Codeine API Manufacturers & Suppliers
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Codeine | CAS No: 76-57-3 | GMP-certified suppliers
A medication that provides appropriate relief for mild to moderately severe pain and suppresses persistent cough in adults for clinical symptom management.
Therapeutic categories
AlkaloidsAnalgesicsAntitussive AgentsCentral Nervous System AgentsCentral Nervous System DepressantsCough and Cold Preparations
Generic name
Codeine
Molecule type
small molecule
CAS number
76-57-3
DrugBank ID
DB00318
Approval status
Approved drug, Illicit drug
ATC code
N02AA79
Primary indications
- Codeine sulfate is a form of this drug that is commonly used
- It is available in tablet form [FDA label] and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate [FDA label]
- The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged 18 and above ,
Product Snapshot
- Codeine is an oral and parenteral small‑molecule opioid available in multiple solid and liquid formulations, including tablets, syrups, and solutions
- It is used for pain management and as an antitussive in adult cough preparations
- It is approved in the US and Canada, with additional controls in markets where certain formulations may be classified as illicit
Clinical Overview
Codeine (CAS 76-57-3) is a morphinan opioid used globally for the management of mild to moderately severe pain when an opioid analgesic is appropriate. Oral solution formulations are also used alone or in combination products as an antitussive in adults. Its clinical utility spans analgesic, sedative, antinociceptive, and antiperistaltic effects, with established use in settings requiring symptom control for pain or persistent cough.
Pharmacologically, codeine acts as a weak mu‑opioid receptor agonist. Central receptor engagement reduces nociceptive transmission through G protein–mediated decreases in intracellular cAMP and calcium levels, leading to neuronal hyperpolarization. While codeine undergoes O‑demethylation to morphine via CYP2D6, only a small fraction is converted, and this pathway is not considered the dominant analgesic mechanism. Codeine‑6‑glucuronide is a major metabolite with mu‑receptor affinity and may contribute substantially to clinical effect.
Codeine produces dose‑dependent sedation and respiratory depression. Its antitussive activity reflects suppression of the medullary cough center. Effects on gastrointestinal motility are both central and local, often resulting in constipation; prolonged use can exacerbate obstructive bowel conditions in susceptible patients. Peripheral vasodilation may compromise blood pressure, particularly in compromised patients.
Absorption is reliable after oral administration, followed by hepatic metabolism primarily via glucuronidation and minor CYP2D6 conversion. Codeine and its metabolites are excreted renally. Interindividual variability arises from metabolic polymorphisms, particularly CYP2D6 poor metabolizer status, which can attenuate analgesic response.
Codeine is available in various national markets under multiple brand and generic products, including codeine sulfate or phosphate tablets and combination cough preparations.
For API procurement, sourcing should prioritize suppliers with demonstrated control of opiate alkaloid manufacturing, secure precursor handling, and full compliance with controlled‑substance regulations. Robust documentation of impurity profiles, validated assays, and traceable supply chain controls is essential for regulatory submissions and formulation development.
Pharmacologically, codeine acts as a weak mu‑opioid receptor agonist. Central receptor engagement reduces nociceptive transmission through G protein–mediated decreases in intracellular cAMP and calcium levels, leading to neuronal hyperpolarization. While codeine undergoes O‑demethylation to morphine via CYP2D6, only a small fraction is converted, and this pathway is not considered the dominant analgesic mechanism. Codeine‑6‑glucuronide is a major metabolite with mu‑receptor affinity and may contribute substantially to clinical effect.
Codeine produces dose‑dependent sedation and respiratory depression. Its antitussive activity reflects suppression of the medullary cough center. Effects on gastrointestinal motility are both central and local, often resulting in constipation; prolonged use can exacerbate obstructive bowel conditions in susceptible patients. Peripheral vasodilation may compromise blood pressure, particularly in compromised patients.
Absorption is reliable after oral administration, followed by hepatic metabolism primarily via glucuronidation and minor CYP2D6 conversion. Codeine and its metabolites are excreted renally. Interindividual variability arises from metabolic polymorphisms, particularly CYP2D6 poor metabolizer status, which can attenuate analgesic response.
Codeine is available in various national markets under multiple brand and generic products, including codeine sulfate or phosphate tablets and combination cough preparations.
For API procurement, sourcing should prioritize suppliers with demonstrated control of opiate alkaloid manufacturing, secure precursor handling, and full compliance with controlled‑substance regulations. Robust documentation of impurity profiles, validated assays, and traceable supply chain controls is essential for regulatory submissions and formulation development.
