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PHRM 513 > Drug stability > Flashcards

Drug stability Flashcards

1
Q

What is drug stability?

A

The ability of a pharmaceutical dosage form to remain within established limits of identity,
potency, and purity

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2
Q

Broad categories of drug stability

A
  • Physical
  • Microbiological
  • Chemical
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3
Q

Why is drug stability important?

A

Drugs can degrade upon storage

Drugs can inherently degrade at different rates based on their formulation

Drugs can degrade at different rates depending on storage conditions

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4
Q

Drug product:

A

dosage form in the final formulation intended for marketing

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5
Q

Drug substance

A

unformulated active drug

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6
Q

Excipient:

A

Anything other than the drug substance in the dosage form

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7
Q

Shelf-life

A

The time period during which a drug product is expected to remain within the approved shelf-life specification provided it is stored under listed conditions

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8
Q

Expiration date:

A

Date listed on the product packaging designating the time prior to which a
drug product is expected to remain within the approved shelf-life specification

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9
Q

Solvolysis

A

Splitting of molecule by solvent (usually water, hence, hydrolysis

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10
Q

Oxidation

A

Loss of electrons

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11
Q

Photolysis

A

Light induced degradation

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12
Q

Dehydration

A

Loss of water

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13
Q

Epimerization

A

Conversion of one stereochemical center into another
- Stereroisomers have the same molecular and
structural formula

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14
Q

Hydrolysis

A

Splitting of a molecule by water

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15
Q

Nucleophile:

A

“Nucleus loving”
• Likes positively-charged
• Donates electrons to electrophiles

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16
Q

Oxidation reactions

A

Oxidation is the loss of electrons – Reduction is the gain of electrons
• OILRIG
• For every oxidation, there must be a reduction and vice versa

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17
Q

Photolysis

A

Photons of light are absorbed by the drug and may cause molecular rearrangement
- The shorter the wavelength, the more energy is present

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18
Q

Energy is inversely proportional to

A

wavelength

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19
Q

Many drugs degrade upon exposure to light

A

Functional groups containing double bonds tend to be photolabile, in particular esters and imides

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20
Q

Diastereomers

A

differ in configuration at a single chiral
center
• Diastereomeric structures are not mirror images of each other
• Have similar, but different physical properties

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21
Q

Tetracycline

A

Commonly prescribed broad-spectrum antibiotic

• Has a very narrow pH stability (pH 8.2-8.7)

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22
Q

At low pH: At low pH

A

Epimerizes at low pH to yield 4-epitetracycline which has no antibacterial activity
• Dehydrates to form anhydrotetracycline which has no antibacterial activity
• And does both to form epianhydrotetracycline which is toxic

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23
Q

Physical Stability

A
  • Evaporation of alcohol
  • Loss of water
  • Saturated solutions can become supersaturated and precipitate
  • Emulsions can form biphasic mixture
  • Creams can become dry
  • Change in product consistency
  • Tablets may become hardened – change in dissolution/change in bioavailability
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24
Q

Degradation by microorganisms

A

Enzymatic processes

• Often a problem in aqueous formulations and those containing natural polymers

25
Q

Manufacturing side

A

Raw materials, containers, closures
• Personnel and manufacturing equipment
• Sterilization is often done on containers and some raw materials, but these processes can
negatively impact the final product

26
Q

Consumer side

A 
Repetitive dosing (ex.-eye drops)
• Improper storage
27
Q

Effects of Drug Instability

A
  • Change in physical appearance
  • Change in color, uniformity, odor,
  • Change in consumer acceptance
  • Change in odor, color, flavor, uniformity
  • Change in dissolution/drug release properties
  • Possible reduction in bioavailability
  • Change in strength of active ingredient
  • Loss of labeled strength/potency
  • But, could also have unintended activation of prodrugs
  • Potential formation of toxic degradants
28
Q

Which processes are responsible for

elimination?

