Technical Information
`
`Cremophor姞 RH 40
`
`ME 069 e
`(262) August 1997 (MPM)
`
`Register 5
`
`® = Registered trademark of
`BASF Aktiengesellschaft
`
`For the pharmaceuticals industry
`
`Cremophor RH 40 is a solubilizer for fat-soluble vitamins, essential oils and
`other hydrophobic pharmaceuticals. Particular features are that it has very
`little odour and in aqueous solutions is almost tasteless.
`
`The use of Cremophor RH 40 grades in cosmetic preparations is the
`subject of a separate leaflet.
`
`Fine Chemicals
`
`

`
`Generic name
`
`Chemical nature
`
`Polyoxyl 40 Hydrogenated Castor Oil (USP/NF).
`Macrogol-Glycerolhydroxystearat (DAB).
`Polyoxyethylenglyceroltrihydroxystearat (DAC).
`
`Cremophor RH 40 is a nonionic solubilizer and emulsifying agent obtained
`by reacting 45 moles of ethylene oxide with 1 mole of hydrogenated castor
`oil.
`
`The main constituent of Cremophor RH 40 is glycerol polyethylene glycol
`oxystearate, which, together with fatty acid glycerol polyglycol esters,
`forms the hydrophobic part of the product. The hydrophilic part consists of
`polyethylene glycols and glycerol ethoxylate.
`
`Properties
`
`Cremophor RH 40 is a white to yellowish thin paste at 20 °C. The HLB
`value lies between 14 and 16.
`
`Specification
`
`Solubility
`
`Stability
`
`Particular features are that it has very little odour and in aqueous solutions
`is almost tasteless.
`
`Solidification point
`Saponification value
`Hydroxyl value
`Acid value
`lodine value
`Water content, K. Fischer
`pH value of 10 % aqueous solution
`Colour strength of 10 % aqueous solution (Ph. Eur.)
`Viscosity, Hoeppler, at 25 °C, 30 % aqueous solution
`Ash
`Heavy metals
`
`20 – 28 °C
`50 – 60
`60 – 75
`ⱕ 1
`ⱕ 1
`ⱕ 2 %
`6 – 7
`Yellow 6 max.
`20 – 40 mPa · s
`ⱕ 0.25 %
`ⱕ 10 ppm
`
`Unless stated otherwise, the analytical methods have been taken from the
`monograph “Macrogol-Glycerolhydroxystearat” in DAB. The product fulfills
`the requirements of this monograph and those of USP/NF monograph
`“Polyoxyl 40 Hydrogenated Castor Oil”.
`
`Cremophor RH 40 forms clear solutions in water, ethanol, 2-propanol,
`n-propanol, ethyl acetate, chloroform, carbon tetrachloride, toluene and
`xylene.
`
`Solutions become cloudy as the temperature increases.
`
`Cremophor RH 40 can be mixed with all other Cremophors. At elevated
`temperatures it forms clear mixtures with fatty acids and fatty alcohols.
`
`Pure Cremophor RH 40 is chemically very stable. Prolonged exposure to
`heat can cause physical separation into a liquid and a solid phase on cool-
`ing but the product can be restored to its original form by homogenization.
`
`Cremophor RH 40 is stable in aqueous alcohol and purely aqueous solu-
`tions. However, it must be noted that strong bases or acids should not be
`added, as otherwise the ester components may be saponified.
`
`Aqueous Cremophor RH 40 solutions can be sterilized by heating to
`120 °C. Allowance must be made for the fact that this can cause a slight
`decrease in the pH value. The phases may also separate during steriliza-
`tion, but this can be remedied by agitating the solution while it is still hot.
`
`The preservatives normally used in the pharmaceuticals industry may be
`added to the aqueous solutions. The requisite concentrations should be
`determined in tests.
`
`Cremophor RH 40 is largely insensitive to water hardness.
`
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`
`Page 2
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`

