List of Excipients in Branded Drug HYDROCODONE BITARTRATE AND ACETAMINOPHEN

Generic Drugs Containing HYDROCODONE BITARTRATE AND ACETAMINOPHEN

Company	Ingredient	NDC	Excipient
Hikma Pharmaceuticals USA Inc	hydrocodone bitartrate and acetaminophen	0054-0843	ANHYDROUS CITRIC ACID
Hikma Pharmaceuticals USA Inc	hydrocodone bitartrate and acetaminophen	0054-0843	D&C RED NO. 33
Hikma Pharmaceuticals USA Inc	hydrocodone bitartrate and acetaminophen	0054-0843	ETHYL MALTOL
Hikma Pharmaceuticals USA Inc	hydrocodone bitartrate and acetaminophen	0054-0843	FD&C RED NO. 40
Hikma Pharmaceuticals USA Inc	hydrocodone bitartrate and acetaminophen	0054-0843	GLYCERIN
Hikma Pharmaceuticals USA Inc	hydrocodone bitartrate and acetaminophen	0054-0843	METHYLPARABEN

What are the Most Frequently-Used Excipients in HYDROCODONE BITARTRATE AND ACETAMINOPHEN?

# Of NDCs	Excipient
14	ALCOHOL
1	ALUMINUM OXIDE
13	ANHYDROUS CITRIC ACID
2	ANHYDROUS LACTOSE
232	CELLULOSE, MICROCRYSTALLINE
1	CITRIC ACID

Hydrocodone Bitartrate and Acetaminophen Excipient Strategy, Patent Position, and Commercial Opportunities

Last updated: August 25, 2026

Hydrocodone bitartrate and acetaminophen is a mature, immediate-release opioid combination marketed primarily as tablets, capsules, and oral solutions. The active pharmaceutical ingredient burden is low for hydrocodone and high for acetaminophen, making blend uniformity, dissolution control, tablet robustness, dose flexibility, and abuse-deterrence positioning the main formulation priorities. The strongest commercial opportunities are in low-cost generic manufacturing, differentiated oral liquids, physically robust tablets, tamper-resistant platforms, and contract development and manufacturing services.

What is the FDA status of hydrocodone bitartrate and acetaminophen?

Hydrocodone bitartrate and acetaminophen products are FDA-approved prescription opioid analgesics for the management of pain severe enough to require an opioid analgesic when alternatives are inadequate. Oral products are generally classified as Schedule II controlled substances in the United States. FDA-approved strengths commonly include hydrocodone bitartrate equivalent to 5 mg, 7.5 mg, or 10 mg of hydrocodone with 300 mg of acetaminophen per dosage unit.[1][2]

Product attribute	Commercial position
Active ingredients	Hydrocodone bitartrate and acetaminophen
Primary dosage forms	Immediate-release tablets, capsules, and oral solutions
Typical unit strengths	5/300 mg, 7.5/300 mg, and 10/300 mg hydrocodone/acetaminophen
Regulatory pathway	NDA reference products and ANDA generic products
Controlled-substance class	Schedule II in the United States
Therapeutic category	Opioid analgesic combination
Main formulation issue	Low-dose opioid uniformity combined with high-dose acetaminophen loading
Main safety constraint	Opioid respiratory depression and acetaminophen-associated hepatotoxicity
Biosimilar exposure	None; this is a chemically synthesized small-molecule combination

In 2014, FDA requested that manufacturers of prescription combination products containing hydrocodone and acetaminophen limit acetaminophen to no more than 325 mg per dosage unit. The change reduced the risk of inadvertent acetaminophen overdose from combination products.[3]

What excipients are used in hydrocodone-acetaminophen tablets?

Common excipient classes include fillers, binders, disintegrants, lubricants, glidants, pigments, film-coating polymers, plasticizers, and printing inks. Exact compositions vary by manufacturer and dosage strength.

