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Chapter 3
Drug and Excipients profile
CHAPTER-III
DRUG AND EXCIPIENTS PROFILE
3.1.
PROFILE OF ACTIVE DRUG ISOTRETINOIN (Martindale Extra
pharmacopoeia, 2007)
Chemical name
: Retinoic acid, 13-cis-.3,7-Dimethyl-9-(2,6,6-trimethyl1-cyclohexen-1-yl)2-cis-4-trans-6-trans-8-transnonatetraenoic acid.
Molecular formula
:
C20H28O2
Molecular weight
:
300.44
Excretion
:
Renal and faeces
cLogP
:
4.65
LogP
:
6.74
BCS class
:
Class II
Therapeutic indications
Severe forms of acne (such as nodular or conglobate acne or acne at risk of
permanent scarring) resistant to adequate courses of standard therapy with
systemic anti-bacterials and topical therapy.
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Posology and method of administration
Isotretinoin should only be prescribed by or under the supervision of physicians
with expertise in the use of systemic retinoids for the treatment of severe acne and
a full understanding of the risks of Isotretinoin therapy and monitoring
requirements. The capsules should be taken with food once or twice daily.
Adults including adolescents and the elderly
Isotretinoin therapy should be started at a dose of 0.5 mg/kg daily. The
therapeutic response to Isotretinoin and some of the adverse effects are doserelated and vary between patients. This necessitates individual dosage adjustment
during therapy. For most patients, the dose ranges from 0.5-1.0 mg/kg per day.
Long-term remission and relapse rates are more closely related to the total
dose administered than to either duration of treatment or daily dose. It has been
shown that no substantial additional benefit is to be expected beyond a cumulative
treatment dose of 120-150 mg/kg. The duration of treatment will depend on the
individual daily dose. A treatment course of 16-24 weeks is normally sufficient to
achieve remission.
In the majority of patients, complete clearing of the acne is obtained with a
single treatment course. In the event of a definite relapse a further course of
Isotretinoin therapy may be considered using the same daily dose and cumulative
treatment dose. As further improvement of the acne can be observed up to 8
weeks after discontinuation of treatment, a further course of treatment should not
be considered until at least this period has elapsed.
Patients with severe renal insufficiency
In patients with severe renal insufficiency treatment should be started at a
lower dose (e.g. 10 mg/day). The dose should then be increased up to 1 mg/kg/day
or until the patient is receiving the maximum tolerated dose.
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Children
Isotretinoin is not indicated for the treatment of prepubertal acne and is not
recommended in patients less than 12 years of age due to a lack of data on
efficacy and safety.
Patients with intolerance
In patients who show severe intolerance to the recommended dose,
treatment may be continued at a lower dose with the consequences of a longer
therapy duration and a higher risk of relapse. In order to achieve the maximum
possible efficacy in these patients the dose should normally be continued at the
highest tolerated dose.
Contra indications
Isotretinoin is contraindicated in women who are pregnant or breastfeeding.
Isotretinoin is contraindicated in women of childbearing potential unless all of the
conditions of the Pregnancy Prevention Programme are met.
Isotretinoin is also contraindicated in patients with hypersensitivity to Isotretinoin
or to any of the excipients.
Isotretinoin is also contraindicated in patients
• With hepatic insufficiency
• With excessively elevated blood lipid values
• With hypervitaminosis A
• Receiving concomitant treatment with tetracyclines
Special warnings and precaution for use
This medicinal product is TERATOGENIC.
Isotretinoin is contraindicated in women of childbearing potential
unless all of the following conditions of the Pregnancy Prevention
Programme are met.
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Interaction with other medicinal products and other forms of interaction
Patients should not take vitamin A as concurrent medication due to the risk
of developing hypervitaminosis A. Cases of benign intracranial hypertension
(pseudotumor cerebri) have been reported with concomitant use of Isotretinoin
and tetracyclines. Therefore, concomitant treatment with tetracyclines must be
avoided.
Concurrent administration of Isotretinoin with topical keratolytic or
exfoliative anti-acne agents should be avoided as local irritation may increase.
Table 3.1. Adverse Drug Reactions of Isotretinoin
Infections:
Very Rare (
1/10 000)
Gram
positive
(mucocutaneous)
bacterial
infection
Blood and lymphatic system disorders:
Very common (
1/10)
Anaemia, red blood cell sedimentation rate
increased, thrombocytopenia, thrombocytosis
Common ( 1/100, < 1/10)
Neutropenia
Very Rare (
Lymphadenopathy
1/10 000)
Immune system disorders:
Rare ( 1/10 000,< 1/1000)
Allergic skin reaction, anaphylactic reactions,
hypersensitivity
Metabolism and nutrition disorders:
Very Rare (
1/10 000)
Diabetes mellitus, hyperuricaemia
Psychiatric disorders:
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Rare ( 1/10 000,< 1/1000)
Depression, depression aggravated, aggressive
tendencies, anxiety, mood alterations.
Very Rare (
1/10 000)
Abnormal
behaviour,
psychotic
disorder,
suicidal ideation suicide attempt, suicide
Nervous system disorders:
Common ( 1/100, < 1/10)
Headache
Very Rare (
Benign intracranial hypertension, convulsions,
1/10 000)
drowsiness, dizziness
Eye disorders:
Very common (
Very Rare (
1/10)
Blepharitis, conjunctivitis, dry eye, eye irritation
1/10 000)
Blurred vision, cataract, colour blindness (colour
vision deficiencies), contact lens intolerance,
corneal opacity, decreased night vision, keratitis,
papilloedema (as sign of benign intracranial
hypertension), photophobia, visual disturbances.
Ear and labyrinth disorders:
Very Rare (
1/10 000)
Hearing impaired
Vascular disorders:
Very Rare (
1/10 000)
Vasculitis
(for
example
Wegener's
granulomatosis, allergic vasculitis)
Respiratory, thoracic and mediastinal disorders:
Common ( 1/100, < 1/10)
Epistaxis, nasal dryness, nasopharyngitis
Very Rare (
Bronchospasm (particularly in patients with
1/10 000)
asthma), hoarseness
Gastrointestinal disorders:
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Very Rare (
Drug and Excipients profile
1/10 000)
Colitis,
ileitis,
haemorrhage,
dry
throat,
gastrointestinal
haemorrhagic
diarrhoea
and
inflammatory bowel disease, nausea, pancreatitis
Hepatobiliary disorders:
Very common (
Very Rare (
1/10)
1/10 000)
Transaminase increased
Hepatitis
Skin and subcutaneous tissues disorders:
Very common (
1/10)
Cheilitis,
dermatitis,
dry
skin,
localised
exfoliation, pruritus, rash erythematous, skin
fragility (risk of frictional trauma)
Rare ( 1/10 000,< 1/1000)
Alopecia
Very Rare (
Acne fulminans, acne aggravated (acne flare),
1/10 000)
erythema (facial), exanthema, hair disorders,
hirsutism,
nail
dystrophy,
paronychia,
photosensitivity reaction, pyogenic granuloma,
skin hyperpigmentation, sweating increased
Frequency unknown*
Erythema
multiforme,
Stevens-Johnson
syndrome, toxic epidermal necrolysis
Musculo-skeletal and connective tissue disorders:
Very common (
1/10)
Arthralgia, myalgia, back pain (particularly in
children and adolescent patients)
Very Rare (
1/10 000)
Renal and urinary disorders:
Arthritis, calcinosis (calcification of ligaments
and tendons), epiphyses premature fusion,
exostosis, (hyperostosis), reduced bone density,
Glomerulonephritis
tendonitis
General disorders and administration site conditions:
Very Rare (
1/10 000)
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Very Rare (
Drug and Excipients profile
1/10 000)
Granulation tissue (increased formation of),
malaise
Investigations:
Very common (
1/10)
Blood triglycerides increased, high density
lipoprotein decreased
Common ( 1/100, < 1/10)
Blood cholesterol increased, blood glucose
increased, haematuria, proteinuria
Very Rare (
1/10 000)
Blood creatine phosphokinase increased
* cannot be estimated from the available data
The incidence of the adverse events was calculated from pooled clinical trial data
involving 824 patients and from post-marketing data.
Overdose
Isotretinoin is a derivative of vitamin A. Although the acute toxicity of
isotretinoin is low, signs of hypervitaminosis A could appear in cases of
accidental overdose. Manifestations of acute vitamin A toxicity include severe
headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and
symptoms of accidental or deliberate overdosage with isotretinoin would probably
be similar. These symptoms would be expected to be reversible and to subside
without the need for treatment.
Pharmacodynamic properties
Mechanism of action
Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The
exact mechanism of action of Isotretinoin has not yet been elucidated in detail, but
it has been established that the improvement observed in the clinical picture of
severe acne is associated with suppression of sebaceous gland activity and a
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histologically demonstrated reduction in the size of the sebaceous glands.
Furthermore, a dermal anti-inflammatory effect of Isotretinoin has been
established.
Efficacy
Hypercornification of the epithelial lining of the pilosebaceous unit leads
to shedding of corneocytes into the duct and blockage by keratin and excess
sebum. This is followed by formation of a comedone and, eventually,
inflammatory lesions. Isotretinoin inhibits proliferation of sebocytes and appears
to act in acne by re-setting the orderly program of differentiation. Sebum is a
major substrate for the growth of Propionibacterium acnes so that reduced sebum
production inhibits bacterial colonisation of the duct.
Pharmacokinetic properties
Absorption
The absorption of Isotretinoin from the gastro-intestinal tract is variable
and dose-linear over the therapeutic range. The absolute bioavailability of
Isotretinoin has not been determined, since the compound is not available as an
intravenous preparation for human use, but extrapolation from dog studies would
suggest a fairly low and variable systemic bioavailability. When Isotretinoin is
taken with food, the bioavailability is doubled relative to fasting conditions.
Distribution
Isotretinoin is extensively bound to plasma proteins, mainly albumin (99.9
%). The volume of distribution of isotretinoin in man has not been determined