A

• B.) Distribution and excretion

29
Q

The Dark Side of Drug Stability

A
  • Drugs usually lose potency upon storage
  • This can be important especially for narrow
    therapeutic index drugs
30
Q

A narrow therapeutic index drug has

A

a small ratio of plasma drug concentrations where it is toxic relative to where it is effective

31
Q

Zantac OTC (Ranitidine) recalled

A

Histamine H2-blocker
• N-nitrosodimethylamine (NMDA) found as a degradation
product
• Probable human carcinogen
• Also found in valsartan, losartan, and irbesartan (angiotensin
II receptor blockers)
• Also recalled 2019

32
Q

Where is the
histamine H2
receptor primarily
expressed?

A

GI tract

33
Q

• Drug (D) reacts with water (W)

A

to yield degradation products (P)

D + W -> P

34
Q

A very small concentration of drug [D]

A

ss lost in a very small amount of time (dt)

• d[D]/dt

35
Q

As we are losing, not gaining [D], with time

A

the sign is (-)

• -d[D]/dt

36
Q

The rate at which drug is lost is proportional

A

to the concentration of drug and that of water

• -d[D]/dt α [D][W]

37
Q

• The absolute rate of drug loss is dictated by

A

a rate constant, k

• -d[D]/dt =-k[D][W]

38
Q

For intravenous administration:

A

The drug is injected
• Almost immediately reaches a high concentration
in the plasma
• Then the concentration reduces due to elimination
processes
• Unlike in oral administration, there is no
absorption phase
- first order process

39
Q

Similarly, for a drug in a container:

A

The drug is initially at a high concentration
• Then the concentration reduces due to
degradation processes
- zero order process

40
Q

k (rate constant) dictates the:

A

rate of elimination (body)

• or rate of degradation (container)

41
Q

Ke

A

Constant reflecting the rate of drug elimination to the amount of drug in the body
• Small elimination rate constant, slow elimination from the body
• Large elimination rate constant, fast elimination from the body

42
Q

• Drug stability: k

A

Constant reflecting the rate of drug degradation to the amount of drug in the container
• Small rate constant, slow degradation process
• Large rate constant, fast degradation process

43
Q

Pseudo zero order

A

A first order reaction that mimics a zero order reaction

44
Q

Pseudo first order

A

A second order reaction that mimics a first order reaction

45
Q

Zero-Order Reactions Proceed

A

independently of reactant concentration
Rate = Rate constant
-Rate = Rate constant * concentration
- linear

46
Q

First Order Reactions

• Proceed linearly on the basis on

A

a single reactant
concentration
Rate = Rate constant * concentration
Some fraction or percentage of the drug is lost per unit
time
- Initial conc. matters
- non-linear and exponential relationship

47
Q

Half-life (t ½)

A

Time required for the drug
concentration to decrease by half
-

48
Q

For zero-order processes, the half-life is

A

dependent on the concentration
• t½=[D]0/2*k
-It will take more time to reduce higher initial
concentrations by half than lower concentrations

49
Q

For 1st order processes, half-life is not

A

dependent on the concentration
• t1/2 = 0.693/k

It will take the same amount of time to reduce
higher initial concentrations by half as it will lower concentrations

50
Q

We need drug stability studies 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

51
Q

Shelf-life (t90%)

A

how long it takes to
reach 90% of the original drug concentration
- 90% of drug is left

52
Q

• For 1st order processes, shelf life is

A

t90 = 0.105 /k

53
Q

For zero order, shelf life is

A

t90%=0.1[D]0 /k

54
Q

For zero-order processes, like half-life, the

shelf-life is

A

dependent on the concentration

55
Q

Pseudo Reaction Order Degradation

A
  • A higher order reaction appears as a lower order reaction
    • A first order reaction appears as a zero order reaction
    • A second order reaction appears as a first order reaction
56
Q

Pseudo-zero order: A first order reaction appears to have zero-order kinetics

A

If the solubility of a drug is exceeded (e.g.-saturated solution), there will be a fixed amount of drug in solution
• The rest remains as excess solid
• Only the drug in solution degrades
• Its concentration in solution is replenished by the pool of solids
• The 1st order degradation rate constant (k1) incorporates the constant concentration into an apparent
degradation constant kapp

57
Q

Second order reactions:

A
  • Proceed linearly on the basis of two reactant concentrations
  • Rate = Rate constant * [concentration1] [concentration2]
58
Q

Pseudo First Order Degradation

A

Two reactants, but proceed effectively on the basis of a single
reactant concentration

PHRM 513 (13 decks)

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