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Lab 2 > stability & degradation > Flashcards

stability & degradation Flashcards

1
Q

3 types of instability?

A
  • Physical stability
  • Chemical stability
  • Microbiological stability- for sterile products and other implictaions
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2
Q

what does instability impact?

A

shelf life of a product

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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:
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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
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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

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6
Q

what to Also look out for - physical stability?

A

• Changes in viscosity, pourability, spreadability, colour, odour, consistency etc.

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7
Q

whats High moisture content of gelatin shell makes capsules susceptible to?

A

changes in air humidity

also consider cross linking

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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

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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

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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

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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

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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

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13
Q

What is meant by leaching in the context of physical instability?

A

something from packaging goes into preparation

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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

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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

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16
Q

What physical instability can occur in ovc bags for parenteral use?

A

leaching from plastcizers in pvc bags

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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

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18
Q

What type of instability is due to changes induced by microbial contamination?

A

microbiological instability

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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

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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

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21
Q

List some of the mechanisms by which chemical instability can occur? 5

A 
Hydrolysis
oxidation
isomerisation
dimerization + polymerisation
phototoxic drug degredation
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22
Q

Which chemical mechanism is responsible for drug degredation as a result of a reaction with water?

A

hydrolysis

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23
Q

list some functional groups which increase a drugs suseptibility to hydrolysis?

A

Esters, amides, lactams, lactones, imides and carbamate

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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

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25
Q

What requirement must be met by the drug or excipient in order for hydrolysis to take place?

A

must be in solution

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26
Q

How can the reaction rate of hydrolysis be decreased?

A
  • decreasing solubility by adding additives
  • or solubilising in surfactant micelles- protected from water
  • or formulating as a suspension
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27
Q

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?

A

dessicant

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28
Q

Hydrolysis requires drug to be in solution. Less likely in solid dosage forms but, Impact of: (3)

A
  • Moisture content
  • Shell material (capsules)
  • Packaging (including a dessicant)
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29
Q

whats oxidation?

A

Degradation process in the presence of oxygen

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30
Q

presence of what group increases susceptibliity to oxidation?

A

phenols: e.g: morphine, adrenaline, steroids

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31
Q

explain how unsaturated lipids can undergo oxidative rancidity?

A

heat, light and metal impurities cause free radical formation which produces a smell

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32
Q

oxidation in accelerated in presence of what? (2)

A
  • Light/heat: free radicals formation

* Trace metals: impurities and contamination during processing

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33
Q

what can oxidation be controlled by only? (4)

A

• 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

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34
Q

name a lipophilic antioxidant which can be used to control oxidation or oxidative rancidity?

A

BHA

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35
Q

name a hydrophilic antioxidant which can be used to control oxidation or oxidative rancidity?

A

ascorbic acid

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36
Q

what would be the rationale behind adding reducing agents like sodium metabisulphate to drugs formulations that are susceptible to oxidation?

A

it is preferentially oxidised instead of the drug

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37
Q

what packaging to select to prevent oxidation?

A

amber or opaque bottle

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38
Q

whats Isomerisation? 3 types?

A

Conversion from one isomer to another

Optical isomers
geometric
structural

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39
Q

describe optical isomers - 2 types?

A

Change from one enantiomer to another
Racemization: single chiral centre
Epimerisation: more than one chiral centres

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40
Q

describe geometric isomers

A

Differences in conformation around a C=C. Change from cis to trans

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41
Q

describe structural isomers

A

Same formula but bonds in a different order
e.g. betamethasone-17-valerate// 21-valerate

occurs in Ad

42
Q

difference between Dimerisation and polymerisation

A

Dimerisation:
Combination of two drug molecules

Polymerisation:
Combination of multiple molecules to create a long chain
Polymer = long chain of repeating unit

43
Q

what type of instability may be responsible for penicilloyl-specific allergies

A

Dimerisation of B-lactams

• Dimerisation of amino-penicillins in concentrated solutions
• Susceptibility increases with increasing basicity of side chain
Cyclacillin &laquo_space;ampicillin < epicillin < amoxicillin

44
Q

what are photochemical reactions catalysed by?

A

light

45
Q

name some functional groups that if present in drugs, they would be subject to photochemical degredation ?

A

carbonyl, nitro, alkene, aryl chloride and phenolic compounds
e.g. folic acid, hydrocortisone, retinol

photosensitive drugs

46
Q

photo-oxidation involves involvement of what?

A

free radicals

47
Q

although sodium metabisulphate can be added to adrenaline solution to protect it from oxidation, what process does it make it more susceptible to?

A

photochemical degredation

48
Q

Photochemical drug degradation sometimes due to incompatibilities within formulation
Example

A

adrenaline + sodium metabisulphite

Promotion of photo-degradation of adrenaline

49
Q

Photochemical degradation can be prevented by: (2)

A

• 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
Q

name a uv blocking agent that may be added to polymeric coating?