since isotretinoin is not available as an intravenous preparation for human use. In
humans little information is available on the distribution of isotretinoin into tissue.
Concentrations of isotretinoin in the epidermis are only half of those in serum.
Plasma concentrations of isotretinoin are about 1.7 times those of whole blood due
to poor penetration of isotretinoin into red blood cells.
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Metabolism
After oral administration of Isotretinoin, three major metabolites have been
identified in plasma: 4-oxo-isotretinoin, tretinoin, (all-trans retinoic acid), and 4oxo-tretinoin. These metabolites have shown biological activity in several in vitro
tests. 4-oxo-isotretinoin has been shown in a clinical study to be a significant
contributor to the activity of Isotretinoin (reduction in sebum excretion rate
despite no effect on plasma levels of isotretinoin and tretinoin). Other minor
metabolites includes glucuronide conjugates. The major metabolite is 4-oxoisotretinoin with plasma concentrations at steady state, that are 2.5 times higher
than those of the parent compound.
Isotretinoin and tretinoin (all-trans retinoic acid) are reversibly
metabolised (interconverted), and the metabolism of tretinoin is therefore linked
with that of Isotretinoin. It has been estimated that 20-30 % of an Isotretinoin dose
is metabolised by isomerisation.
Enterohepatic
circulation
may
play
a
significant
role
in
the
pharmacokinetics of Isotretinoin in man. In vitro metabolism studies have
demonstrated that several CYP enzymes are involved in the metabolism of
Isotretinoin to 4-oxo-isotretinoin and tretinoin. No single isoform appears to have
a predominant role. Isotretinoin and its metabolites do not significantly affect
CYP activity.
Elimination
After oral administration of radiolabelled Isotretinoin approximately equal
fractions of the dose were recovered in urine and faeces. Following oral
administration of Isotretinoin, the terminal elimination half-life of unchanged drug
in patients with acne has a mean value of 19 hours. The terminal elimination halflife of 4-oxo-isotretinoin is longer, with a mean value of 29 hours.
Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are
reached within approximately two weeks following the end of Isotretinoin
therapy.
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Pharmacokinetics in special populations
Since Isotretinoin is contraindicated in patients with hepatic impairment,
limited information on the kinetics of Isotretinoin is available in this patient
population. Renal failure does not significantly reduce the plasma clearance of
Isotretinoin or 4-oxo-isotretinoin.
Preclinical safety data
Acute toxicity
The acute oral toxicity of Isotretinoin was determined in various animal
species. LD50 is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg
in mice, and over 4000 mg/kg in rats.
Chronic toxicity
A long-term study in rats over 2 years (Isotretinoin dosage 2, 8 and 32
mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides
in the higher dose groups. The side effect spectrum of Isotretinoin in the rodent
thus closely resembles that of vitamin A, but does not include the massive tissue
and organ calcifications observed with vitamin A in the rat. The liver cell changes
observed with vitamin A did not occur with Isotretinoin.
All observed side effects of hypervitaminosis A syndrome were
spontaneously reversible after withdrawal of Isotretinoin. Even experimental
animals in a poor general state had largely recovered within 1–2 weeks.
Teratogenicity
Like other vitamin A derivatives, Isotretinoin has been shown in animal
experiments to be teratogenic and embryotoxic.
Due to the teratogenic potential of Isotretinoin there are therapeutic
consequences for the administration to women of a childbearing age.
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Fertility
Isotretinoin, in therapeutic dosages, does not affect the number, motility
and morphology of sperm and does not jeopardise the formation and development
of the embryo on the part of the men taking Isotretinoin.
Mutagenicity
Isotretinoin has not been shown to be mutagenic in in-vitro or in-vivo
animal tests.
Dosage forms existing in market:
Isotretinoin 20mg and 10mg soft gelatin Capsules, Isotretinoin gel.
3.2.
PROFILE OF EXCIPIENTS USED IN FORMULATION
3.2.1. Polyoxyethylene Sorbitan Fatty Acid Esters (Rowe, et al., 2003)
1. Nonproprietary Name
Polysorbate 80
2. Synonyms
Atlas E; Armotan PMO 20; Capmul POE-O; Cremophor PS 80; Crillet 4; Crillet
50; Drewmulse POE-SMO; Drewpone 80K; Durfax 80; Durfax 80K; E433;
Emrite 6120; Eumulgin SMO; Glycosperse O-20; Hodag PSMO-20; Liposorb O20; Liposorb O-20K; Montanox 80; polyoxyethylene 20 oleate; polysorbatum 80;
Protasorb O-20; Ritabate 80; (Z)-sorbitan mono-9-octadecenoate poly(oxy1,2ethanediyl) derivatives; Tego SMO 80; Tego SMO 80V; Tween 80.
3. Chemical Name and CAS Registry Number
Chemical Name: Polyoxyethylene 20 sorbitan monooleate
CAS Registry Number: [9005-65-6]
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4. Empirical Formula and Molecular Weight
Empirical Formula: C64H124O26
Molecular Weight: 1310
5. Structural Formula
6. Functional Category
Dispersing agent; emulsifying agent; nonionic surfactant; solubilizing
agent; suspending agent; wetting agent.
7. Applications in Pharmaceutical Formulation
Polyoxyethylene sorbitan fatty acid esters (polysorbates) are a series of
partial fatty acid esters of sorbitol and its anhydrides copolymerized with
approximately 20, 5 or 4 moles of ethylene oxide for each mole of sorbitol and its
anhydrides. The resulting product is therefore a mixture of molecules of varying
sizes rather than a single uniform compound. Polysorbates containing 20 units of
oxyethylene are hydrophilic nonionic surfactants that are used widely as
emulsifying agents in the preparation of stable oil-in-water pharmaceutical
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emulsions. They may also be used as solubilizing agents for a variety of
substances including essential oils and oil-soluble vitamins, and as wetting agents
in the formulation of oral and parenteral suspensions. They have been found to be
useful in improving the oral bioavailability of drug molecules that are substrates
for p-glycoprotein. Polysorbates are also widely used in cosmetics and food
products.
Table 3.2. Uses of Polysorbates
S.No. Uses
Concentration
(%)
1.
Emulsifying agent
-
2.
Used alone in oil-in-water emulsions
1–15
3.
Used in combination with hydrophilic
emulsifiers in oil-in-water emulsions
1–10
4.
Used to increase the water-holding properties
of ointments
1–10
5.
Solubilizing agent
-
6.
For poorly soluble active constituents in
lipophilic bases
1–10
7.
Wetting agent
-
8.
For insoluble active constituents in lipophilic
bases
0.1–3
8. Pharmacopoeial Specifications (Official in USP 29-NF32)
Polysorbate 80 is an oleate ester of sorbitol and its anhydrides
copolymerized with approximately 20 moles of ethylene oxide for each mole of
sorbitol and sorbitol anhydrides.
Packaging and storage: Preserve in tight containers.
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Identification
A: To 5 mL of a solution (1 in 20) add 5 mL of sodium hydroxide TS. Boil for a
few minutes, cool, and acidify with 3 N hydrochloric acid: the solution is strongly
opalescent.
B: To 2 mL of a solution (1 in 20) add 0.5 mL of bromine TS, dropwise: the
bromine is decolorized.
C: A mixture of 60 volumes of it and 40 volumes of water yields a gelatinous
mass at normal and lower than normal room temperatures.
Specific gravity: Between 1.06 and 1.09.
Viscosity: Between 300 and 500 centistokes when determined at 25.
Acid value: Weigh 10.0 g into a wide-mouth, 250-mL conical flask, and add 50
mL of neutralized alcohol. Heat on a steam bath nearly to boiling, shaking
thoroughly occasionally while heating. Invert a beaker over the mouth of the flask,
cool under running water, add 5 drops of phenolphthalein TS, and titrate with 0.1
N sodium hydroxide VS: not more than 4 mL of 0.100 N sodium hydroxide is
required, corresponding to an acid value of 2.2.
Hydroxyl value: Between 65 and 80.
Saponification value: Between 45 and 55.
Water: Not more than 3.0%.
Residue on ignition: Not more than 0.25%.
Heavy metals: 0.001%.
9. Stability and Storage Conditions
Polysorbates are stable to electrolytes and weak acids and bases; gradual
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saponification occurs with strong acids and bases. The oleic acid esters are
sensitive to oxidation. Polysorbates are hygroscopic and should be examined for
water content prior to use and dried if necessary. Also, in common with other
polyoxyethylene surfactants, prolonged storage can lead to the formation of
peroxides.
Polysorbates should be stored in a well-closed container, protected from
light, in a cool, dry place.
10. Incompatibilities
Discoloration and/or precipitation occur with various substances,
especially phenols, tannins, tars, and tar like materials. The antimicrobial activity
of paraben preservatives is reduced in the presence of polysorbates.
11. Method of Manufacture
Polysorbates are prepared from sorbitol in a three-step process. Water is
initially removed from the sorbitol to form a sorbitan (a cyclic sorbitol anhydride).
The sorbitan is then partially esterified with a fatty acid, such as oleic or stearic
acid, to yield a hexitan ester. Finally, ethylene oxide is chemically added in the
presence of a catalyst to yield the polysorbate.
12. Safety
Polysorbates are widely used in cosmetics, food products, and oral,
parenteral and topical pharmaceutical formulations, and are generally regarded as
nontoxic and nonirritant materials. There have, however, been occasional reports
of hypersensitivity to polysorbates following their topical and intramuscular use.
Polysorbates have also been associated with serious adverse effects, including
some deaths, in low-birthweight infants intravenously administered a vitamin E
preparation containing a mixture of polysorbates 20 and 80. When heated to
decomposition, the polysorbates emit acrid smoke and irritating fumes.
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The WHO has set an estimated acceptable daily intake for polysorbates 20,
40, 60, 65, and 80, calculated as total polysorbate esters, at up to 25 mg/kg bodyweight.
Moderately toxic by IV route. Mildly toxic by ingestion. Eye irritation.
Experimental tumorigen, reproductive effects. Mutagenic data.

