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PHRM 513 > Drug stability II > Flashcards

Drug stability II Flashcards

1
Q

For zero-order degradation, the rate of degradation is dependent on the rate
constant only.
• A. agree
• B. disagree

A

• A. agree

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2
Q

For first-order degradation, a fixed amount of drug is degraded per unit time.
• A. agree
• B. disagree

A

• B. disagree

- its a percentage

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3
Q

If a small concentration of drug is in a large volume of water, we can neglect the concentration of water when determining the rate of hydrolysis.
• A. agree
• B. disagree

A

A. agree

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4
Q

Half-life:

A

Time required for the drug concentration to decrease by half

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5
Q

Shelf-life

A

Time required for the drug concentration to decrease by 10%

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6
Q

If there is a large energy barrier (activation energy) to drug degradation,

A

degradation is less likely to take place

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7
Q

Activation Energy (Ea)

A

To reach this activated state, a certain amount of energy needs to be added

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8
Q

In an exothermic reaction,

A

the products possess less energy than the reactants by an amount ∆H

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9
Q

• k is the

A

apparent rate constant
The magnitude of k dictates the rate of reaction
• Example: for zero-order reactions, the reaction rate = k
The number of molecules with sufficient energy increases with temperature

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10
Q

Arrhenius Equation

A

Describes the effect of temperature on reaction rate constant

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11
Q

k=Ae-Ea/RT

A

k is the apparent rate constant
• Ea: activation energy – only those molecules that have energy above a certain value can react
• A: frequency factor – the frequency of collisions between reactant molecules
• R: ideal gas constant (1.987 cal/°K*mol)
• T: temperature (K)
• Recall that to convert from °C to °K, add 273

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12
Q

• If there are many molecules with enough kinetic energy to react, degradation is

A

likely to take place quickly

• k will be large

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13
Q

If the temperature rises

A

there are more molecules with more kinetic energy

• It is easier for them to overcome the activation energy barrier

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14
Q

Arrhenius Equation: As T increases, k

A

increases

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15
Q

Arrhenius Equation: As k increases, the rate of reaction

A

increases

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16
Q

Arrhenius Equation: As the activation energy increases, k ->

A

decreases

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17
Q

Arrhenius Equation: As k decreases, the rate of reaction

A

decreases

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18
Q

If the activation energy (Ea) is small relative to the kinetic energy (RT),

A

k will be

large and the reaction will proceed quickly!

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19
Q

Thermal Degradation

A

There is a linear relationship between the
natural log of the rate constant and inverse
of temperature
This linear relationship allows us to
extrapolate the stability determined at
higher temperatures to that expected at
ambient temperature
• This is especially useful for long-term stability

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20
Q

We need drug stability testing to

A

Establish the shelf-life for a drug product
• Determine proper storage conditions for a drug product
• Identify degradation products that occur during storage
• Ensure efficacy over the shelf-life of a product
• Gain approval by regulatory agencies

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21
Q

Accelerated Stability

A

These increase rate of degradation- Elevated temperature- Temperature increase the rate of reaction

  • Elevated humidity- • Humidity increases opportunity for hydrolysis
  • Exposure to light- • Artificial light can be used to mimic sunlight
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22
Q

Accelerated Stability Studies

A

Long-term:
• ICH: sufficient time beyond 12 months to cover shelf-life of product
• 25°C, 60% relative humidity for 12 months
• Intermediate:
• ICH: Required when marked change noted during accelerated conditions
• 30°C, 60% relative humidity for 6 months
• Accelerated:
• ICH: >15°C above ambient storage conditions
• 40°C, 75% relative humidity for 6 months

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23
Q

• Stress testing

A

More severe conditions than used for accelerated testing
• Identify likely degradation products and pathways
• Wide range of pH, temperature, humidity, oxidative and photolysis conditions

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24
Q

Increasing the temperature increases the kinetic energy of molecules.
• A. agree
• B. disagree

A

• A. agree

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25
Q

The Q10 method allows

A

estimates of shelf-life with respect to changes in temperature that are
independent of the reaction order

26
Q

What does it mean for the reaction rate if k2/k1 equals 2?

