Technical Information (-)-Ephedrine HCI

July 2007
Supersedes issue dated February 2006

MEMP 030701e-04/Page 1 of 8

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1. Medical indication
Medical and pharmacological Ephedrine is an alkaloid that is derived from ephedra plants which have been
background 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 (1S,2S)-2-Methylamino-1-phenyl-1-propanol hydrochloride or

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
(-)-Ephedrine HCl Powder Below 0.300 mm (No. 50) not less than 100%
Retest period: 48 months

PRD No.: 30057960

Package sizes
Available are 50 kg or 25 kg fibre drums.

(-)-Ephedrine HCL cryst. Below 2.00 mm (No. 10) not less than 97%
Below 0.30 mm (No. 50) not more than 10%
Retest period: 48 months

PRD No.: 30057959

Package sizes
Available are 50 kg fibre drums.

4. Physical and chemical Colourless crystals or white, crystalline powder with a bitter taste
properties Solubility
Water: freely soluble
Ethanol 90%: freely soluble

5. Quality and regulatory (-)-Ephedrine HCl meets the requirements of the current editions of Ph.Eur. and USP.
EDMF, JDMF, and CEP (CoS) are available upon request and when necessary. US-
standards DMF has been filed with the FDA.

6. Specification See separate document: „Standard Specification (not for regulatory purposes)“ avai-
lable via BASF‘s WorldAccount: https://worldaccount.basf.com (registered access).
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7. Particle characterization
7.1 Ephedrine HCl, powder

Particle size specification Below 0.300 mm (No. 50) not less than 100%

Density Loose bulk density: approx. 0.28 g/ml

Bulk density: approx. 0.31 g/ml
Tapped density: approx. 0.42 g/ml

SEM Photographs

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7.2 Ephedrine HCl, crystal

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: approx. 0.63 g/ml

Bulk density: approx. 0.67 g/ml
Tapped density: approx. 0.71 g/ml

SEM Photographs

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8. Differences in the various

grades for use
General information 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 (-)-Ephedrine HCl or (-)-Ephedrine Sulfate
Tabletose Directly compressible lactose
Avicel Microcrystalline cellulose
Aerosil 200 Silica
Kollidon® CL Cross-linked polyvinylpyrrolidone
Kollidon® VA 64 Polyvinylpyrrolidone polyvinyl acetate copolymer
Tablet diameter 7 mm
Tablet weight 100 ± 3 mg
Compression force About 5 kN
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2. Direct compression using BASF’s Ludipress

Tablet composition
(-)-Ephedrine HCl powder or sulfate powder 15.0 mg
Ludipress 84.5 mg
Magnesium stearate 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) 12 mg
Lactose 58 mg
Maize starch 20 mg
Kollidon® 30 4 mg
Kollidon® CL 5 mg
Magnesium stearate 0.5 mg
Aerosil 200 0.5 mg
Tablet weight 100 mg
Batch size 3.0 kg
0.360 kg (-)-Ephedrine HCl powder or (-)-Ephedrine Sulfate powder, 1.74 kg lac-
tose, 0.60 kg maize starch and 0.120 kg Kollidon® 30 are mixed in a Stefan gra-
nulator 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 sui-
table for tableting.

Tableting: Korsch EK-0,

excentric press
Weight: 100 mg
Tablet punch: 7 mm diameter
Compression force: 5-7 kN
Hardness: 90-100 N
Disintegration in 0.1 N HCl (37°C) 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 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
the various grades 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 recom-
mend 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 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.

July 2007

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