Representative excipient functions are:

Excipient class	Typical function	Commercial relevance
Microcrystalline cellulose	Filler and dry binder	Supports direct compression and tablet strength
Lactose or other soluble filler	Bulking agent	Can improve mouthfeel and tablet compactability
Povidone	Binder	Improves granule and tablet cohesion
Pregelatinized starch	Binder and disintegrant	Supports robust immediate release
Croscarmellose sodium	Superdisintegrant	Accelerates tablet breakup
Crospovidone	Superdisintegrant	Supports rapid dissolution with low use levels
Sodium starch glycolate	Superdisintegrant	Useful when tablet hardness must be balanced against disintegration
Colloidal silicon dioxide	Glidant	Improves powder flow and blend uniformity
Magnesium stearate	Lubricant	Reduces ejection force but can slow dissolution if overused
Hypromellose	Film former	Provides color, handling protection, and branding
Polyethylene glycol	Plasticizer	Improves coating flexibility
Titanium dioxide or iron oxides	Opacifier or colorant	Supports product differentiation
Sodium benzoate or other approved preservative	Liquid preservation	Relevant to multidose oral solutions
Sweeteners and flavors	Palatability	Critical for oral liquids and pediatric-use positioning

The formulation should be evaluated against FDA’s Inactive Ingredient Database, the applicable USP-NF monographs, and the approved labeling of the reference product.[4][5]

How should the tablet excipient strategy be designed?

The primary technical challenge is the concentration imbalance between hydrocodone and acetaminophen. Hydrocodone is present at a comparatively low level, while acetaminophen constitutes most of the active mass. A process that distributes hydrocodone poorly can produce content-uniformity failures even when the overall blend appears homogeneous.

Blend uniformity and low-dose drug distribution

A robust strategy typically uses:

• Controlled particle-size distributions for both active ingredients.
• Pre-blending or geometric dilution of hydrocodone bitartrate with a portion of filler.
• Low-shear blending before final lubrication.
• Segregation testing during transfer, hopper discharge, and tablet compression.
• In-process controls for blend assay, tablet weight, hardness, friability, and content uniformity.

Direct compression can be commercially attractive because it reduces equipment, solvent, drying, and cycle-time requirements. It is viable when acetaminophen and the excipient system have suitable flow and compactability. Wet granulation may be preferable when the powder blend has poor flow, excessive segregation, or inadequate tablet strength.

Disintegration and dissolution

The target product is generally immediate release. Superdisintegrant selection should account for:

• Acetaminophen particle size.
• Tablet compression force.
• Hydrophobic lubricant exposure.
• Coating weight.
• Storage humidity.
• Desired dissolution profile.

Crospovidone, croscarmellose sodium, and sodium starch glycolate can each support rapid disintegration, but they produce different swelling and wicking behavior. A formulation with high tablet hardness may require a more efficient disintegrant or a dual-disintegrant system.

Magnesium stearate concentration and blending time require close control. Excessive lubrication can reduce wettability and delay acetaminophen dissolution. A supplier or manufacturer with a low-shear lubrication process may gain a quality advantage without changing the active ingredients.

Tablet strength and handling

Hydrocodone-acetaminophen tablets must withstand automated bottling, shipping, counting, and dispensing. The formulation must balance:

• Hardness sufficient to prevent chipping.
• Friability low enough for commercial handling.
• Rapid disintegration.
• Consistent ejection from the tablet press.
• Low risk of capping and lamination.

Microcrystalline cellulose, pregelatinized starch, and selected binders can provide tablet strength. Excess binder or excessive compression can slow drug release and increase the risk that tablets are perceived as difficult to split or crush.

What formulation patents protect hydrocodone-acetaminophen products?

The market is dominated by mature immediate-release products and generic versions. Broad composition-of-matter protection for the active ingredients is not the principal commercial barrier. Relevant intellectual-property categories may include:

1. Specific tablet compositions. These claims can cover defined excipient ratios, hardness ranges, dissolution profiles, or manufacturing steps.
2. Oral liquid formulations. Claims may address preservative systems, flavoring, pH, solubilization, viscosity, or stability.
3. Abuse-deterrent formulations. These may cover hardening polymers, ion-exchange systems, physical barriers, or extraction-resistant matrices.
4. Manufacturing processes. Claims may cover granulation, blending, coating, particle engineering, or controlled addition of hydrocodone.
5. Method-of-use patents. These can cover specific dosing regimens, patient groups, or risk-management applications, although their value depends on labeling and enforceability.
6. Device or packaging patents. Unit-dose, child-resistant, tamper-evident, or dispensing systems may create secondary protection.

