List of Excipients in Branded Drug ACETAMINOPHEN AND CODEINE PHOSPHATE

Generic Drugs Containing ACETAMINOPHEN AND CODEINE PHOSPHATE

Company	Ingredient	NDC	Excipient
Teva Pharmaceuticals USA Inc	acetaminophen and codeine phosphate	0093-0050	CELLULOSE, MICROCRYSTALLINE
Teva Pharmaceuticals USA Inc	acetaminophen and codeine phosphate	0093-0050	CROSCARMELLOSE SODIUM
Teva Pharmaceuticals USA Inc	acetaminophen and codeine phosphate	0093-0050	MAGNESIUM STEARATE

What are the Most Frequently-Used Excipients in ACETAMINOPHEN AND CODEINE PHOSPHATE?

# Of NDCs	Excipient
16	ALCOHOL
6	ANHYDROUS CITRIC ACID
1	AQUA

Acetaminophen and Codeine Phosphate Excipient Strategy and Commercial Opportunities

Last updated: July 31, 2026

Acetaminophen and codeine phosphate is a mature immediate-release oral combination with limited composition-of-matter patent protection and substantial generic competition. Commercial differentiation depends on excipient selection, tablet performance, abuse-deterrence positioning, manufacturing efficiency, supply reliability, and regulatory execution rather than on new-molecule exclusivity. The strongest opportunities are low-cost robust tablets, pediatric-risk-controlled products, swallowability improvements, and differentiated packaging or distribution models.

What is acetaminophen and codeine phosphate?

Acetaminophen and codeine phosphate combines a non-opioid analgesic with an opioid analgesic. U.S. dosage strengths commonly include:

Product strength	Acetaminophen	Codeine phosphate	Typical use
300/15	300 mg	15 mg	Mild to moderate pain
300/30	300 mg	30 mg	Moderate pain
300/60	300 mg	60 mg	Moderate to moderately severe pain

The combination is generally supplied as an immediate-release tablet or oral solution. Codeine phosphate is the salt form used in many products, while acetaminophen is present as the active analgesic. U.S. labeling identifies the product as an opioid-containing analgesic and includes respiratory-depression, misuse, addiction, neonatal opioid-withdrawal, and hepatotoxicity warnings.[1]

The commercial product is usually prescribed for short-term pain where a non-opioid component is combined with a lower opioid dose. Acetaminophen exposure must be controlled because excessive cumulative daily intake can cause severe liver injury.

What excipients are used in acetaminophen and codeine phosphate tablets?

Common excipient systems include diluents, binders, disintegrants, lubricants, glidants, pigments, and film-coating materials.

Excipient function	Common materials	Formulation purpose
Diluent	Microcrystalline cellulose, lactose, starch, dibasic calcium phosphate	Provides tablet mass and improves compression
Binder	Povidone, pregelatinized starch, hydroxypropyl cellulose	Improves granule and tablet strength
Disintegrant	Croscarmellose sodium, crospovidone, sodium starch glycolate	Promotes tablet breakup and dissolution
Lubricant	Magnesium stearate, sodium stearyl fumarate	Reduces ejection force and tooling friction
Glidant	Colloidal silicon dioxide	Improves powder flow
Film coat	Hypromellose, polyethylene glycol, titanium dioxide, iron oxides	Improves appearance, handling, swallowability, and identification
Sweetener and flavor	Sucrose, saccharin sodium, sucralose, fruit flavors	Used mainly in oral liquids
Suspending agent	Xanthan gum, microcrystalline cellulose and carboxymethylcellulose, sodium carboxymethylcellulose	Maintains uniformity in oral suspensions

The formulation target is difficult because acetaminophen is present at a much higher mass than codeine phosphate, while the active ingredients have different powder-flow, particle-size, dissolution, and segregation characteristics. The excipient system must maintain content uniformity for a low-dose opioid without compromising acetaminophen dissolution.

How should an excipient strategy address acetaminophen and codeine phosphate?

A practical strategy begins with the manufacturing route and the target dosage form.