Identification & chemistry
| Generic name | Codeine |
|---|---|
| Molecule type | Small molecule |
| CAS | 76-57-3 |
| UNII | UX6OWY2V7J |
| DrugBank ID | DB00318 |
Pharmacology
| Summary | Codeine is an opioid analgesic and antitussive that acts primarily through mu‑opioid receptor agonism, leading to reduced neuronal excitability and impaired transmission of nociceptive signals. Its activity involves direct receptor binding as well as contributions from metabolites such as codeine‑6‑glucuronide. Pharmacologic effects include analgesia, cough suppression, sedation, and reduced gastrointestinal motility. |
|---|---|
| Mechanism of action | Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors.Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine.However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine.Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα<sub>i</sub>, causing a decrease in intracellular cAMP and Ca<sup>2+</sup> level.This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals. |
| Pharmacodynamics | **General effects** Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression . **Antitussive activity** This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing . Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla . **Effects on intestinal motility** Codeine may reduce intestinal motility through both a local and possibly central mechanism of action . This may possibly lead to constipation . The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility [FDA label]. **Effects on the central nervous system** Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the _mu_ opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine . Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system . **Effects on blood pressure** This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms [FDA label]. **Effects on chronic cancer pain and other types of pain** Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours . Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms , . |
Targets
| Target | Organism | Actions |
|---|---|---|
| Mu-type opioid receptor | Humans | agonist, regulator |
| Kappa-type opioid receptor | Humans | agonist |
| Delta-type opioid receptor | Humans | agonist |
ADME / PK
| Absorption | **Absorption** Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration [FDA label]. **Food Effects** When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine [FDA label]. **Steady-state concentration** The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours [FDA label]. |
|---|---|
| Half-life | Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours [FDA label]. |
| Protein binding | 7-25% bound to plasma proteins [FDA label]. |
| Metabolism | Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to _codeine-6 glucuronide_ (C6G) and by O-demethylation to _morphine_ (about 5-10%) and N-demethylation to _norcodeine_ (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, _codeine 6 glucuronide_. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to _norcodeine_. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are _morphine-3-glucuronide_ (M3G) and_ morphine-6-glucuronide _(M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties [FDA label]. |
| Route of elimination | About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine [FDA label]. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine . |
| Volume of distribution | Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues [FDA label]. |
| Clearance | Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study . Renal impairment may decrease codeine clearance [LABEL]. |
Formulation & handling
- Oral formulations dominate and require attention to moderate aqueous solubility, with solutions, syrups, and elixirs benefiting from pH control and co‑solvents to maintain solubilization.
- Extended‑release tablets and capsules rely on controlling codeine’s moderate lipophilicity and first‑pass metabolism; matrix or coated systems must ensure stable release without dose dumping.
- Parenteral solutions (IM/SC) require codeine to remain in clear aqueous solution; stability is generally good but formulations should control pH to limit precipitation and degradation.
Regulatory status
| Lifecycle | The API is marketed in the United States and Canada, with key U.S. patent protections extending through 2027, 2029, and 2032. Earlier patents have already expired, indicating a market transitioning toward later‑stage exclusivity based on the remaining active protections. |
|---|
| Markets | Canada, US |
|---|
Supply Chain
| Supply chain summary | Codeine is an established analgesic with no single originator controlling the active substance, and its supply is supported by one primary listed API manufacturer and a large number of U.S.‑focused repackagers and distributors. Branded combination products appear in Canada and the United States, but the molecule itself is long off‑patent globally. The listed U.S. patents extend into the late 2020s–early 2030s and relate to specific formulations, indicating that broad generic competition for codeine APIs and standard products is already well established. |
|---|
Safety
| Toxicity | **Oral LD50**: 427 mg kg-1 (rat) [MSDS]. **Overdose/toxicity** Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite. In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal , [FDA label]. **Teratogenic effects** This drug is classified as a pregnancy Category C drug. There are no adequate and well-controlled studies completed in pregnant women. Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus [FDA label]. Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose [FDA label]. Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification. Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison [FDA label]. **Nonteratogenic effects** Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery. Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs may be observed shortly following birth and may require specific treatment [FDA label]. Codeine (30 mg/kg) given subcutaneously to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth. The dose given was 0.8 times the maximum recommended human dose of 360 mg/day [FDA label]. **The use in breastfeeding/nursing** Codeine is secreted into human milk. The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants [FDA label]. |
|---|
High Level Warnings:
- Oral LD50 in rats is 427 mg/kg, and toxic exposures can produce CNS and respiratory depression, with progression to life‑threatening circulatory or respiratory failure at high doses
- Reproductive toxicity includes embryolethal and fetotoxic effects in multiple animal models at exposures roughly 2–4 times human therapeutic levels, with skeletal abnormalities at maternally toxic doses
- Codeine transfer via placenta and breast milk is associated with neonatal withdrawal, increased neonatal mortality in animal studies, and risk of severe adverse reactions in nursing infants
Codeine is a type of Opioid analgesics
Opioid analgesics are a subcategory of pharmaceutical Active Pharmaceutical Ingredients (APIs) that are commonly used for pain management. These potent substances interact with specific receptors in the central nervous system, producing analgesic effects and reducing the perception of pain. Opioid analgesics are derived from opium alkaloids or synthetic compounds that mimic their effects. They are classified based on their strength, with some being classified as strong opioids (e.g., morphine, fentanyl) and others as weak opioids (e.g., codeine, tramadol). These APIs work by binding to opioid receptors, primarily located in the brain, spinal cord, and gastrointestinal tract. By activating these receptors, opioid analgesics modulate pain signals, resulting in pain relief. Additionally, they can induce feelings of euphoria, sedation, and respiratory depression, which can be both beneficial and potentially harmful.
