Suppliers and packagers for generic pharmaceutical drug: DIPHENHYDRAMINE HYDROCHLORIDE

DIPHENHYDRAMINE HYDROCHLORIDE

Listed suppliers include manufacturers, repackagers, relabelers, and private labeling entitities.

Applicant	Tradename	Generic Name	Dosage	NDA	NDA/ANDA	Supplier	Package Code	Package	Marketing Start
Pharm Assoc	DIPHENHYDRAMINE HYDROCHLORIDE	diphenhydramine hydrochloride	ELIXIR;ORAL	087513	ANDA	PAI Holdings, LLC dba PAI Pharma	0121-0489-00	10 TRAY in 1 CASE (0121-0489-00) / 10 CUP, UNIT-DOSE in 1 TRAY / 5 mL in 1 CUP, UNIT-DOSE (0121-0489-05)	1982-02-10
Pharm Assoc	DIPHENHYDRAMINE HYDROCHLORIDE	diphenhydramine hydrochloride	ELIXIR;ORAL	087513	ANDA	PAI Holdings, LLC dba PAI Pharma	0121-0978-00	10 TRAY in 1 CASE (0121-0978-00) / 10 CUP, UNIT-DOSE in 1 TRAY / 10 mL in 1 CUP, UNIT-DOSE (0121-0978-10)	1982-02-10
Pharm Assoc	DIPHENHYDRAMINE HYDROCHLORIDE	diphenhydramine hydrochloride	ELIXIR;ORAL	087513	ANDA	Medical Purchasing Solutions, LLC	71872-7242-1	1 CUP, UNIT-DOSE in 1 BAG (71872-7242-1) / 10 mL in 1 CUP, UNIT-DOSE	1982-02-10
App Pharms	DIPHENHYDRAMINE HYDROCHLORIDE	diphenhydramine hydrochloride	INJECTABLE;INJECTION	040466	ANDA	HF Acquisition Co LLC, DBA HealthFirst	51662-1348-1	1 mL in 1 VIAL (51662-1348-1)	2018-11-26
App Pharms	DIPHENHYDRAMINE HYDROCHLORIDE	diphenhydramine hydrochloride	INJECTABLE;INJECTION	040466	ANDA	HF Acquisition Co LLC, DBA HealthFirst	51662-1374-1	1 mL in 1 VIAL, SINGLE-DOSE (51662-1374-1)	2019-11-11

Diphenhydramine Hydrochloride Pharmaceutical Supply Chain Analysis

Last updated: February 19, 2026

This report analyzes the global supply chain for diphenhydramine hydrochloride, a widely used antihistamine. Key manufacturing regions include China and India, with significant production of active pharmaceutical ingredients (APIs) and intermediates. Major suppliers are identified, along with their production capacities and regulatory standing. The analysis also covers price trends, patent landscape, and potential supply chain risks.

What are the primary components and manufacturing processes for diphenhydramine hydrochloride?

Diphenhydramine hydrochloride is a first-generation antihistamine with anticholinergic and sedative properties. Its synthesis involves several key chemical steps, typically starting with diphenylmethanol and N,N-dimethylaminoethanol or related precursors.

The primary reactants include:

• Diphenylmethanol: This is often synthesized from benzophenone or through Grignard reactions involving phenylmagnesium bromide and benzaldehyde.
• N,N-dimethylaminoethanol (DMAE): This can be produced via the reaction of dimethylamine with ethylene oxide.

A common synthesis route involves the etherification of diphenylmethanol with a haloalkylamine, or a related nucleophilic substitution reaction. For instance, diphenylmethanol can be reacted with 2-chloro-N,N-dimethylethylamine in the presence of a base. Alternatively, a related route might involve the reaction of benzhydryl bromide with N,N-dimethylaminoethanol.

The final product, diphenhydramine, is then converted to its hydrochloride salt to enhance solubility and stability. This is typically achieved by reacting diphenhydramine base with hydrochloric acid.

The manufacturing process requires controlled reaction conditions, including temperature, pressure, and solvent selection, to ensure yield and purity. Purification steps, such as crystallization and filtration, are critical to meet pharmaceutical grade specifications.

Who are the leading global manufacturers and suppliers of diphenhydramine hydrochloride API?

The global supply of diphenhydramine hydrochloride active pharmaceutical ingredient (API) is concentrated in a limited number of manufacturers, primarily located in Asia. China and India are the dominant production hubs due to cost efficiencies and established chemical manufacturing infrastructure.

Company Name	Country	Primary Product Focus	Regulatory Approvals (Examples)
Zhejiang NHU Co., Ltd.	China	API	US FDA, EDQM
Zhejiang Medicine Co., Ltd.	China	API	US FDA, EDQM
Jubilant Pharmova Limited	India	API	US FDA, EDQM
Divi’s Laboratories Limited	India	API	US FDA, EDQM
Granules India Limited	India	API	US FDA, EDQM
Sun Pharma Advanced Research Company Ltd.	India	API	US FDA

These companies are significant contributors to the global supply chain, often serving both generic drug manufacturers and contract development and manufacturing organizations (CDMOs) worldwide. Production volumes can vary based on market demand and contractual agreements with pharmaceutical clients.

