List of Excipients in Branded Drug ACETAMINOPHEN WITH CODEINE

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Generic Drugs Containing ACETAMINOPHEN WITH CODEINE

Company	Ingredient	NDC	Excipient
PharmPak Inc	acetaminophen, codeine phosphate	54348-015	CELLULOSE, MICROCRYSTALLINE
PharmPak Inc	acetaminophen, codeine phosphate	54348-015	MAGNESIUM STEARATE
PharmPak Inc	acetaminophen, codeine phosphate	54348-015	POVIDONES
PharmPak Inc	acetaminophen, codeine phosphate	54348-015	SODIUM METABISULFITE
PharmPak Inc	acetaminophen, codeine phosphate	54348-015	SODIUM STARCH GLYCOLATE TYPE A POTATO

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

# Of NDCs	Excipient
1	CELLULOSE, MICROCRYSTALLINE
1	MAGNESIUM STEARATE
1	POVIDONES
1	SODIUM METABISULFITE
1	SODIUM STARCH GLYCOLATE TYPE A POTATO

Acetaminophen With Codeine Excipient Strategy and Commercial Opportunities

Last updated: August 9, 2026

Acetaminophen with codeine is a mature fixed-dose analgesic combination with limited conventional patent value and substantial regulatory constraints. The strongest commercial opportunities are in differentiated dosage forms, excipient systems that improve manufacturability and patient use, abuse-deterrent design, and markets where reliable supply or differentiated packaging commands a premium.

Standard immediate-release tablets are generally commodity products. Product value depends more on cost, regulatory execution, controlled-substance compliance, manufacturing reliability, and channel access than on active-ingredient exclusivity.

What is acetaminophen with codeine?

Acetaminophen with codeine combines the non-opioid analgesic acetaminophen with codeine phosphate, an opioid that is metabolized in part to morphine through CYP2D6. Common U.S. strengths include:

Product strength	Acetaminophen	Codeine phosphate	Typical dosage form
300 mg/15 mg	300 mg	15 mg	Immediate-release tablet or capsule
300 mg/30 mg	300 mg	30 mg	Immediate-release tablet or capsule
300 mg/60 mg	300 mg	60 mg	Immediate-release tablet or capsule
120 mg/12 mg per 5 mL	120 mg	12 mg	Oral solution
120 mg/12 mg per 5 mL equivalent	Variable	Variable	Pediatric or adult liquid products

The combination is used for pain severe enough to require an opioid when alternative treatments are inadequate. The acetaminophen component creates a ceiling on total daily exposure because excessive acetaminophen can cause severe liver injury. The codeine component creates opioid-related risks, including respiratory depression, misuse, dependence, and overdose [1].

In the United States, many acetaminophen-codeine products containing no more than 90 mg of codeine per dosage unit are federally classified as Schedule III controlled substances. State scheduling, dispensing requirements, and product classification can differ [2].

What patents protect acetaminophen with codeine products?

Standard acetaminophen-codeine immediate-release products generally have little commercially relevant active-ingredient patent protection in the United States. Acetaminophen and codeine are long-established active ingredients, and conventional tablet combinations have been marketed for decades.

IP category	Commercial relevance for standard products
Acetaminophen composition patents	Generally expired or irrelevant to conventional products
Codeine composition patents	Generally expired or irrelevant to conventional products
Fixed-dose combination patents	Limited for conventional immediate-release tablets
Conventional excipient patents	Usually weak unless tied to a specific manufacturing or performance result
Modified-release formulations	Potentially relevant if technically differentiated
Abuse-deterrent formulations	Potentially relevant, but requires clinical and regulatory support
Taste-masked liquids or orally disintegrating products	Potentially protectable through formulation claims
Manufacturing processes	Can create narrower barriers where process performance is difficult to replicate
Packaging and dispensing systems	Possible secondary protection, usually modest in scope

The commercial question is rarely whether an innovator patent blocks a standard generic tablet. The more relevant question is whether a reformulated product can obtain a defensible formulation, process, or device patent before competitors reproduce the same performance.

