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DD2 PAC3252 > Drug Stability Part 2 > Flashcards

Drug Stability Part 2 Flashcards

1
Q

Chemical Instability

A

Hydrolytic, Oxidative, Photochemical

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2
Q

Heterolytic Reaction

A

Bond rupture by transfer of electron pair from molecular orbital of the substrate to one of the two fragments which had made up the bond (Both charged)
Unimolecular reactions - spontaneous charge separation of substrate leads to polarised intermediate which fragments into ions
Bimolecular - dipolar or charged reagent attacks the substrate leading to displacement of the leaving group

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3
Q

Homolytic reaction

A

bond rupture by transfer of each one of the two electrons of an electron pair from a molecular orbital to each of the two fragments which made up the bond. This forms a pair of radicals

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4
Q

Heterolytic - Acyl Transfers

A

Acyl - hydrocarbon attached to carbonyl group which is also attached to an electronegative leaving group
Nucleophile attacks electron deficient carbonyl carbon, C-X bond breaks and C-Y bond forms (transfer of acyl group from one leaving group to another)
Eg. Hydrolysis (water)
Alcoholysis (esterification - OH)
Aminolysis (ammonia, amine)

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5
Q

Ester Hydrolysis

A
  • hydrolysed by acid/base catalysis, slow spontaneous water attack only when good leaving group is present
  • reversible only in concentrated solution (esp. acid catalysed)
  • Involves tetrahedral intermediates (sp3)
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6
Q

Base catalysed ester hydrolysis

A

Hydroxyl group attacks electron deficient carbonyl carbon
Attacks at 120 deg orientation from the direction of C=O bond
*more efficient mechanism as OH group is a better nucleophile compared to water in acid hydrolysis therefore pH for max stability is always on acid side of neutrality

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7
Q

Acid catalysed ester hydrolysis

A

Hydronium ion protonates the molecule to make carbonyl carbon more positive so that it is more likely to be attacked by water (weaker nucleophile)

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8
Q

Acyl-oxygen cleavage VS Alkyl-oxygen cleavage

A

If alcohol portion of molecule can stabilise carbonic ions (carbocations) then there is potential for alkyl-oxygen cleavage

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9
Q

Hydrolysis of Aspirin

A

pH 9 specific base catalysis
Intermediate pH spontaneous water attack
- anions formation should give slower reaction rate due to increased electron density (inductive effect) repelling the partial negatively charged nucleophilic water BUT IT IS ACTUALLY INCREASED. Due to intramolecular general base catalysis - ionised carboxylate group acts as a buffer and generates OH group from water (forms free acid), OH is a better nucleophile which accounts for faster reaction rate at pH range 5-9. OH is in correct location and orientation to attack when in the form of free acid (lower energy required as shown in the energy minimised model to support OH attack hypothesis)

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10
Q

Hydrolysis of Amide

A
  1. AMIDES MORE STABLE THAN ESTERS
    except b-lactam rings - due to classical ring strain (due to small angles of 4 membered ring b-lactam ring) and fused ring strain (bridgehead strain due to fusion of b-lactam ring fusion to thiazolidine ring in benzylpenicillin)
  2. IRREVERSIBLE
    Base - Equilibrium in the last step lies more forward in direction, more difficult to reverse than esters (amide ion less stable). But it is more difficult to form the amide ion in second reversible step therefore may explain overall slower hydrolysis of amides
    Acid - Irreversible due to end product of protonated amine
    Stabilise
    - keep away from moisture
    - aq solution or reconstituted suspensions are to be dispensed, stored in a fridge or cool place
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11
Q

Hydrolysis of Lignocaine

A

Benzocaine and procaine are esters of benzoic acid
- unstable at normal temp and extreme pH due to EWG of phenol group promoting reactivity at acyl carbon
Lignocaine
- amide of N,N-diethylglycine which is more stable to hydrolysis
- carbonyl carbon is also protected from hydrolysis by di-o-methyl substitution (stops nucleophilic attack)

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12
Q

Stability of frozen solutions of a-aminobenzylpenicillins

A

Self-Aminolysis
- Amino group of one molecule attacks the b-lactam carbonyl group of a second molecule
- have second and third order dependence on substrate concentration therefore only occur in concentrated solutions
This occurs in:
1. Solid state - in drug saturated layer of moisture on the surface of solid drugs stored in a moist atmosphere
2. Frozen solutions
- can speed up decomposition
- The first solid in a compound solution freezes has the lowest solubility at the temperature system. If it is the active, then pure solid active becomes stabilised. But if active is not in excess of its solubility at the freezing point of the solvent, then first solid will become pure solvent (ice) –> this results in concentration of actives into liquid pockets as the solution freezes.

