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Properties and Uses of Common Formulation

Lipids, Surfactants and Cosolvents

Colin W. Pouton
Victorian College of Pharmacy, Monash University, Melbourne,
Australia
E-mail: colin.pouton@vcp.monash.edu.au
Phone: + 61 3 9903 9562

1 AAPS Workshop March 2007


Excipients for lipid formulations

liquids waxes

Hydro mineral oils petrolatum


phobic vegetable oils hydrogenated vegetable oils
MCT oil, diglycerides monoglycerides

glyceryl mono-oleate glyceryl mono-stearate


sorbitan oleates (Spans 80, 85) sorbitan stearate
esters

POE-oleate esters
POE triglcerides
polysorbate 85 POE hydrogenated veg oils

polysorbate 80, Cremophor EL polysorbate 20


Hydro
philic
PEG 400, propylene glycol PEG > 1500
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General Issues in excipient selection

• Regulatory issues – irritancy, toxicity, knowledge and experience


• Solvent capacity
• Miscibility
• Morphology at room temperature (i.e. melting point)
• Self-dispersibility and role in promoting self-dispersion of the
formulation
• Digestibility, and fate of digested products
• Capsule compatibility
• Purity, chemical stability

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Regulatory Issues in excipient selection

• Amongst typical excipients for lipid materials surfactants cause the


most concern
• Hydrophobic surfactants can penetrate membranes causing
changes in membrane fluidity and permeability. Generally single
alkyl chains are more penetrative, so bulky surfactants such as
polysorbates and triglyceride ethoxylates are less ‘toxic’
• Hydrophilic surfactants can extract lipids into the aqueous phase and
destroy membranes.
• In animal toxicity studies – cationics > anionics > nonionics
• Toxicity of nonionics – single chain ethers > single chain esters >
bulky esters (most commonly used are bulky esters)
• Acute LD50 values for nonionics in rodents are 5-10 g/kg (IV),
>50g/kg (oral). Some chronic studies are available for a wide variety
of surfactants (see textbooks of Schick, and Attwood and Florence)

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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

• Lipid systems can be filled into soft or hard gelatin providing an


effective sealing system is available for hard gelatin
• Maintaining water in formulations is difficult – note that water moves
into and out of softgel capsules. w/o emulsions and microemulsions
can lose water quickly during drying of softgels.
• Other low molecular weight polar compounds (eg propylene glycol)
can cause compatibility problems at high concentration
• Virtue of working with capsule filling companies is to access the
wealth of knowledge on gelatin formulation and excipient compatibility
• Soft and hard gel manufacturers are working hard to improve
compatibility and move to non-animal sources for capsule shell
materials

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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

• Monoglycerides crystallize at higher temps than di- or triglycerides

• Hydrophilic surfactants with high PEG content tend to be waxy, unless unsaturated
glycerides are predominant

• Liquid formulations are desirable to avoid morphological changes due to crystallization


during storage – but beware of slow crystallization if close to a phase boundary

• ‘Solid solutions’ could allow presentation of the drug in an amorphous form but are at
risk of re-crystallization

Typical liquid excipients

• 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

• ‘Pure’ lipids relatively easy to classify


• Typically glycerides derived from plants
• Most simply triglycerides, but also more polar mono and di-
glycerides
• Fatty acids also occasionally used, although possible problems
with stability (esterification) and irritancy (especially with shorter
chain lipids)
• Key issues for glycerides are residual fatty acids
• Several providers of refined or super-refined lipids, usually more
specific wrt fatty acid chain lengths/unsaturation, and or residual
fatty acid

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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

• e.g. lipids such as monoglycerides, propylene glycol esters and


diesters, and sorbitan esters
• these materials typically are poorly soluble in water but have free
hydroxyl groups which can hydrogen bond with water,
surfactants, cosolvents etc.
• polar lipids typically are better solvents for drugs
• polar lipids act as ‘co-surfactants’ which promote mutual solubility
between excipients, enhance water uptake, and promote self-
dispersibility of lipid formulations
• Polar lipids are vital components of Type II and Type III lipid
formulations

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Medium Chain Triglycerides

• Triglycerides of fractionated vegetable C8 and C10 fatty acids


(usually fractionated coconut oil). Several manufacturers produce
MCTs which meet USP/EP spec.
• Saturated, stable, liquids, good solvent properties
• Miglyol 810/812
– 810 C8 (65-80%); C10 (20-35%)
– 812 C8 (50-65%); C10 (30-45%)
• Captex 300, 355, Neobee M5, Crodamol GTC/C
• Labrafac Lipophile WL 1349 (EP/USP Spec)
– C8 (50-80%); C10 (20-50%); C12 (<3%)
• Also variations on a theme with slightly differing FA proportions
– Miglyol 818 C8 (45-65%); C10 (30-45%); C18:2 (2-5%)
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– Captex 810D C8-10 (max 40%); C18:2 (max 40%)
Medium Chain Mono and Diglycerides

Usually mono and diglycerides of capric (C10) and caprylic (C8)