Patent applicants may seek protection for:

• Controlled-release matrices
• Multiparticulate dosage forms
• Abuse-deterrent tablets
• Low-dust or tamper-resistant granules
• Taste-masked oral liquids
• Orally disintegrating tablets
• Effervescent or rapidly dissolving formulations
• Moisture-stable tablets
• Low-acetaminophen formulations intended to reduce cumulative exposure
• Manufacturing processes that improve content uniformity or tablet robustness

A formulation patent must do more than list familiar excipients. The strongest claims usually connect a defined composition to measurable performance, such as dissolution, tamper resistance, stability, reduced dose dumping, improved palatability, or manufacturing yield.

What is the Orange Book status of acetaminophen with codeine?

The FDA Orange Book lists approved prescription drug products and related patent and exclusivity information for eligible products. Standard acetaminophen-codeine products are commonly approved through abbreviated new drug applications or legacy approvals, rather than protected by a current, commercially significant innovator patent estate [3].

A product-specific Orange Book review should distinguish among:

1. An approved reference listed drug.
2. Approved ANDA products.
3. Any listed patents.
4. Pediatric exclusivity or other regulatory exclusivity.
5. Whether a listed patent remains unexpired.
6. Whether the patent covers the product, formulation, method of use, or packaging.

For a new acetaminophen-codeine formulation, an applicant may pursue an NDA under section 505(b)(2) if it relies partly on published literature or an approved product while introducing a material change. A conventional duplicate product would more likely follow the ANDA pathway, provided the reference product and bioequivalence requirements support that route [4].

When does acetaminophen with codeine lose exclusivity?

The active ingredients and conventional fixed-dose combination do not normally create a current exclusivity barrier for standard tablets. Market entry is therefore governed primarily by FDA approval, controlled-substance requirements, manufacturing capacity, state rules, and commercial contracting.

Potential exclusivity mechanisms for a new product include:

Exclusivity route	Potential application
New chemical entity exclusivity	Generally unavailable because both active ingredients are old
Three-year clinical investigation exclusivity	Possible for an NDA containing qualifying new clinical investigations
Orphan-drug exclusivity	Generally irrelevant to ordinary analgesic use
Pediatric exclusivity	Possible only through qualifying FDA-requested pediatric studies
Five-year new product exclusivity	Generally unavailable for an old combination unless statutory conditions are met
Patent term	Available for qualifying new formulation, method, process, or device claims

A reformulated product should not assume that a new excipient blend will generate regulatory exclusivity. FDA exclusivity depends on statutory criteria, while patentability depends on novelty, non-obviousness, written description, enablement, and claim scope.

What excipients are used in acetaminophen-codeine tablets?

Immediate-release tablets commonly use excipients from established pharmaceutical classes. Exact compositions vary by manufacturer and strength.

Excipient class	Common examples	Strategic purpose
Diluent	Microcrystalline cellulose, lactose, dibasic calcium phosphate	Controls tablet weight and improves compressibility
Binder	Povidone, pregelatinized starch, hydroxypropyl cellulose	Improves granule and tablet strength
Disintegrant	Croscarmellose sodium, sodium starch glycolate, crospovidone	Promotes rapid tablet breakup
Lubricant	Magnesium stearate, sodium stearyl fumarate	Reduces ejection force and sticking
Glidant	Colloidal silicon dioxide	Improves powder flow
Sweetener	Sucralose, saccharin sodium, sorbitol	Supports liquid or orally disintegrating products
Flavor	Cherry, grape, mint, vanilla	Masks codeine bitterness in liquids
Suspending agent	Xanthan gum, sodium carboxymethylcellulose, microcrystalline cellulose blends	Maintains dose uniformity in liquids
Preservative	Depending on formulation and packaging	Controls microbial growth in multidose liquids
Film coating	Hypromellose, polyethylene glycol, pigments	Improves swallowability, appearance, and handling

The most important excipient constraint is dissolution control. Acetaminophen has relatively high-dose loading, while codeine is present at a much lower dose. The formulation must maintain content uniformity for codeine without creating an overly dense or poorly disintegrating tablet.