A

For every 10°C increase in temperature, the reaction rate doubles

27
Q

What does it mean for the reaction rate if k2/k1 equals 2?

A

For every 10°C increase in temperature, the reaction rate doubles
-The rate of reaction will be twice as fast at 30°C as it will at 20°C
The value of Q indicates the thermal dependence on a rate of reaction

28
Q

The value of Q indicates

A

the thermal dependence on a rate of reaction

- Q10 doesn’t depend on the order of the reaction

29
Q

For every 10°C increase in temperature, the degradation rate constant

A

increases 2x, 3x or 4x

30
Q

Conversely, for every 10°C decrease in temperature, the degradation rate constant

A

decreases 2x, 3x or 4x

31
Q

𝑡2 = 𝑡1 / 𝑄10 ^(∆𝑇/10)

A
  • t1 is the known shelf-life at a known temperature
  • t2 is the estimated shelf-life at a new temperature
  • ∆T is the difference in the temperatures T2 and T1
  • ∆T = (T2 – T1)
32
Q

Drug decomposition typically yields Ea values between

A

12 and 24 kcal/mol
• Most commonly, between 19-20 kcal/mol
• We can estimate shelf-life using Q10 values, rather than measure
• Q=3 is usually appropriate for most drugs (Ea=19.4 kcal/mol)

33
Q

For every 10°C decrease, the degradation rate

A

decreases by a factor of 3

34
Q

For every 10°C decrease

A

our shelf-life increases by a factor of 3

35
Q

Chemical Stability

A

Hydrolysis (moisture)
• Oxidation (oxygen)
• Photolysis (light)

36
Q

Primary confounding factors:

A
  • Temperature
  • Water
  • Light
  • pH
37
Q

As we decrease pH, our solution becomes more __________.
• A. acidic
• B. basic

A

• A. acidic

38
Q

As we decrease pH, our hydrogen ion concentration_____________.
• A. increases
• B. decreases

A

• A. increases

39
Q 
If we decrease pH by 1 unit, our hydrogen ion concentration is \_\_\_\_-fold \_\_\_\_\_\_\_.
• A. 100, greater
• B. 100, less
• C. 10, greater
• D. 10, less
A

• C. 10, greater

40
Q

Generalities

A

• If there is a large energy barrier (activation energy) to drug degradation, degradation is less
likely to take place
• Acid or base catalysis can lower Ea for the hydrolysis of some drugs

41
Q

Hydrolysis is often

A

pH-dependent

• Can be base-catalyzed or acid catalyzed

42
Q

pH stability profile

A

Dilute drug in different pH solutions
• Monitor concentration of drug remaining over time
• Plot the natural log of the drug concentration versus time
• Determine k
• Plot log k versus pH

43
Q

• If log k increases with decreasing pH,

A

, acid catalysis may be occurring

44
Q

If log k increases with increasing pH

A

base catalysis may be occurring

45
Q

If there is a point where k (or log k) is at a minimum,

A

this is the pH of optimal stability.

46
Q

pH Stability Profile

A

the pH of lowest k (or ln k
or log k) is the pH of greatest
stability
- Drugs are the most stable at pH where theres the lowest k

47
Q

pH Stability Profile

A

the pH of lowest k (or ln k
or log k) is the pH of greatest
stability
- Drugs are the most stable at pH where theres the lowest k

48
Q

Drug Stability Example

A

Levothyroxine
• Small molecule drug used to treat hypothyroidism
• Sensitive to light, pH, moisture, temperature, and oxidation
• Narrow therapeutic index
• Too much causes hyperthyroidism
• Too little causes hypothyroidism
• 12 different tablet strengths varying in as little as 9% active ingredient content reflect the
need to manage the needs of individual patients
• Stability found to be highly variable
• Some products lost <5% within 24 months
• Other products lost ~10% within 9 months
• 2007: FDA tightened potency specification
• Must maintain at least 95% potency for shelf-life