Direct-compression strategy

Direct compression can reduce processing time and eliminate a wet-granulation drying step. Microcrystalline cellulose, spray-dried lactose, dibasic calcium phosphate, crospovidone, colloidal silicon dioxide, and a low-level lubricant are common candidates.

The main risks are:

• Segregation of low-dose codeine phosphate from high-load acetaminophen
• Poor flow caused by fine acetaminophen particles
• Capping or lamination at high tablet compression force
• Slower dissolution from excessive compaction or hydrophobic lubrication
• Tablet-weight variability during high-speed compression

Direct compression is most attractive when the active ingredients have been engineered for compatible particle-size distributions or are premixed using a controlled blending process.

Wet-granulation strategy

Wet granulation can improve flow, reduce segregation, and increase tablet tensile strength. Povidone, pregelatinized starch, or hydroxypropyl cellulose can be used as binders. The process adds drying, solvent, energy, and validation requirements.

Wet granulation is generally favored when:

• Acetaminophen has poor flow or compressibility
• Codeine phosphate requires improved distribution
• Tablets fail friability or mechanical-strength targets
• The formulation needs high batch-to-batch robustness
• The product will be manufactured at scale with demanding compression speeds

The process must control exposure to moisture because excipient and active-ingredient interactions can affect assay, degradation, and dissolution.

Roller compaction

Roller compaction offers a dry-granulation route for formulations that require better flow but cannot tolerate wet processing. It can improve blend uniformity and reduce drying costs. Process development must manage ribbon density, granule-size distribution, fines generation, and dissolution behavior.

What formulation problems create commercial opportunities?

The highest-value formulation opportunities are linked to performance failures rather than to new active ingredients.

Content uniformity

Codeine phosphate is a low-dose component in many strengths. The formulation must prevent segregation during blending, transfer, hopper storage, and tablet compression. A controlled premix or ordered blending process can improve uniformity.

Potential commercial advantages include:

• Lower assay variability
• Improved batch release consistency
• Reduced blend rejection
• Better suitability for high-speed manufacturing
• More reliable scale-up across sites

Dissolution

Acetaminophen tablets must dissolve promptly, while codeine phosphate must remain available for absorption. Excessive binder, over-compression, or magnesium stearate can slow dissolution. Disintegrant selection and particle-size control are therefore central to generic development.

A formulation that consistently meets dissolution specifications across multiple media can reduce post-approval manufacturing risk and support broader supplier flexibility.

Tablet size and swallowability

The high acetaminophen load creates a relatively large tablet. A smaller tablet can improve patient acceptability but may require higher-density fillers, granulation, or a more efficient compression profile.

Potential approaches include:

• High-density dibasic calcium phosphate
• Spray-dried lactose
• Co-processed excipients
• Bilayer or multilayer designs, where justified
• Film coating optimized for swallowability rather than cosmetic thickness

The commercial value is higher in older adults, patients with dysphagia, and short-course outpatient use.

Moisture and stability

Codeine phosphate and acetaminophen can be sensitive to formulation and packaging conditions. The stability program should evaluate:

• Water activity
• Tablet hardness and friability over time
• Assay and degradation products
• Dissolution after accelerated storage
• Container-closure performance
• Color or coating changes

Blister packaging, high-barrier bottles, desiccants, or unit-dose pouches can support stability and improve dispensing control.

What oral-liquid excipient opportunities exist?

Oral liquids create more formulation complexity and more meaningful differentiation than conventional tablets.

A liquid product may use water, glycerin, sorbitol solution, sucrose, propylene glycol, citric acid or citrate buffers, flavoring agents, preservatives, and suspending polymers. The formulation must maintain:

• Uniform codeine concentration throughout the bottle
• Acetaminophen solubility or stable suspension characteristics
• Acceptable taste
• Microbial control
• Dose-measurement accuracy
• Chemical stability
• Compatibility with oral syringes and dosing cups

A solution offers dose uniformity advantages if both active ingredients remain dissolved. A suspension may allow higher drug loading but requires sedimentation control, redispersibility testing, and clear labeling.

