stability & degradation Flashcards
(102 cards)
1
Q
3 types of instability?
A
- Physical stability
- Chemical stability
- Microbiological stability- for sterile products and other implictaions
2
Q
what does instability impact?
A
shelf life of a product
3
Q
what does stability depend on?
A
- Drug/excipient properties
- Compatibility with excipients
- Dosage form
- Manufacturing method
- Packaging-preventing some issues in stability
- Environmental conditions:
4
Q
What changes would you expect to see as result of physical instability in…
- solutions
- suspensions
- emulsions
- oiintments
A
- precipitation
- caking and ostwald ripening
- creaming, cracking and ostwald ripening
- bleeding
5
Q
For solid dosage forms, physical instability is unlikely if 3 things are retained. Suggest what they might be?
A
size, shape and colour
and uniform coating where applicable
6
Q
what to Also look out for - physical stability?
A
• Changes in viscosity, pourability, spreadability, colour, odour, consistency etc.
7
Q
whats High moisture content of gelatin shell makes capsules susceptible to?
A
changes in air humidity
also consider cross linking
8
Q
What can the consqeunce of evaporation of a volatile compound be?
A
loss of drug or another component from the dosage form
• This differs from chemical degradation
9
Q
Loss of drug or another component from the dosage form can be due to evaporation of volatile compound or sorption. what could occur? (2)
A
o Adsorption on the surface the container/closure
o Absorption into plastic or rubber container or closure
10
Q
Why does the shelf life of glyceryl trinitrate reduce from 2 years to 8 weeks after opening?
A
Risk of evaporation of volatile compound
11
Q
Why should glyceryl trinitrate tablets not be repackaged and nothing added to their bottles?
A
risk of evaporation of volatile compound and liklihood is increased in these circumstances
12
Q
What type of physical instability is more likely for non polar compounds and worse if conc of drug or excipient such as preservatives is low?
A
sorption
13
Q
What is meant by leaching in the context of physical instability?
A
something from packaging goes into preparation
14
Q
What are some drugs such as taxol or taxotere at risk of due to their packaging?
A
leaching as they contain ethanol and surfactants
15
Q
whats leaching made worse by?
A
Worse if the formulation contains organic solvents/surfactants
• Taxol® and Taxotere® contain both ethanol and surfactants- have warnings
16
Q
What physical instability can occur in ovc bags for parenteral use?
A
leaching from plastcizers in pvc bags
17
Q
leaching can occur as a result of autoclave sterilsation for some glass bottles. Outline what happens and which type of bottle this is unlikely to happen with?
A
OH ions from glass enter the solution, unlikely to happen with type 1 borosilicate glass
18
Q
What type of instability is due to changes induced by microbial contamination?
A
microbiological instability
19
Q
Which type of instability is likely to be the reason why multi dose eye drops can sometimes see there shelf life decreased from 24 months to 1 month after opening?
A
microbiological instability
20
Q
Outline the consequences of chemical instability? 3
A
drug degredation leading to inactive products and loss of therapeutic efficacy
producing toxic degredation products therefore increased risk of side effects
producing changes in products appearance
21
Q
List some of the mechanisms by which chemical instability can occur? 5
A
Hydrolysis oxidation isomerisation dimerization + polymerisation phototoxic drug degredation
22
Q
Which chemical mechanism is responsible for drug degredation as a result of a reaction with water?
A
hydrolysis
23
Q
list some functional groups which increase a drugs suseptibility to hydrolysis?
A
Esters, amides, lactams, lactones, imides and carbamate
24
Q
Why is it important to control the pH carefully for drugs suseptible to hydrolysis?
A
hydrolysis can be catalysed at high and low pH
25
What requirement must be met by the drug or excipient in order for hydrolysis to take place?
must be in solution
26
How can the reaction rate of hydrolysis be decreased?