`
`Application
`
`Solubilization
`
`Aqueous solutions of vitamins A, D, E and K for oral and topical adminis-
`tration can be prepared with the aid of Cremophor RH 40. The fact
`that the solubilizer has very little taste and odour is an asset for such
`applications.
`
`In order to ensure that clear, aqueous solutions are obtained, the fat-
`soluble vitamins must first be intimately mixed with the solubilizer. Best
`results with vitamin A are obtained if it is in the form of vitamin A palmitate
`1.7 million I. U./g, or vitamin A propionate 2.5 million I. U./g; or, in the case
`of vitamin K, if it is in the form of vitamin K 1 (phytomenadione).
`
`As the method of preparing the solubilizate is very important, the produc-
`tion of a 150 000 I. U./ml aqueous vitamin A palmitate solution is described
`in detail as a typical example:
`
`Vitamin A palmitate 1.7 million I. U./g
`Cremophor RH 40
`Water
`
`8.8 g
`25.0 g
`ad 100 ml
`
`The vitamin is mixed with Cremophor RH 40 and heated to 60 – 65 °C. The
`water, also heated to 60 – 65 °C, is added very slowly with thorough stir-
`ring into this mixture. As a result of hydration, the solution thickens, with
`the viscosity attaining a maximum after about half of the water has been
`added. Further addition of water then decreases the viscosity again. If the
`first half of the water is added too quickly, the solution can become opal-
`escent. Alternatively, the warm mixture of the vitamin and Cremophor RH
`40 can be slowly stirred into the water, which results in a lower increase in
`intermediate viscosity.
`
`The following three diagrams demonstrate the use of Cremophor RH 40
`for producing clear, highly concentrated, aqueous solutions of vitamin A
`palmitate, vitamin A propionate and vitamin E acetate.
`
`40
`
`30
`
`20
`
`10
`
`Cremophor RH 40, %
`
`0
`
`0
`
`50000
`
`100000
`
`150000
`
`200000
`
`
`
`Vitamin A, I.U./ml
`
`Fig. 1 Solubilization of vitamin A palmitate 1.7 million I. U./g
`
`3
`
`Page 3
`
`

`
`40
`
`30
`
`20
`
`10
`
`Cremophor RH 40, %
`
`0
`
`0
`
`50000 100000 150000 200000 250000 300000 350000 400000
`
`Vitamin A, I.U./ml
`
`Fig. 2 Solubilization of vitamin A propionate 2.5 million I. U./g
`
`50
`
`100
`
`150
`
`200
`
`Vitamin E acetate, mg/ml
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`Cremophor RH 40, %
`
`Fig. 3 Solubilization of vitamin E acetate
`
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`Page 4
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`

`
`Miscellaneous
`solubilizer applications
`
`Use as emulsifier
`
`Toxicity
`
`Acute toxicity
`
`Subacute toxicity
`
`Chronic toxicity
`
`Likewise, the following vitamin quantities can be solubilized by a 6 %
`Cremophor RH 40 solution.
`
`8 – 9 mg/ml Vitamin D2 (400 000 I. U.), or
`5 mg/ml Vitamin D3 (125 000 I. U.), or
`10 mg/ml Vitamin K1
`
`Less Cremophor RH 40 is usually required for mixtures of vitamins.
`
`A small addition of polyethylene glycol (Lutrol® E 400),1,2-propylene glycol
`or glycerol allows the preparation temperature and sometimes also the
`concentration of Cremophor RH 40 to be reduced. Typical formulations are
`contained in the brochure “Vitamin formulations – Solutions and tablets”.
`The stability of most solubilized vitamins is affected by light.
`
`Clear, aqueous solutions of hydrophobic substances other than vitamins
`can be obtained with Cremophor RH 40. Examples are essential oils and
`certain drugs for oral and topical application. A feature of the solutions
`thus obtained is their good stability. The following substances serve as
`examples:
`
`Hexachlorocyclohexane
`Hexeditine
`Levomepromazine
`Thiopental
`Benzocaine
`Clotrimazole
`Diazepam
`
`Miconazole
`Gramicidin
`Eucalyptol
`Azulene
`Oil of anise
`Oil of sage
`
`Cremophor RH 40 shows little tendency to foaming, which is particularly
`important for solutions in aqueous ethanol. Further foam suppression can
`be obtained by the addition of a small quantity of Polypropylene Glycol
`2000.
`
`Cremophor RH 40 is also very suitable as an emulsifying agent. It will
`emulsify a wide range of hydrophobic substances, e. g. fatty acids, fatty
`alcohols and drugs.
`
`The following values for the average lethal dose (LD 50) with a seven-day
`follow-up period were determined for Cremophor RH 40:
`
`Species
`
`Route
`
`Rat
`Mouse
`Mouse
`
`oral
`intraperitoneal
`intravenous
`
`LD 50
`
`g/kg body weight
`
`> 16.0
`> 6.4
`> 12.0
`
`For four weeks, rats were given feed containing Cremophor RH 40 in pro-
`portions of 3.2 % and 6.4 %. None of the animals displayed any symptoms
`whatever of poisoning.
`
`Similarly, beagles tolerated Cremophor RH 40 in concentrations of 1%,
`3 % and 9 % in their feed for four weeks without any clinically detectable
`symptoms.
`
`The tolerance of Cremophor RH 40 was checked by intravenous adminis-
`tration in rats over a period of four weeks. It was found that, of the three
`dosages tested, the lowest, 300 mg/kg body weight/day was tolerated
`locally, while the next, 900 mg/kg body weight/day was tolerated generally.
`
`In feeding tests that lasted for six months, Cremophor RH 40 was toler-
`ated in concentrations of up to 5 % by dogs and in concentrations of up to
`10 % by rats.
`
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`Page 5
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`

