Stability for Parenteral Drugs

An kamaturoan han stability

1. Stability differs with each manufacturer

2. It also differs with each diluent used
3. Expiry date changes when mixed it diluent
4. There are written rules, but these change
form time to time… thus the need for
updates…
Stability

Picture of lab
Picture of pharmacy
Stability
 Length of time that the
product retains the labeled
potency of the active
ingredient(s) under the
labeled storage conditions
Extended Stability
 Maximum time period in which
90 percent or greater of the
labeled active ingredient is
measurable in the solution and
container specified, under the
stated storage conditions.
Instability

 Chemical processes that result in drug

product degradation
1. Hydrolysis
2. Oxidation
3. Reduction
4. Photodegradation

Result:
1.Therapeutically inactive
2.Toxic
Incompatibility

 Physical or chemical phenomenon that

reduces the concentration of active
ingredient
– Physical incompatibility results in visually
observable change (e.g. haze, precipitate,
color change, effervescence).
– Chemical incompatibility is not readily
observed
Incompatibility

Causes:
1. Oxidation-Reduction
2. Hydrolysis
3. Decarboxylation
4. Racemization
5. Photochemical Reactions
Oxidation

 Prime cause of product instability

 Addition of Oxygen or addition of Hydrogen
 Loss of electron
 Factors:
– Temperature
– Radiation
– Catalyst (cupric, chromic, ferrous, or ferric ion)
Hydrolysis

 Ester or amide linkage

 Cocaine, Thiamine, Procaine, Tetracaine,
Physostigmine, Benzylpenicillin
 Factors:
– Temperature
– pH
Decarboxylation

 Very rare
 Pyrolytic solid-state degradation
 Para-aminosalicylic acid to m-aminophenol and
carbon dioxide is pH-dependent and is
catalyzed by hydronium ions
Racemization
 Action or process of changing from an optically
active compound into a racemic compound or
an optically inactive mixture of dextro- and
levo- forms
 L-epinephrine is 15-20 times more active than
d-epinephrine
 Factors:
– Temperature
– Solvent
– Catalyst
– Light
Photochemical Reactions
 Factor:
– Ability of drug to absorb the wavelength
– Energy of reaction
– Intensity of the wavelength
– Size, shape, composition and color of container
 Photosensitizer – molecules that absorb the
wavelength but pass the energy to other reacting
molecules
 Yellow-green containers – best protection from UV
 Amber containers – considerable protection from UV
but little from infrared
Product Sterility and Stability

 Product sterility versus chemical

stability
 Parenteral drugs in ampoules
 Total Parenteral Nutrition
 Distilled water and other
preparations without preservative
 Common Factors Affecting Drug
Stability

1. Contact with metals

- chemical reaction
- Hydralazine, Metronidazole
2. Freezing temperature
- Inactivation or denaturation
- Heparin, filgrastim, erythropoeitin
3. Large organic anions and cations
- Precipitation of formation of insoluble complex
- Heparin with Aminoglycosides
 Common Factors Affecting Drug
Stability
4. Light (natural and room)
- Accelerated chemical degrdation reactions
- Dobutamine, furosemide, Cisplatin, Hydroxyzine,
Carboplatin
5. Low temperature (refrigeration)
- Crystallization or precipitation
- 5-Fluorouracil, furosemide, acyclovir, metronidazole
6. Plastic containers
- Adsorption of lipophilic agents – especially important at
low concentrations
- Sufentanil, filgrastim, calcitriol, lorazepam, aldesleukin
 Common Factors Affecting Drug
Stability

7. PVC container permeability

- Evaporation, with resultant overconcentration of
solution
- All PVC containers distributed in overwrap bags; small
volume bags are most susceptible
8. Plastisizer content of containers and sets
- Leaching carcinogenic plastisizer DEHP from PVC
container
- Paclitaxel, lipid emulsion, cyclosporine
Common Factors Affecting Drug
Stability

9. Saturation solubility exceeded

- Precipitation
- Morphine sulfate, etoposide

10. Temperature above 8 degree

Celcius
- Accelerated chemical degradation reactions
Assigning Expiration Dates
 Stability
– Is it light sensitive? Heat sensitive? How should it be
administered in relation to its storage requirements?
 Compatibility
– With the diluents, flush solutions
 Sterility
– What is the risk for microbial contamination?
 Final Concentration
– Final concentration affects stability
– Should be computed
Clarifying questions for
compatibility queries

1. What is the container?

a. PVC bags
b. Ethyvinyl Acetate (ETA)
c. Syringes, plastic
d. Bottle
e. Infusion pumps
f. RTU bags/bottle
Clarifying questions for
compatibility queries

2. What is the resulting concentration?

3. What is the diluent?
4. What is the manufacturer or brand name of
the drug?
5. How was it stored?
Search Strategies
Are data from the Are data available
manufacturer from primary sources?
available?

Are data available Yes No

Yes No in tertiary sources?

What is the compatibility Yes No

and stability of the drug
to the conditions
specified (container,
concentration, diluent,
storage temperature)? Drug Info
Service
Tertiary resources for Stability and
Incompatibility

1. Handbook on Injectable Drugs

2. Pocket guide to Injectable Drugs
3. Extended Stability for Parenteral Drugs
4. AHFS Drug Information
5. Pharmacist’s Drug Handbook
Websites with Stability and Incompatibility
Data

1. www.icomm.ca/shsc/index/minibag.html
2. https://www.medmarx.com/index.jsp
3. www.ashp.org
Drug – Specific Information
EXAMPLES ONLY
Acyclovir

 Special attention must be paid to the drug’s

potential for precipitation. Precipitation
depends on preparation, storage conditions,
concentration, pH and diluent.
 Refrigeration may cause precipitation, but
resolubilizes at room temperature without loss
of potency.
Amikacin

 Degrades with B-Lactam Antibiotics

Amphotericin B

 Protect from light.

Ampicillin Sodium

 Stability decreases as concentration increases

Carboplatin

 Protect from light

Cyclophosphamide

 Do not se benzyl alcohol – preserved diluents

Cytarabine

 Solutions stored in the dark

Dacarbazine

 Solutions stored in the dark

Dobutamine

 Protect from light.

Doxorubicin Hydrochloride

 Solutions stored in the dark.

Erythromycin Lactobionate

 Precipitates with inorganic ions, including

sodium chloride
Fluconazole

 Do not freeze.
Fluorouracil

 Solutions protected from light.

Furosemide

 Precipitates on refrigeration, but resolubilizes

in room temperature without drug loss.
 Do not use if solution turns yellow.
Gentamicin

 Incompatible with Heparin

Heparin

 Do not freeze
Metronidazole

 Do not refrigerate RTU vials

Paclitaxel

 Containers and administration sets should not

contain DEHP plasticizer
 Solution contains 20-25% ethanol