Fentanyl Citrate: Structure,Synthesis,SAR,Mechanism,Uses

Fentanyl Citrate

Structure –

Fentanyl citrate is a synthetic opioid analgesic medication that is used to treat severe pain. Its molecular formula is C22H28N2O∙C6H8O7, and its molecular weight is 528.6 g/mol. The structure of fentanyl citrate consists of a fentanyl molecule linked to a citric acid molecule.

The fentanyl molecule itself is a phenylpiperidine derivative with a molecular weight of 336.5 g/mol. It has a highly lipophilic core consisting of a piperidine ring linked to a phenyl ring. The phenyl ring has a substituent at the para position consisting of a N-phenylpropanamide group, which gives fentanyl its potent analgesic properties.

The citric acid molecule is a tricarboxylic acid with a molecular weight of 192.1 g/mol. It contains three carboxylic acid functional groups, which are responsible for its acidity and ability to chelate metal ions.

The fentanyl molecule is covalently linked to the citric acid molecule through an ester linkage between the carboxylic acid group of the citric acid and the N-phenylpropanamide group of the fentanyl molecule. The resulting fentanyl citrate molecule is a white crystalline powder that is highly water-soluble and readily bioavailable.

Here is the chemical structure of Fentanyl Citrate:

Fentanyl Citrate
In this structure, the fentanyl molecule (the part to the left of the ester linkage) is shown in its three-dimensional conformation, with the piperidine ring and phenyl ring oriented in a nearly planar arrangement. The citric acid molecule (the part to the right of the ester linkage) is shown in a simplified two-dimensional form, with the carboxylic acid groups represented as COO- and the carbon atoms and hydrogen atoms implicit. The ester linkage itself is shown as the single bond between the oxygen atom of the carboxylic acid group and the nitrogen atom of the fentanyl molecule.

Synthesis –

The synthesis of Fentanyl Citrate involves the reaction of Fentanyl with Citric Acid, leading to the formation of an ester bond between the carboxylic acid group of citric acid and the nitrogen atom of the fentanyl molecule. Here is the chemical equation for the synthesis of Fentanyl Citrate:

Fentanyl Citrate

The chemical equation can also be written as:

Fentanyl Citrate
The reaction takes place under reflux conditions in the presence of a catalyst such as sulfuric acid or hydrochloric acid. The reaction mechanism involves the protonation of the carboxylic acid group of citric acid by the catalyst, followed by the attack of the nitrogen atom of the fentanyl molecule on the carbonyl group of the protonated citric acid. This leads to the formation of an intermediate which undergoes a dehydration step to form the ester bond between the two molecules. The resulting Fentanyl Citrate product is a white crystalline powder that is highly water-soluble and readily bioavailable.
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The synthesis of fentanyl citrate involves the esterification of fentanyl with citric acid. Here are the general steps involved in the synthesis:

  1. First, fentanyl is synthesized by a multistep process involving the reaction of N-phenethyl-4-piperidone with aniline, followed by reduction, N-alkylation, and acylation steps.
  2. The fentanyl base is then converted to the fentanyl citrate salt by reacting it with citric acid in an appropriate solvent such as water, methanol, or ethanol.
  3. The reaction is typically carried out under reflux conditions with stirring, and a catalyst such as sulfuric acid or hydrochloric acid may be added to promote the esterification reaction.
  4. After the reaction is complete, the fentanyl citrate salt is typically isolated by filtration or evaporation of the solvent, followed by recrystallization from a suitable solvent such as ethanol or methanol.
  5. The final product is a white to off-white crystalline powder that is highly water-soluble and stable under normal storage conditions.

It is worth noting that the synthesis of fentanyl citrate is a highly controlled process due to the potent and potentially dangerous nature of the compound. It is typically carried out in a specialized laboratory by trained professionals, and strict safety protocols are followed throughout the process.

