CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE: Pharmaceutical manufacturers, suppliers, and wholesalers

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Applicant	Tradename	Generic Name	Dosage	NDA	NDA/ANDA	Supplier	Package Code	Package	Marketing Start
Cosette	PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE	codeine phosphate; promethazine hydrochloride	SYRUP;ORAL	200386	ANDA	Cosette Pharmaceuticals, Inc.	0713-0823-75	473 mL in 1 BOTTLE, PLASTIC (0713-0823-75)	2025-12-19
Cosette	PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE	codeine phosphate; promethazine hydrochloride	SYRUP;ORAL	200386	ANDA	ATLANTIC BIOLOGICALS CORP.	17856-0065-1	72 CUP, UNIT-DOSE in 1 BOX, UNIT-DOSE (17856-0065-1) / 5 mL in 1 CUP, UNIT-DOSE	2018-03-12
Cosette	PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE	codeine phosphate; promethazine hydrochloride	SYRUP;ORAL	200386	ANDA	ATLANTIC BIOLOGICALS CORP.	17856-0065-2	1 CUP, UNIT-DOSE in 1 BAG (17856-0065-2) / 5 mL in 1 CUP, UNIT-DOSE	2018-03-12
Cosette	PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE	codeine phosphate; promethazine hydrochloride	SYRUP;ORAL	200386	ANDA	Cranbury Pharmaceuticals, LLC	27808-065-02	473 mL in 1 BOTTLE, PLASTIC (27808-065-02)	2018-03-12
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>NDA/ANDA	>Supplier	>Package Code	>Package	>Marketing Start

Last updated: February 19, 2026

The pharmaceutical market for codeine phosphate and promethazine hydrochloride relies on a network of manufacturers and distributors capable of producing these active pharmaceutical ingredients (APIs) to stringent regulatory standards. Key suppliers operate globally, with significant production capacities concentrated in regions with established chemical manufacturing infrastructure and favorable regulatory environments. The supply chain is characterized by a need for consistent quality, regulatory compliance, and reliable delivery to meet the demands of finished dosage form manufacturers.

What are the primary API manufacturers for Codeine Phosphate?

Primary API manufacturers for codeine phosphate are established chemical synthesis companies with expertise in opioid alkaloid extraction and modification. These entities are subject to strict governmental controls due to the controlled substance nature of codeine.

Perrigo Company plc is a significant supplier of over-the-counter and prescription pharmaceutical ingredients, including controlled substances.
Mallinckrodt Pharmaceuticals has historically been a major producer of opioid APIs, though recent market shifts and legal challenges have impacted its operations.
Aurobindo Pharma Limited is an Indian pharmaceutical company with a broad API portfolio, including controlled substances, manufactured at cGMP-compliant facilities.
ANI Pharmaceuticals, Inc. supplies a range of prescription drugs and APIs, with capabilities in handling controlled substances.

These manufacturers adhere to Good Manufacturing Practices (GMP) and often hold specific licenses from regulatory bodies like the U.S. Drug Enforcement Administration (DEA) to handle and distribute scheduled substances. Production volumes are influenced by demand for combination products, such as those used in cough and cold remedies, and pain management.

What are the primary API manufacturers for Promethazine Hydrochloride?

Promethazine hydrochloride, an antihistamine and antiemetic, is produced by several API manufacturers globally. Unlike codeine phosphate, it is not a controlled substance, which broadens the supplier base and potentially simplifies regulatory hurdles for manufacturers.

Sanofi S.A., through its divisions, has been involved in the production of pharmaceutical ingredients, including antihistamines.
Sun Pharmaceutical Industries Ltd. is a global pharmaceutical company with extensive API manufacturing capabilities, including antihistamines.
Divi's Laboratories Limited is a prominent Indian API manufacturer with a diverse product list that can include antihistamines.
Cipla Limited is another Indian pharmaceutical giant with a substantial API manufacturing presence, capable of producing various therapeutic classes of APIs.

