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The Medicine 2 - Sem 2 > Stability of drugs > Flashcards

Stability of drugs Flashcards

1
Q

Lactams are more susceptible to hydrolysis than esters. True or false?

A

True

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2
Q

Which are the most susceptible to hydrolysis, esters of amides?

A

Esters

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3
Q

Imides are less susceptible to hydrolysis than amides. True or false?

A

True

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4
Q

Hydrolysis is a zero order reaction. True or false?

A

False

First order

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5
Q

Hydrolysis is pH dependent – so the lower the logK, the higher the rate of hydrolysis and so the more the drug will degrade. True or false?

A

False

The higher the logK the more the drug will degrade

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6
Q

Oxidation is promoted in the presence of oxygen. What else promotes oxidation?

A

Presence of oxidising agents, light and trace metals

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7
Q

Highly conjugated metals are susceptible to photodegradation. True or false?

A

True

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8
Q

Energy increase as wavelength increases. True or false?

A

False

Energy increases with decreasing wavelength

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9
Q

What is light induced degradation called?

A

Photolysis

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10
Q

Isomeric change may affect pharmacological and toxicological activity. True or false?

A

True

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11
Q

The L form of adrenaline is more active than the D form. True or false?

A

True

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12
Q

Optical rotation is used to detect isomeric change because there is no change in mass spec etc. it is not useful. True or false?

A

True

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13
Q

The chemical stability of proteins and peptides is dependent on amino acid composition and sequence. True or false?

A

True

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14
Q

How do inert gases stabilize pharmaceutical preparations?

A

They protect from auto oxidation

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15
Q

Why is procaine more prone to hydrolysis than lidocaine?

A

procaine is an ester so more prone to hydrolysis than lidocaine which is an amide

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16
Q

What is the eqn for half-life of a first order reaction?

A

T1/2 – ln(2)/k

17
Q

What is the eqn for shelf life of a first order reaction?

A

T90 = ln(1.11)/k

18
Q

What are the limitations of accelerated stability testing?

A

kinetics of degradation may change at higher temps, additional complex reactions may take place at higher temps, temp may change nature of dosage form, change in physical properties with unpredictable effect

19
Q

What is the acceptable level of therapeutics?

A

therapeutic effect remains unchanged

20
Q

Toxicological expectations?

A

no significant increase in toxicity occurs

21
Q

Define shelf life

A

*The shelf life is that length of time during which a pharmaceutical product retains acceptable chemical, physical and microbiological stability so that the product remains fit for its intended purpose.

Ideally >3yrs and < 5% loss in potency without exceeding allowed limits of toxic degradation productions

22
Q

Factors affecting stability

A
  1. pH - acid and base catalysis tends to raise chemical degradation. Extreme pH changes cause epimerisation
  2. Temperature - high temperature can induce oxidation, reduction and hydrolysis
  3. Humidity - promotes hydrolysis, oxidation/reduction reactions and encourage microbial growth
  4. Light - photons provide energy leading to radical formation, oxidation and polymerisation reactions. Photolysis of covalent bonds can also occur
  5. Dosage form - solid usually more stable than liquid dosage form
  6. Oxygen - promotes autoxidation
  7. Metal ions - promotes oxidation
23
Q

Explain hydrolysis

A

Often the most common cause of drug instability. It involves nucleophilic attack of labile bonds by water.
Reactivity ranking: lactam > ester > amide > imide
Hydrolysis is a first order reaction.
pH dependent

24
Q

Explain oxidation

A

Oxidation reactions tend to be complex, giving a variety of degradation products.
Oxidation taking place at ambient temperature in presence of molecular oxygen is called autoxidation. This reaction typically involves free radicals:
RH→ R. + H. (initiation)
R. + O2.→ RO2- (propagation)
RO2. + RH → ROOH + R.

The hydroperoxides (ROOH) react further to produce stable oxidation products.
In the termination phase, the availability of oxygen or drug diminishes, the rate of reaction slows and free radicals combine to produce unreactive end-products.
25
Q

How is oxidation promoted and stopped?

A

Promoted - presence of oxygen ,oxidizing agents, light and trace metals

Stopped - Antioxidants used in formulations to suppress oxidation. More readily oxidised than drug

26
Q

EDTA as a stabilising agent

A

Chelates trace metal ions to minimise metal ion catalysed oxidation
Can also enhance action of preservatives such as benzalkonium chloride

27
Q

Susceptible amino acids to:

1) oxidation
2) deamidisation

A

1) oxidation - Methionine, Cysteine

2) deamidisation -Asparganine, Glutamine

28
Q

What is the problem with Tryptophan

A

Photosensitive and oxidation prone

29
Q

Why add a co-solvent?

A

reducing the aqueous with another solvent can reduce hydrolysis

30
Q

Why add inert gas?

A

Prevents autoxidation

31
Q

Why add complexing agent?

A

Addition of complexing agent can slow down hydrolysis

e.g. caffeine in the case of procaine

32
Q

Accelerated stability testing

A

n accelerated stability testing, the drug is stored at elevated temperatures (e.g. 40 ,50 ,600C and the reaction rate is calculated in a short time period (from minutes to days depending on the relative stability of the drug). The Arrhenius equation is used to predict the reaction rate at a realistic storage temperature.
`

33
Q

Limitations of accelerated stability testing

A

kinetics of degradation may change at higher temperatures
(ex. at elevated temperatures, the concentration of dissolved oxygen tends to decrease.
Additional complex reactions may take place at higher temperatures

Temperature may change the nature of the dosage form
(ex. melting of some solid ingredients at elevated temperature)

Change in physical properties with unpredictable effect.
(ex. changes in viscosity, reduction of the moisture level in a solid dosage form, etc.)

The Medicine 2 - Sem 2 (14 decks)

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