What excipient strategy is best for immediate-release tablets?

The base-case strategy is a robust direct-compression or dry-granulation platform with fast disintegration, low weight variation, and controlled lubricant exposure.

A practical development approach includes:

• Use microcrystalline cellulose or a co-processed filler for compressibility.
• Use crospovidone or croscarmellose sodium to achieve rapid disintegration.
• Control magnesium stearate blending time because over-lubrication can slow dissolution.
• Use separate premixes or geometric dilution to improve low-dose codeine uniformity.
• Evaluate segregation during hopper discharge and tablet compression.
• Set dissolution targets that protect against delayed release after scale-up.
• Use film coating only when it does not materially delay disintegration.
• Validate blend uniformity at commercial batch scale.

For a patent strategy, the formulation should be linked to measurable advantages. Examples include a narrower dissolution profile, improved tablet hardness at lower compression force, lower friability, reduced sticking, or reduced content- uniformity variability.

A patent claim directed only to "acetaminophen, codeine, microcrystalline cellulose, and magnesium stearate" is vulnerable if the combination is routine. A claim supported by defined ratios, processing conditions, particle-size distributions, and demonstrated performance is stronger.

What formulation patents are available for acetaminophen with codeine?

The strongest formulation opportunities are outside the conventional tablet.

Abuse-deterrent formulations

Abuse-deterrent approaches may include:

• High-viscosity polymer matrices
• Gel-forming excipients
• Crush-resistant granules
• Ion-exchange resins
• Insoluble or waxy barriers
• Physical properties that resist powdering
• Formulations that reduce opioid extraction

The presence of acetaminophen creates a design problem. A formulation that makes codeine difficult to extract must also prevent unintended rapid acetaminophen release or excessive exposure. FDA evaluates abuse-deterrent products under product-specific guidance and does not treat a formulation claim as proof of abuse-deterrent effectiveness [5].

Taste-masked oral liquids

Codeine is bitter, and acetaminophen can contribute to taste and mouthfeel problems. Useful excipient systems include:

• Ion-exchange resin complexes
• Polymer coatings
• Flavor and sweetener systems
• Viscosity modifiers
• pH adjustment
• Suspensions with controlled particle size
• Unit-dose packaging to reduce dosing errors

A liquid product has commercial potential where pediatric, geriatric, or swallowing-impaired patients need an oral dosage form. The regulatory risk is higher because palatability, preservative effectiveness, microbial quality, sedimentation, redispersibility, and measuring-device accuracy must be controlled.

Orally disintegrating tablets

Orally disintegrating tablets can improve administration for patients who cannot swallow conventional tablets. The principal challenges are codeine bitterness, tablet friability, moisture sensitivity, and dose uniformity.

Potential excipient platforms include mannitol-based fillers, crospovidone, low-substituted hydroxypropyl cellulose, flavor systems, and taste-masking coatings. Commercial differentiation is possible, but reimbursement and opioid prescribing restrictions limit the addressable market.

Modified-release products

Modified-release acetaminophen-codeine products face substantial technical and regulatory barriers. The formulation must prevent rapid codeine release, avoid acetaminophen dose dumping, and demonstrate pharmacokinetic comparability or clinical benefit. A matrix that controls one active ingredient but not the other may produce an unstable exposure relationship.

Modified release is more defensible when it addresses a specific clinical need. Without a clear benefit, the product may incur higher development costs without sufficient pricing power.

What FDA regulatory issues affect commercial development?

FDA risk is driven by the opioid component, the acetaminophen toxicity ceiling, and the age of the intended population.

The FDA labeling framework includes important restrictions:

• Codeine should not be used in children younger than 12 years.
• Codeine is contraindicated for postoperative pain management in patients younger than 18 after tonsillectomy and/or adenoidectomy.
• Breastfeeding is contraindicated because of the potential for serious adverse reactions in infants.
• Ultra-rapid CYP2D6 metabolizers may convert codeine to morphine rapidly, increasing toxicity risk [1].