What is the current market pricing and trend for diphenhydramine hydrochloride API?

The pricing of diphenhydramine hydrochloride API is subject to several factors, including raw material costs, manufacturing capacity utilization, regulatory compliance expenses, and global demand. Historically, pricing has remained relatively stable, reflecting the mature nature of the product and the presence of multiple established suppliers.

• Recent Price Range (USD/kg, estimated): $25 - $60
• Key Influencers:
  • Raw Material Availability: Fluctuations in the cost of key intermediates like benzophenone derivatives or dimethylaminoethanol can impact API pricing.
  • Energy Costs: Manufacturing processes are energy-intensive, making energy prices a significant factor.
  • Regulatory Scrutiny: Increased compliance costs associated with Good Manufacturing Practices (GMP) and environmental regulations can lead to price adjustments.
  • Geopolitical Factors: Supply chain disruptions due to trade policies or regional instability can affect availability and pricing.

The market is generally considered competitive, with price being a critical factor for purchasers of bulk API. However, supply reliability and quality assurance are equally important considerations. Price trends are typically incremental, responding to macro-economic shifts rather than rapid spikes, unless significant supply disruptions occur.

What is the patent landscape surrounding diphenhydramine hydrochloride?

Diphenhydramine hydrochloride is a well-established drug and its original composition of matter patents have long expired. The molecule itself is in the public domain.

• Original Composition of Matter Patent: Expired.
• Key Patent Expirations: The foundational patents for diphenhydramine were filed in the late 1940s and early 1950s.

While the API itself is off-patent, new patent filings may relate to:

• Novel Formulations: Extended-release versions, combination products, or formulations with improved bioavailability or reduced side effects.
• Manufacturing Processes: New, more efficient, or environmentally friendly synthesis routes.
• Specific Polymorphs or Crystal Forms: Patented crystalline forms of the API might offer improved stability or handling characteristics.
• New Therapeutic Uses: Patents for using diphenhydramine or its derivatives for previously undiscovered medical conditions.

The absence of composition of matter patents allows for generic manufacturing, driving competition based on cost and quality rather than intellectual property exclusivity for the molecule itself. Companies holding patents on advanced formulations or manufacturing processes may still possess market advantages.

What are the regulatory requirements and compliance standards for diphenhydramine hydrochloride API manufacturing?

Manufacturing of diphenhydramine hydrochloride API for pharmaceutical use is subject to stringent regulatory oversight to ensure product quality, safety, and efficacy. Key regulatory bodies and their requirements include:

• U.S. Food and Drug Administration (FDA):

  • Current Good Manufacturing Practices (cGMP): Manufacturers must adhere to 21 CFR Parts 210 and 211, covering all aspects of production, quality control, and facility management.
  • Drug Master Files (DMFs): API manufacturers typically file DMFs with the FDA, providing confidential detailed information about facilities, processes, and controls used in the manufacturing of the API.
  • Inspections: FDA conducts regular facility inspections to verify cGMP compliance.

• European Medicines Agency (EMA) & National Competent Authorities (NCAs) in EU Member States:

  • European Pharmacopoeia (Ph. Eur.): API must comply with the monographs outlined in the Ph. Eur., which specify tests and acceptance criteria for identity, purity, and assay.
  • Good Manufacturing Practice (GMP) Guidelines: Compliance with EudraLex Volume 4 is mandatory.
  • Certificates of Suitability to the Monographs of the European Pharmacopoeia (CEP): Issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM), a CEP demonstrates compliance with Ph. Eur. standards.

• Other Jurisdictions: Similar regulatory frameworks exist in Japan (PMDA), Canada (Health Canada), and other major pharmaceutical markets.

Key Compliance Areas:

• Quality Management Systems (QMS): Robust QMS are essential, encompassing change control, deviation management, CAPA (Corrective and Preventive Actions), and regular internal audits.
• Impurity Profiling: Detailed characterization and control of impurities, including genotoxic impurities, are critical.
• Stability Testing: Demonstrating the API’s stability under various storage conditions is required.
• Supply Chain Security: Ensuring the integrity and traceability of raw materials and finished API.

Manufacturers must maintain high standards of documentation, validation, and ongoing quality monitoring to retain regulatory approval and market access.

What are the potential supply chain risks and mitigation strategies for diphenhydramine hydrochloride?

The diphenhydramine hydrochloride supply chain, like many pharmaceutical APIs, faces several inherent risks. These risks can impact availability, cost, and quality.

Potential Supply Chain Risks:

1. Raw Material Dependency and Price Volatility:

   • Description: Reliance on a limited number of suppliers for key precursors can lead to price fluctuations and supply disruptions if those suppliers encounter issues.
   • Impact: Increased API cost, potential shortages.

2. Geographic Concentration of Manufacturing:

   • Description: The concentration of API production in specific regions (e.g., China, India) creates vulnerability to regional events like natural disasters, geopolitical tensions, trade disputes, or localized regulatory crackdowns.
   • Impact: Widespread supply shortages, extended lead times.