Taste masking is commercially important because codeine is bitter and acetaminophen can contribute additional taste burden. Sweeteners and flavors alone may be insufficient. Polymer-based taste masking, ion-exchange resins, coated particles, or multiparticulate systems may improve acceptability, but each approach creates additional regulatory and manufacturing complexity.

Because of opioid safety concerns, oral liquids should prioritize calibrated oral syringes, tamper-evident packaging, child-resistant closures, and clear concentration labeling. Concentration confusion is a recognized medication-error risk in liquid products.

What regulatory status applies to acetaminophen and codeine phosphate?

Acetaminophen and codeine phosphate products are generally approved through the U.S. drug application system as prescription products. Generic manufacturers typically use the abbreviated new drug application pathway when an appropriate reference listed drug is available.

Relevant FDA requirements include:

• Pharmaceutical equivalence
• Bioequivalence
• Assay and content uniformity
• Dissolution
• Impurity and degradation control
• Stability
• Labeling conformity
• Manufacturing under current good manufacturing practice
• Controlled-substance security and recordkeeping

Codeine combination products are subject to opioid labeling requirements. FDA has stated that codeine-containing products should not be used in children younger than 12 years and should not be used for pain control after tonsillectomy or adenoidectomy in patients younger than 18 years. Breastfeeding warnings apply because of the risk of serious adverse reactions in infants.[2]

The product also remains subject to acetaminophen safety controls. A commercial product must communicate maximum daily acetaminophen exposure and warn against concurrent use with other acetaminophen-containing medicines.

What is the Orange Book and patent status of acetaminophen and codeine phosphate?

The combination is a mature product with no meaningful new-chemical-entity exclusivity. Generic competition has existed for many years, and commercial protection is generally based on manufacturing economics, product quality, supply reliability, regulatory approvals, and customer contracts.

The Orange Book identifies approved reference products, therapeutic-equivalence information, and any applicable patent or exclusivity listings. The exact listing status depends on the specific reference product and must be reviewed by strength, dosage form, application number, and current FDA publication.[3]

Core acetaminophen and codeine phosphate tablets are not generally protected by an enforceable composition-of-matter patent comparable to a modern branded drug. Any remaining patent exposure would more likely arise from:

• A particular formulation
• A modified-release design
• A taste-masked oral liquid
• A delivery device
• A manufacturing process
• A specific method of treatment
• A later-developed abuse-deterrent platform

For a conventional immediate-release generic, the principal legal pathway is usually an ANDA with Paragraph III or Paragraph IV certifications, depending on the Orange Book record. A Paragraph IV certification can trigger patent litigation under the Hatch-Waxman framework if a listed patent is asserted.

When does acetaminophen and codeine phosphate lose exclusivity?

The conventional product has already lost practical market exclusivity. There is no single future loss-of-exclusivity date controlling the entire category because different reference products, strengths, dosage forms, and applications may have different regulatory histories.

Protection type	Commercial relevance
New chemical entity exclusivity	Not relevant to this mature combination
Pediatric exclusivity	Product-specific and historical
Orphan exclusivity	Not applicable to ordinary analgesic use
Core composition patent	Generally expired or absent
Formulation patent	Relevant only to a specifically claimed formulation
Method-of-use patent	Potentially relevant if listed and enforceable
ANDA exclusivity	May apply to a specific first generic approval
Market exclusivity	Depends on the reference application and FDA record

The practical entry risk for conventional tablets is therefore high from a competition perspective and low from a core-patent perspective. A new entrant must compete on cost, availability, quality, and channel access.

Are Paragraph IV challenges likely for this product?

Paragraph IV activity is less strategically important for long-established immediate-release acetaminophen and codeine phosphate products than for newer branded medicines. The relevant question is whether the proposed product relies on a reference listed drug with an unexpired Orange Book patent.

A conventional generic developer may instead face:

• Bioequivalence requirements
• Controlled-substance registration and quotas
• Manufacturing-site inspection
• Supply-chain scrutiny
• Product-specific labeling restrictions
• Customer qualification requirements

Paragraph IV litigation becomes more relevant if the developer pursues a differentiated product with a patented formulation, abuse-deterrence feature, extended-release profile, or specialty delivery system.

