Technical Information
(-)-Ephedrine Hydrochloride
January 2010
Supersedes issue dated May 2008
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® = Registered trademark of BASF group
Ph. Eur., USP
Pharma Ingredients
& Services
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(-)-Ephedrine Hydrochloride
1. Medical indication
Medical and pharmacological
background
Ephedrine is an alkaloid that is derived from ephedra plants which have been
known in Chinese medicine for more than 500 years. It is used as a diaphoretic
and antipyretic drug, circulatory stimulant and antitussive.
The chemical isolation and elucidation of Ephedrine’s structure had been completed
by the end of the 19th century. In 1923 Chen and Schmidt started to systematically
investigate the pharmacological effects of all isomers and derivatives (4 isomers
of Ephedrine are possible). These are (-)-Ephedrine, which is available as hydro­
chloride and sulphate salt and is the isomer described here; (+)-Ephedrine, which
is less important from a medical viewpoint; (+)-Pseudoephedrine, which is used
in pharmacological applications worldwide; and (-)-Pseudoephedrine.
In 1934, the former BASF subsidiary Knoll started to develop the chemical
synthesis of the naturally occurring (-)-Ephedrine and set up a plant in Minden,
Northern Germany, on the river Weser. Minden has been the production site for
BASF’s Ephedrines and Pseudoephedrines ever since.
Major indications for Ephedrine
Ephedrine’s major indications are bronchial asthma, chronic bronchitis, urticaria,
essential hypotension and related conditions.
Today, Ephedrine is combined with other drug substances indicated in the conditions
listed above. The usual dosage is about 10 mg; the most common forms currently
on the market include syrups and tablets.
Pharmacology
Pharmacologically, Ephedrine is a sympathomimetic drug. Its effects largely resemble
those of adrenaline, the classical representative of adrenergic substances. Like
adrenaline, Ephedrine produces an increase of blood pressure, improves cardiac
performance, dilates coronary vessels and bronchi, reduces swelled and inflamed
mucosa and stimulates the respiratory centre. Moreover, Ephedrine stimulates
the central nervous system, although this is not generally the desired effect.
Unlike adrenaline, Ephedrine is absorbed in the small intestine and effective when
administered by the oral route.
2. Chemical information
Name
(-)-Ephedrine Hydrochloride
Chemical name
(1R,2S-)2-Methylamino-1-phenyl-1-propanol hydrochloride
CAS-No. 50-98-6
EINECS-No. 200-074-6
Structural formula
Empirical formula
C10H15NO HCl
Molecular weight
201.69 g/mol
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3. Grades
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(-)-Ephedrine Hydrochloride
PRD-No. Particle size
30057960 B
elow 0.300 mm (No. 50) not
less than 100%
(-)-Ephedrine Hydrochloride
Powder
50 kg
0.1 kg (sample)
(-)-Ephedrine Hydrochloride
Crystalline
30057959 Below 2.00 mm (No. 10)
not less than   97%
50 kg
0.1 kg (sample)
Below 0.30 mm (No. 50)
not more than 10%
Retest period
See separate documentation: “Q&R PI (not for regulatory purposes)” available at
BASF’s WorldAccount: https://worldaccount.basf.com (registered access).
4. Physical and chemical
properties
Colourless crystals or white, crystalline powder with a bitter taste
5. Regulatory status
Solubility
Water: Ethanol 90%:
freely soluble
freely soluble
Meets current Ph. Eur. and USP monographs.
EDMF, JDMF, and CEP (CoS) are available upon request and when necessary.
US-DMF has been filed with the FDA.
6. Specification
See separate document: “Standard Specification (not for regulatory purposes)”
available via BASF‘s WorldAccount: https://worldaccount.basf.com (registered
access).
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(-)-Ephedrine Hydrochloride
7. Particle characterization
7.1 Ephedrine Hydrochloride Powder
Particle size specification
Below 0.300 mm (No. 50) not less than 100%
Density
Loose bulk density: Bulk density: Tapped density: SEM Photographs
approx. 0.28 g/ml
approx. 0.31 g/ml
approx. 0.42 g/ml
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(-)-Ephedrine Hydrochloride
7.2 Ephedrine Hydrochloride Crystalline
Particle size specification
Below 2.00 mm   (No. 10) not less than   97%
Below 0.300 mm (No. 50) not more than 10%
Density
Loose bulk density: Bulk density: Tapped density: SEM Photographs
approx. 0.63 g/ml
approx. 0.67 g/ml
approx. 0.71 g/ml
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8. Differences in the various
General information
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(-)-Ephedrine Hydrochloride
grades for use
BASF cannot make a general recommendation on whether the hydrochloride or
the sulfate is better suited to the customer’s application; this decision is up to the
customer. BASF does not have any internal preference for either of the two salts.
However, BASF recommends using the (-)-Ephedrine HCl crystal grade for syrups
and oral solutions because larger, dust-free crystals provide for easy handling.
Because of their very high solubility, there is practically no difference between
crystal and powder grades as far as the dissolution rate is concerned.
Customers should be aware that the shelf life of the hydrochloride is 48 months;
the sulfate has a shelf life of 24 months only.
(-)-Ephedrine HCl and (-)-Ephedrine sulfate absorb extremely high quantities of
water at high ambient humidity (approximately 80%). This is a characteristic feature
of Ephedrines and is a distinguishing characteristic of the powder grade of Ephedrine
HCl. Ephedrine HCl also shows a strong hysteresis curve: In other words, the water
absorbed cannot be easily desorbed at low ambient humidity.
