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PMP-102 > 3. Stability of Medicines > Flashcards

3. Stability of Medicines Flashcards

1
Q

Define Stability:

A

capacity of a product to remain within specifications to ensure potency, quality or purity

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2
Q

Chemical degradation:

A

Decomposition of chemical moiety

Due to effects of moisture, oxygen, light & heat

Results in loss of active drug

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3
Q

Physical degradation

A

Formulation-specific =

Caking in suspensions, phase separation in emulsions

Hardness & brittleness of tablets

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4
Q

Microbial degradation

A

Microbial contamination =

Metabolism of drug molecule

Physical spoilage of dosage form

Infection-causing

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5
Q

Drug instability: may cause

A

Inconsistent dosage

Undesired change in performance – dissolution/bioavailability

Changes in physical appearance of the dosage form

Product failures

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6
Q

Drug instability: may cause

A

Inconsistent dosage

Undesired change in performance – dissolution/bioavailability

Changes in physical appearance of the dosage form

Product failures

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7
Q

Chemical degradation reactions

A
  1. Hydrolysis
  2. Oxidation
  3. Photodegradation
  4. Polymerisation and dimerisation
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8
Q
  1. Hydrolysis
A

Most common chemical degradation

Water present in many pharmaceuticals
> As ingredient or contaminant

Carboxylic acid derivatives are common in medicines
> Esters and amides

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9
Q

Examples of hydrolosis:

A

Hydrolysis of aspirin (ester)

Hydrolysis of chloramphenicol (amide)

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10
Q

Functional groups prone to hydrolysis

A

Ester
Amide
Imide
Urea
Lactone
Lactam

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11
Q

Hydrolysis reduction:

A

Dry formulations (powder for reconstitution, solid dosage form)

Adjusting pH to maximum stability in aqueous solution

Storage temperature

Coating

Choice of packaging

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12
Q

the rate of hydrolysis is reduced by:

A
  • Complexation
    Caffeine (a xanthine) complexes with local
    anesthetics, such as benzocaine and procaine
  • Surfactants
    Drug molecules become trapped in the micelle
    Hydrolytic groups such as OH cannot penetrate
    the micelle and reach the drug molecules
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13
Q
  1. Oxidation
A

Second most common pathway for drug breakdown

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14
Q

Define Oxidation

A

removal of H, loss of e-, addition of O

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15
Q

Oxidation - Generally occurs via the action of free radicals

A

Highly reactive species possessing one or more unpaired electrons

Generated by the action of light energy (UV), heat or trace metals such as Fe2+ or Cu+

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16
Q

Auto-oxidation

A

Uncatalysed and proceeds slowly under the influence of molecular oxygen

Reaction of free radicals with drugs or biomolecules leads to the formation of peroxyl radicals, which initiate and propagate auto-oxidation

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17
Q

Circumvention of auto-oxidation

A
  1. Remove initiators
  2. Exclude O2
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18
Q
  1. Remove Initiators
A

Chelation of trace metals with chelating agents: ethylene diamine tetraacetic acid (EDTA), citric acid & tartaric acid

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19
Q

Exclude O2

A

Sparge liquids with inert gases such as nitrogen to displace oxygen

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20
Q

Circumvention of auto-oxidation

A

Add free-radical scavengers/antioxidants

>Butylated hydroxytoluene (BHT) more readily 
  oxidised than oils, used to stabilise fatty/oily 
  products

> Ascorbic acid possesses lower redox potential 
   than drug, more readily oxidised
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21
Q
  1. Photochemical degration
A

Energy of a photon increases with decreasing wavelength (𝐸=1/𝜆)

> UV light has high energy which can catalyse reactions

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22
Q

UV light may induce complex reactions

A
  1. Oxidation
  2. Polymerisation
  3. Ring rearrangement
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23
Q
  1. Polymerisation
A

> A process by which two (dimerisation) or more identical drug molecules combine together to from a complex molecule

> UV radiation induces the polymerisation of chlorpromazine (in anoxic conditions)

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24
Q

Dimerisation and hydrolysis of ampicillin

A

** diagrams shown on lecture slide 21**

Lactam ring&raquo_space; Opened lactam ring

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25
Q

Define Photolysis:

A

The decomposition or separation of molecules by the action of light

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26
Q

Photolysis of the pentacyanonitrosylferrate (II) ion in sodium nitroprusside (administered by IV infusion for the management of acute hypertension)

Advantages?