What manufacturing and intellectual-property barriers matter?

Manufacturing barriers are more significant than patent barriers for the standard product.

Manufacturing barriers

Key technical barriers include:

• Achieving codeine content uniformity at low dosage
• Maintaining consistent acetaminophen dissolution
• Managing tablet weight and hardness
• Controlling blend segregation
• Establishing reliable lubricant distribution
• Avoiding cross-contamination in opioid manufacturing areas
• Meeting controlled-substance reconciliation requirements
• Maintaining uninterrupted acetaminophen and codeine-phosphate supply

Opioid products require controlled access, inventory controls, security procedures, and detailed records. These requirements can increase operating cost and reduce the number of qualified manufacturing sites.

Intellectual-property barriers

Potentially defensible areas include:

• Abuse-deterrent matrices
• Sequestered or aversive codeine formulations
• Multiparticulate systems
• Taste-masked oral liquids
• Unit-dose delivery systems
• Stable high-concentration liquids
• Low-moisture manufacturing processes
• Specific excipient combinations that improve dissolution or uniformity

A formulation patent is more valuable when it covers a reproducible product attribute and is difficult to design around. Broad claims based only on routine excipients are less likely to create durable commercial protection.

What commercial opportunities exist for manufacturers?

Low-cost generic tablets

The largest opportunity is a reliable, low-cost supply of 300/15, 300/30, and 300/60 mg tablets. Buyers value consistent fill rates, low defect rates, predictable lead times, and competitive pricing.

Contract manufacturing and private-label supply

Retail, hospital, and institutional buyers may source approved products through private-label or contract-manufacturing arrangements. A manufacturer with controlled-substance capability can create value through:

• Flexible batch sizes
• Multi-strength manufacturing
• Backup supply agreements
• Regional packaging
• Unit-dose hospital formats
• Serialization and track-and-trace capability

Unit-dose and institutional packaging

Blister cards, unit-dose pouches, and tamper-evident formats can target hospitals, ambulatory surgery centers, correctional-health systems, and long-term-care facilities. Packaging does not eliminate opioid risk but can improve inventory control and dispensing accountability.

Oral-liquid products

A stable, palatable, accurately measurable liquid can address patients who cannot swallow tablets. Differentiation may come from:

• Preservative system
• Flavor profile
• Oral-syringe compatibility
• Low-sedimentation suspension
• Child-resistant packaging
• Clear concentration presentation
• Smaller dispensing volumes

Supply-chain resilience

Acetaminophen and codeine phosphate manufacturers can compete through dual sourcing, domestic production, validated alternate suppliers, and inventory planning. Shortages or allocation constraints can shift market share quickly in mature generic categories.

How does acetaminophen and codeine phosphate compare with competing analgesics?

Product	Opioid exposure	Acetaminophen exposure	Main commercial advantage	Main risk
Acetaminophen/codeine	Yes	Yes	Established combination and broad generic supply	Respiratory depression, dependence, liver toxicity
Ibuprofen/codeine	Yes	No	Avoids acetaminophen exposure	NSAID gastrointestinal, renal, and cardiovascular risks
Tramadol/acetaminophen	Yes, atypical opioid	Yes	Different prescribing profile	Seizure, serotonin, dependence, and liver risks
Oxycodone/acetaminophen	Yes	Yes	Higher opioid potency	Greater abuse, overdose, and respiratory-depression concerns
Acetaminophen alone	No	Yes	Low-cost non-opioid option	Insufficient efficacy for some pain conditions
NSAID alone	No	No	Anti-inflammatory activity	Gastrointestinal, renal, and cardiovascular risk

The principal competitive pressure comes from non-opioid analgesics and other opioid combinations. A product with lower codeine content may be attractive where clinicians want to limit opioid exposure, while the 300/60 mg strength may face greater scrutiny because of higher codeine exposure.