Thus, lumping may occur under prolonged storage in drums at high temperatures.
However, degradation of the product has never been observed. The problem of
lumping is of no relevance when preparing syrups or oral solutions; for the preparation
of tablets using the wet granulation method, however, we recommend stirring the
lumpy material thoroughly to eliminate almost all lumps.
9. Formulating examples
1.Tablets containing 12 mg (-)-Ephedrine HCl Powder or (-)-Ephedrine
Sulfate Powder by direct compression
Example 1
Example 2
Example 3
12 mg Ephedrine salt
12 mg Ephedrine salt
12 mg Ephedrine salt
65 mg Tabletose
65 mg Avicel PH 200
65 mg DiTab
12 mg Avicel PH 102
12 mg Avicel PH 102
12 mg Avicel PH 102
6 mg Kollidon CL
6 mg Kollidon CL
6 mg Kollidon CL
4 mg Kollidon VA 64
4 mg Kollidon VA 64
4 mg Kollidon VA 64
®
0.5 mg Mg-stearate
0.5 mg Mg-stearate
0.5 mg Mg-stearate
0.5 mg Aerosil 200
0.5 mg Aerosil 200
0.5 mg Aerosil 200
100 mg Tablet weight
100 mg Tablet weight
100 mg Tablet weight
Cross-index
Ephedrine salt
Tabletose
Avicel
Aerosil 200
Kollidon CL
Kollidon VA 64
Tablet diameter
Tablet weight
Compression force
(-)-Ephedrine HCl or (-)-Ephedrine Sulfate
Directly compressible lactose
Microcrystalline cellulose
Silica
Cross-linked polyvinylpyrrolidone
Polyvinylpyrrolidone polyvinyl acetate copolymer
7 mm
100 ± 3 mg
About 5 kN
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(-)-Ephedrine Hydrochloride
2. Direct compression using BASF’s Ludipress®
Tablet composition
(-)-Ephedrine HCl Powder or Sulfate Powder
Ludipress®
Magnesium stearate
15.0 mg
84.5 mg
0.5 mg
Mix all ingredients and compress into tablets with a diameter of 7 mm using low
compression forces of 4 – 7 kN. Resulting hardness: approximately 60 – 70 N,
disintegration time 2 – 5 minutes. The drug dissolves within 10 minutes.
3.Tablets containing 12 mg (-)-Ephedrine HCl or (-)-Ephedrine Sulfate
using a wet granulation process
Tablet composition
(-)-Ephedrine HCl or Sulfate (both powder grade)
Lactose
Maize starch
Kollidon 30
Kollidon CL
Magnesium stearate
Aerosil 200
Tablet weight
Batch size
12 mg
58 mg
20 mg
4 mg
5 mg
0.5 mg
0.5 mg
100 mg
3.0 kg
0.360 kg (-)-Ephedrine HCl Powder or (-)-Ephedrine Sulfate Powder, 1.74 kg lactose,
0.60 kg maize starch and 0.120 kg Kollidon 30 are mixed in a Stefan granulator
and subsequently moistened with deionised water until an earth-moist mass is
obtained (snowball effect), stirred vigorously for 2 minutes and passed through
a sieve with a mesh size of 3 mm. The wet granules are dried in a fluid bed drier
(laboratory drier from Glatt, inlet air temperature of 60 °C, homogenized with a sieve
of 1 mm mesh size and mixed with the additives (0.150 kg Kollidon CL, 0.015 kg
Aerosil 200 and 0.015 kg magnesium stearate) to form granules suitable for tableting.
Tableting:
Weight:
Tablet punch:
Compression force:
Hardness:
Disintegration in 0.1 N HCl (37 °C)
Korsch EK-0,
excentric press
100 mg
7 mm diameter
5 – 7 kN
90 – 100 N
2 – 3 minutes
This manufacturing procedure is well suited to combine (-)-Ephedrine salts with
other active ingredients to produce combinations.
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10. Recommended uses
for the various grades
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(-)-Ephedrine Hydrochloride
For oral liquid formulations, such as syrups, the (-)-Ephedrine HCl crystals grade
is recommended. If a different form of the salt is required, the (-)-Ephedrine Sulfate
Powder grade may be used.
The (-)-Ephedrine HCL crystals grade should not be recommended for tablet
formulations because the crystals are too large and not suited to tableting.
For tablets that have been subjected to granulation during production, the “powder”
grades of the hydrochloride and the sulfate are suitable since a new particle
distribution is achieved by granulation per se.
Both grades are suitable for the direct compression method without prior granulation.
If the (-)-Ephedrine salt is to be separated from other active ingredients in the tablet
or capsule because of chemical and physical incompatibilities, we recommend
only the crystal grade of (-)-Ephedrine HCl to be coated.
The BASF excipients Kollicoat SR 30D or Kollicoat IR are suitable products for
special coatings. Those products can be combined as well.
Note
This document, or any answers or information provided herein by BASF, does not
constitute a legally binding obligation of BASF. While the descriptions, designs,
data and information contained herein are presented in good faith and believed to
be accurate, it is provided for your guidance only. Because many factors may affect
processing or application/use, we recommend that you make tests to determine
the suitability of a product for your particular purpose prior to use. It does not relieve
our customers from the obligation to perform a full inspection of the products upon
delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS
OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS
FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED
OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS,
DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE
INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE
DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED
A PART OF OUR TERMS AND CONDITIONS OF SALE.
January 2010
BASF SE - Care Chemicals Division - Pharma Ingredients & Services - 67117 Limburgerhof - www.pharma-ingredients.basf.com