Typical Degradation Methods (3)
- Hydrolysis
- Oxidation
- Photochemical
Hydrolysis
- Adding water to a product to reverse its creation reaction (condensation)
- A LOT of drugs and excipients are made using condensation reactions
Carbon and Nitrogen Examples of Hydrolysis
Carbon: R-OOH + R’-OH = R-OO-R’ + H2O
Nitrogen: Carboxylic Acid + Amine = Amide + H2O
R-OOH + H-NR’ = R-ON-R’ + H2O
Prodrug Process
Produrg ==> Chemical Change ==> Active Drug
Reasons to have Prodrugs (5)
- Accidents : cell/animal screens
- Increased solubility - makes non-polar APIs have better dissolution
- Decreased polarity - make polar APIs have better absorption and by extension enhances its bioavailability
- Increases bioavailability in other ways
- Taste making
Why are prodrugs susceptible in hydrolysis?
- Need to have (sometimes) fast, easy, and predictable conversion into an active drug
- Leads to chemistry that makes the drug intrinsically susceptible to hydrolytic degradation (mostly esters)
- Therefore we need to protect the prodrug from degradation via the dosage form
Oxidation
- Often complex, free radical reactions
- Radicals form from transistion metals, radiation, UV, and excess heat
Typical Radical Series of Reactions
- Key Initiation: R-H ==> R*
- Oxygen Addition: R* + O2 ==> ROO*
- Cyclic Step: ROO* + R’H ==> ROOH + R’*
If the series ends in a RO*, this can go on to fragment aldehydes, ketones, and carboxylic acids
How to Control Oxidation? (3)
- Control O2 - limit O2 via scavengers, reduced diffusion barriers, N2 overpacking
- Scavenge radicals with antioxidants - when antioxidant takes up the radical, it becomes stable and inactive
- Control transition metals ions - Fe-chelator complex (inactive)
Usually utilize more than one of these to control oxidation
Photochemical Degradation
- also complex
- need a chromophore to absorb the light
- enough energy in UV and visible light photons
- two types of photochemical reactions: Type 1 & 2
Photochemical Degradation Chemistries
- Direct absorption
- Type 1 Photosensitized
- Type 2 Photosensitized
Direct Absorption
- photon absorbed excited molecule
- excited molecule undergoes reaction and creates radicals
Ex: R-X + hv ==> {R—-X} ==> R* + X*
Type 1 Photosensitized
- photon absorption by ground state photosensitizer
- photosensitizer goes on to react with the reactant
PS + hv ==> PS*
PS* + R-H ==> PS- + R* + H+
PS- + O2 ==> O2- + PS
O2- ==>==> H2O2, HO*
Type 2 Photosensitized
- photon absorbed by ground state photosensitizer
- photosensitizer transfers energy to O2
- Makes highly reactive “singlet oxygen”
- “singlet oxygen” is denoted by (1)O2 or (1)[delta]2, where the (1) are superscripts and the 2 are subscripts
PS + hv ==> PS*
PS* + O2 ==> (1)[delta]2 + PS
Why worry about UV light?
- higher energy photons created
- UV chromophores are much more common than visible light chromophores
- UV absorption & filtering by packaging & dosage form = much stronger
Chemical Groups liable to Hydrolysis
- those made via hydrolysis (condensation reactions)
- esters (prodrugs!), amides, etc.
- VERY common functional groups for drugs
Chemical Groups liable to Oxidation
- Alkenes, especially if polyunsaturated or conjugated
- Thiols (R-SH) - not common in drugs, but an example is captopril
- Other oxidizable groups - examples are epineprhine or catecholamine
Environmental Factors + Degradation
- Water - for hydrolysis
- Oxygen - for oxidation
- Also light, heat, radiation from environment
(Drugs are made from water, oxygen, and air)
Gases + Degradation
- very uncommon in drugs
- shipped in metal containers to protect from environmental factors
Liquids + Degradation
- common in drugs
a) Solutions - API in water. Liable to hydrolysis, light & oxygen can also degrade it depending on the container
b) Emulsions, creams, micelles, etc - mixes of hydrophobic materials in aqueous state. Location of API depends on its solubility - *If in oil phase, oxygen solubility is higher than water and can drive oxidation
- *If in aqueous phase, susceptible is hydrolysis instead
Solid + Factors of Degradation (4)
-most common
Factors favoring degradation:
1. Increased SA:M ratio, more molecules at surface to interact with factors that drive degradation
2. Amorphous state - better penetration of solid by H2O/O2
3. Porosity of dosage form (hard + compact = more difficult to degrade)
4. Uncoated tablets - coatings can slow down H2O/O2 penetration
These same factors can favor rapid dissolution/absorption in the GI tract. Fixing the dissolution could mess up the stability
Goal of Solid Drug Forms
Want the most resistant physical state with good dissolution.
Ex: Large, perfect crystalline with lowest H2O crystallization is the best
(fine, amorphous particles = worst)
Two Physical Protections of API
- Dosage form that hinders water/oxygen/light access
Ex: tablet coatings or low diffusion coefficient capsule materials - Packing that hinders water/light/oxygen access
Ex: brown glass & absorbents (silica gel packets)
Chemical Protections of API (2)
- Using antioxidants to break free radical chain reactions (needs to be in correct phase of multi-phase system)
- Using chelating agents to bind transition metals like Fe^+3. Example is EDTA
