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May 2007
Supersedes issue dated September 2004
MEMP 030711e-04/Page 1 of 8
® = Registered trademark of olubiliser and emulsifying agent for the human and veterinary
S
BASF Aktiengesellschaft pharmaceutical industries; used in aqueous preparations of
hydrophobic API‘s.
Excipients
s
Contract Manufacturing
Value Added
MEMP 030711e-04 May 2007 Page of 8 Cremophor EL
Chemical nature Cremophor EL is a nonionic solubiliser and emulsifier made by reacting castor oil
with ethylene oxide in a molar ratio of 1 : 35.
Description Cremophor EL is a pale yellow oily liquid that is clear at temperatures above
26°C. It has a faint but characteristic odour.
Solubility Cremophor EL forms clear solutions in water. It is also soluble in many organic
solvents, e.g. ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethyl acetate,
chloroform, carbon tetrachloride, trichloroethylene, toluene and xylene.
Cremophor EL is miscible with all the other Cremophor grades and, on heating,
also with fatty acids, fatty alcohols and certain animal and vegetable oils. It is
thus miscible with oleic and stearic acids, dodecyl and octa-decyl alcohols,
castor oil, and a number of lipid-soluble substances.
Unless otherwise indicated, the methods used to determine the figures quoted
above are those given in the Ph.Eur. monograph, “Macrogolglycerol Ricinoleate”
and USP-NF monograph, “Polyoxyl 35 Castor Oil”. The product fulfills the
requirements of these monographs.
Stability Cremophor EL is stable for at least 2 years if stored in the unopened original
containers at room temperature (max. 25°C).
To ensure that the fat-soluble vitamins yield clear aqueous solutions, they must
first be intimately mixed with the solubilizer. The preferred forms of vitamin A for
this purpose are Vitamin A Palmitate 1,700,000 I.U./g or Vitamin A Propionate
2,500,000 I.U./g; the preferred form of vitamin K is the K1 form
(phytomenadione).
The vitamin is mixed with the Cremophor EL, heated to 60–65°C and incorpo
rated into the water also heated to 60–65°C. Initially, thickening occurs as a
result of hydration, which reaches a maximum when about half of the water has
been added. On addition of the remaining water, the viscosity decreases again. If
the first half of the water is added too rapidly, a turbid solution may be obtained.
MEMP 030711e-04 May 2007 Page of 8 Cremophor EL
The following three diagrams show that clear aqueous solutions with very high
concentrations of vitamin A palmitate, vitamin A propionate or vitamin E acetate
can be obtained with the aid of Cremophor EL. The concentrations refer to the
finished solubilisates.
Fig. 3 Vitamin E acetate
1. Formulations
I. Vitamin A Palmitate 1,700,000 I. U./g 7.10 g –
Vitamin A Propionate 2,500,000 I. U./g – 4.80 g
Vitamin D3 40,000,000 I. U./g 0.15 g 0.15 g
Vitamin E Acetate 4.20 g 4.20 g
Butylhydroxytoluene 0.06 g 0.06 g
Cremophor EL 30.0 g 30.0 g
II. Glycerin 6.50 g 6.50 g
Preservative q. s. q. s.
Water ad 100 ml ad 100 ml
2. Procedure
Heat Mixtures I and II to about 65°C and slowly incorporate Mixture II into Mix
ture I with stirring.
1. Formulation
I. Vitamin E Acetate 10 mg
Cremophor EL 4.0–5.0 g
II. Water 57.0 g
Ethanol 38.0 g
2. Procedure
Heat Mixture I to about 60°C and slowly incorporate the warm solvent mixture II
with stirring.
For oral dosage forms in human medicine, it is recommended to use the hydrog
enated form, Cremophor RH 40 which is tasteless. The characteristic taste of
Cremophor EL can usually be masked best with banana aroma.
Animal nutrition and By virtue of its good dispersing action, Cremophor® EL enhances the
Veterinary medicine bioavailability of substances such as vitamins in feed and veterinary medi
cines, improving their efficacy. This fact is of particular interest for compoun-
ded feeds containing oils and fats. A special application of
Cremophor EL is the production of cod-liver oil emulsions in veterinary
medicine.
Toxicology After having signed a secery agreement, reports of the toxicological studies are
available on request under Secrecy Agreement.
Important note The fine dispersion of compounds that can be achieved with the aid of
Cremophor EL improves their absorption characteristics and efficacy.
Cattle that have been given certain vaccines or medicaments parenterally and
have subsequently been injected with preparations containing Cremophor EL
or similar solubilizers have displayed anaphylactic reactions in isolated cases
involving exceptional circumstances. Anaphylactic reactions have occasionally
been observed in humans after injections containing Cremophor EL. For this
reason, the health authorities in the Federal Republic of Germany and the UK,
for instance, have laid down that the content of polyethoxylated castor oil in injec
tions for parenteral administra-tion to humans must be declared, and that atten
tion must be drawn to the possibility of side effects in the package insert. This is
an aspect to which companies producing pharmaceuticals for human use must
pay particular attention.
No side effects of this kind have been observed after oral administration of
preparations containing Cremophor EL.
MEMP 030711e-04 May 2007 Page of 8 Cremophor EL
PBG-Number 10000647
PRD-Number 30035152
Packaging 60-kg and 120-kg removable-head steel drums with a Lupolen® inliner with its
own lid.
Storage Cremophor EL should be stored in tightly closed containers protected from light.
Prolonged storage is not recommended unless the containers are completely
full.
Safety Data Sheet A Safety Data Sheet is available for Cremophor EL.
Note The data contained in this publication are based on our current knowledge
and experience. In view of the many factors that may affect processing and
application of our product, these data do not relieve processors from carrying
out their own investigations and tests; neither do these data imply any guarantee
of certain properties, nor the suitability of the product for a specific purpose.
Any descriptions, drawings, photographs, data, proportions, weights etc. given
herein may change without prior information and do not constitute the agreed
contractual quality of the product. It is the responsibility of the recipient of our
products to ensure that any proprietary rights and existing laws and legislation
are observed.
May 2007
MEMP 030711e-04 May 2007 Page of 8 Cremophor EL
BASF Aktiengesellschaft
Fine Chemicals Division - Pharma Solutions - 67117 Limburgerhof - www.pharma-solutions.basf.com