An excipient combination is commercially valuable only if it creates a measurable product advantage and can be linked to enforceable claims, regulatory differentiation, or manufacturing cost reduction. A routine substitution of one filler or disintegrant for another generally has limited patent strength.

What is the Orange Book status of hydrocodone-acetaminophen?

Orange Book treatment depends on the specific approved NDA or ANDA and the reference-listed drug. FDA’s Orange Book identifies approved drug products, therapeutic equivalence evaluations, patent information submitted for listed products, and regulatory exclusivity data.[6]

For mature hydrocodone-acetaminophen products, the commercial pattern is generally:

• Original NDA exclusivity periods have expired.
• Generic products are approved through ANDAs.
• Therapeutically equivalent generic tablets are available.
• Any remaining listed patents must be assessed product by product.
• New formulation or abuse-deterrent products may have separate NDA-linked patents and exclusivity.

An ANDA applicant must address applicable listed patents through certification under sections I, II, III, or IV of the Hatch-Waxman framework. Paragraph IV litigation risk exists when an applicant asserts that a listed patent is invalid, unenforceable, or not infringed. For a mature immediate-release product, the primary entry risks are usually manufacturing readiness, controlled-substance compliance, supply continuity, and commercial pricing rather than broad active-ingredient patent barriers.

When does hydrocodone-acetaminophen lose exclusivity?

The conventional hydrocodone-acetaminophen immediate-release market has already passed its principal branded exclusivity period. The timing of generic entry therefore depends on the specific NDA, patent listings, regulatory exclusivity, and ANDA approval status rather than a single market-wide expiration date.

Exclusivity category	Typical status for mature immediate-release products
Active-ingredient patent	Expired or not the primary barrier
Original NDA exclusivity	Generally expired
Formulation patent	Product-specific; may remain for differentiated products
Method-of-use patent	Product-specific and dependent on approved labeling
Orphan exclusivity	Not generally relevant
Pediatric exclusivity	Product-specific and generally expired if granted
ANDA market exclusivity	May apply to an individual first generic, but not to the entire category
Controlled-substance approval	Remains a regulatory and operational requirement

Manufacturers evaluating entry should use the current Orange Book and FDA Drugs@FDA records for each target reference product. FDA’s approval database and labeling records are the controlling sources for current approval status.[6][7]

What abuse-deterrent excipient strategies are commercially relevant?

Abuse-deterrent development is the most technically differentiated excipient opportunity, but it also has the highest development and regulatory burden. FDA evaluates abuse-deterrent products against specific abuse routes and scientific testing standards. A formulation described as abuse-deterrent is not abuse-proof.[8]

Potential platform approaches include:

Polymer-based hardening

Hydrophilic or hydrophobic polymers can increase tablet hardness and reduce powder formation after mechanical manipulation. The formulation must still meet immediate-release dissolution requirements under normal administration.

Matrix and gelling systems

Certain polymers can form viscous gels when exposed to water, limiting syringeability or extraction. The system must be evaluated for dose dumping, food effects, alcohol interactions, and unintended release changes.

Ion-exchange approaches

Ion-exchange resins can bind hydrocodone and reduce extraction under selected conditions. They can complicate release control, content uniformity, and long-term stability.

Multi-layer or coated particles

Drug particles may be coated or embedded in a matrix designed to resist crushing or extraction. This approach can create patentable process and composition claims but increases manufacturing complexity.

Physical and chemical barriers

A product may combine high mechanical strength with excipients that respond to solvents or heat. The commercial value depends on demonstrated performance against defined manipulation methods, not on the presence of a particular polymer.