A

Protected from light, stable for ~1 year
Exposed to normal room light, a shelf life of only 4 hours

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27
Q

Circumvention of photochemical effects

A

How to:

  1. Exclude from light
  2. Filter out light
28
Q

Photolysis - Exclude from light…

A
  • Storing in the dark
  • Packaging in foil
29
Q

Photolysis - Filter out light by…

A
  • Storage in amber glass or
  • Coating tablets with pigmented polymers
30
Q

Stability of meds - broken down…

A

CHEMICAL DEGRADATION REACTIONS > hydrolysis > Oxidation > Photo-degradation > Polymerisation& Dimerisation [Circumvention]

KINETICS OF CHEMICAL DECOMPOSITION > Zero order > First order / Pseudo zero order > Second order / Pseudo first order

31
Q

What is circumvention?

A

the action of overcoming a problem or difficulty, typically in a clever and surreptitious way

32
Q

What is a Pseudo order?

A

A Pseudo first-order reaction can be defined as a second-order or bimolecular reaction that is made to behave like a first-order reaction

33
Q

Kinetics of chemical decomposition in solution

A

Consider all conditions to which product may be subjected to in normal use plus all probable abuses (within reason) and subject the product to all these conditions

Prediction of shelf life requires an understanding of the kinetics of breakdown

34
Q

Reactions are classified according to the number of reacting species:

A
  • Zero order & pseudo zero order reactions
  • First order & pseudo first order reactions
  • Second order reactions
35
Q

Zero order reactions

A

Drug molecule —>Product of degradation
The rate of degradation of A is independent of the concentration of the reactants

36
Q

Zero order reaction equations

A

−𝑑[𝐴]/𝑑𝑡=𝑘
[𝐴]_𝑡 =[𝐴]_0−𝑘𝑡

37
Q

Other equations from zero

A

[𝐴]𝑡=[𝐴]0−𝑘𝑡
1/2 [𝐴]_0= [𝐴]_0−𝑘𝑡(1/2)
𝑡(1/2)=[𝐴]_0/2𝑘

38
Q

Half-life is dependent on…

A

the initial concentration, i.e. half-life decreases with decreasing concentration

39
Q

First order reactions

A

Drug molecule A —> Product of degradation
The rate of degradation of A is directly proportional to its concentration, [𝐴]

40
Q

First order reactions equations

A

−𝑑[𝐴]/𝑑𝑡=𝑘[𝐴]_𝑡
[𝐴]_𝑡=[𝐴]_0 𝑒^(−𝑘𝑡)
ln[𝐴]_𝑡 =ln⁡[𝐴]_0−𝑘𝑡

41
Q

Additional equations for first order reaction:

A

ln⁡[𝐴]𝑡 =ln[𝐴]0 −𝑘𝑡
ln⁡(1/2[𝐴]_0 )=ln⁡[𝐴]_0 −𝑘𝑡(1/2)
𝑡(1/2)=ln⁡2/𝑘

42
Q

Half-life is depemendant on____ in first order reactions.

A

concentration

43
Q

Pseudo order reactions

A

If the degradation of A follows first order kinetics
−𝑑[𝐴]/𝑑𝑡=𝑘[𝐴]_𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛

44
Q

Equations - Pseudo zero oder reactions

A

−𝑑[𝐴]/𝑑𝑡=𝑘[𝐴]_𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛

−𝑑[𝐴]/𝑑𝑡=𝑘_𝑜𝑏𝑠

45
Q

Second order reactions

A

A + B —> Product of degradation

The rate of degradation of A is directly proportional to its concentration and the concentration of the reactant B

46
Q

Equations fro Second order reactions

A

−𝑑[𝐴]/𝑑𝑡=𝑘[𝐴][𝐵]

1/[𝐴]_𝑡 =1/[𝐴]_0 +𝑘𝑡

47
Q

Second order reactions - additional equations

A

1/[𝐴]_𝑡 =1/[𝐴]_0 +𝑘𝑡

1/(1/2 [𝐴]_0 )=1/[𝐴]0 +𝑘𝑡(1/2)

𝑡_(1/2)=1/(𝑘[𝐴]_0 )

48
Q

Half-life is dependant of the _________ in a 2nd order reaction.