FDA also issued a 2018 safety communication recommending that prescription cough and cold medicines containing codeine or hydrocodone not be used in children younger than 18 years. That action does not eliminate all analgesic uses, but it narrows pediatric commercial positioning [6].

For combination products, total acetaminophen exposure must be addressed across all medicines. Labeling, unit-dose design, prescriber education, and dispensing controls can reduce accidental duplicate use.

What generic entry risks exist for acetaminophen with codeine?

Generic entry risk is high for standard immediate-release products because:

• The active ingredients are old.
• The dosage forms are technologically familiar.
• Multiple manufacturers can source the excipients.
• Bioequivalence is usually more straightforward than for modified-release products.
• Brand switching is relatively easy for pharmacies and wholesalers.
• Payers generally favor low-cost alternatives.

The principal barriers are operational rather than patent-based:

• Controlled-substance registration and security controls
• Quota and supply-management requirements
• FDA inspection readiness
• Raw-material availability
• Tablet weight and content-uniformity control
• Product listing and labeling compliance
• State opioid rules
• Wholesaler and pharmacy acceptance

A new immediate-release product should assume rapid generic substitution unless it has a clear delivery, safety, adherence, supply, or contracting advantage.

Which companies compete in acetaminophen-codeine products?

Competition includes branded legacy products, generic manufacturers, contract manufacturers, and regional pharmaceutical companies. The market is fragmented, and the leading commercial position can change with shortages, wholesaler contracts, and manufacturing discontinuations.

Relevant competitive groups include:

• Large generic manufacturers with controlled-substance infrastructure
• Specialty pharmaceutical companies with reformulation capabilities
• Contract development and manufacturing organizations
• Regional manufacturers supplying oral liquids
• Hospital and institutional suppliers
• International manufacturers selling country-specific formulations

A company entering the market should evaluate not only approved competitors but also discontinued products, shortage history, manufacturing-site concentration, and the availability of alternate strengths.

How does acetaminophen with codeine compare with competing analgesics?

Product	Main commercial advantage	Main constraint
Acetaminophen with codeine	Low-cost combination and established prescribing familiarity	Opioid restrictions, CYP2D6 variability, acetaminophen toxicity
Tramadol/acetaminophen	Alternative opioid combination with broader branded history	Seizure and serotonin risks, opioid controls
Hydrocodone/acetaminophen	Stronger opioid analgesic effect and established use	Greater controlled-substance and misuse scrutiny
Oxycodone/acetaminophen	High analgesic potency	Higher abuse, dependence, and overdose concerns
NSAID combinations	Non-opioid mechanism and lower opioid exposure	Gastrointestinal, renal, cardiovascular, and bleeding risks
Acetaminophen alone	Low regulatory burden and broad accessibility	Less effective for severe acute pain

The commercial position of acetaminophen-codeine is strongest where low acquisition cost and familiar dosing outweigh the disadvantages of codeine variability and opioid restrictions.

What licensing opportunities exist?

Licensing opportunities are more credible for enabling technology than for the old active ingredients. Potential deal structures include:

• An abuse-deterrent formulation licensed to a generic manufacturer
• A taste-masking platform licensed for oral liquids
• A co-processed excipient system that improves tablet manufacturability
• A controlled-substance manufacturing partnership
• A regional commercialization license
• A unit-dose packaging and dispensing system
• A 505(b)(2) reformulation with territory-specific rights

The licensor should protect the formulation with composition, process, performance, and use claims where support exists. Royalty economics are likely to be limited for standard tablets and stronger for products with regulatory differentiation, supply exclusivity, or demonstrable abuse-deterrent performance.

How strong is the patent estate for acetaminophen with codeine?

The patent estate is weak for conventional immediate-release products and potentially moderate for technically differentiated formulations.