49
Q

Glass containers: Stability losses

A
  • Generally resistant to chemical/physical change
  • Alkaline surface may cause rise in pH
  • Transparent to UV light
  • Release of ions which may be reactive
50
Q

Plastic containers: Stability losses

A

Plasticizers may leach into products
• Drug may leach into plastic
• Transfer of moisture/oxygen into product

51
Q

How can Stability Losses be Minimized?

A
  1. Choice of container
  2. Avoid contact with moisture/oxygen
  3. Change chemical structure of the drug (when possible)
  4. Addition of anti-oxidants to formulation
  5. Reduce storage temperature
  6. Ensure adequate buffering capacity
  7. Minimize light-induced degradation by preventing light energy from reaching the drug
52
Q

Choice of container

A

Ensure compatibility of container material with formulation
• Use of borosilicate glass (generally less reactive type of glass)
• Less leachate of reactive alkali ions which can raise pH

53
Q

Avoid contact with moisture/oxygen

A
  • Fill headspace of containers with inert gas
  • Seal containers with foil
  • Package individually
  • Formulate in glycerin, propylene glycol, or alcohol rather than water
  • Supply in anhydrous form, requiring pharmacist to reconstitute in water before dispensing
54
Q

Change chemical structure of the drug (when possible)

A

Ester (easily hydrolyzed) to amide

55
Q

Addition of anti-oxidants to formulation

A

Sodium sulfite, sodium bisulfite, sodium metabisulfite, hypophosphorous acid, and ascorbic
acid
• Alpha-tocopherol, butyldroxyanisole, ascorbyl palmitate

56
Q

Reduce storage temperature

A

Lower temperature, fewer molecules with enough energy to overcome activation energy
• Especially important for preparations subject to hydrolysis
• Less microbial growth!

57
Q

• Ensure adequate buffering capacity

A
  • Especially important for preparations subject to hydrolysis
  • Possible degradation (chemical)
  • Formulate in glycerin, propylene glycol, or alcohol rather than water
  • Supply in anhydrous form, requiring pharmacist to reconstitute in water before dispensing
58
Q

• Minimize light-induced degradation by preventing light energy from reaching the drug

A
  • Manufacture light-sensitive products in an environment with a longer wavelength (500-800 nm, brown light)
  • Storage in opaque plastics
  • Storage in amber colored bottles
  • Amber-colored glass prevents light transmission below 470 nm
  • Blocks UV light/some visible
  • Storage in secondary packaging
  • If clear, packaging in cardboard box
  • Storage in aluminum blister packs
  • Coat tablets with a layer of colored material
  • Storage in a dark cabinet
59
Q

Stability of ‘Biologics’

A

Drugs intended for intravenous infusions are often formulated with sugars
- Some biologics are formulated with or diluted for IV infusion with ‘reducing sugars’
• A reducing sugar is one that can act as a reducing agent
• Can convert to an open-chain form yielding an aldehyde
• Examples include maltose, lactose, fructose, and glucose
• ‘Reducing sugars’ are capable of reacting with amino groups of biological molecules
• This non-enzymatic reaction is known as ‘glycation’
• May impact stability, efficacy, and safety

60
Q

Small molecules are typically fairly robust

A

Biological drugs (i.e.-antibodies, fusion proteins, etc.) are much more sensitive

61
Q

Biologics have more complex structures

A

Primary, secondary, tertiary, and quaternary structures

• Can denature, unfold, misfold, aggregate, and precipitate

62
Q

Drugs are More susceptible to:

A

Thermal degradation
• pH variation
• Adsorption
• Microbial contamination

PHRM 513 (13 decks)

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