A differentiated abuse-deterrent product may support a 505(b)(2) strategy if it relies on a previously approved active ingredient but introduces a materially different formulation. The economic case must account for clinical bridging, human abuse-potential studies where required, specialized equipment, and higher quality-control costs.[9]

What oral-liquid excipient opportunities exist?

Oral solutions and suspensions create opportunities for specialty manufacturers, hospital suppliers, and controlled-substance compounding platforms. The main challenges are chemical stability, preservative effectiveness, palatability, dose measurement, and diversion control.

A commercial oral-liquid formulation should address:

• Hydrocodone solubilization and uniform distribution.
• Acetaminophen solubility and precipitation risk.
• pH control.
• Preservative compatibility.
• Flavor masking of bitter opioid and acetaminophen notes.
• Multidose microbial protection.
• Child-resistant packaging.
• Accurate dosing with oral syringes or calibrated cups.
• Stability after opening.
• Low-sedimentation behavior for suspensions.

Excipients such as glycerin, sorbitol, propylene glycol, citrate buffers, approved sweeteners, flavors, and preservatives may be relevant, subject to concentration limits and route-specific safety data. High-viscosity systems can improve dosing control but may reduce patient acceptability or create measurement errors.

The strongest liquid opportunity is not a routine syrup. It is a product with a specific advantage, such as improved stability, lower sugar content, better taste, preservative robustness, unit-dose packaging, or supply reliability.

How does hydrocodone-acetaminophen compare with competing opioid products?

Product category	Main differentiation	Excipient opportunity
Hydrocodone-acetaminophen IR	Familiar oral opioid combination	Low-cost, robust tablets and stable liquids
Oxycodone-acetaminophen IR	Alternative opioid-acetaminophen combination	Similar blend-uniformity and acetaminophen-control needs
Tramadol-acetaminophen	Different opioid and pharmacology	Lower controlled-substance burden in some markets, but different formulation profile
Oxycodone extended release	Long-acting delivery	Abuse-deterrent and release-control technology
Hydrocodone extended release	Long-acting hydrocodone	Polymer matrices and abuse-deterrent systems
Non-opioid analgesics	Avoid opioid exposure	Excipient opportunity shifts toward tolerability and modified release

Hydrocodone-acetaminophen competes on prescribing familiarity, availability, dosage flexibility, and generic price. It is less differentiated than products with extended-release delivery or proprietary abuse-deterrent platforms. Excipient innovation must therefore deliver measurable manufacturing, stability, handling, or abuse-deterrence benefits.

What manufacturing and intellectual-property barriers affect entry?

The main manufacturing barriers are operational rather than molecule-specific.

Controlled-substance handling

Manufacturers need controlled-substance registrations, inventory controls, reconciliation systems, secure storage, diversion monitoring, and compliant waste management. These requirements can limit the number of qualified contract manufacturers.

Acetaminophen process performance

Acetaminophen has challenging flow and compression characteristics in some grades. Particle engineering, granulation, and lubricant control can materially affect tablet quality.

Low-dose hydrocodone uniformity

Hydrocodone distribution must remain consistent across the blend and throughout tablet compression. Segregation during hopper refill or transport is a recurring process risk.

Stability and packaging

The product must maintain assay, dissolution, content uniformity, and appearance under ICH stability conditions. Blister packaging, high-barrier bottles, desiccants, and unit-dose formats may support stability and diversion control.

Patentability of excipient systems

A patent application is stronger when the excipient system is linked to:

• A defined dissolution or extraction profile.
• Improved stability.
• Reduced tablet damage.
• Lower manufacturing cost.
• A validated abuse-deterrent effect.
• A clinically relevant dosing or tolerability benefit.

Routine formulation optimization alone may produce regulatory value without producing durable patent protection.

Which companies are challenging or supplying the market?