The production of promethazine hydrochloride requires specialized chemical synthesis processes to achieve the required purity and specifications for pharmaceutical use. Manufacturers must comply with international quality standards and pharmacopeial requirements.

Which regions dominate the supply of these APIs?

The global supply of codeine phosphate and promethazine hydrochloride APIs is concentrated in specific geographical regions due to several factors, including established chemical manufacturing infrastructure, regulatory frameworks, and cost efficiencies.

India is a leading supplier for both APIs. Indian manufacturers benefit from a strong domestic pharmaceutical industry, skilled workforce, and a well-developed regulatory system that aligns with international standards (e.g., US FDA, EMA). Companies like Aurobindo Pharma and Sun Pharmaceutical Industries are major contributors from this region.
The United States has domestic production capabilities, particularly for controlled substances like codeine phosphate. Manufacturers like Mallinckrodt and ANI Pharmaceuticals operate within a highly regulated environment that ensures strict quality control and compliance.
Europe, particularly Western European countries, has established chemical and pharmaceutical manufacturing bases. While some manufacturing has shifted, European companies continue to be significant players in specialized API production.

The dominance of these regions is driven by their ability to meet stringent GMP requirements, secure necessary licenses for controlled substances, and maintain competitive pricing.

What are the regulatory considerations for sourcing these APIs?

Sourcing codeine phosphate and promethazine hydrochloride APIs involves navigating a complex regulatory landscape that ensures product safety, efficacy, and compliance.

For Codeine Phosphate:

DEA Regulations (U.S.): As a Schedule II controlled substance, codeine phosphate is subject to strict quotas, licensing, record-keeping, and security requirements enforced by the U.S. Drug Enforcement Administration. Manufacturers and distributors must obtain specific registrations.
International Narcotics Control Board (IN পদার্থের: Manufacturers and exporters must comply with international treaties and UN conventions governing narcotic drugs, overseen by the IN substances.
FDA Compliance: APIs must be manufactured in FDA-registered facilities, and drug master files (DMFs) detailing manufacturing processes, quality control, and stability must be submitted and reviewed by the FDA.
State-Specific Regulations: In addition to federal controls, individual U.S. states may have additional licensing or reporting requirements.

For Promethazine Hydrochloride:

FDA Compliance: Manufacturers must adhere to cGMP regulations. DMFs are required for FDA review as part of new drug applications (NDAs) or abbreviated new drug applications (ANDAs).
Pharmacopeial Standards: APIs must meet the standards outlined in the United States Pharmacopeia (USP) or equivalent pharmacopeias like the European Pharmacopoeia (Ph. Eur.) or Japanese Pharmacopoeia (JP).
ICH Guidelines: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on quality, safety, and efficacy are crucial for global regulatory acceptance.

Compliance is mandatory for any pharmaceutical company wishing to use these APIs in their finished products. Failure to comply can result in warning letters, import alerts, and product recalls.

How has the supply chain for these APIs evolved?

The supply chain for codeine phosphate and promethazine hydrochloride APIs has undergone significant evolution driven by regulatory changes, geopolitical factors, and market dynamics.

Increased Scrutiny on Controlled Substances: Post the opioid crisis, regulatory bodies worldwide have intensified their oversight of opioid manufacturing and distribution, including codeine phosphate. This has led to stricter quotas, enhanced track-and-trace requirements, and greater emphasis on supply chain security.
Globalization and Diversification: While India and other Asian countries have become major API production hubs, there has also been a push in some Western countries to reshore or nearshore critical API manufacturing to reduce reliance on single regions and mitigate supply chain disruptions.
Consolidation and Market Shifts: The pharmaceutical API market has seen periods of consolidation, with some established players exiting or restructuring operations. This can impact the availability and pricing of specific APIs. Mallinckrodt's financial restructuring, for instance, has altered the landscape for opioid API supply.
Focus on Quality and Compliance: Regulatory agencies have continuously raised the bar for GMP compliance. This has led to greater investment in quality systems by API manufacturers and more frequent inspections, weeding out less compliant suppliers.
Technological Advancements: Innovations in chemical synthesis and analytical testing have improved API purity, efficiency of production, and ability to detect impurities.

