chemcial stability 2

What is oxidation?

• Addition of oxygen

• Removal of hydrogen

• Loss of electrons

What is reduction?

• Removal of oxygen

• Addition of hydrogen

• Gain of electrons

Why is autooxidation important in pharmaceuticals?

• Most important oxidation process in drugs

• Molecular oxygen (O₂) usually the source of oxidation

What makes autooxidation reactions complex?

• Involve multiple reactive oxygen species (ROS)

• Reactions often multi-step and unpredictable

What ROS are produced in autooxidation?

• Superoxide anion (O₂⁻·)

• Hydrogen peroxide (H₂O₂)

• Hydroxyl radical (HO·)

• Singlet oxygen (¹O₂)

What is required for free radical-mediated autooxidation?

• Involvement of light or redox-active metal ions

• Common metals: Fe(II)/Fe(III), Cu(I)/Cu(II)

What are the 3 key requirements for ROS chemistry in vitro?

• Transition metal ion

• Good chelating ligand

• Reducing agent

What is the Fenton reaction?

• Reactants: H₂O₂ + Fe(II)

• Generates hydroxyl radicals (HO·)

• Purpose: produces reactive oxygen species (free radicals)

What is the Udenfriend reaction?

• Reactants: Fe(II), ascorbic acid, EDTA, air

• Complex multistep process → includes a Fenton-type step

• Produces reactive oxygen species / free radicals

The chemistry…

How can agents like polyvinylpyrrolidone (povidone) and polyethylene glycol (PEG) degrade?

• They can undergo autocatalytic degradation

• This means they can reduce hydrogen peroxide by themselves

• This process can cause their self-degradation without needing external catalysts or radicals

Udenfriend reaction – requirements & substitutes

• Metal ion: Fe²⁺ → Cu⁺, Sn²⁺, Co²⁺, Ti²⁺

• Chelator: EDTA → citrate, DTPA, pyrophosphate, drugs

• Reducing agent: Ascorbic acid → phenols, bisulfite, catechols

• Note: Any metal-chelating drug can react

: Common drug oxidation reactions – functional groups and products

• Phenol/catechol → Quinones (keto form)

• Phenol → Dimeric products

• Amines → N-oxides

• Thioether → S-oxide

• Thiol → Disulfide

Difference between homolytic and heterolytic bond cleavage?

• Homolytic: bond breaks evenly → each atom gets 1 electron → forms radicals (unpaired electrons)

• Heterolytic: bond breaks unevenly → one atom gets both electrons → forms ions (cation + anion)

What happens in carbon radical formation by homolysis?

• Breaking C–Br bond evenly → carbon radical + Br· radical

• Carbon radical has 7 valence electrons (one unpaired)

• Carbon radical is planar, sp² hybridized

• Compare to carbocation (6 valence electrons, positive charge)

Which radicals are more stable: methyl, primary, secondary, or tertiary?

• Tertiary radicals are most stable

• Stability order: tertiary > secondary > primary > methyl

• Why tertiary is most stable:

  1. More alkyl groups donate electrons (electron donation via hyperconjugation)

  2. Better delocalization of the unpaired electron

  3. Steric hindrance reduces unwanted reactions, stabilizing the radical

Which molecules are prone to C–H oxidation? Why?

• Ethers, aliphatic amines, aldehydes

• Why: These have C–H bonds next to heteroatoms or functional groups that weaken the bond, making hydrogen easier to remove during oxidation.

Which molecules are prone to O–H and N–H oxidation? Why?

• Phenols (O–H), aromatic amines (N–H)

• Why: The O–H and N–H bonds are reactive sites that can lose hydrogen easily, leading to oxidation products. Aromatic rings stabilize radicals formed after oxidation.

a quiunone sructure

Why are drugs containing phenolic groups often formulated at low pH?

• At low pH, phenolic groups stay in their neutral form rather than forming the phenoxide ion.

• The phenoxide ion has higher electron density, making it more reactive and more easily oxidised.

• The phenoxide ion is more susceptible to oxidation, so keeping the pH low helps improve drug stability.

• phenols are weak acids

Why are many basic drugs (e.g. aromatic amines) formulated as their salts?

• Aromatic aminest.he nitrogen lone pair can partially delocalize into the ring, onates electron density into the ringmaking them basic.

• When protonated (forming a salt), the lone pair is no longer available electron density on nitrogen drops → nucleophilicity decreases.

• Salt formation also increases solubility in water, improving drug absorption and stability.

If we have oxidation of SH bonds what do we get?

• thiols

• thioesters

• thiols=dimer

• thioesters= sulfoxide + sullfone

oxidation happes in a chain reaction what are the three things?

• initiation

• propgation

• termiantion

How can oxidation of drugs be minimised?4

all these prevent the iniitation

• Protect from light

• Limit peroxides (prevent initiation)

• Use optimum pH:

  • Acidic drugs → degrade faster when ionised (high pH)

  • Basic drugs → more stable in acidic pH

• Add chelating agents (e.g. EDTA, citric acid)

  • → remove metal ions that promote oxidation

How do we stop propagation?

• Exclude oxygen

  • Pack with nitrogen

  • Use tablet strips

• Add antioxidants

  • Ascorbic acid → sacrificial

  • BHT → radical trap (stops chain reaction)

Two ways radicals are produced

• Initiation (main way)

  • External factors create radicals

  • e.g. light, heat, metal ions

  • Starts the chain reaction

• From peroxides (e.g. H₂O₂)

  • Peroxides can break down to form radicals (•OH)

  • Then enter radical chain reactions

How do peroxides (e.g. H₂O₂) cause oxidation?

1. Radical pathway

• H₂O₂ → forms •OH radicals

• → chain reaction (propagation)

2. Non-radical pathway

• Directly oxidises amines & sulfides

• → SN2 mechanism (no radicals)

• → Peroxides can cause oxidation by both radical and non-radical mechanisms

Why are aliphatic amines more easily oxidised than aromatic amines?

• Aliphatic amines:

  • Lone pair localised on N

  • → High electron density

  • → More nucleophilic → more oxidation

• Aromatic amines:

  • Lone pair delocalised into ring

  • → Less available → less oxidation

How does pKa affect oxidation of amines?

• Higher pKa = more basic

• → Lone pair more available

• → More susceptible to oxidation

How can oxidation of amines be prevented?

• Convert to HCl salt (protonated form)

• → No lone pair on N

• → No nucleophilicity → no oxidation

Aroamtic amines efefcts ofthe susbsutuient

Reactions of H₂O₂ with other functional groups

• Carboxylic acids (RCOOH) → Carboxylic peracids (RCO₃H)

• Bicarbonate (HCO₃⁻) → Peroxymonocarbonate (CO₄H)

• Nitriles (R–C≡N) → Peroxycarbimidic acids

Oxidation of thioethers

• Thioethers (R–S–R′) react with H₂O₂ or other peroxides.

• Mechanism: Nucleophilic attack by sulfur on the peroxide.

• Product: Sulfoxide (R–S(=O)–R′)