Stability for Parenteral Drugs

Ang kamaturoan sa stability

1. Stability differs with each manufacturer2. It also differs with each diluent used3. Expiry date changes when mixed it diluent4. There are written rules, but these change

form time to time… thus the need for updates…

Stability

Picture of lab

Picture of pharmacy

                            

          

                                                                                                                  

StabilityLength of time that the

product retains the labeled potency of the active ingredient(s) under the labeled storage conditions

Extended StabilityMaximum 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. Hydrolysis2. Oxidation3. Reduction4. Photodegradation

Result:1.Therapeutically inactive2.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-Reduction2. Hydrolysis3. Decarboxylation4. Racemization5. 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)

0.2 mg of copper ion per liter reduces stability of penicillin

Hydrolysis

Ester or amide linkage Cocaine, Thiamine, Procaine, Tetracaine,

Physostigmine, Benzylpenicillin Factors:

– Temperature– pH (generally 3-4)

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 (presence or absence)

Photochemical Reactions

Factor: – Ability of drug to absorb the wavelength– Energy of reaction (if it exceeds threshold)– 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 ampoulesTotal Parenteral NutritionDistilled water and other

preparations without preservative

Common Factors Affecting Drug Stability

1. Contact with metals- chemical reaction- Hydralazine, Metronidazole (with Aluminum)

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 bagsb. Ethyvinyl Acetate (ETA)c. Syringes, plasticd. Bottlee. Infusion pumpsf. 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 StrategiesAre data from the

manufacturer available?

What is the compatibility and stability of the drug to the conditions specified (container, concentration, diluent, storage temperature)?

Yes NoAre data available in tertiary sources?

Yes No

Are data available from primary sources?

NoYes

Drug Info Service

Tertiary resources for Stability and Incompatibility

1. Handbook on Injectable Drugs2. Pocket guide to Injectable Drugs3. Extended Stability for Parenteral Drugs4. AHFS Drug Information5. Pharmacist’s Drug Handbook

Websites with Stability and Incompatibility Data

1. www.icomm.ca/shsc/index/minibag.html2. https://www.medmarx.com/index.jsp3. www.ashp.org

Drug – Specific InformationEXAMPLES 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