The market has historically included branded and generic manufacturers, with generic supply distributed among companies such as Amneal, Hikma, Mallinckrodt, Rhodes Pharmaceuticals, Teva, and other ANDA holders depending on strength, dosage form, and current supply status. Product ownership, marketing status, shortages, and active approvals change over time and must be verified against FDA records and current labeling.[6][7]

Competition is fragmented across:

• Large generic pharmaceutical companies.
• Specialty controlled-substance manufacturers.
• Hospital and institutional suppliers.
• Oral-liquid manufacturers.
• Contract development and manufacturing organizations.
• Abuse-deterrent technology developers.

The strongest partner targets are manufacturers with existing Schedule II infrastructure, validated high-containment operations, and commercial access to retail pharmacies, hospitals, or government accounts.

What commercial opportunities exist for excipient suppliers and drug developers?

Cost-reduction platform

A direct-compression formulation using standard compendial excipients can reduce processing steps and improve gross margin. The opportunity is strongest where the manufacturer can preserve dissolution and content uniformity while reducing granulation and drying costs.

Premium oral liquid

A stable, palatable, low-sugar or unit-dose liquid can target institutional care, patients with swallowing difficulty, and controlled dispensing settings. Packaging and dosing accuracy may be as important as the liquid composition.

Abuse-deterrent reformulation

An abuse-deterrent product can create a differentiated 505(b)(2) opportunity. It requires a stronger evidence package and faces reimbursement and prescriber-adoption constraints.

Excipient supply contracts

Suppliers can compete through:

• Consistent particle-size specifications.
• Low-peroxide or low-moisture grades.
• Functional excipients with documented compaction behavior.
• Reliable supply under controlled-substance manufacturing schedules.
• Technical support for scale-up and process validation.

Manufacturing services

CDMOs can offer value through validated blending, granulation, compression, coating, liquid filling, packaging, and controlled-substance compliance. Capacity reliability may be a decisive commercial factor because opioid products face procurement, quota, and supply-chain restrictions.

How strong is the patent estate for hydrocodone-acetaminophen?

The patent estate for conventional immediate-release hydrocodone-acetaminophen is generally weak as a barrier to generic entry because the active ingredients and basic dosage form are mature. Patent strength improves when protection covers a clinically or commercially meaningful formulation distinction.

Patent category	Relative strength for conventional product	Value for differentiated product
Active ingredients	Low	Low
Basic immediate-release tablet	Low	Low
Specific excipient ratio	Low to moderate	Moderate if performance-linked
Oral-liquid stability system	Moderate	Moderate to high if difficult to design around
Abuse-deterrent matrix	Moderate to high	High
Manufacturing process	Moderate	Moderate to high if scale-sensitive
Packaging and dispensing system	Low to moderate	Moderate in institutional channels
Method of use	Variable	Variable and labeling-dependent

Patent analysis should separate blocking rights from incremental formulation patents. A patent that covers a narrow excipient ratio may be enforceable yet commercially avoidable. A patent tied to an extraction-resistant performance profile or a difficult-to-reproduce manufacturing process may present a more meaningful entry barrier.

What generic launch scenarios exist?

Low-cost conventional tablet

This is the most likely entry model. The developer uses a conventional immediate-release composition, establishes bioequivalence, and competes on price, manufacturing reliability, and channel access. Margin pressure is high.

Supply-constrained entry

A manufacturer may gain share when incumbent suppliers experience shortages or withdraw a strength. The commercial advantage depends on approved strengths, DEA quota availability, and rapid scale-up.

Institutional liquid entry

A preservative-stable and easy-to-dose oral liquid can target hospitals, long-term care, and specialty pharmacies. Differentiation is stronger than in standard tablets but volume is smaller.

Abuse-deterrent product

A new formulation may command a premium or obtain formulary advantages if it generates credible abuse-deterrent evidence. Development time, regulatory cost, and payer response are the principal risks.

Private-label or co-development product

A specialty manufacturer can provide the controlled-substance platform while a commercial partner supplies distribution and pharmacy access. This model reduces commercial infrastructure requirements but creates licensing and supply obligations.

What is the revenue exposure to patent and generic competition?

Revenue exposure is highest for branded products relying on conventional immediate-release tablets without meaningful formulation differentiation. Once multiple therapeutically equivalent generics are available, price erosion can be rapid.