LD50 (mouse, IP): 7.6 g/kg

LD50 (mouse, IV): 4.5 g/kg

LD50 (mouse, oral): 25 g/kg

LD50 (rat, IP): 6.8 g/kg

LD50 (rat, IV): 1.8 g/kg
13. Handling Precautions
Observe normal precautions appropriate to the circumstances and quantity
of material handled. Eye protection and gloves are recommended
14. Regulatory Status
Polysorbates 60, 65, and 80 are GRAS listed. Polysorbates 20, 40, 60, 65,
and 80 are accepted as food additives in Europe. Polysorbates 20, 40, 60, and 80
are included in the FDA Inactive Ingredients Guide (IM, IV, oral, rectal, topical,
and vaginal preparations). Polysorbates are included in parenteral and
nonparenteral medicines licensed in the UK. Polysorbates 20, 21, 40, 60, 61, 65,
80, 81, 85, and 120 are included in the Canadian List of Acceptable Nonmedicinal Ingredients.
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3.2.2. Sorbitan monooleate (Rowe, et al., 2003)
1. Nonproprietary Names
Span 80
2. Synonym
Ablunol S-80; Arlacel 80; Armotan MO; Capmul O; Crill 4; Crill 50; Dehymuls
SMO; Drewmulse SMO; Drewsorb 80K; E494; Glycomul O; Hodag SMO;
Lamesorb SMO; Liposorb O; Montane 80; Nikkol SO-10; Nissan Nonion OP80R; Norfox Sorbo S-80; Polycon S80 K; Proto-sorb SMO; Protachem SMO; SMaz 80K; Sorbester P17; Sorbirol O; sorbitan oleate; Sorgen 40; Sorgon S-40-H;
Span 80; Tego SMO.
3. Chemical name
(Z)-Sorbitan mono-9-octadecenoate
4. Structure
5. Empirical formula and molecular weight
Empirical formula: C24H44O6
Molecular weight: 429
6. Colour and form
Yellow viscous liquid
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7. Typical properties of Sorbitan monooleate
S.No. Properties
Value
1.
Acid value
≤ 8.0
2.
Density (g/cm3)
1.01
3.
HLB value
4.3
4.
Hydroxyl value
193 - 209
5.
Saponification value
149 - 160
6.
Viscosity at 25°C (mPas)
970 - 1080
7.
Water content (%)
≤ 0.5
8. Functional Category
Dispersing agent; emulsifying agent; nonionic surfactant; solubilizing
agent; suspending agent; wetting agent.
9. Applications in Pharmaceutical Formulation or Technology
Sorbitan monoesters are a series of mixtures of partial esters of sorbitol
and its mono- and dianhydrides with fatty acids. Sorbitan diesters are a series of
mixtures of partial esters of sorbitol and its monoanhydride with fatty acids.
Sorbitan esters are widely used in cosmetics, food products, and
pharmaceutical formulations as lipophilic nonionic surfactants. They are mainly
used in pharmaceutical formulations as emulsifying agents in the preparation of
creams, emulsions, and ointments for topical application. When used alone,
sorbitan esters produce stable water-in-oil emulsions and microemulsions, but are
frequently used in combination with varying proportions of a polysorbate to
produce water-in-oil or oil-in-water emulsions or creams of varying consistencies,
and also in self-emulsifying drug delivery systems for poorly soluble compounds.
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10. Stability and Storage Conditions
Sorbitan esters should be stored in a well-closed container in a cool, dry
place.
11. Safety
Sorbitan esters are widely used in cosmetics, food products, and oral and
topical pharmaceutical formulations, and are generally regarded as nontoxic and
nonirritant materials. However, there have been occasional reports of
hypersensitive skin reactions following the topical application of products
containing sorbitan esters. When heated to decomposition, the sorbitan esters emit
acrid smoke and irritating fumes.
The WHO has set an estimated acceptable daily intake of sorbitan
monopalmitate, monostearate, and tristearate and of sorbitan monolaurate and
monooleate at up to 25 mg/kg body-weight calculated as total sorbitan esters.
12. Regulatory Status
Certain sorbitan esters are accepted as food additives in the UK. Sorbitan
esters are included in the FDA Inactive Ingredients Database (inhalations; IM
injections; ophthalmic, oral, topical, and vaginal preparations). Sorbitan esters are
used in nonparenteral medicines licensed in the UK. Sorbitan esters are included
in the Canadian List of Acceptable Non-medicinal Ingredients.
3.2.3. Polyoxylglycerides
1. Nonproprietary Names
BP: Caprylocaproyl Macrogolglycerides
Lauroyl Macrogolglycerides
PhEur: Caprylocaproyl Macrogolglycerides
Lauroyl Macrogolglycerides
USP-NF: Caprylocaproyl Polyoxylglycerides
Lauroyl Polyoxylglycerides
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2. Synonyms
Polyoxylglycerides are referred to as macrogolglycerides in Europe.
Lauroyl polyoxylglycerides - Gelucire 44/14; hydrogenated coconut oil PEG 1500
esters; hydrogenated palm/palm kernel oil PEG 300 esters; macrogolglyceridorum
laureates.
3. Chemical Name and CAS Registry Numbers
Chemical Name: Lauric acid, diester with glycerol; poly(oxy-1,2-ethanediyl), α(1-oxododecyl)-ω-[(1-oxododecyl)oxy]CAS Registry Numbers: [57107- 95-6]; [27194-74-7]
4. Empirical Formula and Molecular Weight
Lauroyl polyoxylglycerides - Mixtures of monoesters, diesters, and triesters of
glycerol and monoesters and diesters of polyethylene glycols with mean relative
molecular mass between 300 and 1500. They are obtained by partial alcoholysis
of saturated oils mainly containing triglycerides of lauric (dodecanoic) acid, using
polyethylene glycol, or by esterification of glycerol and polyethylene glycol with
saturated fatty acids, or by mixing glycerol esters and condensates of ethylene
oxide with the fatty acids of these hydrogenated oils.
5. Functional Category
Dissolution enhancer; emulsifying agent; nonionic surfactant; penetration
agent; solubilizing agent; sustained-release agent.
6. Applications in Pharmaceutical Formulation or Technology
Polyoxylglycerides are used as self-emulsifying and solubilizing agents in
oral and topical pharmaceutical formulations. They are also used in cosmetic and
food products.
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7. Description
Polyoxylglycerides are inert liquid or semi-solid waxy materials and are
amphiphilic in character. Caprylocaproyl polyoxylglycerides are pale-yellow oily
liquids. Lauroyl polyoxylglycerides and stearoyl polyoxylglycerides occur as
pale-yellow
waxy
solids.
Oleoyl
polyoxylglycerides
and
linoleoyl
polyoxylglycerides occur as amber oily liquids, which may give rise to a deposit
after prolonged periods at 20°C.
8. Typical Properties
Solubility - Caprylocaproyl and lauroyl polyoxylglycerides: dispersible in hot
water; freely soluble in methylene chloride.
9. Stability and Storage Conditions
Polyoxylglycerides should be preserved in their original containers,
and exposure to air, light, heat, and moisture should be prevented.
10. Safety
Polyoxylglycerides are used in oral and topical pharmaceutical
formulations, and also in cosmetics and food products. They are generally
regarded as relatively nonirritant and nontoxic materials.
Lauroyl polyoxylglycerides: LD50 (rat, oral) : >2004 mg/(kg day).
11. Regulatory Status
Lauroyl polyoxylglycerides and stearoyl polyoxylglycerides are approved
as food additives in the USA. Included in the FDA Inactive Ingredients Database
(oral route: capsules, tablets, solutions; topical route: emulsions, creams, lotions;
vaginal route: emulsions, creams). Oleyl polyoxylglycerides are included in a
topical cream formulation licensed in the UK.
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3.2.4. Polyoxyethylene Castor Oil Derivatives
1. Nonproprietary Names
BP: Polyoxyl Castor Oil
Hydrogenated Polyoxyl Castor Oil
PhEur: Macrogolglycerol Ricinoleate
Macrogolglycerol Hydroxystearate
USP-NF: Polyoxyl 35 Castor Oil
Polyoxyl 40 Hydrogenated Castor Oil
2. Synonyms
Polyoxyl 40 hydrogenated castor oil
Cremophor RH 40; Croduret 40; Eumulgin HRE 40PH; glycerol
polyethyleneglycol oxystearate; Hetoxide HC40; hydrogenated castor oil
POE-40;
Jeechem
CAH-40;
PEG-40
hydrogenated
castor
oil;
polyethoxylated hydrogenated castor oil; polyoxyethylene 40 hydrogenated
castor oil; Lipocol HCO-40; Lipocol LAV HCO 40; Nikkol HCO 40
Pharma; Nonionic GRH-40; Protachem CAH-40.
3. Chemical Name and CAS Registry Number
Chemical Name: Polyethoxylated castor oil
CAS Registry Number: [61791-12-6]
4. Functional Category
Emulsifying agent; solubilizing agent; wetting agent.
5. Applications in Pharmaceutical Formulation or Technology
Polyoxyl 40 hydrogenated castor oil may be used in preference to polyoxyl
35 castor oil in oral formulations as a solubilizer for fat soluble vitamins, essential
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oils and other hydrophobic pharmaceuticals. It has very little odor and it is almost
tasteless. In aqueous alcoholic or completely aqueous solutions, polyoxyl 40
hydrogenated castor oil can be used to solubilize vitamins, essential oils, and
certain drugs. Using 1 mL of a 25% v/v aqueous solution of polyoxyl 40
hydrogenated castor oil, it is possible to solubilize approximately 88 mg of
vitamin A palmitate, or approximately 160 mg of vitamin A propionate. Other
materials that can be solubilized are alfadolone, alfaxalone, anise oil, clotrimazole,
diazepam,
eucalyptol,
gramicidin,
hexachlorophene,
hexetidine,
levomepromazine, miconazole, propanidid, sage oil and thiopental.
Polyoxyl 40 hydrogenated castor oil is also used as an emulsifier of fatty
acids and alcohols.
Cremophor RH 40 and RH 60 have been used as additives to enhance the
drug release from suppository formulations
6. Description
Polyoxyl 40 hydrogenated castor oil occurs as a white to yellowish,
semisolid paste at 20°C that liquefies at 30°C. It has a very faint characteristic
odor and is almost tasteless in aqueous solution.
7. Typical Properties
S.No. Properties
Value
1.
Acid value
≤ 1.0
2.
Melting point (°C)
≈30
3.
HLB value
14 - 16
4.
Hydroxyl value
60 - 75
5.
Saponification value
50 - 60
6.
Solidification point (°C)
16 - 26
7.
Water content (%)
≤ 2.0
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8. Stability and Storage Conditions
Polyoxyethylene castor oil derivatives should be stored in a well-filled,
airtight container, protected from light, in a cool, dry place. They are stable for at
least 2 years if stored in the unopened original containers at room temperature
(maximum 25°C).
9. Safety
Polyoxyethylene castor oil derivatives are used in a variety of oral, topical,
and parenteral pharmaceutical formulations.
Acute and chronic toxicity tests in animals have shown polyoxyethylene
castor oil derivatives to be essentially nontoxic and nonirritant materials;
Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) Mouse (IP) >12.5
Mouse (IV) >12.0
Rat (oral)
>16.0
10. Regulatory Status
Included in the FDA Inactive Ingredients Database (IV injections and
ophthalmic solutions). Included in parenteral medicines licensed in the UK.
Included in the Canadian List of Acceptable Non-medicinal Ingredients.
3.2.5. Polyethylene Glycol
1. Nonproprietary Names
BP: Macrogols
JP: Macrogol 400
Macrogol 1500
Macrogol 4000
Macrogol 6000
Macrogol 20000
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PhEur: Macrogols
USP-NF: Polyethylene Glycol
2. Synonyms
Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; macrogola; PEG; Pluriol E;
polyoxyethylene glycol.
3. Chemical Name and CAS Registry Number
Chemical Name: α-Hydro-ω-hydroxypoly(oxy-1,2-ethanediyl)
CAS Registry Number: [25322-68-3]
4. Empirical Formula and Molecular Weight
HOCH2(CH2OCH2)mCH2OH where m represents the average number of
oxyethylene groups.Alternatively, the general formula H(OCH2CH2)nOH may be
used to represent polyethylene glycol, where n is a number m in the previous
formula + 1.
The average molecular weights of typical polyethylene glycols are given in below
table
Grade
m
Average molecular weight
PEG 200
4.2
190–210
PEG 600
13.2
570–613
PEG 8000 181.4
7 000–9 000
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5. Structural Formula
6. Functional Category
Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant.
7. Applications in Pharmaceutical Formulation or Technology
Polyethylene glycols (PEGs) are widely used in a variety of
pharmaceutical formulations, including parenteral, topical, ophthalmic, oral, and
rectal preparations. Polyethylene glycol has been used experimentally in
biodegradable polymeric matrices used in controlled-release systems.
Polyethylene glycols are stable, hydrophilic substances that are essentially
nonirritant to the skin. They do not readily penetrate the skin, although the
polyethylene glycols are water-soluble and are easily removed from the skin by
washing, making them useful as ointment bases. Solid grades are generally
employed in topical ointments, with the consistency of the base being adjusted by
the addition of liquid grades of polyethylene glycol.
Mixtures of polyethylene glycols can be used as suppository bases for
which they have many advantages over fats. For example, the melting point of the
suppository can be made higher to withstand exposure to warmer climates; release
of the drug is not dependent upon melting point; the physical stability on storage
is better; and suppositories are readily miscible with rectal fluids. Polyethylene
glycols have the following disadvantages: they are chemically more reactive than
fats; greater care is needed in processing to avoid inelegant contraction holes in
the suppositories; the rate of release of water-soluble medications decreases with
the increasing molecular weight of the polyethylene glycol; and polyethylene
glycols tend to be more irritating to mucous membranes than fats.
