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Pharmaceutical Technology > Drug Stability 2 > Flashcards

Drug Stability 2 Flashcards

1
Q

What is the effect of increasing temperature on reaction rates? By how many fold?

A
  • Increasing temperature leads to increased reaction rates
  • Rates increase 2-3 fold with every 10oC increase in temperature
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2
Q

What is the Arrhenius equation used for? What order reactions can it be applied to?

A

Arrhenius equation explains the relationship between rate constant and temperature

  • Frequency factor (A) is a constant indicating the frequency of correctly aligned collisions between reactants

> Arrhenius equation can be applied to zero, first or second order reactions

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3
Q

Draw a labeled Arrhenius plot (log graph).

A) What is the effect of higher activation energy on temperature change

B) What does a steeper slope mean?

C) What happens as temperature is lowered?

A

A)

The greater the effect of temperature change

B)
The steeper the slope, the greater the activation energy

C)

Rate will drop

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4
Q

What is the relationship between activation energy effect on the rate at increased storage temperature

A

Increase activation energy = increased storage temperature

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5
Q

What is the 2 temperature Arrhenius Equation? When can you use it?

A
  • k1 represents the rate constant at temperature T1
  • k2 represents the rate constant at temperature T2
  • Ea is the activation energy in Joules/mol (not kJ/moL)
  • R is the Universal Gas Constant (8.314JK-1mol-1)
  • T1 and T2 are two different temperatures but must be in Kelvin (oC + 273)

temperature in kelvin (k = c + 273)

ALLOWS CALC OF RATE AT A DIFFERENT TEMPERATURE IF ACTIVATION ENERGY AND RATE AT ONE TEMPERATURE ARE KNOWN

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6
Q

Accelerated stability tests allow prediction of likely shelf life, this is done through testing at high temperatures then plotted on an Arrhenius plot. What is the Arrhenius plot used for and why must results be validated?

A

Arrhenius plot is used to estimate the shelf-life at a (lower) temperature of interest

  • Results must be validated by a parallel study at nominated storage temperature and conditions. This is because accelerated stability testing cannot exceed 3 years.
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7
Q

List 5 reasons that shelf-life and expiry dating depend on

A
  • Pharmacopoeial specifications
  • Time for the least stable ingredient to degrade to 90% of its original potency OR toxic degradants to accumulate to an unacceptable level
  • An arbitrary maximum of 5 years
  • Degradation product limitation
  • Product is stability-tested in its final packaging
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8
Q

Shelf-life is based upon degradants, what does this mean?

A

Shelf-life is based upon degradants (conc of toxic degradants must be minimised)

> shelf life will be based on an allowable level of any given impurity

> includes its likelihood of toxicity

> bases upon daily intake levels

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9
Q

Whats the expiry requirements for;

A) freshly prepared drug

B) Recently prepared

C) Extemporaneously prepared

A

A)

Within 24 hours of preparation

B)

Within one week of preparation

C)

Usually 28 days expiry, max 6 months with scientific data

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10
Q

What are climatic zones used for in drug stability regulations? Whata are the 2 different sets of testing conditions?

A

4 international climatic zones derived to account for different ambient storage conditions worldwide –> derived from measurement of average temperatures and humidities without air- conditioning

  • Zones I and II require stability testing at 25°C/60% RH
  • Zones III and IV at 30°C/70% RH

Australia assigned to II (Mediterranean/ Subtropical) but has areas of II, III and IV

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11
Q

What are some APF standard storage conditions?

A
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12
Q

What is mean kinetic temperature? What does take into account?

A

A single calculated temperature at which total amount of degradation over a period is equal to the sum of individual degradations at different temperatures

> Takes into account temperature fluctuations during storage

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13
Q

How is mean kinetic temperature calculated?

A

It is calculated at <-25*C. Range may be limited (eg 15-30C)

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14
Q

For freezing effects (drug instability);

A) What does freezing above the eutectic point of a product do?

B) What happens to pH of buffers?

C) What happens to reaction rate?

D) What is irreversibly damaged by the freezing process?

A

A)

Freezing at temperatures above the eutectic point of a product produces areas of very high concentration drug solution within the frozen solvent

B)

pH of buffers may change on freezing

C)

Reaction rates in the pockets of highly concentrated solution can increase by several orders of magnitude

D)

  • Proteins and vaccines
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15
Q

What does the term cold chain mean? What are some ways of assuring this occurs?

A

System of transporting and storing temperature-sensitive products (including vaccines) within the products’ specified temperature range from manufacturer to point of administration

  • Transport in coolers using conditioned ice packs to prevent freezing
  • Cold chain monitors: freeze monitors, dual–time monitors, vaccine vial monitors
  • Vaccine refrigerator
  • Temperature monitoring: recording of daily max/min temps, alarms when conditions outside requirements
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16
Q

When do pharmacists need to reconsider shelf-life and storage?