- decreasing solubility by adding additives
- or solubilising in surfactant micelles- protected from water
- or formulating as a suspension
27
Hydrolysis is less likely for solid dosage forms but they can still interact with moisture in the environment. What excipient type could be added to prevent damage to capsule shells etc?
dessicant
28
Hydrolysis requires drug to be in solution. Less likely in solid dosage forms but, Impact of: (3)
* Moisture content
* Shell material (capsules)
* Packaging (including a dessicant)
29
whats oxidation?
Degradation process in the presence of oxygen
30
presence of what group increases susceptibliity to oxidation?
phenols: e.g: morphine, adrenaline, steroids
31
explain how unsaturated lipids can undergo oxidative rancidity?
heat, light and metal impurities cause free radical formation which produces a smell
32
oxidation in accelerated in presence of what? (2)
* Light/heat: free radicals formation
| * Trace metals: impurities and contamination during processing
33
what can oxidation be controlled by only? (4)
• Adding antioxidants- more lipo/hydrophilic
BHA, BHT, gallates, tocopherols- reducing agents. Protect drug
Ascorbic acid and sodium ascorbate
• Adding reducing agents
Sodium metabisulphite
Preferential oxidation vs. drug
• Controlling temp, pH and ionic strength, protect from light
In some cases, oxidation can be controlled by decreasing pH
• Selecting packaging impermeable to gases
34
name a lipophilic antioxidant which can be used to control oxidation or oxidative rancidity?
BHA
35
name a hydrophilic antioxidant which can be used to control oxidation or oxidative rancidity?
ascorbic acid
36
what would be the rationale behind adding reducing agents like sodium metabisulphate to drugs formulations that are susceptible to oxidation?
it is preferentially oxidised instead of the drug
37
what packaging to select to prevent oxidation?
amber or opaque bottle
38
whats Isomerisation? 3 types?
Conversion from one isomer to another
Optical isomers
geometric
structural
39
describe optical isomers - 2 types?
Change from one enantiomer to another
Racemization: single chiral centre
Epimerisation: more than one chiral centres
40
describe geometric isomers
Differences in conformation around a C=C. Change from cis to trans
41
describe structural isomers
Same formula but bonds in a different order
e.g. betamethasone-17-valerate// 21-valerate
occurs in Ad
42
difference between Dimerisation and polymerisation
Dimerisation:
Combination of two drug molecules
Polymerisation:
Combination of multiple molecules to create a long chain
Polymer = long chain of repeating unit
43
what type of instability may be responsible for penicilloyl-specific allergies
Dimerisation of B-lactams
• Dimerisation of amino-penicillins in concentrated solutions
• Susceptibility increases with increasing basicity of side chain
Cyclacillin << ampicillin < epicillin < amoxicillin
44
what are photochemical reactions catalysed by?
light
45
name some functional groups that if present in drugs, they would be subject to photochemical degredation ?
carbonyl, nitro, alkene, aryl chloride and phenolic compounds
e.g. folic acid, hydrocortisone, retinol
photosensitive drugs
46
photo-oxidation involves involvement of what?
free radicals
47
although sodium metabisulphate can be added to adrenaline solution to protect it from oxidation, what process does it make it more susceptible to?
photochemical degredation
48
Photochemical drug degradation sometimes due to incompatibilities within formulation
Example
adrenaline + sodium metabisulphite
| Promotion of photo-degradation of adrenaline
49
Photochemical degradation can be prevented by: (2)
• Adequate packaging
Primary pack e.g. amber glass, opaque blister pack- directly in contact with prep. Must protect from UV light and moisture.