A

oxybenzone

51
Q

Chemical degradation can result in (3)

A
  • Lower efficacy
  • Higher toxicity
  • Changes to the physical appearance
52
Q

summarising chemcial instability

A

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
Q

what would be the main product formed by hydrolysis of ester …
a) acid- catalysed
b_ base- catalysed

A

a) R-OOH + ROH

b) R-OO- + ROH

54
Q

Chloramphenicol is relatively susceptible to hydrolysis for an amide-containing drug. Why?

A
  • 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
Q

what is the term given to the no of moles taking part in a given reaction?

A

molecularity

56
Q

What 2 things can be followed to determine chemical reactions?

A

appearance of products and disappearance of reactants

57
Q

what order is a reaction if the rate does not depend on the conc of reactants?

A

0

58
Q

in zero order reactions the conc of reactants is constant and in reservoir. Is this the case for solutions or suspensions?

A

solutions

59
Q

which order reaction has the equation C= C0 - kt?

A

0

60
Q

if the units of K are conc time -1 , what does this suggest about the order of a reaction?

A

0

61
Q

if the half life equation is C0/2K what is the order of the reaction?

A

0

62
Q

what is the term given to reactiosn where the rate is determined by the 1 concentration?

A

first order

63
Q

what is the order of the reaction to the rate equation Ln C = LnC0-kt ?

A

1

64
Q

what are units for K for first order reactions?

A

time -1

65
Q

what is the half life equation for first order reactions?

A

Ln2/K

66
Q

why do pseudo first order reactions follow first order even though there are two reactants?

A

why do pseudo first order reactions follow first order even though there are two reactants?

67
Q

what is the order of a reaction , where the rate depends on 2 reactants?

A

second

68
Q

what is the order of the reaction that has the equation 1/C = 1/C0 + Kt?

A

2nd

69
Q

if the units of K are conc -1 time -1, what does this suggest about the order of the reaction?

A

2nd

70
Q

if the half life equation for a reaction is 1/coK , what does this suggest about the order of the reaction?

A

2nd

71
Q

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?

A

very small difference

72
Q

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?

A

1st

73
Q

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?

A

low

74
Q

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?

A

low

75
Q

the shelf life for most drugs is the time required for the Co to drop by what %?

A

10

76
Q

the shelf life for potent drugs is the time required for Co to drop by what %?

A

5

77
Q

if the shelf life calc is Co/10K, what order is the reaction?

A

0

78
Q

if the shelf life calc is in(100/90) / K, what is the order is the reaction?

A

1

79
Q

if the shelf life calc is 1/9CoK, what is the order of the reaction?

A

2

80
Q

shelf life for…

  • most drugs
  • potent drugs
A

o C = 90%C0

o : C = 95%C0

81
Q

whats Overage?

A

excess of the active ingredient that can be added to a dosage form to prevent a loss of drug potency due to degradation

82
Q

overage depends on what?

A
  • 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
Q

first order… an eqn

A

C = (C0 + Cx) – kt

84
Q

stability testing

A 10°C increase in temperature is estimated to increase the rate of reaction by how much?

A

2-5x

big impact, rule of thumb

85
Q

What equation is used to determine the effect of temperature on reaction rate? What is the normal and ln form of this equation?

A

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
Q

How do you convert from Celsius to Kelvin?

A

How do you convert from Celsius to Kelvin?

87
Q

What is the activation rate/factor (Ea)?

A

the difference between the average energy of the reactants and the minimum energy required for them to react

constant and NOT A CONCENTRATION

88
Q

What is the Arrhenius constant also known as?

A

the frequency factor

89
Q

What parameters of the Arrhenius equation are constants for a given reaction?

A

the Arrhenius constant and the activation factor (Ea)

90
Q

For a graph showing the effect of temperature on the rate of a reaction, what equation forms the basis of y = mx + c

A

lnk = lnA - Ea/RT

91
Q

For a graph showing the effect of temperature on the rate of a reaction, what are the x- and y-axis?

A

x-axis: 1/T

y-axis: lnk

upside down graoh

92
Q

For a graph showing the effect of temperature on the rate of a reaction, what is the gradient and what is x?

A

m = -Ea/RT

x = 1/T

93
Q

For a graph showing the effect of temperature on the rate of a reaction, what is the y-intercept?

A

lnA

94
Q

For a graph showing the effect of temperature on the rate of a reaction, what is y?

A

lnK

95
Q

whats Activation rate Ea:

affect of temp

A

Difference between the average energy of the reactants and the minimum energy required for them to react

96
Q

When medicines are tested for stability, what temperatures are they tested at?

A

4°C, room temperature (15-25°C), 30°C, 37°C

97
Q

When medicines are tested for stability, what humidities are they tested at?

A

ambient, 50% humidity, 75% humidity

98
Q

It’s not practical to test the shelf-life of medicines at their actual storage conditions. What do we do instead?

A

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
Q

What are the benefits of accelerated testing?

A

allows for a reduction in testing time and early rejection of unsatisfactory formulations

100
Q

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?

A

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
Q

From an lnk against 1/T graph, what would you do to find the rate constant for a certain temperature?

A
  • 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
Q

• Accelerated testing is performed at what condition?

A

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

Lab 2 (12 decks)

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