`
`Inhalation toxicity
`
`Air saturated at 20 °C with any volatile components that may have been
`given off by the product was inhaled by rats for eight hours without any
`injury. It should also be noted that the use of Cremophor RH 40 in surface
`active inhalants for aerosol application to the mucous membranes of the
`human respiratory tract does not cause any irritation.
`
`Compatibility with the skin
`and mucous membranes
`
`Swab tests have demonstrated that Cremophor RH 40 is compatible with
`human skin.
`
`Sensitization
`
`Teratogenicity
`
`General
`
`Storage
`
`The compatibility with the mucous membranes was investigated by apply-
`ing a 30 % aqueous solution of Cremophor RH 40 to the eyes of rabbits.
`This solution did not cause any inflammation.
`
`Cremophor RH 40 solutions of 20 % and 50 % concentration in acetone
`were brushed ten times onto the skin of guinea pigs. They did not cause
`any sensitization of the skin. Likewise, no indications of a sensitizing effect
`on the skin of guinea pigs were observed in the Magnusson and Kligman
`maximization test (J. invest. Derm., 52, 268 – 276 [1969]).
`
`This was investigated by the FDA guidelines for reproduction studies for
`safety evaluation of drugs for human use (Food and Drug Administration,
`Washington, January 1966). Cremophor RH 40 was administered orally ten
`times in doses of 5 000 and 10 000 mg/kg of body weight to pregnant
`NMRI mice from the sixth to the fifteenth day post coitum. No teratogenic
`or embryotoxic effects were detected.
`
`Likewise, 5 % and 10 % of Cremophor RH 40 added on days zero to
`twenty post coitum to the feed of pregnant Sprague-Dawley rats did not
`exert any embryotoxic or teratogenic effects.
`
`In common with other surfactants, Cremophor RH 40 may alter the rate of
`absorption of active substances. For this reason, it is advisable to subject
`preparations containing Cremophor RH 40 to pharmacological and clinical
`tests before they are released for general use. Attention is also drawn to
`local legislation concerning the handling of foodstuffs, food wrappings,
`cosmetics etc.
`
`As there have been isolated reports of an anaphylactic reaction in animals
`and humans to the parenteral use of pharmaceutical products containing
`Cremophor EL (see technical leaflet Cremophor EL, BASF), similar reac-
`tions cannot be precluded for products containing Cremophor RH 40.
`
`No such reactions have been observed after oral administration.
`
`The drums in which Cremophor RH 40 is stored should be kept tightly
`closed.
`
`The method of production employed for Cremophor RH 40 ensures that it
`is practically sterile. If the containers are repeatedly opened, microorga-
`nisms may grow in the product, particularly if the equipment used is not
`sterile.
`
`Packaging
`
`Product No.
`
`Drums of 40 kg capacity.
`
`67 363/1/36
`
`Safety Data Sheet
`
`A Safety Data Sheet is available.
`
`Note
`
`The data submitted in this publication are based on our current knowledge
`and experience. They do not constitute a guarantee in the legal sense of
`the term and, in view of the manifold factors that may affect processing
`and application, do not relieve processors from the responsibility of carry-
`ing out their own tests and experiments. Any relevant patent rights and
`existing legislation and regulations must be observed.
`
`Printed in Germany
`
`BASF Aktiengesellschaft
`Unternehmensbereich Feinchemie
`67056 Ludwigshafen, Germany
`
`Page 6