Due to their potency and potential for abuse, opioid analgesics are tightly regulated substances. They are primarily prescribed for acute and chronic pain management, such as post-surgical pain, cancer pain, and severe injuries. However, their misuse and addiction potential have led to a public health crisis in many countries.
In conclusion, opioid analgesics are a subcategory of pharmaceutical APIs that play a crucial role in pain management. While they provide effective pain relief, their use requires careful monitoring and adherence to prescribing guidelines to mitigate the risks associated with their potential for abuse and addiction.
Codeine (Opioid analgesics), classified under Analgesics
Analgesics are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that are commonly used to relieve pain. They are designed to alleviate discomfort by targeting the body's pain receptors or by reducing inflammation. Analgesics are widely utilized in the medical field to manage various types of pain, ranging from mild to severe.
One of the primary classes of analgesics is nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs work by inhibiting the production of prostaglandins, substances that contribute to pain and inflammation. This class includes well-known drugs like ibuprofen and naproxen. Another class of analgesics is opioids, which are derived from opium or synthetic compounds that mimic the effects of opium. Opioids act on the central nervous system to reduce pain perception and provide potent pain relief. Examples of opioids include morphine, codeine, and oxycodone.
Analgesics are available in various forms, such as tablets, capsules, creams, and injections, allowing for different routes of administration based on the patient's needs. They are commonly used to manage pain associated with conditions like arthritis, headaches, dental procedures, and post-operative recovery.
It is important to note that analgesics should be used under medical supervision, as improper use or overuse can lead to adverse effects, including gastrointestinal complications, addiction, and respiratory depression in the case of opioids. Therefore, it is crucial for healthcare professionals to assess each patient's individual needs and prescribe the appropriate analgesic and dosage.
In summary, analgesics are a vital category of pharmaceutical APIs used to alleviate pain by targeting pain receptors or reducing inflammation. With various classes and forms available, they provide valuable options for pain management when used responsibly and under medical guidance.
Frequently asked questions about Codeine API
Sourcing
What matters most when sourcing GMP-grade Codeine?
Key considerations are compliance with U.S. and Canadian GMP and controlled‑substance requirements, including appropriate licensing and documentation for narcotic handling. Verify that the API comes from a manufacturer with an inspected quality system, supported by valid certificates of analysis and traceable supply chain records. Ensure the material matches compendial specifications and that import, repackaging, and distribution steps maintain full regulatory control.
Which documents are typically required when sourcing Codeine API?
Request the core API documentation set: CoA (8 companies), GMP (5 companies), CEP (3 companies), USDMF (3 companies), FDA (1 company). Confirm versions and validity dates match the destination market to avoid delays in qualification.
Which manufacturers are known to produce Codeine API?
Known or reported manufacturers for Codeine: Hänseler AG, Temad Co.. Evaluate their GMP history, scale, and regional coverage before requesting dossiers or allocating demand.
How can I request quotes for Codeine API from GMP suppliers?
Submit quote requests through the supplier listings with your specs and required documents (specifications, target volume, delivery timeline, and destination). Providing consistent details upfront speeds comparable offers and clarifies technical feasibility.
Is a GMP audit report available for Codeine manufacturers?
Audit reports may be requested for Codeine: 2 GMP audit reports available. Confirm the scope and recency of any audit before relying on it for qualification decisions.
How many suppliers offer Codeine API on Pharmaoffer?
Reported supplier count for Codeine: 8 verified suppliers. Filter listings by certifications, regions, and delivery options to match your qualification plan.
Which countries are known to manufacture Codeine API?
Production countries reported for Codeine: Norway (1 producer), Iran (1 producer), United States (1 producer). Knowing the manufacturing geography helps anticipate logistics lead times and import compliance needs.
Which certifications do suppliers of Codeine usually hold?
