ephedrine hcl

(-)-Ephedrine HCI

® = Registered trademark of BASF Aktiengesellschaft

Technical Information

July 2007 Supersedes issue dated February 2006

MEMP 030701e-04/ of 8

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Contract Manufacturing

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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 (1S,2S)-2-Methylamino-1-phenyl-1-propanol hydrochloride or

CS No. 50-98-6

EINECS No. 200-074-6

Structural formula

Empirical formula C10H15NO HCl

Molecular weight: 201.69 g/mol

MEMP 030701e-04 July 2007 of 8 (-)-Ephedrine Hydrochloride

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 properties

Colourless crystals or white, crystalline powder with a bitter taste Solubility Water: freely soluble Ethanol 90%: freely soluble

5. Quality and regulatory standards

(-)-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-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).


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


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


8. Differences in the arious 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 312 mg Ephedrine salt 12 mg Ephedrine salt 12 mg Ephedrine salt65 mg Tabletose 65 mg icel PH 200 65 mg DiTab12 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-stearate0.5 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 SulfateTabletose Directly compressible lactoseAvicel Microcrystalline celluloseAerosil 200 SilicaKollidon® CL Cross-linked polyvinylpyrrolidoneKollidon® VA 64 Polyvinylpyrrolidone polyvinyl acetate copolymer Tablet diameter 7 mmTablet weight 100 ± 3 mgCompression force About 5 kN


2. Direct compression using BSF’s Ludipress

Tablet composition(-)-Ephedrine HCl powder or sulfate powder 15.0 mgLudipress 84.5 mgMagnesium 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 mgLactose 58 mgMaize starch 20 mgKollidon® 30 4 mgKollidon® CL 5 mgMagnesium stearate 0.5 mgAerosil 200 0.5 mgTablet weight 100 mgBatch 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 mgTablet punch: 7 mm diameterCompression force: 5-7 kNHardness: 90-100 NDisintegration 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.


BSF ktiengesellschaftFine Chemicals Division - Pharma Solutions - 67117 Limburgerhof - www.pharma-solutions.basf.com

10. Recommended uses for the arious grades

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 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


ephedrine hcl

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