Ephedrine Guide

Introduction

Ephedrine, a naturally occurring alkaloid, has a rich history deeply entwined with traditional medicine and modern pharmacology. Ephedrine was first isolated in 1885 and came into commercial use in 1926. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. Derived from plants like Ephedra sinica, this compound has found applications ranging from decongestants to weight loss aids. This exhaustive guide aims to shed light on ephedrine, exploring its physical and chemical properties, synthesis methods, applications, legal status, storage, disposal, toxicity, and the rules governing its handling.

Ephedrine hydrochloride crystals 

Ephedrine Chemical Properties

Ephedrine, classified as a sympathomimetic amine and substituted amphetamine, shares a molecular structure resemblance with phenylpropanolamine, methamphetamine, and epinephrine (adrenaline). In its chemical composition, this alkaloid with a phenethylamine skeleton is commonly found in various plants within the Ephedra genus of the Ephedraceae family. Its primary mode of action involves augmenting the activity of norepinephrine (noradrenaline) on adrenergic receptors. Typically, it is marketed in the form of the hydrochloride or sulfate salt.

Ephedrine structure

Displaying optical isomerism and possessing two chiral centers, ephedrine gives rise to four stereoisomers. The convention designates the enantiomer pair with stereochemistry (1R,2S) and (1S,2R) as ephedrine, while the enantiomer pair with stereochemistry (1R,2R) and (1S,2S) is termed pseudoephedrine. Functionally, ephedrine is a substituted amphetamine and structurally analogous to methamphetamine, distinguished only by the presence of a hydroxyl group (—OH).

The commercially available isomer is specifically (-)-(1R,2S)-ephedrine. In the obsolete D/L system, (+)-ephedrine is identified as D-ephedrine, and (-)-ephedrine is referred to as L-ephedrine, with the phenyl ring placed at the bottom in the Fisher projection.

It's important to note that confusion often arises between the D/L system (with small caps) and the d/l system (with lowercase), leading to misnomers. In this scenario, the levorotary l-ephedrine is erroneously labeled as L-ephedrine, and the dextrorotary d-pseudoephedrine (its diastereomer) is inaccurately termed D-pseudoephedrine. The IUPAC names for the two enantiomers are (1R,2S)-2-methylamino-1-phenylpropan-1-ol and (1S,2R)-2-methylamino-1-phenylpropan-1-ol, with a synonym being erythro-ephedrine.

Ephedrine isomers

Ephedrine Physical Properties

Ephedrine is a crystalline powder, boasting a pristine white hue, odourless or slight aromatic. It has distinctive bitter taste. In terms of form, ephedrine exhibits a crystalline structure with well-defined geometric patterns. Notably, ephedrine demonstrates appreciable solubility in water, a trait that influences its formulation in pharmaceuticals and medicinal preparations.

In warm weather it slowly volatilizes. The anhydrous substance melts at 36°C and the hemihydrate melts at 42°C. It is a weak base, with a pKa = 9.6. Ephedrine decomposes with light. Solutions in oil can have a garlicky odour. It is soluble in water (1 in 20) and in alcohol, chloroform, ether, glycerol, olive oil and in liquid paraffin (Windholz, 1983). Nearly insoluble in petroleum ether upon cooling. 

Being a strong base, ephedrine displaces ammonia from its salts. Solutions of the salts in water varying from 1 to 10 percent were found to be exceedingly stable. No change in strength occurred after 6 months storage at room temperature. The solutions are quite sable at boiling temperature. 