This reaction can lead to oligo/polymerisation of a-aminobenzylpenicillin –> a proposed mechanism of penicillin hypersensitivity

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13
Q

Racemisation (epimerisation) of drugs

A

Actives are optical isomers when they contain one or more asymmetric carbons (with 4 different substituents)
Acid/base reactions can cause racemisation/epimerisation of the optically active carbon
Eg. Pilocarpine has a very weakly acidic H adjacent to carbonyl group. When in solution with water, only small concentration of ionised pilocarpine exists
Anionic state of molecule is flat, it can recombine with H approaching from either side of the plane to form R/S enantiomer (50:50 chance)
Initial conc of S-pilocarpine is higher, higher probability of becoming ionised, but eventually there will be a 1:1 ratio of R/S due to racemisation. However this is a very slow process due to low conc of ionised species.

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14
Q

Homolytic Reaction - Oxidation

A
  • involves addition of oxygen
  • removal of hydrogen
  • removal of one or more electrons in one-electron steps
    O2 in ground state is a di-radical (reactive triplet)
  • two unpaired electrons with parallel spins therefore needs to share 2 further electrons to fill its two-half occupied p-orbitals
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15
Q

Autooxidation

A
  • spontaneous reaction under mild conditions of temperature, pressure and light exposure
    Chain reactions
    1. Initiation step - Form free radical species. Initiators: light, traces of transition metals, traces of peroxides
    2. One or more chain propagation reactions - Oxygen incorporation
    3. Termination steps - producing inert products
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16
Q

Kinetics of oxidation

A

First order - In large excess of oxygen or when oxygen content is very limited
Second order - Oxygen mole fraction is the same as that of the substrate
Includes ANY fractional order between 1 and 2.
Eg
1. Cumene
2. Alchohol autooxidised to aldehydes
3. Aldehydes - fast esp aromatics (benzaldehydes)
4. Ethers - dangerous because oxidation product ether peroxides are highly explosive
5. thiols - easily oxidised e.g. captopril
6. Phospholipids - stabilisers in emulsion and liposomes

17
Q

Autoxidation of morphine

A

N-oxidation to morphine-N-oxide (10%)
Autoxidative dimerisation to pseudomorphine 90% - non-cyclisable orientation more stable as it has lower energy so chain polymerisation more likely
Autoxidation rates are highly pH dependent - 2 acid-base functional groups: phenolic OH pka 9.51 and 3 amine pka 8.31
pH independent up to 4, followed by sigmoidal curve up to 7
Most stable at pH <4.5

18
Q

Prevention of autoxidation

A
  1. Exclusion of oxygen using dosage form and type
  2. Control of pH in aq solution
  3. Protect from light
  4. Use of chelating agents and antioxidants
19
Q
  1. Exclusion of oxygen using dosage form and type
A
  • Captopril: Single dose small volume injectables by oxygen free solutions packed in glass ampoules in an inert atmosphere
  • single dose large volume inj and other solutions in glass container with rubber stopper or plastic bag (O2 permeable)
  • Multidose inj solutions packed in rubber stopper vials (O2 diffusable through stopper
  • Solid dosage forms packed in individual strip packs. Screw cap containers allow permeability
20
Q
  1. Control of pH in aq solution
A
  • When in neutral forms (at low pH), they lack a spare pair of electrons available for removal in one-electron steps to form the initial free radical e.g. mercaptans, phenols, Vit C
21
Q
  1. Protect from light
A
  • Cardboard package, amber glass containers

- sugar coated tablets for oral use

22
Q
  1. Use of chelating agents
A
  • Trace metals promote autoxidation therefore chelating agents inhibit oxidation by sequestering metal ions in equilibrium complexes
23
Q

