injection formulations Flashcards
what is parenteral liquid?
A sterile preparation of drugs for injection through one
or more layers of the skin or mucous membrane
what volume considerations would there be for IV injections?
solution, suspension, emulsion, powder for
reconstitution (POR)
– Max. volume 20 mL, > 5mL considered as “large”
– Bolus (1-2mL), rapid effect
what volume considerations would there be for IV infusions?-sol or emulsions
e.g. total parenteral nutrient (TPN), patient controlled analgesia
– Intermittent (25 -100 mL) or continuous (up to 1 L)
what volume considerations would there be for sc injections?
max.1 mL
– Injected slowly otherwise painful, e.g. hormones
what volume consideraions would there be for IM injections?
• Intramuscular (I.M.): max. 5 mL
– Volume based on muscle mass, e.g. steroids
what volume considerations would there be for ID injections?
max 0.2 mL, e.g. immunological tests
what are the bulking agents availibe?
water for injection
water miscible organic solvents
oily vehicles
to enhance solubilisation
what are the traits for water for injection?what are the probelms?
– Free of microbial, pyrogen and particulate contamination
– Problems with hydrolysis and solubility issues
what are the probelms with water miscible organic solvents?
Problems with irritation and toxicity → small volume
– One phase system (co-solvent)
– e.g. alcohol, glycerin, propylene glycol, liquid PEGs
what are the probelms associated with oily vehicles? give an example
– Fixed oils e.g. arachis oil, ethyl oleate
– Depot effect and high consistency (warm preparation)
– Slow injection rate otherwise painful
what is the purpose of the bulking agent?
to enhance solubilisation
– Surfactants, e.g. Tween 80, Solutol HS15, Cremophor EL
– Buffers → adjust according to pKa of drugs
how does osmotic pressure affect the solution?
• Deviation from isotonicity: • Hypotonic solution : (diluted) – Cell swell and burst → haemolysis • Hypertonic solution : (concentrated) – Cell shrink → vein sclerosis
why do we want an isotonic solution?
Isotonic solution: – Same osmotic pressure to tissue fluids – Freezing point depression (ΔTf) – ΔTf for blood: (-) 0.52oC – e.g. 0.9% NaCl
what is the osmotic pressure of an IV injection?
• Intravenous:
– Small volume (slightly hypertonic)
– Infusion (isotonic)
what is the osmotic pressure of an intralhecal solution?
Intrathecal (I.T.) (isotonic)
→otherwise headache and vomiting
what is the osmotic pressure of an im injection?
• Intramuscular (Isotonic or slightly hypertonic)
→local effusion of tissue fluids to enhance absorption
what is the osmotic pressure of an ID injection?
Intradermal (I.D.): To prevent skin irritation (isotonic)
what is the osmotic pressure of a subcutaneous injection?
– Isotonic less painful, can be mildly hypertonic or hypotonic
what are the additives in injection which can affect the osmotic pressure?
Tonicity modifiers (sodium chloride, glucose, dextrose, mannitol); other additives (buffers, antioxidant) can affect
how does ph affect sterile liquid?
problems which cehemical stability
probelm with solubility and physiological activity
affect microbiological stability
affect compliance
what is the summary of the formulation components?
• Active ingredient
• Vehicle
• Tonicity agent
• Buffering agent or pH modifier
• Preservative (multi-dose)
– e.g. benzyl alcohol, thimerosal, parabens
– Concentration, pH, compatibility issue
• Surfactants – non toxic, non ionic form
• Antioxidant
– Oxygen radical scavengers (alpha tocopherol, BHT)
– Reducing agents (ascorbic acid and sodium bisulphite)
• Chelating agent
what affects a parenteral suspension?
-nature of drugs
-problem with particle size
prevent needle blockage
promote wettability and dispersion
prevent agglomeration and caking
how does the nature of drugs affect parenteral suspensions?
poorly solublised and chemically labile drugs
high purity via re-crystallization and associated polymorphic form
how does problems with particle size affect a parenteral suspension?
ideal drug diameter- 5 -10 m, <100 m)
– Large crystals → longer depot effect but more painful
how do you prevent needle blockage in a parenteral suspension?
isodiametric shape for drug particles (needle vs spherical shape)
what promotes wettability and disperson in parenteral suspensions?
non-ionic surfactants
how do you prevent agglomeration and caking in parenteral suspensions?
– Control flocculation → partially deflocculated (e.g. SAA, electrolyte)
– Adjust sedimentation rate (e.g. viscosity modifier)
– Optimise consistency, e.g. aluminium stearate → thixotrophic
when manufacturing a parenteral suspension how does a high purity grade drug affect it?
recrystallization occurs
polymorphism affects solubility
what do you have to consider when manufacturing parenteral suspensions?
high purity grade drug
sterilisation
production of suspension under aseptic condition
how do you produce a suspension under an aseptic condition?
– Wetting and dispersion of drug powder in vehicle
– Milling of bulk suspension to deagglomerate wetted
powder
– Filling into final containers and closure
what size are the droplets in parenteral emulsions? what is the reason for this?
• Droplet size (0.5 - 1.0 μm)
– mimic chylomicra, fat transporter; size >3 μm →thrombosis
why do parenteral emulsions have problems with stability?
Problem with emulsion stability:
– Coalescence on storage → emulsifying agents
– e.g. lecithin, Tween 80 → non toxic
what types of containers are there for a small volume?
• Single dose – Container not resealable on opening – e.g. pre-filled syringe, cartridges, fusion-sealed ampoules – No preservative & volume in excess of indicated volume • Multi-dose containers/vials – Container affixed with rubber closure – Aluminium sealed and plastic capped – Permit needle penetration – Need preservative
what types of containers are there for a large volume?
– e.g. glass bottle, PVC collapsible bag and polythene container
what are the types of materials that can be used for containers?
glass
plastic
how is glass used for a container? what are the different types?
Heat sealing; packed under vacuum
– Type 1: borasilicate with low leachability
– Type 2: soda- lime & leachable, resistance to acid & water
– Type 3: soda- lime & leachable
what are the features of plastic as a container?
– Blow- fill- seal procedure; need not packed under vacuum
– e.g. PVC, polyethylene, polyolefin
– Adsorption to container wall
– Leaching of plastizicer into content
how do you sterilize drugs and solid additives?
– dry heat (DH)
– ethylene oxide (EO) or ionization radiation (IR)
how do you steralise vehicles?
– Oily
– Aqueous but thermostable
– Aqueous but thermolabile
→ Cellulose nitrate or polycarbonate membrane
→ Cutoff 0.22m for microbial; 5m for particulate
during the mixing process what is the diameter of agitator to vessel?
1:10 to 1:20
during the mixing process what is the speed of the mixing?
1-20rps
what type of mixing occurs in the manufacturing process?
axial=propeller
radial=radial
how does clarification occur?
by filtration
pressure filters
cartridge filters
what are the 3 approaches to prepare isotonic solutions?
– Use tabulated ΔTf1% values
– Determine ΔTf of drug or excipient
– Calculate NaCl equivalent (E) using Liso value