Clue: 4 instances

A
  • Repackaging medications (eg Webster packs)
  • Transporting temperature sensitive products
  • Supplying reconstituted preparations
  • Compounding
17
Q

What are the factors that influence loss of stability at altered storage conditions?

A
  • Type of degradation reaction
  • The activation energy (if higher = more sensitive to temp changes)
  • Length of exposure to new conditions
  • Degree of variation from specified conditions
  • Freezing conditions
18
Q

What are the two factors affecting stability?

A

Solvent Polarity and Ionic Strength

19
Q

The polar nature of a solvent governs its ability to dissolve/solvate ions. How can solvent polarity (factors affecting drug stability) be described?

A

By dielectric constant and dipole moment. Low polar solvent = low dielectric constant.

20
Q

The polarity of solvent (factors affecting drug stability) used can influence reaction rate and therefore drug stability.

A) how does it do this?

B) what happens if the transition state is more polar than the initial state or if the transition state is less polar than the initial state?

A

A)

Transition state: between the state in which molecules exist as reactants and the state in which they exist as products.

Transition state theory says that the reaction rate is determined by the concentration of the transition state species. The concentration is controlled by the equilibrium between the initial and transition states

B)

G‡ = Activation Energy

  • If the transition state is more polar than the initial state, then an increase in solvent polarity will stabilize the transition state relative to the initial state, decreasing ‘G‡ and increasing the rate
  • If the transition state is less polar than the initial state, an increase in solvent polarity will increase ‘G‡ and decrease the rate
21
Q

Answer the following questions for solvent polarity (factors affecting drug stability)

A) Does solvent polarity have any effect on neutral non-polar reactants –> non polar transition state –> non polar products?

B) Does solvent polarity have any effect on neutral reactants –> more polar transitions state –> charged products?

C) Does solvent polarity have any effect on neutral molecule- Ion reactions –> less polar transition state?

D) What happens to transition state and solvent polarity if reactants are ions of opposite charge?

E) What happens to transition state and solvent polarity if reactants are ions of the same charge?

A

A)

  • Solvent polarity has little influence on rate

B)

  • Increasing solvent polarity should increase rate.

C)

  • Increasing solvent polarity should decrease rate.

D)

  • transition state will have less or no charge ie less polar
  • Increasing solvent polarity should decrease rate.

E)

  • Transition state more polar
  • Increase solvent polarity and increase rate
22
Q

What effect does increased ionic strength of the solution have on:

A) between ions and molecules with dipole moments

B) oppositively charged ions

C) similarly charged ions

The effect of the total concentration of dissolved electrolytes on the rate of hydrolysis reactions results from the influence of ionic strength on interionic attraction, through solvation effects

A

A)

little change in reaction rate of reactions between ions and molecules with dipole moments, and reactions between neutral molecules (zAzB = 0)

B)

decrease the rate of reaction between oppositely charged ions, (e.g. drug cation and excipient anions) (zAzB -ve)

C)

increase the rate of reaction between similarly charged ions (zAzB +ve)

23
Q

Explain what is meant by the “Activation Energy” of a reaction

A

Energy level that the reactant molecules must overcome before a reaction can occur

24
Q

Discuss the factors that influence assignment of expiry dates

A

​Time for the least stable ingredient to degrade to 90% of its original potency (or toxic degradants to accumulate to an unacceptable level)

Depends on pharmacopoeial specfications

> An arbitrary maximum of 5 years

> Degradation product limitation

> Product is stability tested in its final packaging

Also depends on if it has been freshly prepared (< 24 hours preparation time), recently prepared (issued within one week of preparation) or extemporaneously prepared (usually 28 days expiry)

> compounded preparations have a maximum of 6 months

25
Q

Explain the meaning and application of Mean Kinetic Temperature

A

Mean Kinetic Temperature is calculated from the average of weekly high and low temperatures over the preceding 52 weeks

  • Takes into account temperature fluctuations during storage

Application –> can calculate MKT in the following circumstances

  • Impact on transportation
  • Pharmacy temperatures
  • Webster packs
  • Mail order
  • Doctor/Reps Cars
26
Q

Discuss how the magnitude of the Ea (activation energy) influences the shelf-life of a product that is stored above its specified storage temperature

A

As activation energy gets higher –> the greater the effect of the temperature change and the higher the rate of reaction.

Therefore higher activation energy would mean a lower shelf-life if the product was stored above its specified storage temperature

Also a higher rate constant value will lead to a decrease in shelf-life

27
Q

The rate constant for a drug at 40oC is 0.011day-1 and the Activation Energy is 57.7 kJmol-1. Calculate the rate constant and shelf-life at 0oC

A

Pharmaceutical Technology (9 decks)

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