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Aqueous polyethylene glycol solutions can be used either as suspending
agents or to adjust the viscosity and consistency of other suspending vehicles.
When used in conjunction with other emulsifiers, polyethylene glycols can act as
emulsion stabilizers.
Liquid polyethylene glycols are used as water-miscible solvents for the
contents of soft gelatin capsules. However, they may cause hardening of the
capsule shell by preferential absorption of moisture from gelatin in the shell.
In concentrations up to approximately 30% v/v, PEG 300 and PEG 400
have been used as the vehicle for parenteral dosage forms.
In solid-dosage formulations, higher-molecular-weight polyethylene
glycols can enhance the effectiveness of tablet binders and impart plasticity to
granules. However, they have only limited binding action when used alone, and
can prolong disintegration if present in concentrations greater than 5% w/w. When
used for thermoplastic granulations a mixture of the powdered constituents with
10–15% w/w PEG 6000 is heated to 70–75°C. The mass becomes paste like and
forms granules if stirred while cooling. This technique is useful for the preparation
of dosage forms such as lozenges when prolonged disintegration is required.
Polyethylene glycols can also be used to enhance the aqueous solubility or
dissolution characteristics of poorly soluble compounds by making solid
dispersions with an appropriate polyethylene glycol. Animal studies have also
been performed using polyethylene glycols as solvents for steroids in osmotic
pumps.
In film coatings, solid grades of polyethylene glycol can be used alone for
the film-coating of tablets or can be useful as hydrophilic polishing materials.
Solid grades are also widely used as plasticizers in conjunction with film-forming
polymers. The presence of polyethylene glycols in film coats, especially of liquid
grades, tends to increase their water permeability and may reduce protection
against low pH in enteric-coating films. Polyethylene glycols are useful as
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plasticizers in microencapsulated products to avoid rupture of the coating film
when the microcapsules are compressed into tablets.
Polyethylene glycol grades with molecular weights of 6000 and above can
be used as lubricants, particularly for soluble tablets. The lubricant action is not as
good as that of magnesium stearate, and stickiness may develop if the material
becomes too warm during compression. An antiadherent effect is also exerted,
again subject to the avoidance of overheating.
Polyethylene glycols have been used in the preparation of urethane hydrogels,
which are used as controlled-release agents. Polyethylene glycol has also been
used in insulin-loaded microparticles for the oral delivery of insulin it has been
used in inhalation preparations to improve aerosolization; polyethylene glycol
nanoparticles have been used to improve the oral bioavailability of cyclosporine;
it has been used in self-assembled polymeric nanoparticles as a drug carrier; and
copolymer networks of polyethylene glycol grafted with poly(methacrylic acid)
have been used as bioadhesive controlled drug delivery formulations.
8. Typical Properties
Density
1.11–1.14 g/cm3 at 25°C for liquid PEGs;
1.15–1.21 g/cm3 at 25°C for solid PEGs.
Flash point
182°C for PEG 200;
250°C for PEG 600.
Freezing point
<−65°C PEG 200 sets to a glass;
15–25°C for PEG 600.
Melting point
55–63°C for PEG 6000;
60–63°C for PEG 8000;
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Moisture content - Liquid polyethylene glycols are very hygroscopic, although
hygroscopicity decreases with increasing molecular weight. Solid grades, e.g.
PEG 4000 and above, are not hygroscopic.
Refractive index
n25D = 1.459 for PEG 200;
n25D = 1.467 for PEG 600.
Solubility
All grades of polyethylene glycol are soluble in water and miscible in all
proportions with other polyethylene glycols (after melting, if necessary). Aqueous
solutions of higher-molecular-weight grades may form gels. Liquid polyethylene
glycols are soluble in acetone, alcohols, benzene, glycerin, and glycols. Solid
polyethylene glycols are soluble in acetone, dichloromethane, ethanol (95%), and
methanol; they are slightly soluble in aliphatic hydrocarbons and ether, but
insoluble in fats, fixed oils, and mineral oil.
Surface tension
Approximately 44 mN/m (44 dynes/cm) for liquid polyethylene glycols;
approximately 55 mN/m (55 dynes/cm) for 10% w/v aqueous solution of solid
polyethylene glycol.
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Viscosity (kinematic)
Type
Viscosity
Viscosity
(dynamic)
(kinematic)
[mPas (cP)]
[mm2/s (cSt)]
340–394
80–105
71–94
15–25
178–197
15–20
13.9–18.5
1.080
55–61
16–22
200–270
185–250
1.080
55–62
12–16
260–510
240–472
Density
Freezing
Hydroxyl
(g/cm3)
point (°C)
value
200
1.120
—
600
1.080
6000
8000
of
PEG
9. Stability and Storage Conditions
Polyethylene glycols are chemically stable in air and in solution, although
grades with a molecular weight less than 2000 are hygroscopic. Polyethylene
glycols do not support microbial growth, and they do not become rancid.
Polyethylene glycols should be stored in well-closed containers in a cool, dry
place. Stainless steel, aluminum, glass, or lined steel containers are preferred for
the storage of liquid grades.
10. Description
The USP32–NF27 describes polyethylene glycol as being an addition
polymer of ethylene oxide and water. Polyethylene glycol grades 200–600 are
liquids; grades 1000 and above are solids at ambient temperatures.
Liquid grades (PEG 200–600) occur as clear, colorless or slightly yellow-colored,
viscous liquids. They have a slight but characteristic odor and a bitter, slightly
burning taste. PEG 600 can occur as a solid at ambient temperatures.
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Solid grades (PEG>1000) are white or off-white in color, and range in consistency
from pastes to waxy flakes. They have a faint, sweet odor. Grades of PEG 6000
and above are available as free-flowing milled powders.
11. Safety
Polyethylene glycols are widely used in a variety of pharmaceutical
formulations. Generally, they are regarded as nontoxic and nonirritant materials.
Adverse reactions to polyethylene glycols have been reported, the greatest
toxicity being with glycols of low molecular weight. However, the toxicity of
glycols is relatively low.
Polyethylene glycols administered topically may cause stinging, especially
when applied to mucous membranes. Hypersensitivity reactions to polyethylene
glycols applied topically have also been reported, including urticaria and delayed
allergic reactions.
The most serious adverse effects associated with polyethylene glycols are
hyperosmolarity, metabolic acidosis, and renal failure following the topical use of
polyethylene glycols in burn patients. Topical preparations containing
polyethylene glycols should therefore be used cautiously in patients with renal
failure, extensive burns, or open wounds.
Oral administration of large quantities of polyethylene glycols can have a
laxative effect. Therapeutically, up to 4 L of an aqueous mixture of electrolytes
and high-molecular-weight polyethylene glycol is consumed by patients
undergoing bowel cleansing.
Liquid polyethylene glycols may be absorbed when taken orally, but the
higher-molecular-weight polyethylene glycols are not significantly absorbed from
the gastrointestinal tract. Absorbed polyethylene glycol is excreted largely
unchanged in the urine, although polyethylene glycols of low molecular weight
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may be partially metabolized. The WHO has set an estimated acceptable daily
intake of polyethylene glycols at up to 10 mg/kg body-weight.
In parenteral products, the maximum recommended concentration of PEG
300 is approximately 30% v/v as hemolytic effects have been observed at
concentrations greater than about 40% v/v.
LD50 (g/kg)
PEG
grade
Guinea
pig
200
PEG
600
PEG
6000
Rat
(IP)
(IV)
(oral)
(oral)
(IV)
—
7.5
—
34
19.9
—
—
—
28.0
—
—
—
47
—
—
—
—
38.1
50
—
—
—
—
—
6.8
—
—
(oral)
PEG
Mouse Mouse Mouse Rabbit Rabbit Rat Rat
(IP) (IV) (oral)
12. Regulatory Status
Included in the FDA Inactive Ingredients Database (dental preparations;
IM and IV injections; ophthalmic preparations; oral capsules, solutions, syrups,
and tablets; rectal, topical, and vaginal preparations). Included in nonparenteral
medicines licensed in the UK. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.
3.2.6. Propylene Glycol
1. Nonproprietary Names
BP: Propylene Glycol
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JP: Propylene Glycol
PhEur: Propylene Glycol
USP: Propylene Glycol
2. Synonyms
1,2-Dihydroxypropane; E1520; 2-hydroxypropanol; methyl ethylene
glycol; methyl glycol; propane-1,2-diol; propylenglycolum.
3. Chemical Name and CAS Registry Number
Chemical Name: 1,2-Propanediol [57-55-6]; CAS Registry Number : [57-55-6]
Chemical Name: (−)-1,2-Propanediol; CAS Registry Number: [4254-14-2]
Chemical Name: (+)-1,2-Propanediol; CAS Registry Number: [4254-15-3]
4. Empirical Formula and Molecular Weight
C3H8O2 76.09
5. Structural Formula
6. Functional Category
Antimicrobial
preservative;
disinfectant;
humectant;
plasticizer;
solvent;
stabilizing agent; water-miscible cosolvent.
7. Applications in Pharmaceutical Formulation or Technology
Propylene glycol has become widely used as a solvent, extractant, and
preservative in a variety of parenteral and nonparenteral pharmaceutical
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formulations. It is a better general solvent than glycerin and dissolves a wide
variety of materials, such as corticosteroids, phenols, sulfa drugs, barbiturates,
vitamins (A and D), most alkaloids, and many local anesthetics.
As an antiseptic it is similar to ethanol, and against molds it is similar to
glycerin and only slightly less effective than ethanol.
Propylene glycol is commonly used as a plasticizer in aqueous filmcoating formulations.
Propylene glycol is also used in cosmetics and in the food industry as a
carrier for emulsifiers and as a vehicle for flavors in preference to ethanol, since
its lack of volatility provides a more uniform flavor.
8. Description
Propylene glycol is a clear, colorless, viscous, practically odorless liquid,
with a sweet, slightly acrid taste resembling that of glycerin.
9. Typical Properties
Autoignition temperature - 371°C
Boiling point - 188°C
Density - 1.038 g/cm3 at 20°C
Flammability Upper limit -12.6% v/v in air; lower limit, 2.6% v/v in air.
Flash point - 99°C (open cup)
Heat of combustion -1803.3 kJ/mol (431.0 kcal/mol)
Heat of vaporization - 705.4 J/g (168.6 cal/g) at b.p.
Melting point - −59°C
Osmolarity - A 2.0% v/v aqueous solution is iso-osmotic with serum.
Refractive index - n 20D = 1.4324
Specific rotation
[α]20D = −15.0° (neat) for (R)-form;
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[α]20D = +15.8° (neat) for (S)-form.
Solubility
Miscible with acetone, chloroform, ethanol (95%), glycerin, and water;
soluble at 1 in 6 parts of ether; not miscible with light mineral oil or fixed oils, but
will dissolve some essential oils.
Specific heat - 2.47 J/g (0.590 cal/g) at 20°C.
Surface tension - 40.1 mN/m (40.1 dynes/cm) at 25°C.
Vapor density (relative) - 2.62 (air = 1)
Vapor pressure - 9.33 Pa (0.07 mmHg) at 20°C.
Viscosity (dynamic) - 58.1 mPas (58.1 cP) at 20°C.
10. Stability and Storage Conditions
At cool temperatures, propylene glycol is stable in a well-closed container,
but at high temperatures, in the open, it tends to oxidize, giving rise to products
such as propionaldehyde, lactic acid, pyruvic acid, and acetic acid. Propylene
glycol is chemically stable when mixed with ethanol (95%), glycerin, or water;
aqueous solutions may be sterilized by autoclaving.
Propylene glycol is hygroscopic and should be stored in a well-closed
container, protected from light, in a cool, dry place.
11. Safety
Propylene glycol is used in a wide variety of pharmaceutical formulations
and is generally regarded as a relatively nontoxic material. It is also used
extensively in foods and cosmetics. Probably as a consequence of its metabolism
and excretion, propylene glycol is less toxic than other glycols. Propylene glycol
is rapidly absorbed from the gastrointestinal tract; there is also evidence that it is
absorbed topically when applied to damaged skin. It is extensively metabolized in
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the liver, mainly to lactic and pyruvic acids, and is also excreted unchanged in the
urine.
In topical preparations, propylene glycol is regarded as minimally irritant,
although it is more irritant than glycerin. There have been some reports of contact
dermatitis associated with propylene glycol. Some local irritation is produced
upon application to mucous membranes or when it is used under occlusive
conditions. Parenteral administration may cause pain or irritation when propylene
glycol is used in high concentration.
On the basis of metabolic and toxicological data, the WHO has set an
acceptable daily intake of propylene glycol at up to 25 mg/kg body-weight.
Formulations containing 35% propylene glycol can cause hemolysis in humans.
In animal studies, there has been no evidence that propylene glycol is
teratogenic or mutagenic. Rats can tolerate a repeated oral daily dose of up to 30
mL/kg body-weight in the diet over 6 months, while the dog is unaffected by a
repeated oral daily dose of 2 g/kg in the diet for 2 years.

