Technical Information Cremophor® A grades

March 2007
Supersedes issue dated August 2005

MEMP 030710e-04/Page 1 of 8

® = Registered trademark of Macrogol cetostearyl ethers, nonionic emulsifiers for the

BASF Aktiengesellschaft manufacture of pharmaceutical o/w emulsions

Excipients
Actives
Contract Manufacturing
Value Added
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MEMP 030710e-04 March 2007 Page 3 of 8 Cremophor A grades

Chemical nature Nonionic emulsifiers manufactured by reacting higher saturated fatty alcohols
with ethylene oxide. Cremophor A 6 contains additional free fatty alcohols.

Pharmacopoeia synonyms Macrogol (6) cetostearyl ether, macrogol (25) cetostearyl ether (Macrogoli aetherum
cetostearylicum).

Properties Cremophor A 6 is a whitish waxy substance. Cremophor A 25 is supplied in the

form of free-flowing, non-dusting microbeads.

Cremophor A 6 Cremophor A 25
Appearance Whitish waxy substance Whitish microbeads
Degree of ethoxylation 6 25
HLB value 10–12 15–17

Specification
Alkalinity Complies Complies
Saponification value ⱕ 3.0 ⱕ 3.0
Hydroxyl value 115–134 36–45
Iodine value ⱕ 1.0 ⱕ 1.0
Acid value ⱕ 1.0 ⱕ 1.0
Water (K. Fischer) ⱕ 1.0% ⱕ 1.0%
pH (10% in water) – 5–7
Ethylene oxide, ppm ⱕ1 ⱕ1
1,4-Dioxane, ppm ⱕ 10 ⱕ10
Residue on ignition, % ⱕ 0.2 ⱕ 0.2
Appearance of the solution Lighter than BY 5 Lighter than BY 5
(10% in ethanol)
Retained solvents (Ph. Eur.) Complies Complies

Unless otherwise indicated, the figures quoted above are determined in accor-
dance with the Ph. Eur. family monograph, Macrogol cetostearyl ether. The
Cremophor A grades meet the requirements of these monographs.

Solubility, miscibility The Cremophor A grades form colloidal or clear solutions in water and alcohol.
They are soluble in vegetable and mineral oils and fats.

The emulsifiers are miscible with warm mineral, vegetable and synthetic oils and
fats, fatty alcohols, fatty acids, monostearates, distearates and polyethylene
glycols.
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Stability in the presence Aqueous solutions of the Cremophor A grades are largely stable to acids, bases
of electrolytes and salts. Their emulsifying power is not affected by the presence of these elec-
trolytes.

Preservation It may be necessary to add a preservative to emulsion preparations under certain

conditions, depending on the other ingredients and the production conditions.

Applications The products can be used for the manufacture of oil-in-water emulsion prepara-
tions. They are capable of emulsifying hydrophobic pharmaceutical active ingre-
dients to yield very stable o/w emulsions.

The Cremophor A grades are used as emulsifiers for the production of oint-
ments, creams, liquid emulsions, gels and other pharmaceutical preparations.
Blends of the two products give the best results.

When Cremophor A 25 is used in conjunction with cetyl alcohol and/or stearyl

alcohol, homogeneous ointment and cream bases are obtained that can be com-
bined with up to 90% water.

Cremophor A 25 is very effective as a protective colloid and can increase the

stability of dispersed systems.
At higher concentrations of 21–30%, Cremophor A 25 forms gel-like spreadable
hydrates with water. The consistency of these gels can be adjusted from solid to
liquid by adding small amounts of Kollidon® 17 PF.

The Cremophor A grades are used in the usual way to produce emulsions. The
emulsifier or blend of emulsifiers is mixed at 70–80 °C with the oils and fats, and
the lipophilic ingredients. The aqueous phase with all the water-soluble ingredients
is also heated to 70–80 °C. The aqueous phase is slowly added to the oily
phase with continuous stirring.

The time and temperature for emulsification and homogenization depend on the
type of emulsion, its consistency and the ingredients. The usual range of concen-
trations in which Cremophor A 6 and Cremophor A 25 are used is 1–8%.