SAR –

The structure-activity relationship (SAR) of fentanyl citrate is related to the structure of the fentanyl molecule, which is responsible for its potent analgesic properties. The SAR of fentanyl citrate can be summarized as follows:

  1. Substitution on the phenyl ring: The presence of a substituent at the para position of the phenyl ring, such as the N-phenylpropanamide group in fentanyl, is critical for the high potency of the compound. This group enhances the binding affinity of fentanyl to the μ-opioid receptor, which is responsible for its analgesic effects.
  2. Lipophilicity: Fentanyl is highly lipophilic, which enhances its penetration into the central nervous system and binding to the μ-opioid receptor. The lipophilic nature of the fentanyl molecule also contributes to its rapid onset of action and short duration of effect.
  3. Piperidine ring: The piperidine ring of fentanyl is a key component of its structure, and is essential for its binding to the μ-opioid receptor. Substitution on the piperidine ring can affect the potency and selectivity of the compound.
  4. Ester linkage: The ester linkage between fentanyl and citric acid in fentanyl citrate is responsible for its improved solubility and bioavailability. The presence of the citric acid moiety also contributes to the pH-dependent solubility of fentanyl citrate, which can be important for its formulation and administration.

Overall, the SAR of fentanyl citrate is closely related to the structure of the fentanyl molecule, and emphasizes the importance of specific functional groups and structural features for its potent analgesic properties.

Mechanism –

The mechanism of action of Fentanyl Citrate involves its binding to the μ-opioid receptor in the central nervous system, leading to a reduction in pain perception and modulation of other physiological responses. Here are the general steps involved in the mechanism of action of Fentanyl Citrate:

  1. Fentanyl Citrate is administered through a variety of routes, including intravenous, transdermal, and intranasal, depending on the indication and desired onset and duration of action.
  2. Once in the body, Fentanyl Citrate is rapidly distributed to the central nervous system, where it binds to the μ-opioid receptor with high affinity and specificity.
  3. The binding of Fentanyl Citrate to the μ-opioid receptor activates a G-protein coupled signaling pathway, leading to the inhibition of adenylate cyclase and a decrease in the production of cyclic AMP.
  4. This leads to the inhibition of calcium influx and hyperpolarization of neurons, resulting in a reduction in neurotransmitter release and a decrease in pain perception.
  5. Fentanyl Citrate also has other effects on the central nervous system, including sedation, respiratory depression, and nausea, which are mediated through its binding to other opioid receptors and other signaling pathways.
  6. The effects of Fentanyl Citrate are highly dose-dependent and can be influenced by factors such as age, weight, and comorbidities.

Overall, the mechanism of action of Fentanyl Citrate involves its binding to the μ-opioid receptor in the central nervous system, leading to a reduction in pain perception and modulation of other physiological responses. The pharmacokinetics and pharmacodynamics of Fentanyl Citrate are complex and can vary depending on a variety of factors, which must be carefully considered when administering the drug.

Uses –

Fentanyl Citrate is a potent opioid medication that is primarily used for the management of severe pain, especially in cases where other pain medications have proven ineffective or inadequate. Here are some of the main uses of Fentanyl Citrate:

  1. Management of acute pain: Fentanyl Citrate is often used to manage acute pain associated with surgical procedures, trauma, or medical conditions such as cancer or sickle cell disease. It is typically administered intravenously or via transdermal patches.
  2. Management of chronic pain: Fentanyl Citrate is sometimes used for the management of chronic pain that is resistant to other pain medications. It can be administered transdermally, intravenously, or through other routes of administration depending on the patient’s needs.
  3. Anesthesia: Fentanyl Citrate is often used as an adjunct to general anesthesia to provide pain relief during surgical procedures. It can also be used for conscious sedation during minor procedures.
  4. Palliative care: Fentanyl Citrate is sometimes used in palliative care to manage severe pain in patients with advanced or terminal illnesses.
  5. Emergency medicine: Fentanyl Citrate can be used in emergency medicine settings to provide pain relief to patients with severe injuries or conditions such as myocardial infarction.

It’s important to note that Fentanyl Citrate is a highly potent medication that should only be used under the guidance of a healthcare professional experienced in its use. It has a high risk of dependence and addiction, and can cause serious side effects such as respiratory depression and sedation.

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