LD50 (mouse, IP): 9.72 g/kg

LD50 (mouse, IV): 6.63 g/kg

LD50 (mouse, oral): 22.0 g/kg

LD50 (mouse, SC): 17.34 g/kg

LD50 (rat, IM): 0.01 g/kg

LD50 (rat, IP): 6.66 g/kg

LD50 (rat, IV): 6.42 g/kg

LD50 (rat, oral): 0.02 g/kg

LD50 (rat, SC): 22.5 g/kg
12. Regulatory Status
GRAS listed. Accepted for use as a food additive in Europe. Included in
the FDA Inactive Ingredients Database (dental preparations; IM and IV injections;
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inhalations; ophthalmic, oral, otic, percutaneous, rectal, topical, and vaginal
preparations). Included in nonparenteral and parenteral medicines licensed in the
UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
3.2.7. Diethylene Glycol Monoethyl Ether
1. Nonproprietary Names
Diethylene Glycol Monoethyl Ether
2. Synonyms
Dowanol 17, Dowanol DE, Ektasolve DE, Solvolsol, Transcutol, Transcutol P,
Transcutol HP DEGEE
3. Chemical Names and CAS Registry Number
Chemical Names:
2-(2-Ethoxyethoxy)ethanol (IUPAC name) Carbitol, Carbitol solvent,
Diethylene glycol monoethyl ether, 3,6-Dioxa-1-octanol, Diethylene glycol ethyl
ether, , Diglycol monoethyl ether, Dioxitol, Ethanol, 2,2'-oxybis-, monoethyl
ether, Ethyl carbitol, Ethyl diethylene glycol, Ethyl digol,
CAS Registry Number: 111-90-0
4. Empirical Formula and Molecular Weight
C6H14O3
134.2
5. Structural Formula
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6. Functional Category
High performance solubilizer, solvent.
7. Purity, composition and substance codes
The applicant states that from May 1998, the manufacturing process of
DEGEE was improved in order to decrease the content in residual impurities.
Transcutol CG: > 99.5% (cosmetics only)
Transcutol P: > 99.7% (pharmaceutical, topical forms)
Transcutol HP: > 99.9% (pharmaceutical, other administration routes)
8. Applications in Pharmaceutical Formulation or Technology
Purified DEGEE (>99%) is used in cosmetics and dermatological
preparations and as solvent in some medicine products. Its physical properties
make DEGEE useful to solubilise lipophilic and hydrophilic compounds.
Moreover DEGEE enhances the percutaneous absorption through the skin and
mucosal barriers. It is used in some drugs to enhance absorption.
In its previous opinions (SCCP/1044/06, SCCP/1200/08), the SCCP positively
evaluated the use of DEGEE in cosmetic products up to 1.5% and in hair dyes up
to 7.0% in oxidative and 5% in non-oxidative formulations, based on the data
available at the time. According to the recent application to the Commission, the
applicant requested to increase the maximal concentration of DEGEE as a solvent
in cosmetic products in a concentration up to 5.5% in leave-on products and up to
10% in rinse-off products, based on new studies provided.
9. Typical Properties
Solubility : Miscible with water and oils
Partition coefficient (Log Pow): - 0.54 (exp)
Appearance: colourless liquid
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Melting point: - 76 °C
Boiling point: 197 – 205 °C
Density: 0.988
Rel. vapour density: / Vapour Pressure: 0.19 hPa
Conversion:
1 ppm = 5.58 mg/m³
1 mg/m3 = 0.179 ppm
10. Stability and Storage Conditions
Shelf life: At least 3 years of storage under recommended conditions of
original hermetically closed container (The product is packed under nitrogen and
must be used shortly after opening).
11. Safety
Acute oral toxicity
The acute toxicity after oral administration of DEGEE has been
determined in several experiments.
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The studies reported that there were no test substance-related clinical
findings or effects on body weight or food consumption during the escalating-dose
phase of the study, where dose levels of 500, 1000, 1500 and 2000 mg/kg were
administered. They concluded that the oral (gavage) administration of
Transcutol® HP to one female Beagle dog did not result in any test substancerelated effects following single oral doses of 500, 1000, 1500 and 2000 mg/kg .
Human
In an isolated case report, an alcoholic male (aged 44) drank approximately
300 ml of a liquid containing 47% DEGEE (about 2000 mg/kg). Severe symptoms
of central nervous and respiratory injury (dyspnoea) thirst and acidosis occurred.
The urine contained albumin. The subject recovered following symptomatic
treatment.
Skin irritation
Transcutol was tested for potential irritation on human skin in a primary
irritation single patch test as undiluted material. It was applied once at the dose
level of about 0.02 ml per volunteer, on a surface of about 50 mm2 of skin on the
back of 10 volunteers. Transcutol was kept in contact with the skin under an
occlusive patch test for 48 hours. This application was performed in parallel and
under same condition with patch test alone as “negative” control. Cutaneous
macroscopic examinations were performed about 30 min after removal of the
patches. Evaluation of the erythematous and oedematous reactions was made
according to a given numerical scale. After the removal of the patches, only 1
volunteer showed an erythema of grade 1 out of 4 grades (i.e. very slight), while
all other volunteers showed no erythema. It was concluded that the single
epicutaneous application of Transcutol under the experimental conditions used
was “well tolerated”.
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12. Regulatory Status
GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA
Inactive Ingredients Database.
3.2.8. Tetraglycol
1. Nonproprietary Names
None adopted.
2. Synonyms
Glycofurol 75; tetraglycol; α-(tetrahydrofuranyl)-ω-hydroxy-poly(oxyethylene);
tetrahydrofurfuryl alcohol polyethylene glycol ether; THFP.
Note: tetraglycol is also used as a synonym for tetrahydrofurfuryl alcohol.
3. Chemical Name and CAS Registry Number
Chemical
Name:
α-[(Tetrahydro-2-furanyl)methyl]-ω-hydroxy-poly(oxy-1,2-
ethanediyl)
CAS Registry Number: [31692-85-0]
4. Empirical Formula and Molecular Weight
Empirical Formula: C9H18O4 (average); Molecular Weight: 190.24 (average)
5. Structural Formula
Glycofurol 75: n = 1–2
6. Functional Category
Penetration agent; solvent.
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7. Applications in Pharmaceutical Formulation or Technology
Glycofurol is used as a solvent in parenteral products for intravenous or
intramuscular injection in concentrations up to 50% v/v. It has also been
investigated, mainly in animal studies, for use as a penetration enhancer and
solvent in topical and intranasal formulations. Glycofurol has also been used at
20% v/v concentration in a rectal formulation.
8. Description
Glycofurol is a clear, colorless, almost odorless liquid, with a bitter taste; it
produces a warm sensation on the tongue.
9. Typical Properties
Boiling point - 80–100°C for Glycofurol 75
Density - 1.070–1.090 g/cm3 at 20°C
Hydroxyl value - 300–400
Moisture content - 0.2–5% at ambient temperature and 30% relative humidity.
Refractive index - n 40D = 1.4545
Solubility
Solvent
Solubility at 20°C
Arachis oil
Immiscible
Castor oil
Miscible(a)
Ethanol (95%)
Miscible in all proportions
Glycerin
Miscible in all proportions
Isopropyl ether
Immiscible
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Solvent
Solubility at 20°C
Petroleum ether
Immiscible
Polyethylene glycol 400 Miscible in all proportions
Propan-2-ol
Miscible in all proportions
Propylene glycol
Miscible in all proportions
Water
Miscible in all proportions(a)
a. Cloudiness may occur.
Viscosity (dynamic) - 8–18 mPas (8–18 cP) at 20°C for Glycofurol 75.
10. Stability and Storage Conditions
Stable if stored under nitrogen in a well-closed container protected from
light, in a cool, dry place.
11. Safety
Glycofurol is mainly used as a solvent in parenteral pharmaceutical
formulations and is generally regarded as a relatively nontoxic and nonirritant
material at the levels used as a pharmaceutical excipient. Glycofurol can be
irritant when used undiluted; its tolerability is approximately the same as
propylene glycol.
Glycofurol may have an effect on liver function and may have a low potential
for interaction with hepatoxins or those materials undergong extensive hepatic
metabolism.

