/60% RH
3&4: 30C/70% RH
shelf life data marketed in these zones |
|
|
Term
|
Definition
| cold storage while distributed |
|
|
Term
|
Definition
shelf life is at refrigeration but stored at RT
stored for a period at RT
RT expiry and if it need re-sterilisation |
|
|
Term
| Stability and pH (very critical) |
|
Definition
| general graph of hydrolytic decomposition)acid/base catalysis I a v shape |
|
|
Term
|
Definition
stability: glucose sol pH 3.5-5.5 and with low buffer capacity
addition of drug: eg 250mg aminophylline (weak base) to 1L glucose pH 5.5+4.45=9.95 if steroid added at high pH it will degrade in minutes
Control of precipitation: eg TPN with phosphate and calcium |
|
|
Term
|
Definition
pH: 7.3-9.7 irritation 1%
pH: <5.8 to >11.5 irritation 99%
pilocarpine pKa 7.0 eye drops: pH 9=99% in molecular form, pH 4 (pH MIN) 0.1% molecular form |
|
|
Term
|
Definition
aspirin: 2.5
thiamine HCl 1.5-2.5
procaine HCl 3.6
atropine 3.8 |
|
|
Term
| influence of acids and bases (pH effect) catalysis |
|
Definition
remain unchanged at end of reaction
small amount can have large influence of RR
Gibbs is unchanged
MOA: catalyst+substrate-(complex)-products+catalyst
acid base catalysis by H or OH so rate law includes them |
|
|
Term
|
Definition
| observed apparent 1st order rate constant |
|
|
Term
|
Definition
eg. pH 4 (minima) acid catalysed reaction before 4 and base after 4
+1 region every pH unit increase like 7-8 means higher OH, by 10 fold and 10 times higher RR thus if pH is 1 unit higher than target, shelf life is 10 times lower |
|
|
Term
|
Definition
K obs is the observed 1st order
ko is the uncatalysed 1st order rate constant and k2 is 2nd order rate constant for acid catalysis
this describes the shelf life over a pH range |
|
|
Term
|
Definition
| acid to base ratio must be kept constant to maintain constant pH |
|
|
Term
| general acid catalysis of thiamine |
|
Definition
the higher the pH (the higher the slopes) indicate general catalysis taking place, need a buffer that will avoid inducing general catalysis
1st order k of a catalytic decomposition use k1=[2.303/time to decomposition t] x [logV0/v] |
|
|
Term
| Benzyl pg undergoes 4 reactions over the pH range: pKa=2.76 |
|
Definition
H=of molecular pg (low pH)
H=of ionised pg anion (higher pH)
uncatalysed hydrolysis of pg anion
OH of pg anion (high pH) |
|
|
Term
|
Definition
specific acid catalysis (acid solution)
general acid-base catalysis: where catalysis is induced by any acid or base. |
|
|
Term
|
Definition
active principle (preservative and AO should be evaluated)
physical stability should be evaluated
do accelerated stability studies supported by long term stability studies
test under high and low moisture conditions
evaluate 3 separate batches
lighting conditions specified
tested in final container closure system |
|
|
Term
| accelerated stability test |
|
Definition
isothermal method: breakdown at elevated pressure.
Arrhenius plot for predicting drug stability at RT |
|
|
Term
| influence of ionic strength |
|
Definition
u is ionic strength
activity refers the amount of conc available for the reaction, so the more charges the more ionic strength.