Secondary pack e.g. cardboard box
• Polymeric coating containing a UV-light blocking agent e.g: oxybenzone
50
name a uv blocking agent that may be added to polymeric coating?
oxybenzone
51
Chemical degradation can result in (3)
* Lower efficacy
* Higher toxicity
* Changes to the physical appearance
52
summarising chemcial instability
Hydrolysis
• Reaction involving water- more likely for linear and cyclic esters and amides
• Catalysed at low and high pH
• Requires the molecule involves to be in solution and accessible
Oxidation
• Reaction involving oxygen
• Catalysed by light, heat, metal contaminants/impurities
• Prevented by antioxidants (suitable for what we need to protect), reducing agents, controlling pH/temperature/ionic strength/light/oxygen permeability
Photo-chemical degradation
• Typically photo-oxidation
• Phenol-containing molecules may be more susceptible
• Prevented by using suitable packaging or using opacifying agents
• For adrenaline- photo-degradation can result from an incompatibility with sodium metabisulphite
Dimerisation/polymerisation
• Combination of at least two drug molecules
• Possible link between dimerisation and penicilloyl-specific allergies (susceptibility increases with basicity of side chain for amino-penicillins)
Isomerisation
• Change in optical, geometric or structural isomers
53
what would be the main product formed by hydrolysis of ester ...
a) acid- catalysed
b_ base- catalysed
a) R-OOH + ROH
| b) R-OO- + ROH
54
Chloramphenicol is relatively susceptible to hydrolysis for an amide-containing drug. Why?
* Eye drops to be stored in the fridge- lower temperature, slow rate of degradation
* Hydrolysis: reaction with water. More susceptible to attack by OH as:
* The amide in this is different because it has two Cl groups (electron withdrawing) on it – lower electron density
55
what is the term given to the no of moles taking part in a given reaction?
molecularity
56
What 2 things can be followed to determine chemical reactions?
appearance of products and disappearance of reactants
57
what order is a reaction if the rate does not depend on the conc of reactants?
0
58
in zero order reactions the conc of reactants is constant and in reservoir. Is this the case for solutions or suspensions?
solutions
59
which order reaction has the equation C= C0 - kt?
0
60
if the units of K are conc time -1 , what does this suggest about the order of a reaction?
0
61
if the half life equation is C0/2K what is the order of the reaction?
0
62
what is the term given to reactiosn where the rate is determined by the 1 concentration?
first order
63
what is the order of the reaction to the rate equation Ln C = LnC0-kt ?
1
64
what are units for K for first order reactions?
time -1
65
what is the half life equation for first order reactions?
Ln2/K
66
why do pseudo first order reactions follow first order even though there are two reactants?
why do pseudo first order reactions follow first order even though there are two reactants?
67
what is the order of a reaction , where the rate depends on 2 reactants?
second
68
what is the order of the reaction that has the equation 1/C = 1/C0 + Kt?
2nd
69
if the units of K are conc -1 time -1, what does this suggest about the order of the reaction?
2nd
70
if the half life equation for a reaction is 1/coK , what does this suggest about the order of the reaction?
2nd
71
to determine the order without being able to plot, what difference should be observed between the two sets of data points selected if the order was 0?
very small difference
72
if the difference between the two data sets selected for determining the order without plotting is a difference of x10 between them, what does this suggest about the order of the reaction?
1st
73
to confirm that an order is first without plotting you can use lnc1-lnc2/ t1-t2. What would you expect the difference to be between the two data sets in this case, high or very low?
low
74
after testing for zero and first order using two data sets and realising its 2nd the equation 1/c1-1/c2 divided by t1-t2 can be used. Should the difference between the values be high or low?
low
75
the shelf life for most drugs is the time required for the Co to drop by what %?
10
76
the shelf life for potent drugs is the time required for Co to drop by what %?
5
77
if the shelf life calc is Co/10K, what order is the reaction?
0
78
if the shelf life calc is in(100/90) / K, what is the order is the reaction?
1
79
if the shelf life calc is 1/9CoK, what is the order of the reaction?
2
80
shelf life for...
- most drugs
- potent drugs
o C = 90%C0
| o : C = 95%C0
81
whats Overage?
excess of the active ingredient that can be added to a dosage form to prevent a loss of drug potency due to degradation
82
overage depends on what?
