Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Colin W. Pouton
Victorian College of Pharmacy, Monash University, Melbourne,
Australia
E-mail: colin.pouton@vcp.monash.edu.au
Phone: + 61 3 9903 9562
liquids waxes
POE-oleate esters
POE triglcerides
polysorbate 85 POE hydrogenated veg oils
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Regulatory Issues in excipient selection
4
Regulatory Issues in excipient selection – in practice
• Animal data suggests that most nonionic surfactants are equal – but
in practice some are more equal than others!
• The choice of surfactants is often driven by prior use in existing food
and pharmaceutical products, for fear of failure late in toxicity tests
• Food substances classed as GRAS (generally recognized as safe)
will be favoured
• The US FDA Center for Drug Evaluation and Research has now
posted a database of excipients – the ‘Inactive Ingredients
Database’ which states the masses or concentrations of ingredients
used in marketed pharmaceutical products (see www.fda.gov/cder)
• To use a new excipient may imply a cost of about $20 million for full
toxicity evaluation - a new draft guidance document is posted at
cder website (see www.fda.gov/cder/guidance/3812dft.doc)
• The inactive ingredients database will be a major driver in the future
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Capsule compatibility
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Miscibility of excipients
• Oils and cosolvents are generally not miscible, but the inclusion of
polar oils (such as mono and diglycerides) or surfactants create
single phase solutions.
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Solubility in lipid formulations
Take care to ensure solubility measurements in oily formulations are reliable
Always have crystalline solid present in excess – leave enough time for equilibration
In the experiment below testosterone was mixed with a lipid formulation at the
temperature shown then allowed to equilibrate at 25oC over a week
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Waxy versus liquid excipients
• Esters with saturated alkyl chains >C12 tend to crystallize at ambient temperatures
• Hydrophilic surfactants with high PEG content tend to be waxy, unless unsaturated
glycerides are predominant
• ‘Solid solutions’ could allow presentation of the drug in an amorphous form but are at
risk of re-crystallization
• medium chain di and triglycerides (monoglycerides are crystalline but blends with di
and triglycerides are liquid)
• unsaturated long-chain triglycerides (typical vegetable oils) and hydrolysed oils as long
as the monoglyceride content is low (NB - consider Maisine)
• unsaturated or medium chain ethoxylates (eg. polysorbate 80, Labrasol)
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Lipids
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Fatty acid composition of common oils
Oil C8 C10 C12 C14 C16 C18 C18:1 C18:1 C18:2 C18:3
- OH
Apricot kernel 1.0 64.2 28.3 0.2
Canola 4.7 2.0 60.0 21.7 9.1
Castor 2.0 1.0 7.0 87 3.0
Coconut 2.4 2.7 44.4 16.6 9.6 2.8 17.8 3.1 0
Corn 10.7 1.6 24.5 61.3 1.1
Olive 12.9 2.0 71.2 10.7 0.9
Palm 1.0 45.0 4.0 40.0 10.0
Palm kernel 4.0 48.0 16.0 8.0 3.0 15.0 2.0
Peanut 12.0 4.0 48.0 36.0 0
Safflower 5.5 1.6 11.1 81.4 0.4
Sesame 9.0 4.0 41.0 45.0
Soybean 10.4 3.5 21.5 51.5 7.8
Sunflower 6.2 3.5 20.7 67.9 0.2
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Polar Lipids
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Medium Chain Triglycerides
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Long Chain Mono and Diglyceride blends
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Propylene glycol esters
O
R-C-O-CH2CHOH-CH3
Capryol PGMC
Propylene glycol > 60% Monoester 5
caprylate > 90% C8
Labrafac PG V low HLB, actually
Propylene glycol C10/C12 2 functions as
dicaprylocaprate lipophilic solvent cf
16 MCT
Propylene glycol esters: Lauroglycol
O
R-C-O-CH2CHOH-CH3
Lauroglycol 90
Propylene glycol > 90% Monoester 5
monolaurate > 95% C12 (lauric
acid)
Lauroglycol FCC
Propylene glycol 45-70% Monoester 4
laurate 30-55% Diester
> 95% C12
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Notes on surfactants, cosurfactants for lipid formulations
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General Schematic: Surfactant production
O
R-C-(O-CH2-CH2)n-OH
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Polyethoxylated alkyl ethers, e.g. Brij
R-(O-CH2-CH2)n-OH
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Polyethoxylated sorbitan esters (polysorbates) e.g. Tweens
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Polyethoxylated glycerides: e.g. Cremophor
Cremophor RH 40
Polyoxyl 40 hydro- Hydrogenated 1600 40 14-16
genated castor oil Castor oil - TG of
Glycerol polyethylene oxystearic acid
glycol oxystearate
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Waxy Polyethoxylated glycerides: e.g. Gelucire 44/14
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Polyethoxylated glycerides: e.g. Gelucire 50/13
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Poly-glycerol esters: e.g. Plurol Oleique
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Cosolvents
C2H5-O-CH2-CH2-O-CH2-CH2-OH
Propylene glycol
Polyethylene glycol (PEG), polyoxyethylene
Ethanol
Propylene carbonate
Glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether)
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Acknowledgements