eg. log of the rate constant is proportional to the ionic strength (to the power of 0.5) applies for ionic strength up to 0.1 mol |
|
|
Term
| ionic strength of Pen G in citrate buffer |
|
Definition
u up to 0.5 ionic strength no effect unless buffer is catalytic
pH 7 where citrate ion I not catalytic u had no effect on chemical stability
below pH 6.5 u effect was inversely related to pH
where mono and dihydrogen ions were present increase in u by increase NaCl increase rate of degradation
so if reconstituting a drug in ionic sol, ionic strength may have an impact eg glucose sol has no ionic impact but saline does (destabilising) |
|
|
Term
| example of some drugs that react with oxygen |
|
Definition
ascorbic acid
dexamethasone
epinephrine
penicillin
procaine
tetracyclines |
|
|
Term
|
Definition
oxidised if electrons are removed from a compound
most common form of oxidation is autoxidation (a low temp oxidation involving a free radical process) |
|
|
Term
|
Definition
initiation (cleavage of a weak bond by electron transfer by light or metal catalysis)
propogation: reaction with molecular oxygen by hydrogen atom abstraction
Termination: combination of 2 radicals to form non radical product (inactive) |
|
|
Term
| other factors influencing oxidation |
|
Definition
temp
metallic ions
peroxide impurities |
|
|
Term
|
Definition
form hydroperoxide
factors that influence it:
rancidity
acid values
natural AO
oxidising enz
oxygen
moisture
light
temp |
|
|
Term
| AO need higher oxidation scale than the drug |
|
Definition
riboflavin most easily oxidised
ascorbic acid
Na metabisulfite
Na bisulfite
resorcinol
phenol |
|
|
Term
|
Definition
lower pH diminish rate of oxidation
anionic forms of weak acids
as E decreases (drug easier to oxidise) as H decreases |
|
|
Term
|
Definition
free radical inhibition eg at low temp (cold chain)
chelating agents: remove metals like TPN in fat emulsion (EDTA, citric acid) |
|
|
Term
| AO in oil systems phenol group |
|
Definition
quinol group hydroquinone, BHT, BHA by OH, B increases lipid solubility
catechol group: NDGA and gallic ester for 0.02% lipids |
|
|
Term
|
Definition
| oxidised by the weak O-H bond removing ROO radicals |
|
|
Term
| Types of AO in aqueous systems |
|
Definition
Sulfites
ascorbic acid
thioglycolic acid
cysteine HCl |
|
|
Term
|
Definition
selection influenced by pH of sol and final conc
Metasulfite: in acid sol gives alkaline shift and sulphur dioxide gives acid shift
ensure to select acid salt to acid sol and same with base salt to base sol |
|
|
Term
|
Definition
good for pH 4 aqueous injections like
morphine sulphate inj bp(no AO)
morphine sulphate inj bp sigma (sMS)
morphine tartrate inj (SMS 1mg/ml)
zinc and adrenaline ED (SMS 0.05%)
adrenaline ED (SMS 0.1%) |
|
|
Term
|
Definition
rapid oxidation
fall in pH on oxidation
loss to plastic containers |
|
|
Term
|
Definition
reduce discolouration
stabilization
food industry (sulphite)
amount to consider headspace
multi-dose containers |
|
|
Term
|
Definition
| the greater the headspace the more oxygen available for oxidation, but removal of headspace allow is not enough to stop drug loss to oxidation, therefore AO is added |
|
|
Term
| Ascorbic acid aerobic oxidation (with headspace) and anaerobic (without headspace) |
|
Definition
form diketogulonic acid plus oxalic acid which is toxic
forms furfural (slower oxidation and more stable) |
|
|
Term
|
Definition
induced by moisture in air
moisture in materials
aqueous sol
aqueous part of the non-aqueous sol |
|
|
Term
| hydrolysis degradation affecting drugs |
|
Definition
concerned with COOH derivatives like Lactam in penicillin
lactone in warfarin |
|
|
Term
|
Definition
eg alkaline catalysed hydrolysis
the acyl gp has greater influence on RR than the akyl sub |
|
|
Term
| stability of leaving group greater rate of hydrolysis |
|
Definition
acid halide>anhydrine>ester or
HCl>RCOOH>ROH>RNH2 |
|
|
Term
|
Definition
hydrolysed fast
aspirin (susp)-aspirin (sol)-hydrolysis-products
aspirin in suspension is heavily influenced by temp and pH and moisture |
|
|
Term
| aspirin in PEG suppository |
|
Definition
pseudo 1st order kinetics over 4-60 degrees
aspirin degrades with moisture plus tranesterification reaction= acetylated PEG as a product of decomposition |
|
|