FA, with traces of TG
• Capmul (Abitec)
– Capmul MCM (58% MG, 36% DG, 5% TG; 80% C8, 20% C10)
– Capmul MCM C8 (68% MG, 27% DG, 3% TG; >95% C8, 3% C10; )
– Capmul MCM C10 (> 45% MG; >45% C10)
• Imwitor (Sasol)
– Imwitor 988 (MG/DG/TG of primarily caprylic (C8) acid; 47-57% MG)
– Imwitor 742 (MG/DG/TG of C8 and C10 FA; 45-55% MG)
– Imwitor 928 (MG/DG/TG of saturated FA of coconut oil (mainly C12)
min 40% MG)

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Long Chain Mono and Diglyceride blends

• Typically a mixture of MG, DG and smaller quantities of TG


• Typical products:

– Peceol: Glyceryl monooleate HLB 3.3


Glyceride content: MG: 32-52%; DG 30-50%; TG: 5-20%
FA Composition: C18:1>60%; C18:2<35%; C18:0<6%; C16<12% 0-5%

– Maisine 35-1: Glyceryl monolinoleate HLB = 4


Glyceride content: MG: 32-52%, DG: 40-55%, TG 5-20%
FA Composition: C18:2 >50% max; C18:1 10-35%; C18:0 <6%; C16 4-20%

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Propylene glycol esters

O
R-C-O-CH2CHOH-CH3

Name R (fatty acid) HLB Note


Capryol 90
Propylene glycol > 90% Monoester 6 Possible effects on
monocaprylate 90% of C8 (caprylic P-gp (poster
acid) #T3124, AAPS 05)

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

Name R (fatty acid) HLB

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

• Cremophors (castor oil ethoxylates), Gelucires, Labrosol are


remarkably good for SMEDDS formulations with no apparent
advantage of unsaturation (ie. Cremophor EL versus RH40).
• Polar oils (eg. MGs, DGs, oleic acid) are critical components of many
formulations. They promote water penetration and have good solvent
capacity for drugs. Choice of medium chain or long chain materials is
influenced by several considerations:
- medium chain glycerides are better solvents, not prone to oxidation
- digestion products of long chain glycerides may be beneficial
- MGs are more crystalline: glyceryl monooleate is semi-solid
• Surfactants with high ethoxylate content are waxy
• Digestibility of surfactants may have a critical influence – more work is
needed in this area (ethers versus esters, effect of concentration)
• Some unusual surfactants have become popular (TPGS)
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Notes on surfactants

• Ethoxylated surfactants can be synthesised by direct reaction with


ethylene oxide, or by esterification reactions with PEG.
• Many commonly used triglyceride ethoxylates are formed by
hydrolysis of triglycerides and then esterification with PEG. This
results in a wide range of molecules: free oils, ethoxylated TGs,
ethoxylated DGs, ethoxylated MGs, ethoxylated glycerol, free PEG, all
of which are polymeric
• As a result Labrosol, Labrafils, Gelucires, Cremophor RH40 and EL
contain hundreds of individual molecules. Polysorbates are much less
heterogeneous.
• Labrasol (medium chain ethoxylate) acts like a formulated SEDDS
when introduced to water (ie. oil, cosurfactant, surfactant, cosolvent –
all in one excipient).
• Poloxamers are good quality materials but their molecular weight
makes them less mobile and reduces their performance as self-
emulsifying systems
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Surfactants: Polyethoxylated lipids

• Many of the surfactant systems used in contemporary lipid based


formulations are variations on a theme of polyethoxylated lipids
• The lipids may be fatty acids, alcohols or glycerides and are
linked to any number of repeating polyethylene oxide units
typically by ester links (glycerides, fatty acids), and occasionally
by ether linkages (alcohols)
• Although the hydrophilic group is often PEG, this is not always
the case, and can be other glycols etc

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General Schematic: Surfactant production

• Products obtained by esterification of vegetable fats or oils or fatty


acids with glycols, polyethylene glycols or alcohols, or alternatively
by reaction of fatty acids, fatty alcohols with oxyethylene
• Raw materials from vegetable origin
• Combination of a hydroxyl group substrate with an alkyl tail

Lipophilic Hydrophilic head


Chain group

Fatty acids or glycerides PEG


with various lengths: Propylene glycol
Caprylate, caprylic, lauric, Glycerol
stearic, ..

Provides the amphiphilicity of surfactants


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Polyethoxylated fatty acid esters, e.g. Myrj

O
R-C-(O-CH2-CH2)n-OH

Name R (fatty acid) PEG mol wt n HLB


Myrj 45 Stearic (C18) acid 400 8 11.1
PEG 400 monostearate
Polyoxy 8 stearate

Solutol HS 15 12-hydroxystearic 660 15 14-16


PEG 660 hydroxy- (C18) acid
stearate
Macrogol 15 hydroxy-
stearate

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Polyethoxylated alkyl ethers, e.g. Brij

R-(O-CH2-CH2)n-OH

Name R (alcohol) PEG mol wt n HLB


Brij 97 Oleyl (C18:1) ~450 10 12.4
Polyoxyl 10 oleyl ether
Oleth 10
PEG monooleyl ether

Cremophor A 25 Stearic (C18) and ~1100 25 15-17


Macrogol 25 Cetyl (C16)
cetostearyl ether
(Cetomacrogol)

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Polyethoxylated sorbitan esters (polysorbates) e.g. Tweens

Name R (fatty acid) POEn HLB

Tween 80 Oleyl (C18:1) 20 15.0

Tween 85 trioleyl (C18:1) 20 11.5

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Polyethoxylated glycerides: e.g. Cremophor

R is ricinoleic acid based glycerides (ie from castor oil).


