injection formulations Flashcards by Niamh Walsh

what is parenteral liquid?

A sterile preparation of drugs for injection through one

or more layers of the skin or mucous membrane

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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

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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)

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what volume considerations would there be for sc injections?

max.1 mL

– Injected slowly otherwise painful, e.g. hormones

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what volume consideraions would there be for IM injections?

• Intramuscular (I.M.): max. 5 mL

– Volume based on muscle mass, e.g. steroids

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what volume considerations would there be for ID injections?

max 0.2 mL, e.g. immunological tests

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what are the bulking agents availibe?

water for injection
water miscible organic solvents
oily vehicles
to enhance solubilisation

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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

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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

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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

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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

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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

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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

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what is the osmotic pressure of an IV injection?

• Intravenous:
– Small volume (slightly hypertonic)
– Infusion (isotonic)

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what is the osmotic pressure of an intralhecal solution?

Intrathecal (I.T.) (isotonic)

→otherwise headache and vomiting

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what is the osmotic pressure of an im injection?

• Intramuscular (Isotonic or slightly hypertonic)

→local effusion of tissue fluids to enhance absorption

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what is the osmotic pressure of an ID injection?

Intradermal (I.D.): To prevent skin irritation (isotonic)

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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 0.22m for microbial; 5m 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