These evolutions necessitate continuous monitoring by drug manufacturers to ensure a secure and compliant supply of essential APIs.

What are the critical quality attributes for these APIs?

Critical Quality Attributes (CQAs) are physical, chemical, biological, or microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality. For codeine phosphate and promethazine hydrochloride, these are paramount.

For Codeine Phosphate:

Purity: Typically specified as NLT 98.0% and NMT 102.0% on the anhydrous basis, determined by assay. Impurities, including related substances (e.g., morphine, thebaine, papaverine), must be strictly controlled to levels below specified limits.
Identity: Confirmed through spectroscopic methods (e.g., IR, NMR) and chemical tests, ensuring it is indeed codeine phosphate.
Water Content: As it is often supplied as a hydrate, the water content must be within a defined range, typically determined by Karl Fischer titration.
Residual Solvents: Solvents used during synthesis must be controlled to levels defined by ICH Q3C guidelines.
Heavy Metals: Limits for heavy metal contamination are critical for patient safety.
Specific Rotation: A measure of optical activity, which can indicate chiral purity.

For Promethazine Hydrochloride:

Purity: Assay usually specified as NLT 98.0% and NMT 102.0% on the dried basis. Related substances, such as degradation products or synthesis intermediates, must be controlled.
Identity: Verified using spectroscopic and chemical methods.
Water Content: Controlled to ensure stability and accurate dosing.
Loss on Drying: Another measure related to volatile content, including water.
Sulphated Ash: An indicator of inorganic impurities.
pH: The pH of a solution prepared from the API must fall within a specified range, indicative of its acidic or basic properties.

Manufacturers must rigorously test each batch of API against these CQAs to ensure it meets pharmacopeial monographs and customer specifications.

What are the typical packaging and storage requirements?

Proper packaging and storage are essential to maintain the quality, stability, and integrity of codeine phosphate and promethazine hydrochloride APIs throughout the supply chain.

For Codeine Phosphate:

Packaging: Typically packaged in multi-layer, airtight containers to protect from light, moisture, and oxygen. Materials such as HDPE drums with polyethylene liners or specialized foil bags are common. Double-bagging is often employed for controlled substances to enhance security.
Storage: Stored in a cool, dry, and well-ventilated area, protected from light. Temperature control is critical, often specified as ambient controlled room temperature (e.g., 20-25°C) or refrigerated conditions if stability dictates. Due to its controlled substance status, secure storage with limited access is mandatory, compliant with DEA regulations.

For Promethazine Hydrochloride:

Packaging: Similar to codeine phosphate, it is packaged in well-sealed containers to prevent contamination and degradation. Airtight drums, often with inner liners, are standard. Protection from light is also important as the compound can be photosensitive.
Storage: Stored in a cool, dry place, away from direct sunlight and incompatible materials. Recommended storage conditions are usually ambient controlled room temperature. Facilities must maintain appropriate environmental controls to prevent degradation.

Both APIs require clear labeling that includes lot number, manufacturing date, expiry date, net weight, manufacturer’s name and address, and necessary hazard symbols or handling instructions.

Who are the major distributors of these APIs?

Major distributors play a critical role in connecting API manufacturers with finished dosage form manufacturers. They provide logistical expertise, warehousing, and often regulatory support.

AmerisourceBergen Corporation: A global pharmaceutical sourcing and distribution services company that handles a vast array of pharmaceutical ingredients.
Cardinal Health, Inc.: Another leading pharmaceutical distributor with extensive capabilities in the supply chain for both branded and generic pharmaceuticals and their APIs.
McKesson Corporation: A major player in healthcare services, including the distribution of pharmaceutical products and APIs to a wide range of customers.
Univar Solutions: A global distributor of chemicals and ingredients, including pharmaceutical ingredients, with a broad network and supply chain management services.