LD50 (mouse, IV): 3.5 mL/kg
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12. Regulatory Status
Included in parenteral medicines licensed in Europe.
3.2.9. Triacetin
1. Nonproprietary Names
BP: Triacetin
PhEur: Triacetin
USP: Triacetin
2. Synonyms
Captex 500; E1518; glycerol triacetate; glyceryl triacetate; triacetinum; triacetyl
glycerine.
3. Chemical Name and CAS Registry Number
Chemical Name: 1,2,3-Propanetriol triacetate
CAS Registry Number: [102-76-1]
4. Empirical Formula and Molecular Weight
C9H14O6 218.21
5. Structural Formula
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6. Functional Category
Humectant; plasticizer; solvent.
7. Applications in Pharmaceutical Formulation or Technology
Triacetin is mainly used as a hydrophilic plasticizer in both aqueous and
solvent-based polymeric coating of capsules, tablets, beads, and granules; typical
concentrations used are 10–35% w/w.
Triacetin is used in cosmetics, perfumery, and foods as a solvent and as a
fixative in the formulation of perfumes and flavors.
8. Description
Triacetin is a colorless, viscous liquid with a slightly fatty odor.
9. Typical Properties
Autoignition temperature: 432°C
Boiling point: 258°C
Density: 1.16 g/cm3 at 25°C
Explosive limits:
1.05% at 189°C lower limit;
7.73% at 215°C upper limit.
Flash point: 153°C (open cup)
Freezing point: 3.2°C (supercools to about –70°C)
Melting point: −78°C
Refractive index: n 25D = 1.4296
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Solubility
Solvent
Solubility at 20°C
Carbon disulfide
Miscible
Chloroform
Miscible
Ethanol
Miscible
Ethanol (95%)
Miscible
Ether
Miscible
Toluene
Miscible
Water
1 in 14
Vapor density (relative) : 7.52 (air = 1)
Vapor pressure : 133 Pa (1 mmHg) at 100°C
Viscosity (dynamic) :
1111 mPas (1111 cP) at –17.8°C;
107 mPas (107 cP) at 0°C;
17.4 mPas (17.4 cP) at 25°C;
1.8 mPas (1.8 cP) at 100°C.
10. Stability and Storage Conditions
Triacetin is stable and should be stored in a well-closed, nonmetallic
container, in a cool, dry place.
11. Safety
Triacetin is used in oral pharmaceutical formulations and is generally
regarded as a relatively nontoxic and nonirritant material at the levels employed as
an excipient.
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LD50 (dog, IV): 1.5 g/kg
LD50 (mouse, IP): 1.4 g/kg
LD50 (mouse, IV): 1.6 g/kg
LD50 (mouse, oral): 1.1 g/kg
LD50 (mouse, SC): 2.3 g/kg
LD50 (rabbit, IV): 0.75 g/kg
LD50 (rat, IP): 2.1 g/kg
LD50 (rat, oral): 3 g/kg
LD50 (rat, SC): 2.8 g/kg
12. Regulatory Status
GRAS listed. Accepted in Europe as a food additive in certain
applications. Included in the FDA Inactive Ingredients Database (oral capsules
and tablets and gels). Included in nonparenteral medicines licensed in the UK.
Included in the Canadian List of Acceptable Non-medicinal Ingredients.
3.2.10. Medium-chain Triglycerides
1. Nonproprietary Names
BP: Medium-chain Triglycerides
PhEur: Triglycerides, Medium-Chain
USP-NF: Medium-Chain Triglycerides
2. Synonyms
Crodamol GTCC-PN; Bergabest; caprylic/capric triglyceride; Captex 300;
Captex 355; glyceryl tricaprylate/caprate; Labrafac CC; Labrafac Lipo; MCT oil;
Miglyol 810; Miglyol 812; Myritol; Neobee M5; Nesatol; oleum neutrale; oleum
vegetable tenue; thin vegetable oil; triglycerida saturata media; Waglinol 3/9280.
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3. Chemical Name and CAS Registry Number
Chemical Name: Medium-chain triglycerides
CAS Registry Number: [73398-61-5]
4. Empirical Formula and Molecular Weight
≈ 500 (average)
The PhEur 6.0 describes medium-chain triglycerides as the fixed oil
extracted from the hard, dried fraction of the endosperm of Cocos nucifera L. or
from the dried endosperm of Elaeis guineenis Jacq. They consist of a mixture of
triglycerides of saturated fatty acids, mainly of caprylic acid and of capric acid.
They contain not less than 95% of saturated fatty acids.
5. Structural Formula
6. Functional Category
Emulsifying agent; solvent; suspending agent; therapeutic agent.
7. Applications in Pharmaceutical Formulation or Technology
Medium-chain triglycerides have been used in a variety of pharmaceutical
formulations including oral, parenteral, and topical preparations.
In oral formulations, medium-chain triglycerides are used as the base for
the preparation of oral emulsions, microemulsions, self-emulsifying systems,
solutions, or suspensions of drugs that are unstable or insoluble in aqueous media,
e.g. calciferol. Medium-chain triglycerides have also been investigated as
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intestinal-absorption enhancers and have additionally been used as a filler in
capsules and sugar-coated tablets, and as a l ubricant or antiadhesion agent in
tablets.
In parenteral formulations, medium-chain triglycerides have similarly been
used in the production of emulsions, solutions, or suspensions intended for
intravenous administration. In rectal formulations, medium-chain triglycerides
have been used in the preparation of suppositories containing labile materials. In
cosmetics and topical pharmaceutical preparations, medium-chain triglycerides
are used as a component of ointments, creams, and liquid emulsions.
Therapeutically, medium-chain triglycerides have been used as nutritional
agents. Diets containing medium-chain triglycerides are used in conditions
associated with the malabsorption of fat, such as cystic fibrosis, since mediumchain triglycerides are more readily digested than long-chain triglycerides.
Medium-chain triglycerides have been particularly investigated for their use in
total parenteral nutrition (TPN) regimens in combination with long-chain
triglycerides.
8. Description
A colorless to slightly yellowish oily liquid that is practically odorless and
tasteless. It solidifies at about 0°C.
9. Typical Properties
Acid value ≤0.1
Cloud point ≤5°C
Color ≤60 (Hazen color index)
Density 0.94–0.96 g/cm3
Freezing point −5°C
Hydroxyl value ≤8
Iodine number ≤1.0
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Moisture content ≤0.15% w/w
Peroxide value ≤1.0
Refractive index 1.4485–1.4500
Saponification value 325–345
Solubility
Soluble in all proportions at 20°C in acetone, benzene, 2-butanone, carbon
tetrachloride, chloroform, dichloromethane, ethanol, ethanol (95%), ether, ethyl
acetate, petroleum ether, special petroleum spirit (boiling range 80–110°C),
propan-2-ol, toluene, and xylene. Miscible with long-chain hydrocarbons and
triglycerides; practically insoluble in water.
Surface tension 32.2 mN/m
Viscosity (dynamic) 27–30 mPas (27–30 cP)
10. Stability and Storage Conditions
Medium-chain triglycerides are stable over the wide range of storage
temperatures that can be experienced in tropical and temperate climates. Ideally,
however, they should be stored at temperatures not exceeding 25°C and not
exposed to temperatures above 40°C for long periods.
Medium-chain triglycerides may be sterilized by maintaining at 170°C for
1 hour.
Medium-chain triglycerides should be stored protected from light in a
well-filled and well-closed container. When stored dry, in sealed containers,
medium-chain triglycerides remain stable for many years.
11. Safety
Medium-chain triglycerides are used in a variety of pharmaceutical
formulations including oral, parenteral, and topical products, and are generally
regarded as essentially nontoxic and nonirritant materials.
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In acute toxicology studies in animals and humans, no irritant or other
adverse reactions have been observed; for example, when they were patch-tested
on more than 100 individuals, no irritation was produced on either healthy or
eczematous skin. Medium-chain triglycerides are not irritating to the eyes.
Similarly, chronic toxicology studies in animals have shown no harmful
adverse effects associated with medium-chain triglycerides following inhalation or
intraperitoneal, oral, and parenteral administration.
In humans, administration of 0.5 g/kg body-weight medium-chain
triglycerides to healthy individuals produced no change in blood or serum
triglycerides compared to subjects receiving the same dose of the long-chain
triglyceride triolein.
In patients consuming diets based on medium-chain triglycerides, adverse
effects reported include abdominal pain and diarrhea.