Antioxidants and mechanism

A
  • Sulphites are antioxidants and nucleophiles
    Antioxidant mechanisms:
    1. Sacrifice antioxidants - more easily oxidised than the active substance that is being protected due to lower electrochemical oxidation potential e.g. Vit C
    2. Chain terminating antioxidants - generate low conc of stable free radicals that interfere with the oxidation reactions by reacting with the essential free radicals intermediates in the reaction e.g. Vit C This prevents continuation by producing inert products
24
Q

Photolysis

A
  • A ground state molecule absorbs a quantum of light energy to produce an unstable excited state molecule
  • Excited state can lose energy by several mechanisms:
    Chemical Decay - concentration of absorbed energy in a bond which becomes unstable and ruptures
25
Q

Kinetics of Photochemical reaction

A

First order - dilute solutions
Zero order - Very concentrated solutions
Pseudo first - Light is accessible to all parts of the solution, reaction occurs throughout solution. But drug concentration controls rate of reaction (rate limiting factor)

Pseudo zero - limiting factor is the number of incident quanta of radiation on the photosensitive molecule
The more conc drug solution, more light absorbed by the drug. But extreme concentration only drug at the surface are exposed to light
- If conc high +/ light intensity is low, light penetration confined to surface solution surface nearest to light source, light intensity is rate limiting, reaction only at the surface

Fractional order is 0<1
Intermediate conc and light penetrates into the solution but decreasing in intensity as more light is absorbed by drug. Drug and light are both rate limiting factors.

Rate of reaction is the function of diffusion of drug molecules from bulk solution to the surface where the photochemical reaction is occurring

Shading is not showing conc gradient of drug in solution but shows the decreasing intensity of light penetration as light is increasingly absorbed by drug molecules

26
Q

Cis-Trans Isomerisation of Tamoxifen (photolytic degradation)

A

Tamoxifen

  • Trans form more active hormone
  • Absorption of quantum of energy elevates electron pair of the double bond from ground state to excited state anti-bonding orbital which converts the double bond to freely rotatable single bond which increases life time.
27
Q

Dehydrochlorination of meclofenamic acid

A

Removal of HCL giving 2 isomeric products from internal rotation of a single bond in the ground state

  • remove chlorine as a radical, molecule forms a radical
  • remove hydrogen by chlorine and convert molecule into diradical
  • collapse of diradical to a stable molecule
28
Q

Stabilisation of photosensitive drugs

A

Exclude light of wavelength that causes degradation

red>amber

29
Q

Solid State Degradation

A

Physical and Chemical Changes

30
Q

Solid State Physical Decomposition

A
  • no changes in covalent bonds of the drug
  • Polymorphic changes in crystal lattice structure of pure drug or drug-hydrate/ drug-solvate ratios
  • vaporisation of volatile liquid or solid drugs reducing potency
31
Q

Polymorphism on bioavailability

A

Chloramphenicol palmitate

  • ester form disguise bitter taste of parent drug
  • 3 polymorphic forms:
  • Form A has high surface charge which can repel enzymes hence slower rate of hydrolysis
32
Q

Solid state Chemical Decomposition

A
  1. True solid state degradation
  2. Degradation in surface solution phase
    - melt of drug with other components
    - adsorbed moisture from excipients, atmosphere and wet granulation
    - transfer of solvate molecules from crystal lattice to the surface
  • reactions are described in terms of amount of substrate remaining or extent of reaction
  • sigmoidal (ext of reaction vs time)
  • Acceleration phase: may be preceded by lag time (no reaction) for liquefaction to occur to produce the surface solution phase)
33
Q

Vitamin A

A
  • unstable unsaturated alcohol

- stabilise by esterifying the alcohol group

34
Q

Effervescent tablets

A
  • prone to degrade by moisture
  • silica desiccant built onto the cap
  • Solid drugs with COOH can degrade by decarboxylation
35
Q

Stabilising solid drugs

A

Keep away from light
Keep dry
Keep temp low and stable
Reduce drug solubility with appropriate salt, polymorphic form or prodrug

DD2 PAC3252 (10 decks)

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