Injectable Formulations Flashcards
Explain the difference between Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP)
SVP - hermetically (airtight) sealed in a container of 100mL or less
LVP - liquid intended for infusion and hermetically sealed in a container of >100mL
What are some reasons for the use for injectables? (8)
1) Deliver systemically when other route not available
2) Exert direct control (e.g. anaphylaxis)
3) Correct rapid electrolyte imbalance and parenteral nutrion
4) Target specific areas (intrathecal, intra-articular)
5) Local action (anaesthetic)
6) Minimise systemic S/Es
7) Unconscious patients
8) Un-cooperative & Un-controllable patients
What are the 3 primary routes of parenteral administration
Intravenous (IV)
Intramuscular (IM)
Subcutaneous (SC)
List 5 categories of injectable formulations
1) Solutions
2) Suspensions
3) Emulsions
4) Dry solids / Liquid concentrates requiring reconstitution with suitable solvents to form sterile solutions
5) Dry solids requiring reconstitution with vehicles to form sterile suspensions
List some formulation issues that might arise in injections
1) Volume of injection
2) Solvents (solubility)
3) Types of vehicles (aqueous-based vs water miscible solvents)
4) Excipients (Buffers & Antioxidants)
5) Preservatives
6) Tonicity
What must you consider in IV injections when it comes to its volume?
The Rate of administration.
5mL = 1 mL per 20 seconds 100-1000mL = infuse 4-24 hours
List 5 desirable properties of injectable solvent
1) Pharmacologically inert
2) Non-toxic, Non-irritating, Non-sensitizing
3) Fluid at body temperature
4) Miscible with body fluids
5) Capable of being sterilized
What are some methods of increasing solubility?
- Co-solvents
- pH manipulation
- Complexation
- Solubilisation
List 3 desirable properties of a co-solvent
1) Effective at maintaining solubility
2) Physically and chemically stable
3) Unaffected by changes in pH
What is the purpose of Water Miscible Solvents and what are some examples?
They are used to enhance solubility, thus stabilising the drug.
Some examples include:
- glycerol, ethyl alcohol, propylene glycol, polyethylene, glycol 300 and 400
- These are all pharmacologically inert & miscible with body fluid.
- However, they can be irritating and increase toxicity
What type of injections are usually non-aqueous-based?
Intramuscular.
It uses biocompatible metabolisable oils, such as:
- peanut, sesame, corn, olive and cottonseed oil
Explain the term “Guest-Host” interaction and its benefit
Used in context with a cyclic polysaccharide solubilising agent that has a hydrophilic exterior and hydrophobic cavity.
“Guest-host” interaction involves releasing the “guest” from the cavity instantaneously into body fluid.
This increases its solubility, decreases the irritation and decreases the IM precipitation.
Why is air (O2) in the vials of oily injections replaced by N2?
Because the air will oxidise the oil and cause it to precipitate
What sort of injectable formulation allows a depot effect
Non-aqueous-based injections (e.g. oily injections).
Allows slow release of drug from oil and fatty tissues to have a prolonged action (e.g. 2-4 weeks)
List 4 reasons why buffers are used
1) For Solubility (weak acids dissolve stronger in stronger bases)
2) For Stability (prevent degradation due to pH)
3) To maximise biological activity
4) To prevent tissue damage (ideal 7.4 pH)
What are 3 issues to consider when using buffers in injections?
1) Effect on isotonicity
2) Buffer capacity
3) pH change by added acids or bases
Give some examples of buffers used in injectables
- Acetic acid and a salt
- Citric acid and a salt
- Glutamic acid
- Phosphoric acid salts
How do anti-oxidants work?
They oxidise themselves to oxidising agents by donating an electron or H+
What are some issues that can increase oxidation
- pH effects (increase in pH)
- Chelating agents (complex metal ions can catalyse oxidation)
What are some issues with preservatives?
- Container sorption
- Loss into rubber closure
- Partitioning into non-aqueous phase (thus allowing organism growth in aqueous phase)
What affects the effectiveness (MIC) of preservatives (anti-microbial agents)
- pH
- Storage temperature
- Ionisation state/strength
- Packaging materials
Define Isotonic
Same osmotic pressure as blood plasma
What happens when injections are not isotonic?
Painful. Need to inject slowly.
Hypertonic = crenation Hypotonic = haemolysis
What are injectable suspensions principally used for?
IM and SC injections.
NOT IV.
What are some considerations for injectable suspensions?
- Crystal growth and caking
- Easily re-suspendable
- Wetting, suspending and thickening agents
- Inject-ability (thickness?)
- Particle size
- Sterilisation - aseptic filtration (0.22micron)
List 3 limitations of suspensions as injections
1) Microbiological purity (sterility & pyrogenicity)
2) Range of ingredients allowed (safety, biocompatibility)
3) Mechanical flow properties (inject-ability)
What is the purpose of a surfactant in suspension injection?
Wetting and prevent crystal growth
What will suspension injections typically contain?
- Drug
- Vehicle (e.g. WFI)
- Suspending agent (e.g. CMG, mannitol, povidone)
- Surfactant
- Antimicrobial agent
- Buffer
- Antioxidant
Why must emulsions have stable droplets of <1 micron
To prevent emboli in blood vessels
What purposes are emulsion injections used for?
- w/o depot injections (IM)
- o/w emulsions of nutrients (IV) [TPN, lipids]
- w/o emulsions of allergenic (antigenic) substances (SC) [eg. vaccines]
- Slow release
- Prolong effect
What are some limitations of emulsion injections?
- Autoclaving (heat-stress degradation & change in particle size)
- Filtration - particle size
- Pyrogenicity
- Haemolysis
- Risk of solubilising components into container and administration sets
What are some surfactants used in injectable emulsions?
- Lecithin (soybean phospholipid)
- Polymers (PEGs, etc)
- Tweens (Polysorbate 80)
- Silicone antifoam
What 3 things does choice of Surfactants affect?
- Particle size (clearance/circulation time, tissue uptake & tissue penetration)
- Metabolism
- LPL binding
How are sterile powders formed for injection? (3)
- Crystallization (under sterile condition using solvent & water & evaporation
- Spray drying (liquid is sprayed and dried in hot air or N2)
- Freeze drying (lyophilization - for heat and water unstable compounds)
What is overview process of Lyophilization?
- Preparation of solution (dissolving material)
- Sterile filtration
- Filling vials
- Freeze the solution
- Apply vacuum to chamber to remove sublimed water
What type of drugs is lyophilization for?
- Thermo-labile
- Aqueous unstable
List some desired properties of freeze dried material
- Intact cake (same size and mass as frozen mass)
- Strength to prevent cracking or collapse of cake
- Uniform colour and consistency
- Sufficient dryness for stability
- Sufficient porosity and surface area to permit rapid dissolution
What sort of substances are added to freeze dried material and why?
- Inert substances such as lactose or mannitol to provide the bulk to the finished product
- Other excipients may be required as well (e.g. buffer)
List some advantages and disadvantages of freeze drying
ADVANTAGES:
- low temperatures so little degradation
- product is light and porous (readily soluble)
- no concentration of solution during drying
- no contact with air
DISADVANTAGES:
- hygroscopic product (amorphous, unstable, solid state)
- slow process
- equipment expensive
- limited to certain products