The following and further formulations can be found in our compendium, “Generic
Drug Formulations” which is available as a ring-file and on CD-ROM.
MEMP 030710e-04 March 2007 Page 5 of 8 Cremophor A grades

Typical formulations 1 Cream base for active substances

1.1 Formulation

I. Cetostearyl alcohol 7.0 g

Cremophor A 6 [1] 1.5 g
Cremophor A 25 [1] 1.5 g
Paraffin, liquid 12.0 g
Parabens 0.2 g
II. Water 67.8–69.7 g
III. 1,2-Propylene Glycol Pharma 8.0 g
Active substance 0.1–2.0 g

1.2 Procedure

Separately heat the mixture of components under I, and the water, II to 80 °C.
Incorporate the water, II into Solution I with vigorous stirring.
Dissolve the active substance completely in warm propylene glycol. Then mix
active Solution III into the emulsion of Solutions I and II, then cool to room tem-
perature with continued stirring.

1.3 Remarks

This cream base has been tested in the concentration range given with different
active substances dissolved in propylene glycol. These include bifonazole, beta-
methasone, etc.

2 Povidone-iodine cream (10%)

2.1 Formulation

I. PVP-iodine 30/06 [1] 10.0 g

Citric acid solution 0.1 mol/l 24.1 g
Na2HPO4 solution 0.2 mol/l 36.9 g
II. Cremophor A 6 [1] 2.0 g
Cremophor A 25 [1] 2.0 g
Cetostearyl alcohol 10.0 g
Paraffin, liquid 10.0 g
Glycerol 5.0 g

2.2 Procedure

Prepare a cream base from the components of phase II, while the PVP-iodine is
being dissolved in the aqueous buffer system. Vigorously stir aqueous solution I
into the oily phase. A brown cream with a pH value of 4.5 is obtained.
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3 Povidone-iodine foam spray (10%)

3.1 Formulation

PVP-Iodine 30/06 [1] 10.0 g

Cremophor A 25 [1] 8.0 g
Water ad 100.0 g

3.2 Procedure

Dissolve the components in water. Fill the solution into spray cans and pressurize
with 10 parts of a 1+3 mixture of propane and butane for 90 parts of solution.

4 Tretinoin cream

4.1 Formulation

I. Tretinoin [1] 0.05 g

Luvitol EHO [1] 8.0 g
II. Cremophor A 6 [1] 3.0 g
Cremophor A 25 [1] 1.5 g
Glycerol monostearate 3.0 g
Cetyl alcohol 3.0 g
Tegiloxan® 100 [2] 0.5 g
III. Butylhydroxytoluene 0.04 g
1,2-Propylene Glycol 4.0 g
Pharma [1]
Preservative 0.5 g
Fragrance 0.2 g
Water 76.2 g

4.2 Procedure

Separately heat the components of Mixtures I and II to 75 °C to dissolve the

solid components. Heat the components of Mixture III until a clear solution is
obtained. Add Mixture I to Mixture II, then add Mixture III.
Continue stirring this mixture until it is cold.

4.3 Chemical stability

Storage in the dark at 20–25 °C

Months Tretinoin content, % Tretinoin loss, %

10 0.046 –
13 0.047 0
16 0.046 0
19 0.047 0
12 0.047 0
The above values were determined by photometric measurements at 358 nm of
solutions in a 1 : 1 mixture of chloroform and 2-propanol.

4.4 Remarks

The tretinoin cream must be protected from light during storage.

MEMP 030710e-04 March 2007 Page 7 of 8 Cremophor A grades

Stability, storage The Cremophor A grades are stable for at least two years if stored in the
unopened original containers at room temperature (below 25 °C) and protected
from light.

Cremophor A 6 Cremophor A 25
PBG-Number 10 000 644 10609821

PRD-Number 30035137 30267779

Packaging 50-kg drums with polyethylene 25 kg paper sacks with polyethylene

inliner inliner

Safety Data Sheet A Safety Data Sheet is available for the Cremophor A grades.

Suppliers [1] BASF Aktiengesellschaft

67056 Ludwigshafen, Germany

[2] Goldschmidt, Germany

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 prop-
erties, 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.

March 2007
MEMP 030710e-04 March 2007 Page 8 of 8 Cremophor A grades

BASF Aktiengesellschaft
Fine Chemicals Division - Pharma Solutions - 67117 Limburgerhof - www.pharma-solutions.basf.com