These distributors often maintain specialized units for pharmaceutical ingredients, ensuring compliance with temperature controls, security measures, and regulatory documentation required for APIs. Their role is crucial in managing inventory, ensuring timely delivery, and providing a consolidated supply point for pharmaceutical companies.

Key Takeaways

The supply chain for codeine phosphate and promethazine hydrochloride APIs is characterized by stringent regulatory oversight, global manufacturing capabilities, and a reliance on specialized distributors. Codeine phosphate's status as a controlled substance imposes significant compliance burdens on manufacturers and distributors in terms of licensing, security, and reporting. India and the United States are primary manufacturing regions, with European entities also contributing. Manufacturers must adhere to strict GMP standards and pharmacopeial requirements, with purity, identity, and impurity profiles being critical quality attributes. The market has evolved with increased regulatory scrutiny on controlled substances and a global push for supply chain resilience, necessitating continuous adaptation by all stakeholders.

Frequently Asked Questions

Are there specific certifications required for suppliers of codeine phosphate and promethazine hydrochloride? Yes. For codeine phosphate, suppliers must hold DEA registrations and comply with international narcotic control regulations. For both APIs, suppliers must adhere to cGMP standards, and their facilities are subject to inspection by regulatory bodies like the FDA. A Drug Master File (DMF) is typically required for regulatory submissions.
How do price fluctuations in these APIs typically occur? Price fluctuations are influenced by raw material costs, manufacturing capacity utilization, regulatory compliance expenses, global demand, and geopolitical factors impacting supply chains. For codeine phosphate, DEA quota allocations can also affect availability and pricing.
What is the typical lead time for ordering these APIs? Lead times can vary significantly. For standard orders, it might range from 4 to 12 weeks. However, for controlled substances like codeine phosphate, lead times can be extended due to quota limitations and stringent documentation requirements. Custom synthesis or large volume orders may require longer lead times.
What are the primary risks associated with the supply chain for these APIs? Key risks include regulatory non-compliance leading to supply interruptions or product recalls, manufacturing disruptions due to quality issues or facility shutdowns, supply chain security breaches for controlled substances, and volatility in raw material sourcing. Global events such as pandemics or trade disputes can also create significant risks.
Can a pharmaceutical company source these APIs directly from manufacturers or must they use distributors? Pharmaceutical companies can source directly from API manufacturers, especially for large-volume requirements or specialized contracts. However, many companies, particularly smaller ones, opt to use distributors for logistical efficiency, inventory management, regulatory support, and access to a broader range of suppliers. Distributors also play a crucial role in consolidating orders and ensuring compliance for a multitude of products.

Citations

[1] U.S. Drug Enforcement Administration. (n.d.). Controlled Substances Act. Retrieved from [DEA website] [2] International Narcotics Control Board. (n.d.). About INCB. Retrieved from [INCB website] [3] U.S. Food and Drug Administration. (n.d.). Drug Master Files. Retrieved from [FDA website] [4] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (n.d.). ICH Guidelines. Retrieved from [ICH website] [5] United States Pharmacopeial Convention. (n.d.). Pharmacopeial Standards. Retrieved from [USP website] [6] Perrigo Company plc. (2023). Annual Report 2023. [7] Mallinckrodt Pharmaceuticals. (2023). Financial Reports. [8] Aurobindo Pharma Limited. (2023). Annual Report 2023. [9] ANI Pharmaceuticals, Inc. (2023). Annual Report 2023. [10] Sanofi S.A. (2023). Annual Report 2023. [11] Sun Pharmaceutical Industries Ltd. (2023). Annual Report 2023. [12] Divi's Laboratories Limited. (2023). Annual Report 2023. [13] Cipla Limited. (2023). Annual Report 2023. [14] AmerisourceBergen Corporation. (2023). Annual Report 2023. [15] Cardinal Health, Inc. (2023). Annual Report 2023. [16] McKesson Corporation. (2023). Annual Report 2023. [17] Univar Solutions. (2023). Annual Report 2023.

Suppliers and packagers for generic pharmaceutical drug: CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE