Compatibility and Stability of Intravenous preparations

What are the most important aspect of reparation, verification, and administration of compounded sterile preparations (CSPs)?

Compatibility and stability

What does the quality of final preparation depends on?

compatibility and stability parameters

What can incompatibility cause?

Harm or death of patients

What are some peripheral IV considerations?

• Veins in extremities preferred for peripheral access

• Obtaining and maintaining IV access in infants and young children challenging

• Osmolarity through peripheral lines should be limited

  • Typically between 700-900 mOsm/L

  • As high as 900 to 1100 mOsm/L may be tolerated

  • Some recommend max of 600 mOsm/L

What are some central IV access considerations?

• Central venous catheters (CVCs) necessary for prolonged IV therapy

  • Insertion of catheter into large veins

  • Fewer problems with extravasation and infiltration

  • Broviac, Hickman, Groshong catheters

• Higher osmolarities of solutions tolerated

  • 1500 to 2000 mOsm/L

Aspects of intraosseous (IO) access

• Used very rarely in emergency situations when IV access cannot be obtained

• Inserted into anteromedial surface of tibia

  • Highly vascularized long bone marrow

• Intended for less than 6 hours

• Tolerates osmolarities and drug concentrations as with CVC

What are the fundalmentals of stability?

• Stability refers to the retention of properties and characteristics throughout the storage and use periods

• Instability results when a change or degradation of the active ingredients occurs

• Stability parameters established secondary to exposure testing by the manufacturer

What are the types of stability?

• Chemical

• Physical

• Toxicological

• Therapeutic

• Microbiological

What factors influence stability?

• Concentration of medication

• Packaging

• Exposure to Light

• Temperature

• Medication delivery devices (tubing, syringes, etc.)

What difference between BUD and expiration date?

• expiration date

  • Assigned by the manufacturer

  • Determined using extensive analytical testing

• Beyond-use Dates

  • Assigned by a pharmacist

  • Determined based on available scientific evidence or per manufacturer recommendations

How to determine DUB

• Must consider Sterility and Stability data

• USP Chapter <797> provides guidance on determining BUD regarding Sterility

• Chemical Stability BUD often extrapolated based on:

  • Direct testing or literature

  • Manufacturer information

  • Theoretical predictions

• The lesser of the 2 BUDs above is the BUD assigned

Aspect of 797 BUD

• Category 1 (PEC in normal room air)

  • 12 hours at room temperature

  • 24 hours refrigerated

• Category 2 (PEC located in ISO7 buffer room with ISO8 ante room)

  • 4 days at room temperature

  • 10 days in the refrigerator

  • 45 days in the freezer

What are the fundamental of imcompatibility

• Undesirable reaction that can occur between:

  • Two drug substances

  • A drug substance and an excipient

  • Drug substance or excipient with container

What are the types of imcompatibility

• Physical

• Chemical

What are some physical incompatibilities

• Crystallization

• Precipitation

• Sorption and leaching

What are some chemical incompatibilities

• Hydrolysis

• Oxidation

• Complexation

• Displacement

• Evolution of gas

What are some factors that influence incompatibilities?

• Temperature

• pH

• Concentration

• Light

• Time

• Mixing sequence

What are some therapeutic influences on incompatibilities?

• Chemical or physical incompatibilities can result in influences in therapeutic efficacy of drugs

• Loss of efficacy of one or more of active ingredients when administered together

• Can administer separately or with adequate time between drugs

Aspects of Calcium Phosphate incompatibilities

• Formed when calcium salts are added to electrolytes containing phosphate

• Chemical reaction physically manifested as formation of precipitates or haze in preparation

Aspects of Parenteral Nutrition

• Parenteral nutrition (PN) is a common source of incompatibilities resulting in calcium phosphate

  • Calcium and phosphorous are part of nutrition provided parenterally

• Nutrition preparations for neonates at high risk of incompatibility

What are the risk involved in Parenteral Nutrition?

• Suboptimal delivery of calcium and phosphorous

• Occlusion of in-line filter

• Microvascular embolism

• Pulmonary embolism

What are ways of preventing Calcium Phosphate?

• Utilize calcium gluconate over calcium chloride

• Maintain low pH of final admixture

• Increase amino acid concentration

• Store at lower temperatures

• Avoid higher temperatures during administration

• Do not add calcium and phosphate salts in close sequence

• Calculate solubility of calcium

  • Use volume of admixture at time calcium is added

Aspect of utilize resource in terms of preventing incompatibilities

• important to utilize compatibility resources to predict incompatibilities and determine drug characteristics

  • Package inserts

  • Drug databases with compatibility features

  • Books and incompatibility charts

    • Handbook on Injectable Drugs

    • King Guide to Parenteral Admixtures

  • Primary literature

How to minimize risk of incompatibilities

• Use preparation shortly after compounding

• Minimize the number of drugs in a single preparation

• Utilize references and resources to determine compatibility and stability

• Closely review preparations with high or low pH

• Closely review preparations containing calcium, phosphate, or magnesium

Aspects of visual inspects in terms of identifying incompatibilities

• Preparation should be adequately agitated/mixed

  • Add components that will limit visual identification of incompatibilities last

• Hold final preparation up to light to see through

• Check against a contrasting background

What to look for when inspecting for incompatibilities?

• Hazy/cloudy appearance

• Precipitates

• Color change

• Formation of gas

• Separation of contents

• Temperature changes

• Crystallization