• Ephedrine free base (see Fig. 2)
  Molecular formula: C10H15NO
  Molecular mass: 165.2 g/mol
  Structural name: (1R,2S)-2-methylamino-1-phenylpropan-1-ol
• Ephedrine Hydrochloride
  Molecular formula: C10H15ON·HCl
  Prismatic needles, mp 216°C. Easily soluble in alcohol and water. Its aqueous solation is stable at boiling temperature (see Fig. 1).
• Ephedrine Sulfate
  Molecular formula: C10H15ON·H2SO4
  Hexagonal plates; mp 257°C. Difficultly soluble in alcohol, easily soluble in water, neutral to litmus.
• Ephedrine oxalate
  Molecular formula: 2C10H15ON·C2H2O4.
  Prismatic needles from. water; mp 245°C. with decomposition; neutral to litmus; only very slightly soluble in cold water (see Fig. 3).
• Ephedrine Phosphate
  Molecular formula: C10H15ON·H3PO4.
  Crystallized from alcohol in long silky needles; mp 178°C; acid to litmus.
• Pseudoephedrine
  Pure pseudoephedrine crystallized out from alcohol in rhombic prisms, mp 118°C (see Fig. 4). Unlike ephedrine it was only slightly soluble in water. Its salts were prepared and gave the following physical constants.
• Pseudoephedrine Hydrochloride
  Molecular formula: C10H15ON·HCl.
  Crystallized from alcohol in stout needles; mp 179-181°C; very soluble in water and in alcohol (see Fig. 5).
• Pseudoephedrine Sulfate
  Molecular formula: C10H15ON·H2SO4 .
  Prismatic needles; no sharp mp; easily soluble in water and in alcohol.
• Pseudoephedrine Oxalate
  Molecular formula: 2C10H15ON·C2H2O4
  Needles; mp 218°C with decomposition; difficultly soluble in alcohol; very soluble in cold H2O; neutral to litmus (see Fig. 6).

Ephedrine crystalls

Ephedrine Synthesis Ways

One primary avenue for obtaining ephedrine is through traditional extraction methods from the Ephedra plant genus, particularly Ephedra sinica. This natural approach harnesses the alkaloid-rich content of these plants, requiring meticulous extraction and purification processes to isolate ephedrine from the complex matrix.

Also, there is L-PAC way to synthesis ephedrine. L-Phenylacetylcarbinol (L-PAC; (1)) which is a precursor for ephedrine (3) is produced by biotransformation of benzaldehyde using yeast cultures. The chemical conversion of L-PAC to ephedrine has proved to be more advantageous than the extraction route. L-PAC could be converted by a chemical reductive amination with methylamine to optically pure L-ephedrine. The use of microwave irradiation for chemical synthesis is of increasing importance, since it provides a simple alternative to classical chemical routes with rapid reactions yielding high conversion and selectivity.

Alternatively, chemical synthesis methods offer a more controlled and scalable means of producing ephedrine. One such route involves the synthesis method of d,l-Ephedrine from 1-Phenyl-1,2-propandion by means of catalytic reduction with hydrogen gas and Adams' catalyst. 1-Phenyl-1,2-propandion Can be purchased in international chemical market, other reagents are not so hard to buy. This is a one-pot reaction that uses gentle exposure to hydrogen gas. 

Another notable chemical synthesis method use benzene starting material, which is condensed with monochloropropionic acid chlorohydride in the presence of aluminum chloride. The resulting chloroethyl phenyl ketone condenses with methylamine, thus obtaining a secondary amine, which is reduced to ephedrine.

The synthesis of ephedrine from propiophenone involves a multistep process that transforms the precursor compound into the desired alkaloid. One common synthetic route is the amination of propiophenone, a key intermediate in the synthesis. Initially, propiophenone undergoes bromination, introducing a bromine group to the 2 carbon atom of the propanone group. Subsequent steps involve the substitution of the newly formed bromoketone, typically through the use of methylamine. Then, aminoketone reduced with an agents like sodium borohydride (NaBH4) directly to ephedrine. Though various methods exist, the synthesis from propiophenone provides a well-established pathway for producing ephedrine on a scale suitable for pharmaceutical applications.

The choice between natural extraction and chemical synthesis depends on factors such as cost, scalability, and the desired stereochemistry of the final product. Each method presents its own set of challenges and requires a nuanced knowledge of organic chemistry principles.

Ephedrine Applications

Ephedrine, a central nervous system (CNS) stimulant, is commonly employed to prevent hypotension during anesthesia. While it has historical applications for conditions such as asthma, narcolepsy, and obesity, it is not the preferred treatment for these ailments. Its efficacy in alleviating nasal congestion remains unclear. Administration methods include oral ingestion or injection into a muscle, vein, or subcutaneously. Intravenous use results in rapid onset, whereas muscle injection may take about 20 minutes, and oral consumption can take up to an hour for noticeable effects. The duration of action is approximately one hour for injections and up to four hours when taken orally. Ephedrine exerts its effects by augmenting the activity of α and β adrenergic receptors.