LD50 (mouse, IV): 3.7 g/kg

LD50 (mouse, oral): 29.6 g/kg

LD50 (rat, oral): 33.3 g/kg
12. Regulatory Status
GRAS listed. Included in the FDA Inactive Ingredients Database (topical
preparations). Included in nonparenteral and parenteral medicines licensed in
Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
3.2.11. Labrafil M1944 cs
1. Nonproprietary Names
EP: Oleoyl macrogol-6 glycerides
USP-NF: Oleoyl polyoxyl-6 glycerides
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2. Synonyms
Apricot Kernel Oil PEG-6 Esters, Unsaturated polyglycolysed glycerides.
3. Chemical Name and CAS Registry Number
Chemical Name: Apricot Kernel Oil PEG-6 Esters
CAS Registry Number: 69071-70-1 (or 68424-61-3 + 9004-96-0)
4. Functional Category
solvent; suspending agent.
5. Applications in Pharmaceutical Formulation or Technology
This product is a pharmaceutical ingredient. It is recommended for use in
pharmaceutical formulations administered by oral, topical and/or rectal/vaginal
routes.
Oral drug delivery: Excipient used in formulations for solubility and
bioavailability enhancement.
Oral drug delivery: Water dispersible surfactant for SELF (self-emulsifying lipidic
formulation).
Oral/Dermal drug delivery: Solubilizer for actives.
Dermal drug delivery: W/O surfactant. It improves the stability of emulsions.
6. Description
A colorless to slightly yellowish oily liquid
7. Typical Properties
Appearance Liquid
Odour Faint
Colour (gardner scale) < 5.0
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Specific gravity at 20°c (D20/4) 0.935 to 0.955
Refractive index at 20°c 1.465 to 1.475
Viscosity at 20°c 75 to 95 mpa.s
Acid value < 2.00 mgkoh/g
Saponification value 150 to 170 mgkoh/g
Iodine value 75 to 95 gI2/100g
Hydroxyl value 45 to 65 mgkoh/g
Peroxide value < 12.0 meqo2/kg
Alkaline impurities < 80 ppm naoh
Water content < 0.50 %
Free glycerol content < 3.0 %
Heavy metals content (pb) < 10 ppm
Palmitic acid (c16) 4.0 to 9.0 %
Stearic acid (c18) < 6.0 %
Oleic acid (c18:1) 58.0 to 80.0 %
Linoleic acid (c18:2) 15.0 to 35.0 %
Linolenic acid (c18:3) < 2.0 %
Arachidic acid (c20) < 2.0 %
Eicosenoic acid (c20:1) < 2.0 %
1.4-dioxane content < 10 ppm
Ethylene oxide content < 1 ppm
Solubility
Ethanol 96°: Insoluble
Methylene chloride: Very soluble
n-Hexane: Soluble
Water: Dispersible
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8. Stability and Storage Conditions
A partial crystallization of the product may occur during storage at low
temperature with no effect on the properties of the product. It disappears after
heating and homogenization.
Container packaged under nitrogen.
Special temperature storage conditions are not required.
Store the product in its original packaging sealed tightly, protected from light and
moisture.
9. Safety
Acute toxicity by oral route :
Species : Rat
Concentration : 100 %
Result : DL 0 : >= 20 ml/kg (TOX 7979)
Expert conclusion : Not classified
Primary cutaneous irritation :
Concentration : 100 % Result : 0,38 (TOX 7978)
Expert conclusion : Non irritant
10. Regulatory Status
GRAS listed. Included in the FDA Inactive Ingredients Database (topical
preparations). Included in EP and USP-NF.
3.2.12. Labrafil M 2125 Cs
1. Nonproprietary Names
EP: Linoleoyl macrogol-6 glycerides
USP-NF: Linoleoyl polyoxyl-6 glycerides
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2. Synonyms
Corn oil PEG-6 esters
3. Chemical Name and CAS Registry Number
Chemical Name: Corn oil PEG-6 esters
CAS Registry Number: 61789-25-1
4. Functional Category
Solvent; w/o surfactant.
5. Applications in Pharmaceutical Formulation or Technology
This product is a pharmaceutical ingredient. It is recommended for use in
pharmaceutical formulations administered by oral, topical and/or rectal/vaginal
routes.
Dermal drug delivery: W/O surfactant. It improves the stability of
emulsions.
Oral/Dermal drug delivery: Solubilizer for actives.
Oral drug delivery: Water dispersible surfactant for SELF (selfemulsifying lipidic formulation).
Oral drug delivery: Excipient used in formulations for solubility and
bioavailability enhancement.
Bioavailability enhancer: increased oral bioavailability is potentially
associated with the long chain tryglyceride composition and selective absorption
of highly lipophilic APIs by the lymphatic transport system reducing hepatic firstpass metabolism.
6. Description
A colorless to slightly yellowish oily liquid
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7. Typical Properties
Form: liquid
Colour: Yellow
Odour: Light
Boiling point/Boiling range: > 150 °C
Flash point: > 150 °C
Self igniting : Product is not selfigniting.
Density : 0,935 - 0,955 (20°C)
Solubility in / Miscibility with Water: Dispersible.
Organic solvents: Soluble in many organic solvents
8. Stability and Storage Conditions
Container packaged under nitrogen.
Special temperature storage conditions are not required.
Store the product in its original packaging sealed tightly, protected from light and
moisture.
9. Regulatory Status
FDA IIG listed. Included in the FDA Inactive Ingredients Database. Included in
medicines licensed in Europe.
3.2.13. Sesame Oil
1. Nonproprietary Names
BP: Refined Sesame Oil
JP: Sesame Oil
PhEur: Sesame Oil, Refined
USP-NF: Sesame Oil
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2. Synonyms
Benne oil; gingelly oil; gingili oil; jinjili oil; Lipovol SES; sesami oleum
raffinatum; teel oil.
3. Chemical Name and CAS Registry Number
Chemical Name: Sesame oil
CAS Registry Number: [8008-74-0]
4. Empirical Formula and Molecular Weight
A typical analysis of refined sesame oil indicates the composition of the
acids, present as glycerides, to be: arachidic acid 0.8%; linoleic acid 40.4%; oleic
acid 45.4%; palmitic acid 9.1%; and stearic acid 4.3%. Sesamin, a complex cyclic
ether, and sesamolin, a glycoside, are also present in small amounts.
The monographs for Sesame Oil in the USP32–NF27 and Refined Sesame
Oil in the PhEur 6.3 specify the acceptable range of eight triglycerides found in
sesame oil.
5. Structural Formula
A typical analysis of refined sesame oil indicates the composition of the
acids, present as glycerides, to be: arachidic acid 0.8%; linoleic acid 40.4%; oleic
acid 45.4%; palmitic acid 9.1%; and stearic acid 4.3%. Sesamin, a complex cyclic
ether, and sesamolin, a glycoside, are also present in small amounts.
6. Functional Category
Oleaginous vehicle; solvent.
7. Applications in Pharmaceutical Formulation or Technology
The major use of sesame oil in pharmaceutical formulations is as a solvent
in the preparation of sustained-release intramuscular injections of steroids, such as
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estradiol valerate, hydroxyprogesterone caproate, testosterone enanthate, and
nandrolone decanoate, or other oil-soluble drug substances, such as the decanoates
or enanthate esters of fluphenazine. The disappearance of sesame oil from the
injection site, following subcutaneous or intramuscular administration to pigs, has
been reported to have a half-life of about 23 days. The in vitro drug release rates
from oily depot formulations containing sesame oil intended for intra-articular
administration have been reported.
Sesame oil may be used as a solvent in the preparation of subcutaneous
injections, oral capsules, rectal suppositories, and ophthalmic preparations; it may
also be used in the formulation of suspensions and emulsions. Multiple-emulsion
formulations, in which sesame oil was one of the oil phases incorporated, have
been investigated as a prolonged-release system for rifampicin; microemulsions
containing sesame oil have been prepared for the transdermal delivery of
ketoprofen. Sesame oil has also been included in self-microemulsifying drug
delivery systems, and fast-disintegrating lyophilized dry emulsion tablets for oral
administration. It has also been used in the preparation of liniments, pastes,
ointments, and soaps. A sesame paste (tahini), composed of crushed sesame seeds
in sesame oil, has been investigated as a novel suspending agent.
Sesame oil is additionally used as an edible oil and in the preparation of
oleomargarine.
8. Description
Refined sesame oil is a clear, pale-yellow colored liquid with a slight, pleasant
odor and a bland taste. It solidifies to a soft mass at about −4°C.
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9. Typical Properties
Density 0.916–0.920 g/cm3
Flash point 338°C (open cup)
Freezing point −5°C
Refractive index n 40D = 1.4650–1.4665
Solubility
Insoluble in water; practically insoluble in ethanol (95%); miscible with carbon
disulfide, chloroform, ether, hexane, and light petroleum.
Specific rotation [α]25D = +1° to +9°
Viscosity (dynamic) 43 mPas (43cP)
10. Stability and Storage Conditions
Sesame oil is more stable than most other fixed oils and does not readily
become rancid; this has been attributed to the antioxidant effect of some of its
characteristic constituents. The PhEur 6.3 permits the addition of a suitable
antioxidant to sesame oil.
Sesame oil may be sterilized by aseptic filtration or dry heat. It has been
reported that suitable conditions for the sterilization of injections containing
sesame oil are a temperature of 170°C for 2 hours; it has been suggested that
150°C for 1 hour is inadequate.However, it has been demonstrated that dry heat
sterilization of sesame oil at 150°C for 1 hour was sufficient to kill all added
Bacillus subtilis spores.
Sesame oil should be stored in a well-filled, airtight, light-resistant
container, at a temperature not exceeding 40°C. Sesame oil intended for use in the
manufacture of parenteral dosage forms should be stored under an inert gas in an
airtight glass container.
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11. Safety
Sesame oil is mainly used in intramuscular and subcutaneous injections; it
should not be administered intravenously. It is also used in topical pharmaceutical
formulations and consumed as an edible oil.
Although it is generally regarded as an essentially nontoxic and nonirritant
material, there have been rare reports of hypersensitivity to sesame oil, with
sesamin suspected as being the primary allergen. Anaphylactic reactions to
sesame seeds have also been reported. However, it is thought that the allergens in