* Can calculate if familiar with recation rate, to determine suitable shelf life for product
* Depends on order of reaction
* Most: zero/first order kinetics
see p 151
83
first order... an eqn
C = (C0 + Cx) – kt
84
stability testing
A 10°C increase in temperature is estimated to increase the rate of reaction by how much?
2-5x
| big impact, rule of thumb
85
What equation is used to determine the effect of temperature on reaction rate? What is the normal and ln form of this equation?
the Arrhenius equation: k = Ae^(-Ea/RT) or lnk = lnA - (Ea/RT)
```
k = rate constant,
A = Arrhenius constant,
Ea = activation factor,
R = gas constant (8.314 J/mol.K),
T = temperature (K)
```
86
How do you convert from Celsius to Kelvin?
How do you convert from Celsius to Kelvin?
87
What is the activation rate/factor (Ea)?
the difference between the average energy of the reactants and the minimum energy required for them to react
constant and NOT A CONCENTRATION
88
What is the Arrhenius constant also known as?
the frequency factor
89
What parameters of the Arrhenius equation are constants for a given reaction?
the Arrhenius constant and the activation factor (Ea)
90
For a graph showing the effect of temperature on the rate of a reaction, what equation forms the basis of y = mx + c
lnk = lnA - Ea/RT
91
For a graph showing the effect of temperature on the rate of a reaction, what are the x- and y-axis?
x-axis: 1/T
y-axis: lnk
upside down graoh
92
For a graph showing the effect of temperature on the rate of a reaction, what is the gradient and what is x?
m = -Ea/RT
x = 1/T
93
For a graph showing the effect of temperature on the rate of a reaction, what is the y-intercept?
lnA
94
For a graph showing the effect of temperature on the rate of a reaction, what is y?
lnK
95
whats Activation rate Ea:
| affect of temp
Difference between the average energy of the reactants and the minimum energy required for them to react
96
When medicines are tested for stability, what temperatures are they tested at?
4°C, room temperature (15-25°C), 30°C, 37°C
97
When medicines are tested for stability, what humidities are they tested at?
ambient, 50% humidity, 75% humidity
98
It's not practical to test the shelf-life of medicines at their actual storage conditions. What do we do instead?
we use accelerated testing under high stress conditions as this increases the rate of degradation, then use the Arrhenius equation to find the stability under normal storage conditions
99
What are the benefits of accelerated testing?
allows for a reduction in testing time and early rejection of unsatisfactory formulations
100
Ex 1: you are given data for the decomposition of a chemical entity at different temperatures and you need to determine the shelf-life at 20°C. What must you do?
plot the graph for different orders and see which produces a graph with straight lines:
- for zero-order, plot C against t (60 and 70 are not straight)
- for first-order, plot lnC against t - all lines are straight so first-order
- find the equation for each line
- then look at the gradient to find you rate constant (remember for first-order equation is lnC = lnC₀ - kt, so gradient will give -k)
- we need to draw a graph of the effect of temperature on the rate of reaction
- remember that the axis for this are 1/T and lnk
- therefore we need to create a table and find the values for 1/T and lnk for each temperature (convert T to K then do the reciprocal, do the ln of k)
- plot the graph of effect of temperature on stability (lnk against 1/T)
- use the Arrhenius equation to find the rate constant for 20°C
- use the shelf-life equation for first-order reactions (ln(100/90)/k) to find the shelf-life for 20°C
101
From an lnk against 1/T graph, what would you do to find the rate constant for a certain temperature?
- find the equation for curve knowing the corresponding parameters for each in the equation lnk = lnA - Ea/RT (start by using rise/run to find gradient, then sub in points for lnk and 1/T to get lnA and full equation)
- substitute in your temperature (in K) for the found equation, and you'll get lnk
- convert this to k
102
• Accelerated testing is performed at what condition?
high temps
and Aarhenius equation is used to predict the reaction rate at the temperature of interest (usually the storage temperature)
used to predict shelf life