A

initial concentration

49
Q

Pseudo first order reactions

A

If [B] is very high (H2O) or constant (fixed pH)

50
Q

Pseudo first order reaction equations

A

−𝑑[𝐴]/𝑑𝑡=𝑘[𝐴][𝐵]

−𝑑[𝐴]/𝑑𝑡=𝑘_𝑜𝑏𝑠 [𝐴]

51
Q

What is an expression for a first order reaction

A

The rate constant

52
Q

Parallel pseudo first order reactions - EQUATIONS

A

−𝑑[𝐴]/𝑑𝑡=𝑘_1 [𝐴]+𝑘_2 [𝐴]

𝑘_𝑜𝑏𝑠= 𝑘_1+𝑘_2

53
Q

IN REALITY…

A

Stability of ranitidine in acetate buffer may start out first order but more sophisticated mechanisms come into play

54
Q

Extent of acceptable degradation

A

Most medicines are not perfectly stable

Some degradation must be allowed for. How much is reasonable?
5 – 10% loss limit over total shelf life (~ 5 years)

55
Q

Acceptable degradation..

A

1) Toxicity of degradation products
2) Physical properties of dosage form
3) Aesthetics (look & feel)

56
Q

Justification of expiry date & storage conditions

A

1) Simply store product under various conditions
Assess instability at the end of storage period

2) But this takes too long
> Wish to start stability study before final
pack/product defined
> Need idea of storage abuse

57
Q

Degredation?

A

degrading of the solid - dissolving into liquid

58
Q

Industry/regulatory authorities have evolved specific testing protocols

A

Accelerated/stress testing

59
Q

Justification of expiry date & storage conditions

A

Remember must get product onto market ASAP

e.g.
Pfizer/BioNTech vaccine
Oxford/AstraZeneca vaccine
Moderna vaccine
Janssen vaccine

60
Q

Arrhenius equation

A

The relationship between the rate of reaction and temperature is given by Arrhenius’s equation:

𝑘=𝐴𝑒^(−𝐸_𝑎/𝑅𝑇)

61
Q

What does each letter stand for in the Arrhenius equation?

A

𝑘 = rate constant of degradation reaction
𝐴 = frequency factor (number of collisions per unit time)
𝑒^(−𝐸_𝑎/𝑅𝑇) = fraction of the number of successful collisions
𝐸_𝑎 = activation energy
𝑅 = molar gas constant, 8.314 J K-1 mol-1
𝑇 = temperature (Kelvin)

62
Q

Arrhenius equation - re-arranged

A

𝑘=𝐴𝑒^(−𝐸_𝑎/𝑅𝑇)

ln⁡𝑘=ln⁡𝐴−𝐸_𝑎/𝑅𝑇

ln⁡𝑘=ln⁡𝐴−𝐸_𝑎/𝑅 (1/𝑇)

63
Q

Arrhenius equation - re-arranged

A

𝑘=𝐴𝑒^(−𝐸_𝑎/𝑅𝑇)

ln⁡𝑘=ln⁡𝐴−𝐸_𝑎/𝑅𝑇

ln⁡𝑘=ln⁡𝐴−𝐸_𝑎/𝑅 (1/𝑇)

64
Q

Arrhenius plot examples

A

The relationship of the reaction rate constants at two (or more) different temperatures provides the activation energy (𝐸_𝑎) for the degradation reaction

65
Q

Performing reactions at ELEVATED temp instead of allowing process to proceed slowly at room temp…

A

the 𝐸_𝑎 can be calculated and a 𝑘 value for room temperature determined

66
Q

Shelf-life prediction

A

Study kinetics of drug degradation at elevated temperature
>Takes only a short amount of time

Extrapolate to determine rate constant at ambient conditions (298 K)

PMP-102 (49 decks)

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