the seeds may be inactivated or destroyed by heating as heat-extracted sesame
seed oil or baked sesame seeds do not cause anaphylactic reactions in sesame
seed-allergic individuals.
12. Regulatory Status
Included in the FDA Inactive Ingredients Database (IM and SC injections;
oral capsules, emulsions, and tablets; also topical preparations). Included in
parenteral (IM injections) and nonparenteral (oral capsules) medicines licensed in
the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
3.2.14. Soybean Oil
1. Nonproprietary Names
BP: Refined Soya Oil
JP: Soybean Oil
PhEur: Soya-Bean Oil, Refined
USP: Soybean Oil
2. Synonyms
Aceite de soja; Calchem IVO-114; Lipex 107; Lipex 200; Shogun CT; soiae oleum
raffinatum; soja bean oil; soyabean oil; soya bean oil.
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3. Chemical Name and CAS Registry Number
Chemical Name: Soybean oil
CAS Registry Number: [8001-22-7]
4. Empirical Formula and Molecular Weight
A typical analysis of refined soybean oil indicates the composition of the acids,
present as glycerides, to be: linoleic acid 50–57%; linolenic acid 5–10%; oleic
acid 17–26%; palmitic acid 9–13%; and stearic acid 3–6%. Other acids are present
in trace quantities.
5. Structural Formula
A typical analysis of refined soybean oil indicates the composition of the
acids, present as glycerides, to be: linoleic acid 50–57%; linolenic acid 5–10%;
oleic acid 17–26%; palmitic acid 9–13%; and stearic acid 3–6%. Other acids are
present in trace quantities.
6. Functional Category
Oleaginous vehicle; solvent.
7. Applications in Pharmaceutical Formulation or Technology
In pharmaceutical preparations, soybean oil emulsions are primarily used
as a fat source in total parenteral nutrition (TPN) regimens. Although other oils,
such as peanut oil, have been used for this purpose, soybean oil is now preferred
because it is associated with fewer adverse reactions. Emulsions containing
soybean oil have also been used as vehicles for the oral and intravenous
administration of drugs; drug substances that have been incorporated into such
emulsions include amphotericin, diazepam, retinoids, vitamins, poorly watersoluble steroids, fluorocarbons, ibuprofen, and insulin. In addition, soybean oil
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has been used in the formulation of many drug delivery systems such as
liposomes,
microspheres,dry
emulsions,
self-emulsifying
systems,
microemulsions, nanoemulsions and nanocapsules, solid-in-oil suspensions, and
multiple emulsions.
Soybean oil may also be used in cosmetics and is consumed as an edible
oil. As soybean oil has emollient properties, it is used as a bath additive in the
treatment of dry skin conditions.
8. Description
The USP 32 describes soybean oil as the refined fixed oil obtained from
the seeds of the soya plant Glycine max Merr. (Fabaceae); if an antoxidant is
added, the name and quantity must be specified on the label. The PhEur 6.2
defines refined soybean oil as the fatty oil obtained from the seeds of Glycine soja
Sieb. and Zucc. and Glycine max (L.) Merr. (G. hispida (Moench) Maxim.) by
extraction and subsequent refining; it may contain a suitable antioxidant.
Soybean oil is a clear, pale-yellow colored, odorless or almost odorless liquid,
with a bland taste that solidifies between −10 and −16°C.
9. Typical Properties
Autoignition temperature 445°C
Density 0.916–0.922 g/cm3 at 25°C
Flash point 282°C
Freezing point −10 to −16°C
Hydroxyl value 4–8
Interfacial tension 50 mN/m (50 dynes/cm) at 20°C.
Refractive index n 25D = 1.471–1.475
Solubility
Practically insoluble in ethanol (95%) and water; miscible with carbon disulfide,
chloroform, ether, and light petroleum.
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Surface tension 25 mN/m (25 dynes/cm) at 20°C.
Viscosity (dynamic)
172.9 mPas (172.9 cP) at 0°C;
99.7 mPas (99.7 cP) at 10°C;
50.09 mPas (50.09 cP) at 25°C;
28.86 mPas (28.86 cP) at 40°C.
10. Stability and Storage Conditions
Soybean oil is a stable material if protected from atmospheric oxygen.
The formation of undesirable flavors in soybean oil is accelerated by the
presence of 0.01 ppm copper and 0.1 ppm iron, which act as catalysts for
oxidation; this can be minimized by the addition of chelating agents.
Prolonged storage of soybean oil emulsions, particularly at elevated
temperatures, can result in the formation of free fatty acids, with a consequent
reduction in the pH of the emulsion; degradation is minimized at pH 6–7.
However, soybean oil emulsions are stable at room temperature if stored under
nitrogen in a light-resistant glass container. Plastic containers are permeable to
oxygen and should not be used for long-term storage since oxidative degradation
can occur.
The stability of soybean oil emulsions is considerably influenced by other
additives in a formulation. Soybean oil should be stored in a well-filled, airtight,
light-resistant container at a temperature not exceeding 25°C.
11. Safety
Soybean oil is widely used intramuscularly as a drug vehicle or as a
component of emulsions used in parenteral nutrition regimens; it is also consumed
as an edible oil. Generally, soybean oil is regarded as an essentially nontoxic and
nonirritant material. However, serious adverse reactions to soybean oil emulsions
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administered parenterally have been reported. These include cases of
hypersensitivity, CNS reactions, and fat embolism. Interference with the
anticoagulant effect of warfarin has also been reported. Anaphylactic reactions
have also been reported following the consumption of foods derived from, or
containing, soybeans. Recently there has been concern at the concentration of
phytoestrogens in some soy-derived products. Administration of soy protein to
humans has resulted in significantly decreased serum lipid concentrations.
LD50 (mouse, IV): 22.1 g/kg
LD50 (rat, IV): 16.5 g/kg
12. Regulatory Status
Included in the FDA Inactive Ingredients Database (IV injections, oral
capsules, and topical preparations). Included in nonparenteral (chewable tablets;
oral capsules; oral lozenges; topical bath additives) and parenteral (emulsions for
IV injection or infusion) medicines licensed in the UK. Included in the Canadian
List of Acceptable Non-medicinal Ingredients.
3.2.15. Peppermint Oil
Peppermint oil is extracted from Mentha piperita of the Labiatae family
and is also known as brandy mint and balm mint.
This cooling and refreshing essential oil is used in aromatherapy to
stimulate the mind, increase mental agility and to increase focus, while cooling the
skin, reducing redness and calming irritation and itchiness. It furthermore helps to
ease spastic colon, migraine, headaches, sinus and chest congestion and boosts the
digestive system.
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1. Oil properties
Peppermint oil has a fresh, sharp, menthol smell, is clear to pale yellow in
color and watery in viscosity.
2. Origin of peppermint oil
It is a native of the Mediterranean, but is now also cultivated in Italy,
USA, Japan and Great Britain. It is a perennial herb that grows up to 1 meter (3
feet) high and has slightly hairy serrated leaves with pinkish-mauve flowers
arranged in a long conical shape.
It has underground runners by which it easily propagates. This herb has
many species, and peppermint piperita is a hybrid of watermint (M. aquatica) and
spearmint (M. spicata).
It has been cultivated since ancient times in Japan and China. Evidence of
use was found in Egypt in a tomb dating back from 1000 BC.
3. Extraction
Peppermint oil is extracted from the whole plant above ground just before
flowering. The oil is extracted by steam distillation from the fresh or partly dried
plant and the yield is 0.1 - 1.0 %.
4. Chemical composition
The chemical components of peppermint oil are menthol, menthone, 1,8cineole, methyl acetate, methofuran, isomenthone, limonene, b-pinene, a-pinene,
germacrene-d, trans-sabinene hydrate and pulegone.
5. Precautions
Peppermint oil is non-toxic and non-irritant in low dilutions, but
sensitization may be a problem due to the menthol content.
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It can cause irritation to the skin and mucus membranes and should be kept
well away from the eyes. It should be avoided during pregnancy and should not be
used on children under seven.
6. Therapeutic properties
The therapeutic properties of peppermint oil are analgesic, anesthetic,
antiseptic,
carminative,
antigalactagogue,
cephalic,
antiphlogistic,
cholagogue,
cordial,
antispasmodic,
decongestant,
astringent,
emmenagogue,
expectorant, febrifuge, hepatic, nervine, stimulant, stomachic, sudorific,
vasoconstrictor and vermifuge.
7. Uses
Peppermint oil is excellent for mental fatigue and depression, refreshing
the spirit and stimulating mental agility and improving concentration. It helps for
apathy, shock, headache, migraine, nervous stress, vertigo and faintness and in
general respiratory disorders, as well as dry coughs, sinus congestion, asthma,
bronchitis, pneumonia, tuberculosis and cholera.
For the digestive system, peppermint oil is effective for a range of
ailments, as it stimulates the gall bladder and the secretion of bile. It is used for
colic, cramps, dyspepsia, spastic colon, flatulence and nausea and can relieve pain
in cases of toothache, aching feet, rheumatism, neuralgia, muscular pains and
painful periods.
On the skin, peppermint oil is used to relieve skin irritation and itchiness
and also helps to reduce skin redness, where inflammation is present. It is used for
dermatitis, acne, ringworm, scabies and pruritus and also relieves itching, sunburn
and inflammation of the skin, while at the same time having a cooling action.
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8. Safety Information
Avoid Peppermint Oil in cardiac fibrillation, epilepsy, fever. Peppermint
Oil is a mucous membrane irritant and neurotoxic (toxic to the nerves). Some of
this information applies to oral use, but is provided for informational purposes (no
essential oil should be taken internally without the guidance of a qualified
aromatherapy practitioner).
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