Ephedrine Tablets

Originally isolated in 1885, ephedrine entered commercial use in 1926 and holds a place on the World Health Organization's List of Essential Medicines. It is available as a generic medication and is naturally occurring in plants of the Ephedra genus. In the United States, dietary supplements containing ephedrine are generally prohibited, except in traditional Chinese medicine, where it is acknowledged as má huáng.

Má huáng plant

In the medical domain, ephedrine's cardiovascular effects mirror those of epinephrine, inducing increased blood pressure, heart rate, and contractility. It acts as a bronchodilator akin to pseudoephedrine, though with lesser potency. Ephedrine has been explored for mitigating motion sickness and countering sedative effects induced by other motion sickness medications. Additionally, its rapid and sustained efficacy has been observed in congenital myasthenic syndrome, both in early childhood and adults with a novel COLQ mutation.

Concerning weight loss, ephedrine facilitates modest short-term weight loss, particularly in fat, but its long-term impact remains uncertain. The compound stimulates thermogenesis in brown adipose tissue, predominantly found in mice, and reduces gastric emptying. Combined with methylxanthines like caffeine and theophylline, ephedrine forms compound products, such as the ECA stack, popular among bodybuilders aiming to reduce body fat. A 2021 systematic review noted a 2 kg (4.4 lb) weight loss with ephedrine compared to a placebo, accompanied by an elevated heart rate, reduced LDL, raised HDL, and no statistically significant difference in blood pressure.

ECA fatburner

On a cautionary note, due to its structural similarity to amphetamines, ephedrine is susceptible to misuse for the synthesis of methamphetamine. The chemical reduction of ephedrine, removing its hydroxyl group, is a known method in methamphetamine production. Ephedrine is thus classified as a table-I precursor under the United Nations Convention Against Traffic in Narcotic Drugs and Psychotropic Substances.

Methamphetamine synthesis form Ephedrine

Ephedrine Legal Status

The legal status of ephedrine is a complex tapestry shaped by diverse jurisdictions and concerns about its potential for misuse. Its classification varies globally, reflecting the multifaceted nature of this compound.

In the realm of pharmaceuticals, ephedrine is recognized for its therapeutic applications and is often available for medical use under controlled conditions. Regulatory bodies may impose strict guidelines regarding its prescription and administration, ensuring its responsible utilization in clinical settings. However, the legal landscape becomes more intricate when considering ephedrine's inclusion in over-the-counter products, particularly dietary supplements.

Many regions, including the United States, have implemented stringent regulations governing dietary supplements containing ephedrine. Due to safety concerns associated with its misuse for weight loss and athletic performance enhancement, several countries have prohibited or restricted the inclusion of ephedrine in these supplements. However, exceptions exist, notably in traditional Chinese medicine, where formulations involving ephedrine, such as má huáng, are recognized and permitted.

Canada: Ephedrine can be sold for breathing purposes in 8 milligram doses OTC.
Sweden: Ephedrine is a prescription only medication.

Storage

Store this medication at room temperature, between 59 and 77 °F (15 and 25 °C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep ephedrine out of the reach of children and away from pets.

Ephedrine Pharmacology and Toxicology

Toxicodynamics
Ephedrine can produce stimulation at the adrenergic receptors and neuronal norepinephrine release (Kelley 1998).

Pharmacodynamics
Ephedrine has both alpha- and beta-adrenergic activities, and both direct and indirect effects on receptors. It raises blood pressure both by increasing cardiac output and inducing peripheral vasoconstriction (Shufman et al., 1994; Parfitt, 1999). It can produce bronchodilation. In local application it causes pupils dilation. The main metabolic effects in overdose are hyperglycaemia and hypokalaemia. Ephedrine is a centrally acting respiratory stimulant and can increase motor activity.

Toxicity
The ephedrine concentrations in three fatalities were 3.49, 7.85, and 20.5mg/L (Kelley 1998). However survival at levels of 23 mg/L has been reported (Basalt and Cravey 1995)

Conclusion

In conclusion, this exploration has delved into the intricate facets of ephedrine, from its historical roots to its contemporary significance. Ephedrine's crystalline nature, synthesis methods, diverse applications, and legal considerations have been scrutinized.