Common certifications for Codeine suppliers: CoA (8 companies), GMP (5 companies), CEP (3 companies), USDMF (3 companies), FDA (1 company). Always verify issuing authorities and expiry dates when reviewing audit packages.
Technical
What is Codeine (CAS 76-57-3) used for?
Codeine is used for the management of mild to moderately severe pain when an opioid analgesic is appropriate. It is also used as an antitussive in oral solution or combination products to suppress persistent cough. Its clinical effects include analgesic, sedative, antinociceptive, and antiperistaltic actions that support symptom control in these settings.
Which therapeutic class does Codeine fall into?
Codeine belongs to the following therapeutic categories: Alkaloids, Analgesics, Antitussive Agents, Central Nervous System Agents, Central Nervous System Depressants. This positioning helps teams compare alternative APIs, anticipate pharmacology expectations, and align early research priorities.
What conditions is Codeine mainly prescribed for?
The primary indications for Codeine: Codeine sulfate is a form of this drug that is commonly used, It is available in tablet form [FDA label] and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate [FDA label], The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged 18 and above ,. These use cases frame the target patient populations and help prioritize formulation and safety evaluations.
How does Codeine work?
Although the exact mechanism of action of Codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors.Morphine was previously postulated to contribute to the analgesic effect of Codeine due to the O-demethylation of Codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of Codeine.However, this is unlikely to be the main mechanism of action of Codeine as only 5% of Codeine is metabolized to morphine.Other hypotheses also postulate that Codeine-6-glucuronide, the main metabolite of Codeine, mediates the analgesic effect of Codeine as it not only has an affinity to the mu receptors as Codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine.
Binding to the mu receptors by Codeine activates the G-proteins Gαi, causing a decrease in intracellular cAMP and Ca2+ level.This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals.
What should someone know about the safety or toxicity profile of Codeine?
Codeine has dose‑dependent central nervous system and respiratory depression, with severe overdose progressing to circulatory or respiratory failure. It shows reproductive toxicity in animal studies, including embryolethal and fetotoxic effects at exposures moderately above therapeutic levels, and skeletal abnormalities at maternally toxic doses. Placental and breast‑milk transfer can lead to neonatal withdrawal, increased neonatal mortality in animals, and serious reactions in nursing infants. Toxicity also includes sedation, constipation, and blood pressure reductions related to peripheral vasodilation.
What are important formulation and handling considerations for Codeine as an API?
Important considerations include managing Codeine’s moderate aqueous solubility through pH adjustment and use of co‑solvents in oral solutions, syrups, and elixirs to maintain solubilization. Extended‑release tablets or capsules require release‑controlling matrices or coatings that provide stable drug release despite first‑pass metabolism. For parenteral formulations, maintaining a clear aqueous solution with appropriate pH control helps prevent precipitation and degradation during handling and storage.
Is Codeine a small molecule?
Codeine is classified as a small molecule. That classification shapes process design, impurity profiling, and analytical control strategies.
Are there special stability concerns for oral Codeine?
Oral Codeine formulations require attention to its moderate aqueous solubility, which can affect stability in solutions, syrups, and elixirs; these forms typically depend on controlled pH and co‑solvents to maintain solubilization. Extended‑release tablets and capsules must preserve the integrity of matrix or coating systems to ensure consistent release and prevent dose dumping. Stability issues primarily relate to maintaining appropriate pH and preventing precipitation or degradation in solution-based products.
Regulatory
Where is Codeine approved or in use globally?
Codeine is reported as approved in the following major regions: Canada, US. Understanding geographic coverage informs regulatory filings, supply planning, and risk assessments before escalating procurement.
What’s the regulatory and patent landscape for Codeine right now?
In the United States, Codeine is a controlled substance regulated under the Controlled Substances Act, with most formulations classified as Schedule II and some combination products placed in lower schedules. In Canada, it is regulated as a narcotic under the Controlled Drugs and Substances Act, with restrictions that vary by formulation and strength. Patent protection for Codeine has long expired, and the compound is available for manufacture and use without active patent exclusivities.
Pharmaoffer
How does Pharmaoffer’s Smart Sourcing Service help with Codeine procurement?
Pharmaoffer's Smart Sourcing Service coordinates compliant suppliers, documentation, and competitive quotes for Codeine. It centralizes outreach, follow-ups, and document validation to shorten procurement timelines.
Is Codeine included in the PRO Data Insights coverage?
PRO Data Insights coverage for Codeine: 1343 verified transactions across 230 suppliers and 144 buyers worldwide. Use the dataset to benchmark suppliers and monitor regulatory activity where available.
Where can I access the API market report for Codeine?
Market report availability for Codeine: Report Available. The report highlights demand trends, pricing drivers, and supplier landscape insights for procurement planning.
