Hydrolysis of Chloramphenicol
- attack of water on the molecule
- molecule cleaves and breaks into 2 fragments
- Common compounds likely to be hydrolyzed: carbonyl, amide, cyclic amide
- water can react and degrade drugs
- humid environments are not storable places to keep drugs
Accelerated Stability
- test to see how bad degradation and stability is
- rate of breakdown is increased at a high temperature
Stability of Solution Drug
- at a given concentration
- for certain time
- at a certain temperature
- at a certain degree of light exposure
Stability of Solid Drug
- for certain time
- at a certain temperature
- at a certain degree of light
NAPLEX Stability
- solutions decompose 10x faster than solids
- compatibility is a problem for LONG infusion times with piperacillin/tazobactam and will degrade over time
- compatibility is an issue with antibiotics such as azithromycin, ciprofloxacin, tobramycin, vancomycin
- compatibility is an issue with insulin and some vasopressors
Temperature and Stability NAPLEX
- high temperatures speed up chemical reactions and break down drugs
- most IV drugs are refrigerated for longer stability
EXCEPTION: furosemide and phenytoin are crystallized is kept cold
Metronidazole, moxifloxacin, acetaminophen, acyclovir, pentamidine, and valproate are kept at room temperature as well
Light Exposure NAPLEX
- light exposure caues photodegradation and can cause formulations to be toxic (drug changes color)
- medications are kept in amber vials to protect from light
- Vitamin K, Nitroprusside, and Doxycycline cannot be ran through regular light systems
Shelf Life
stability is the extent to which a product retains the same properties and characteristics throughout its period of storage and use
Chemical Reactions that cause Degradation
Redox
Hydrolysis
Photolysis
Oxidation
-OH groups of a drug are oxidized into carbonyl groups
- Example: caramelization of onions as the OH groups are oxidized and onions turn brown
Prevention of Oxidation
- protect from changes in temperature
- control pH with buffers
- Light protection (amber vials)
- Lower temperature slows reactions
- Chelating agents (EDTA) remove metal ions that can cause oxidation
- antioxidants can remove free radicals produced by oxidation
Function of Dosage Forms
- provide accurate dose
- promote drug dissolution
- promote delivery to site of action
- ensure drug stability
- control drug delivery
- determine dosing interval
Hydrolysis Based Mechanism
Slide 36
Prevention of Esters Hydrolysis
- protect from moisture
- protect from heat (hydrolysis is faster at high temp)
- control pH of formulations (pH dependent)
Amide Hydrolysis Mechanism
Slide 49
Prevention of Amide/Lactam Hydrolysis
- protect from moisture
- protect from heat
- control pH of formulations
Auto-oxidation Mechanism
Slide 64
Summary of Drug Reactions
- oxidation is a common, complicated, route of drug degradation
- many functional groups are subject to oxidation
- oxidation can be prevented by protecting from air, light, and metals as well as certain excipients added
- photolysis is drug degradation caused by exposure of light
Zero Order Kinetics
- rate of drug degradation is constant and independent of concentration
- graph is a straight linear line downward
dCa/dt = - k
Stability issues for biologics
- proteins are more fragile than small molecules
- biologics are larger and have more bonds
- biologics can lose activity if they unfold or degrade
- biologics can aggregate: increase/decrease potency & increased potential for adverse reaction
Summary of Biologics
- fastest growing drug class
- include recombinant proteins, vaccines, stem cells, and gene therapy
- proteins are made of amino acids that have folded structure
- proteins are more fragile than small molecule drugs
Biologic Degradation
Chemical Degradation
- breaks correct covalent bonds and forms incorrect ones
- hydrolytic reaction
- oxidation reaction
Physical Degradation
- changes protein structure with breaking bonds
- unfolding
- aggregation
Hydrolytic Reaction of Biologics
- asparagine deamidation
- peptide bond hydrolysis (clipping)
Oxidative Reaction of Biologics
- methionine oxidation
- disulfide bond scrambling