Product concept	Patent strength	Commercial outlook
Conventional 300/30 mg tablet	Low	Price-driven generic market
Standard oral solution	Low to moderate	Opportunity depends on palatability and supply
Taste-masked unit-dose liquid	Moderate	Potential institutional and pediatric-adjacent value, subject to labeling limits
Orally disintegrating tablet	Moderate	Differentiation possible but limited market size
Abuse-deterrent tablet	Moderate to strong if validated	Higher development cost and regulatory burden
Modified-release product	Moderate to strong	Requires substantial clinical and pharmacokinetic investment
Novel manufacturing process	Moderate	Barrier depends on process necessity and detectability
Packaging-only innovation	Low to moderate	Useful as secondary protection

What are the highest-value commercial opportunities?

The most credible opportunities are:

1. A stable, low-cost immediate-release tablet supported by reliable supply.
2. A taste-masked oral liquid with accurate dosing and strong microbial control.
3. A unit-dose product for hospitals, correctional facilities, or institutional pharmacies.
4. A reformulation that reduces tablet damage, powder generation, or manipulation risk.
5. A regional product tailored to local controlled-substance rules and dosage preferences.
6. A manufacturing platform that improves low-dose codeine uniformity and reduces batch failures.

A premium strategy based solely on familiar excipients is unlikely to succeed. The formulation must create an observable benefit that affects approval, prescribing, dispensing, procurement, or patient use.

Key Takeaways

• Acetaminophen with codeine is a mature, highly genericized analgesic combination.
• Conventional immediate-release tablets have limited patent and exclusivity value.
• Excipient strategy should prioritize content uniformity, rapid dissolution, tablet robustness, and manufacturing economics.
• Taste masking, orally disintegrating tablets, unit-dose liquids, and abuse-deterrent systems offer the strongest differentiation paths.
• Pediatric positioning is constrained by FDA codeine restrictions.
• Modified-release products face significant dose-dumping, pharmacokinetic, and clinical-development risks.
• Commercial success depends more on supply reliability, controlled-substance compliance, and formulation performance than on the old active ingredients.
• Patent claims should connect excipient composition to measurable technical performance.

FAQs

Can a new excipient combination obtain a patent for acetaminophen with codeine?

Yes, but routine excipient substitution is unlikely to provide strong protection. Patentability improves when the formulation has a non-obvious composition, defined processing conditions, and documented performance such as faster dissolution, improved stability, taste masking, or abuse deterrence.

Is acetaminophen with codeine eligible for an ANDA?

A duplicate of an approved reference product may be eligible for the ANDA pathway if it meets FDA requirements for pharmaceutical equivalence, bioequivalence, labeling, manufacturing, and controlled-substance compliance [4].

Can an acetaminophen-codeine liquid be positioned for children?

Labeling is heavily restricted because of codeine safety concerns. Products must comply with FDA age-related warnings and contraindications, and a pediatric commercial strategy requires careful review of the intended age group, indication, dosing device, and labeling [1,6].

Do abuse-deterrent excipients eliminate opioid liability?

No. Abuse-deterrent formulation technology may reduce certain forms of manipulation or extraction, but it does not eliminate addiction, overdose, or diversion risk. FDA evaluates abuse-deterrent performance through product-specific studies [5].

Is a 505(b)(2) strategy commercially attractive for this combination?

It can be attractive for a differentiated product with a meaningful clinical or administration advantage. The economics are weaker for a conventional tablet because generic competition can limit pricing and market share.

References

1. U.S. Food and Drug Administration. (2023). Acetaminophen and codeine phosphate tablets: Prescribing information. FDA.
2. U.S. Drug Enforcement Administration. (2024). Drug scheduling. U.S. Department of Justice.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. FDA.
4. U.S. Food and Drug Administration. (2024). Abbreviated new drug application (ANDA) process. FDA.
5. U.S. Food and Drug Administration. (2020). Abuse-deterrent opioids: Evaluation and labeling. FDA.
6. U.S. Food and Drug Administration. (2018). FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. FDA.