The PEG chain is linked to side OH groups of the ricinoleate chains.

Name R (fatty acid) PEG mol wt n HLB


Cremophor EL
Polyoxyl 35 Castor oil Castor oil - TG of 1600 35 12-14
Glycerol polyethylene ricinoleic acid (12-
glycol ricinoleate hydroxyoleic acid)

Cremophor RH 40
Polyoxyl 40 hydro- Hydrogenated 1600 40 14-16
genated castor oil Castor oil - TG of
Glycerol polyethylene oxystearic acid
glycol oxystearate

25 Also contains mono, di and triglycerides, and some free PEG


Polyethoxylated glycerides: e.g. Labrafils

Formed by esterification of PEG 300 and apricot kernel oil.


Labrafil is composed of tri and partial glycerides and esters of PEG 300

Name R (fatty acid) PEG mol wt n HLB


Labrafil M 1944
PEG 300 oleic Mixed glycerides of 300 6 4
glycerides C18:1 - 58-80%
Oleoyl Macrogol-6 C18:2 – 15-35%
glycerides C16 – 4-9%
C18 - <6%
Labrafil M 2125
PEG 300 linoleic As above but
glycerides greater C18:2 300 6 4
Linoleoyl Macrogol-6- composition
glycerides
26 Both also contain mono, di and triglycerides, and some free PEG
Polyethoxylated glycerides: e.g. Labrasol

Formed by esterification of PEG 400 and medium chain triglyceride oil.


Labrasol is composed of tri and partial glycerides and esters of PEG 400

Name R (fatty acid) PEG mol wt n HLB


Labrasol
PEG 8 caprylic/capric Mixed glycerides of 400 8 14
glycerides C8 - 50-80%
Caprylcaproyl C10 – 20-50%
polyoxyglycerides C12 – < 3%
C18 - <6%

Also contains some free PEG

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Waxy Polyethoxylated glycerides: e.g. Gelucire 44/14

Formed by esterification of PEG 1500 and hydrogenated palm kernel oil


Gelucire 44/14 is composed of partial glycerides and esters of PEG 1500
Nomenclature: HLB/Mpt eg 44/14

Name R (fatty acid) PEG mol wt n HLB


Gelucire 44/14
hydrogenated palm Mixed glycerides of 1500 32 14
kernel oil PEG-32 esters C12 – 40-50%
lauryl polyoxyglycerides C14 – 14-24%
lauryl macrogol C8 – 4-10%
glycerides C10 – 3-9%
C16 – 4-14%
C18 – 5-15%

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Polyethoxylated glycerides: e.g. Gelucire 50/13

Formed by esterification of PEG 1500 and hydrogenated palm oil


Gelucire 50/13 is composed of partial glycerides and esters of PEG 1500
Nomenclature: Mpt/HLB eg 50/13

Name R (fatty acid) PEG mol wt n HLB


Gelucire 50/13
stearoyl Mixed glycerides of 1500 32 13
polyoxyglycerides C16 – 40-50%
stearyl C18 – 48-58%
macrogolglycerides C16+18 - >90%

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Poly-glycerol esters: e.g. Plurol Oleique

O OH Primarily di- and tri-


oleic acid esters of
R-C-O- OH-(CH2-CH-CH2-O-)nH polyglcerol

1o Oral applications, Pharma grade

Plurol Oleique CC497; Diesters of oleic acid with a glycerin polymer


(polyglyceryl-3-dioleate) (containing n=3 repeating glycerin units)
HLB = 6

1o cosmetic or topical pharma applications

Plurol Oleique (polyglyceryl- Diesters of oleic acid with a glycerin polymer


6-dioleate) (containing n=6 repeating glycerin units)
HLB = 10
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TPGS and poloxamers

TPGS: D-a-tocopheryl PEG 1000 succinate (MW = 1513)


Formed as esterification product between acid group of Vit E and PEG 1000
Used as an emulsifier (HLB ~13)
Also possible effects on eg P-gp efflux

General structure of poloxamers

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Cosolvents

Diethylene glycol monoethyl ether (Transcutol)

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

University of Bath, UK R P Scherer Ltd.


Mark Wakerly digestion experiments 1991-1994
Debbie Challis
Linda Solomon Cardinal Health
Naser Hasan molecular dynamics modeling 2002-2004
Rajaa Al Sukhun
Abbott Laboratories
Victorian College of Pharmacy recent formulation work 2002-2006
Dallas Warren
Kazi Mohsin Capsugel
Jean Cuine in vitro-in vivo correlation 2003-2006
Chris Porter Support for LFCS
Bill Charman