Revenue protection is more plausible when the product has:

• A differentiated dosage form.
• A stable oral liquid with limited competition.
• A protected abuse-deterrent formulation.
• Institutional purchasing contracts.
• Reliable supply during market shortages.
• A strong pharmacy and wholesaler network.
• A formulation that reduces manufacturing cost.

The mature tablet market is volume-driven and price-sensitive. The differentiated-liquid and abuse-deterrent segments offer better pricing potential but require greater development investment and regulatory support.

Key Takeaways

• Hydrocodone bitartrate and acetaminophen is a mature Schedule II immediate-release opioid combination.
• The main formulation challenge is uniform distribution of a low-dose opioid within a high-load acetaminophen tablet.
• Direct compression is attractive when flow, compactability, and blend segregation are controlled.
• Superdisintegrant selection and magnesium stearate control are central to immediate-release dissolution.
• Conventional active-ingredient and basic tablet patents provide limited generic-entry protection.
• Oral liquids, unit-dose packaging, low-sugar systems, and abuse-deterrent formulations offer stronger differentiation.
• Biosimilar risk does not apply because the product is a small-molecule combination.
• Generic competition is established; commercial success depends on cost, supply reliability, channel access, and product differentiation.
• A credible abuse-deterrent platform may support a 505(b)(2) strategy but requires materially higher regulatory and development investment.
• The most defensible excipient opportunity is a formulation tied to measurable stability, dissolution, extraction resistance, dosing accuracy, or manufacturing performance.

FAQs About Hydrocodone-Acetaminophen Excipient and Commercial Strategy

Can hydrocodone-acetaminophen be formulated as a sustained-release product?

Yes, but a sustained-release version would be a materially different product requiring new formulation development, pharmacokinetic evaluation, safety assessment, and regulatory review. It would not be treated as a routine generic equivalent to an immediate-release tablet.

Which excipient is best for hydrocodone-acetaminophen tablet disintegration?

No single excipient is universally best. Crospovidone, croscarmellose sodium, and sodium starch glycolate are common candidates. The optimal choice depends on compression force, acetaminophen particle properties, lubricant level, humidity, and target dissolution.

Is an oral solution or suspension commercially more attractive?

An oral solution can offer simpler dosing uniformity when both active ingredients remain soluble and stable. A suspension may be useful when solubility is limited but creates additional requirements for redispersibility, dose uniformity, viscosity, and patient instructions.

Can an excipient change create a new patent for hydrocodone-acetaminophen?

Yes, if the formulation produces a non-obvious and measurable technical effect, such as improved stability, extraction resistance, dissolution control, or manufacturing performance. A routine substitution of equivalent inactive ingredients is less likely to support durable patent protection.

What is the largest barrier to launching a generic hydrocodone-acetaminophen tablet?

The largest barriers are usually controlled-substance compliance, manufacturing capacity, ANDA approval, reliable hydrocodone supply, blend uniformity, and commercial pricing. For a mature product, these operational constraints can matter more than basic active-ingredient patent rights.

References

1. U.S. Food and Drug Administration. (n.d.). Hydrocodone bitartrate and acetaminophen prescribing information. FDA.
2. DailyMed. (n.d.). Hydrocodone bitartrate and acetaminophen tablet labels. National Library of Medicine.
3. U.S. Food and Drug Administration. (2014). FDA drug safety communication: Prescription combination drug products with more than 325 mg of acetaminophen. FDA.
4. U.S. Food and Drug Administration. (n.d.). Inactive Ingredient Database. FDA.
5. United States Pharmacopeial Convention. (2024). United States Pharmacopeia and National Formulary, USP-NF.
6. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.
7. U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs database. FDA.
8. U.S. Food and Drug Administration. (2015). Guidance for industry: Abuse-deterrent opioids: Evaluation and labeling. FDA.
9. U.S. Food and Drug Administration. (n.d.). Applications covered by the 505(b)(2) regulatory pathway. FDA.