Drug Stability and Compatibility

What is drug stability?

ability of drug product to maintain its identity, strength, quality, purity and performance throughout its shelf life under specified storage conditions

What is chemical stability?

ability of a drug to retain its chemical structure and labeled potency without significant degradation over time

What is physical stability?

ability of a dosage form to maintain its physical properties, including appearance, clarity, solubility, particle size, and suspendability

What is shelf-life?

period during which a drug product remains within approved specifications when stored under recommended conditions

What is IV admixture?

sterile preparation produced by combining one or more sterile drugs with sterile diluent or infusion solution

What is drug compatibility?

ability of drugs and solutions to be mixed together without significant chemical degradation or physical change during preparation, storage, and administration

What is Y-site compatibility?

ability of two solutions to be compatible when mixed briefly at a Y-site connector during IV administration

What is incompatibility?

undesirable interaction between drugs, excipients, containers or vehicles that adversely affects safety, stability, or efficacy

What are chemical and physical incompatibilities associated with IV administration?

-incompatible drug combo

-non appropriate diluent

-incompatible material

-mixture of incompatible drugs

What does chemical incompatibility cause?

drug degradation, loss of efficacy and toxicity

What are antineoplastics?

loss of potency due to chemical degradation in infusion fluid results from hydrolysis, oxidation, or photolysis

What does an increase of 10C in storage temperatures do to chemical degradation?

enhance by a factor of 2 to 5

What is the single most important factor affecting drug stability?

pH

What does buffer capacity do?

resist pH change and maintain drug stability

What is hydrolysis?

cleavage of a drug by reaction with water

What type of reaction is hydrolysis?

pseudo-first-order

What is hydrolysis dependent on?

pH and temperature

What is the order of lability with hydrolysis?

beta lactams, esters, and amides

What equation is used to describe the effect of temperature on drug stability?

Arrhenius equation

What is the Arrhenius equation?

What is oxidation?

loss of electrons by oxygen or free radical mediated reactions

What is oxidation catalyzed by?

trace metals

What does oxidation cause a loss in?

potency and color changes

What occurs with oxidation and epinephrine?

-catechol ring

-colorless solution turns pink or brown

What occurs with morphine and oxidation?

-phenolic hydroxyl group

-colorless solution turns yellow to brown

What is used to minimize oxidation?

-storage at reduced temperature

-replace oxygen by nitrogen in containers

-antioxidants

What are the steps of oxidation?

-initiation

-propagation

-termination

What are types of antioxidants?

-tocopherol

-EDTA

-Sulfites

What are characteristics of Tocopherol?

-lipid soluble antioxidant

-donates electrons and terminates free-radical chain reactions

What are the characteristics of EDTA?

-metal chelator

-binds iron, copper, and other trace metals that catalyze oxidation

What are the characteristics of sulfites?

-sodium metabisulfide

-oxygen scavenger

What is photolysis?

occurs when the wavelength of incident light is within the wavelength range of absorption of the drug, usually UV range, resulting in drug degradation

What light has higher energy?

UV light has higher energy than visible light

What occurs to tryptophan exposed to fluorescent light?

turns to a blue-green color in 24 to 120 hours in TPN amino acid solutions

What are the amino acids involved in photolysis?

Tryptophan and Tyrosine

What containers and packaging are used to protect from photolysis?

-amber vials

-aluminum foil

What factors influence drug stability?

-oxygen

-temperature

-light

-humidity

-microbial growth

What does physical instability cause?

precipitation, phase separation, gas formation, and changes in color or turbidity

What is the common cause of physical instability?

precipitation of nonionized drug

What are other causes of physical instability?

-addition of IV fluid with acidic pH to a sodium salt of a weak acid

-precipitation of hydrophobic drug after dilution of solubilizing agent

What is salting out?

highly hydrated salts - Ca2+, Mg2+, K+, Na+, and Cl- deprive drugs of water to stay in solution

What do divalent ions cause?

decrease drug solubility more than monovalent anions and cations

What does sodium chloride dehydrate?

amphotericin B, causing precipitation, use D5W instead

What does dehydrating a non electrolyte such as diazepam cause?

precipitation

What is absorption?

lipophilic drug and preservative in solution may partition into plastic bags and rubber stoppers

What is adsorption?

drug in solution adsorbs onto a surface

What is protein adsorption?

binding of protein from solution onto a surface

What do peptides such as insulin adsorb to?

IV tubing and containers

What do proteins adsorb?

PVC tubing, filter membranes, glass containers, plastic bags and syringes

What are the factors for drug stability and compatibility?

-drug concentration

-temperature

-water solubility

-pH impacts

-do components differ in pH

-vehicle: pH of D5W injection is 3.2-6.5

-light: UV light

-order of mixing

-excipients

-containers

-alternative route of administration

-avoid where possible/take place in pharmacy where possible

What are properties of amphoteric drugs?

acts as an acid and base(amino acids)

what is pl?

pH where amphoteric drug has no net charge and lowest water solubility

What are properties of proteins and peptides?

amphoteric and have low water solubility at pI

When may human serum albumin precipitate in a TPN solution?

at pH 4.9, its pI

What is insulins pI?

5.3 - lowest solubility at pH 4.5 to 7.0