3. Regulatory Compliance Issues:

   • Description: A manufacturing facility failing to meet cGMP standards or facing import bans in key markets can immediately halt supply from that source.
   • Impact: Loss of a supplier, need to qualify new sources, potential product recall risks for downstream formulators.

4. Logistical and Transportation Disruptions:

   • Description: Issues with shipping, customs delays, or increased freight costs can affect timely delivery of both raw materials and finished API.
   • Impact: Increased lead times, higher landed costs.

5. Quality Control Failures:

   • Description: Batch failures, contamination, or inconsistent quality from a supplier can lead to rejected shipments and significant rework or replacement efforts.
   • Impact: Production delays for drug product manufacturers, reputational damage.

6. Intellectual Property Landscape Changes (Less Likely for API):

   • Description: While the API is off-patent, unexpected patent grants on novel manufacturing processes or polymorphic forms, though rare for such an old molecule, could theoretically impact supply if a new process becomes dominant.
   • Impact: Potential restriction of certain manufacturing methods.

Mitigation Strategies:

1. Supplier Diversification:

   • Action: Qualify and maintain relationships with multiple API suppliers in different geographic regions.
   • Benefit: Reduces dependency on any single supplier or region.

2. Dual Sourcing of Key Intermediates:

   • Action: Secure critical raw materials from more than one approved vendor.
   • Benefit: Protects against disruptions in the upstream supply chain.

3. Robust Quality Agreements and Audits:

   • Action: Establish comprehensive quality agreements with suppliers and conduct regular, thorough on-site audits to ensure ongoing compliance.
   • Benefit: Proactive identification and resolution of quality issues.

4. Strategic Inventory Management:

   • Action: Maintain appropriate safety stock levels of both critical raw materials and finished API, balancing inventory holding costs against supply security.
   • Benefit: Buffers against short-term supply disruptions.

5. Contingency Planning and Business Continuity:

   • Action: Develop detailed contingency plans for various disruption scenarios, including alternative logistics and emergency procurement strategies.
   • Benefit: Enables swift response to unforeseen events.

6. Regulatory Monitoring:

   • Action: Continuously monitor regulatory changes and the compliance status of key suppliers.
   • Benefit: Avoids surprises related to regulatory actions.

By implementing these strategies, pharmaceutical companies can enhance the resilience of their diphenhydramine hydrochloride supply chains, ensuring consistent product availability and quality for patients.

Key Takeaways

• Diphenhydramine hydrochloride API production is concentrated in China and India, with major suppliers holding significant market share.
• The API is a mature product with expired composition of matter patents, leading to a competitive pricing environment.
• Pricing is influenced by raw material costs, manufacturing capacity, and regulatory compliance, generally remaining stable within a defined range.
• Regulatory compliance with cGMP standards is paramount, with bodies like the FDA and EMA enforcing strict quality and manufacturing requirements.
• Key supply chain risks include raw material dependency, geographic concentration, and regulatory non-compliance, necessitating strategies such as supplier diversification and robust quality control.

Frequently Asked Questions

1. What is the typical shelf life of diphenhydramine hydrochloride API? Diphenhydramine hydrochloride API, when stored under recommended conditions (e.g., cool, dry place, protected from light), typically has a shelf life of 2 to 5 years, subject to specific manufacturer data and stability studies.

2. Are there any significant impurities that pharmaceutical companies must monitor in diphenhydramine hydrochloride API? Pharmaceutical companies must monitor for specified impurities as per pharmacopoeial monographs (e.g., USP, Ph. Eur.), which may include related substances from the synthesis process, degradation products, and residual solvents. Specific attention is paid to any potentially genotoxic impurities.

3. What is the average lead time for ordering diphenhydramine hydrochloride API from major suppliers? Lead times for diphenhydramine hydrochloride API can vary but typically range from 4 to 12 weeks, depending on supplier inventory, production schedules, and order volume. Urgent orders may incur premium pricing or require expedited shipping.

4. Can supply chain disruptions for diphenhydramine hydrochloride API significantly impact the availability of over-the-counter (OTC) diphenhydramine products? Yes, significant disruptions affecting a large portion of global API supply can lead to shortages or increased costs for finished OTC and prescription diphenhydramine products, impacting availability for consumers.

5. What measures do manufacturers take to ensure the environmental sustainability of diphenhydramine hydrochloride production? Manufacturers increasingly focus on greener chemistry principles, including solvent recovery and recycling, waste minimization, optimization of reaction yields to reduce byproducts, and efficient energy usage in manufacturing facilities to reduce their environmental footprint.

Citations

[1] U.S. Food and Drug Administration. (n.d.). Current Good Manufacturing Practice (cGMP) Regulations. Retrieved from [FDA Website] [2] European Directorate for the Quality of Medicines & HealthCare. (n.d.). Certificate of Suitability (CEP). Retrieved from [EDQM Website] [3] European Medicines Agency. (n.d.). EudraLex - The Rules Governing Medicinal Products in the European Union. Retrieved from [EMA Website] [4] United States Pharmacopeia. (n.d.). USP-NF Online. Retrieved from [USP Website] [5] European Pharmacopoeia. (n.d.). Ph. Eur. Online. Retrieved from [EDQM Website]