Lecture 8

Question 1

Typical Degradation Methods (3)

Answer 1

1. Hydrolysis
2. Oxidation
3. Photochemical

Question 2

Hydrolysis

Answer 2

• Adding water to a product to reverse its creation reaction (condensation)
• A LOT of drugs and excipients are made using condensation reactions

Question 3

Carbon and Nitrogen Examples of Hydrolysis

Answer 3

Carbon: R-OOH + R’-OH = R-OO-R’ + H2O

Nitrogen: Carboxylic Acid + Amine = Amide + H2O
R-OOH + H-NR’ = R-ON-R’ + H2O

Question 4

Prodrug Process

Answer 4

Produrg ==> Chemical Change ==> Active Drug

Question 5

Reasons to have Prodrugs (5)

Answer 5

1. Accidents : cell/animal screens
2. Increased solubility - makes non-polar APIs have better dissolution
3. Decreased polarity - make polar APIs have better absorption and by extension enhances its bioavailability
4. Increases bioavailability in other ways
5. Taste making

Question 6

Why are prodrugs susceptible in hydrolysis?

Answer 6

• 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

Question 7

Oxidation

Answer 7

• Often complex, free radical reactions

- Radicals form from transistion metals, radiation, UV, and excess heat

Question 8

Typical Radical Series of Reactions

Answer 8

1. Key Initiation: R-H ==> R*
2. Oxygen Addition: R* + O2 ==> ROO*
3. 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

Question 9

How to Control Oxidation? (3)

Answer 9

1. Control O2 - limit O2 via scavengers, reduced diffusion barriers, N2 overpacking
2. Scavenge radicals with antioxidants - when antioxidant takes up the radical, it becomes stable and inactive
3. Control transition metals ions - Fe-chelator complex (inactive)

Usually utilize more than one of these to control oxidation

Question 10

Photochemical Degradation

Answer 10

• 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

Question 11

Photochemical Degradation Chemistries

Answer 11

1. Direct absorption
2. Type 1 Photosensitized
3. Type 2 Photosensitized

Question 12

Direct Absorption

Answer 12

• photon absorbed excited molecule
• excited molecule undergoes reaction and creates radicals

Ex: R-X + hv ==> {R—-X} ==> R* + X*

Question 13

Type 1 Photosensitized

Answer 13

• 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*

Question 14

Type 2 Photosensitized

Answer 14

• 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

Question 15

Why worry about UV light?

Answer 15

• higher energy photons created
• UV chromophores are much more common than visible light chromophores
• UV absorption & filtering by packaging & dosage form = much stronger

Question 16

Chemical Groups liable to Hydrolysis

Answer 16

• those made via hydrolysis (condensation reactions)
• esters (prodrugs!), amides, etc.
• VERY common functional groups for drugs

Question 17

Chemical Groups liable to Oxidation

Answer 17

1. Alkenes, especially if polyunsaturated or conjugated
2. Thiols (R-SH) - not common in drugs, but an example is captopril
3. Other oxidizable groups - examples are epineprhine or catecholamine

Question 18

Environmental Factors + Degradation

Answer 18

1. Water - for hydrolysis
2. Oxygen - for oxidation
3. Also light, heat, radiation from environment

(Drugs are made from water, oxygen, and air)

Question 19

Gases + Degradation

Answer 19

• very uncommon in drugs

- shipped in metal containers to protect from environmental factors

Question 20

Liquids + Degradation

Answer 20

• 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

Question 21

Solid + Factors of Degradation (4)

Answer 21

-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

Question 22

Goal of Solid Drug Forms

Answer 22

Want the most resistant physical state with good dissolution.
Ex: Large, perfect crystalline with lowest H2O crystallization is the best
(fine, amorphous particles = worst)

Question 23

Two Physical Protections of API

Answer 23

1. Dosage form that hinders water/oxygen/light access
   Ex: tablet coatings or low diffusion coefficient capsule materials
2. Packing that hinders water/light/oxygen access
   Ex: brown glass & absorbents (silica gel packets)

Question 24

Chemical Protections of API (2)

Answer 24

1. Using antioxidants to break free radical chain reactions (needs to be in correct phase of multi-phase system)
2. Using chelating agents to bind transition metals like Fe^+3. Example is EDTA