Which licensing and partnering opportunities exist?

Licensing value is limited for an unprotected standard tablet but can be meaningful for differentiated technology.

Potential licensing targets include:

• Taste-masking platforms
• Abuse-deterrent delivery systems
• Co-processed excipients
• High-load direct-compression technology
• Controlled-substance manufacturing capacity
• Specialty oral-liquid platforms
• Regional regulatory approvals
• Hospital and government supply contracts

A company seeking to license the product should prioritize rights that include formulation know-how, validated manufacturing processes, regulatory dossiers, and commercial supply commitments. A license covering only an old active-ingredient combination is unlikely to create strong bargaining leverage.

What generic launch scenarios exist?

Standard immediate-release tablet

This is the fastest route but has the lowest differentiation. Success depends on approval timing, cost of goods, manufacturing reliability, and channel access.

Premium supply product

A manufacturer can seek premium positioning through consistent availability, domestic or dual-source production, hospital packaging, and superior customer service. The product remains therapeutically substitutable, so price discipline is required.

Differentiated oral liquid

This route has greater technical and regulatory complexity but may create stronger customer retention through taste, stability, dosing, and packaging attributes.

Abuse-deterrent or misuse-resistant formulation

This has the highest potential differentiation but also the greatest development burden. The formulation must demonstrate meaningful performance characteristics and obtain appropriate FDA labeling support. A claim that a product is merely harder to manipulate is not equivalent to FDA-recognized abuse-deterrent labeling.

Key Takeaways

• Acetaminophen and codeine phosphate is a mature, highly genericized opioid analgesic combination.
• Core patent protection is generally not the main commercial barrier.
• Excipient selection should focus on codeine content uniformity, acetaminophen dissolution, tablet size, mechanical strength, and stability.
• Direct compression offers cost advantages, while wet granulation and roller compaction can improve process robustness.
• Oral liquids provide more meaningful differentiation through taste masking, suspension control, dosing accuracy, and packaging.
• Controlled-substance manufacturing, supply reliability, and opioid compliance are material operating barriers.
• The strongest commercial opportunities are reliable generic tablets, unit-dose institutional products, differentiated oral liquids, and licensed manufacturing or formulation technologies.
• Any Orange Book, patent, Paragraph IV, or exclusivity assessment must be conducted by reference product, strength, dosage form, and application.

FAQs

Is acetaminophen and codeine phosphate still patent protected?

The conventional immediate-release combination is generally not protected by a live composition-of-matter patent. Product-specific formulation or method patents must be assessed through the current Orange Book record.

Can a company sell a private-label acetaminophen and codeine product?

Yes, subject to FDA approval, controlled-substance requirements, manufacturing compliance, labeling controls, and an appropriate commercial or contract-manufacturing arrangement.

Which excipient is most important for codeine content uniformity?

No single excipient determines uniformity. Particle-size control, premixing, blending order, granulation, flow properties, and low-segregation processing are usually more important than the identity of one excipient.

Is an acetaminophen and codeine oral liquid commercially attractive?

It can be attractive where patients need a liquid dosage form, but taste, microbial control, concentration labeling, redispersibility, dosing accuracy, and child-resistant packaging create substantial development requirements.

Does an abuse-deterrent formulation automatically receive patent protection?

No. Patentability depends on the claimed formulation or process. FDA abuse-deterrent labeling is a separate regulatory question and requires appropriate evidence under FDA standards.

References

1. U.S. Food and Drug Administration. (2024). Acetaminophen and codeine phosphate tablets: Prescribing information. FDA Drugs@FDA.

2. U.S. Food and Drug Administration. (2017). FDA drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children. https://www.fda.gov

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

4. U.S. Food and Drug Administration. (2020). Clinical drug interaction studies: Study design, data analysis, and clinical implications. FDA.

5. U.S. Food and Drug Administration. (2020). Assessment of abuse deterrent properties of opioid formulations: Guidance for industry. FDA.

6. U.S. Pharmacopeial Convention. (2024). United States Pharmacopeia and National Formulary. USP.