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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/πœ†)

> 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
Define Photolysis:
The decomposition or separation of molecules by the action of light
26
Photolysis of the pentacyanonitrosylferrate (II) ion in sodium nitroprusside (administered by IV infusion for the management of acute hypertension) Advantages?
Protected from light, stable for ~1 year Exposed to normal room light, a shelf life of only 4 hours
27
Circumvention of photochemical effects
How to: 1. Exclude from light 2. Filter out light
28
Photolysis - Exclude from light...
- Storing in the dark - Packaging in foil
29
Photolysis - Filter out light by...
- Storage in amber glass or - Coating tablets with pigmented polymers
30
Stability of meds - broken down...
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
What is circumvention?
the action of overcoming a problem or difficulty, typically in a clever and surreptitious way
32
What is a Pseudo order?
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
Kinetics of chemical decomposition in solution
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
Reactions are classified according to the number of reacting species:
- Zero order & pseudo zero order reactions - First order & pseudo first order reactions - Second order reactions
35
Zero order reactions
Drug molecule --->Product of degradation The rate of degradation of A is independent of the concentration of the reactants
36
Zero order reaction equations
βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜ [𝐴]_𝑑 =[𝐴]_0βˆ’π‘˜π‘‘
37
Other equations from zero
[𝐴]_𝑑=[𝐴]_0βˆ’π‘˜π‘‘ 1/2 [𝐴]_0= [𝐴]_0βˆ’π‘˜π‘‘_(1/2) 𝑑_(1/2)=[𝐴]_0/2π‘˜
38
Half-life is dependent on...
the initial concentration, i.e. half-life decreases with decreasing concentration
39
First order reactions
Drug molecule A ---> Product of degradation The rate of degradation of A is directly proportional to its concentration, [𝐴]
40
First order reactions equations
βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜[𝐴]_𝑑 [𝐴]_𝑑=[𝐴]_0 𝑒^(βˆ’π‘˜π‘‘) ln[𝐴]_𝑑 =ln⁑[𝐴]_0βˆ’π‘˜π‘‘
41
Additional equations for first order reaction:
ln⁑[𝐴]_𝑑 =ln[𝐴]_0 βˆ’π‘˜π‘‘ ln⁑(1/2[𝐴]_0 )=ln⁑[𝐴]_0 βˆ’π‘˜π‘‘_(1/2) 𝑑_(1/2)=ln⁑2/π‘˜
42
Half-life is depemendant on____ in first order reactions.
concentration
43
Pseudo order reactions
If the degradation of A follows first order kinetics βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜[𝐴]_π‘ π‘œπ‘™π‘’π‘‘π‘–π‘œπ‘›
44
Equations - Pseudo zero oder reactions
βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜[𝐴]_π‘ π‘œπ‘™π‘’π‘‘π‘–π‘œπ‘› βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜_π‘œπ‘π‘ 
45
Second order reactions
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
Equations fro Second order reactions
βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜[𝐴][𝐡] 1/[𝐴]_𝑑 =1/[𝐴]_0 +π‘˜π‘‘
47
Second order reactions - additional equations
1/[𝐴]_𝑑 =1/[𝐴]_0 +π‘˜π‘‘ 1/(1/2 [𝐴]_0 )=1/[𝐴]_0 +π‘˜π‘‘_(1/2) 𝑑_(1/2)=1/(π‘˜[𝐴]_0 )
48
Half-life is dependant of the _________ in a 2nd order reaction.
initial concentration
49
Pseudo first order reactions
If [B] is very high (H2O) or constant (fixed pH)
50
Pseudo first order reaction equations
βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜[𝐴][𝐡] βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜_π‘œπ‘π‘  [𝐴]
51
What is an expression for a first order reaction
The rate constant
52
Parallel pseudo first order reactions - EQUATIONS
βˆ’π‘‘[𝐴]/𝑑𝑑=π‘˜_1 [𝐴]+π‘˜_2 [𝐴] π‘˜_π‘œπ‘π‘ = π‘˜_1+π‘˜_2
53
IN REALITY...
Stability of ranitidine in acetate buffer may start out first order but more sophisticated mechanisms come into play
54
Extent of acceptable degradation
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
Acceptable degradation..
1) Toxicity of degradation products 2) Physical properties of dosage form 3) Aesthetics (look & feel)
56
Justification of expiry date & storage conditions
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
Degredation?
degrading of the solid - dissolving into liquid
58
Industry/regulatory authorities have evolved specific testing protocols
Accelerated/stress testing
59
Justification of expiry date & storage conditions
Remember must get product onto market ASAP e.g. Pfizer/BioNTech vaccine Oxford/AstraZeneca vaccine Moderna vaccine Janssen vaccineΒ 
60
Arrhenius equation
The relationship between the rate of reaction and temperature is given by Arrhenius’s equation: π‘˜=𝐴𝑒^(βˆ’πΈ_π‘Ž/𝑅𝑇)
61
What does each letter stand for in the Arrhenius equation?
π‘˜ = rate constant of degradation reaction 𝐴 = frequency factor (number of collisions per unit time) 𝑒^(βˆ’πΈ_π‘Ž/𝑅𝑇) = fraction of the number of successful collisions 𝐸_π‘Ž = activation energy 𝑅 = molar gas constant, 8.314 J K-1 mol-1 𝑇 = temperature (Kelvin)
62
Arrhenius equation - re-arranged
π‘˜=𝐴𝑒^(βˆ’πΈ_π‘Ž/𝑅𝑇) lnβ‘π‘˜=lnβ‘π΄βˆ’πΈ_π‘Ž/𝑅𝑇 lnβ‘π‘˜=lnβ‘π΄βˆ’πΈ_π‘Ž/𝑅 (1/𝑇)
63
Arrhenius equation - re-arranged
π‘˜=𝐴𝑒^(βˆ’πΈ_π‘Ž/𝑅𝑇) lnβ‘π‘˜=lnβ‘π΄βˆ’πΈ_π‘Ž/𝑅𝑇 lnβ‘π‘˜=lnβ‘π΄βˆ’πΈ_π‘Ž/𝑅 (1/𝑇)
64
Arrhenius plot examples
The relationship of the reaction rate constants at two (or more) different temperatures provides the activation energy (𝐸_π‘Ž) for the degradation reaction
65
Performing reactions at ELEVATED temp instead of allowing process to proceed slowly at room temp...
the 𝐸_π‘Ž can be calculated and a π‘˜ value for room temperature determined
66
Shelf-life prediction
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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