List of Excipients in Branded Drug PROMETHAZINE DM

Generic Drugs Containing PROMETHAZINE DM

Company	Ingredient	NDC	Excipient
PAI Holdings LLC dba PAI Pharma	promethazine hydrochloride and dextromethorphan hydrobromide	0121-1070	ALCOHOL
PAI Holdings LLC dba PAI Pharma	promethazine hydrochloride and dextromethorphan hydrobromide	0121-1070	ASCORBIC ACID
PAI Holdings LLC dba PAI Pharma	promethazine hydrochloride and dextromethorphan hydrobromide	0121-1070	CITRIC ACID MONOHYDRATE
PAI Holdings LLC dba PAI Pharma	promethazine hydrochloride and dextromethorphan hydrobromide	0121-1070	D&C YELLOW NO. 10
PAI Holdings LLC dba PAI Pharma	promethazine hydrochloride and dextromethorphan hydrobromide	0121-1070	FD&C YELLOW NO. 6

What are the Most Frequently-Used Excipients in PROMETHAZINE DM?

# Of NDCs	Excipient
9	ALCOHOL
9	ASCORBIC ACID
1	CITRIC ACID
8	CITRIC ACID MONOHYDRATE
9	D&C YELLOW NO. 10

Promethazine DM Excipient Strategy and Commercial Opportunities

Last updated: September 24, 2026

Promethazine DM is an oral prescription cough-and-cold combination containing promethazine hydrochloride and dextromethorphan hydrobromide. The product category is largely generic, with limited value in the active ingredients themselves. Commercial opportunity is concentrated in excipient-led differentiation: alcohol-free and sugar-free formulations, improved palatability, lower-risk pediatric packaging, dose accuracy, and preservative or colorant alternatives. The strongest regulatory pathway for a conventional equivalent is generally an ANDA; materially differentiated delivery systems may require a 505(b)(2) application.

What is Promethazine DM and how is it regulated?

Promethazine DM combines an antihistamine and phenothiazine derivative, promethazine hydrochloride, with the antitussive dextromethorphan hydrobromide. It is marketed primarily as an oral solution or syrup for temporary relief of cough and associated upper-respiratory symptoms.

Attribute	Promethazine DM
Active ingredients	Promethazine hydrochloride and dextromethorphan hydrobromide
Common dosage form	Oral solution or syrup
Route	Oral
U.S. regulatory status	Prescription drug product
Main therapeutic use	Cough and upper-respiratory symptoms
Primary patient sensitivities	Pediatric safety, sedation, alcohol exposure, sugar exposure, dosing accuracy
Main competitive set	Generic promethazine/dextromethorphan oral solutions
Primary differentiation lever	Formulation and delivery system

Promethazine carries a boxed warning against use in children younger than 2 years because of the risk of fatal respiratory depression. The labeling also warns about sedation, impaired mental and physical abilities, and respiratory risks when combined with other central nervous system depressants (FDA, 2024a). Dextromethorphan has abuse and misuse considerations, particularly at doses above the labeled amount.

What excipients are used in Promethazine DM products?

Promethazine DM excipients vary by manufacturer and product strength. Common formulation components include sucrose or another bulk sweetener, purified water, alcohol or ethanol, glycerin, sodium benzoate, citric acid, sodium citrate, flavoring agents, menthol, and colorants. The exact composition must be established from the current product label or DailyMed entry for each National Drug Code.

Typical excipient functions

Excipient category	Common examples	Primary function	Commercial issue
Sweetener	Sucrose, sorbitol, sucralose	Taste masking and bulk	Diabetes, calories, gastrointestinal tolerance
Co-solvent	Ethanol, glycerin, propylene glycol	Solubilization and mouthfeel	Pediatric, religious, institutional and alcohol-sensitive markets
Preservative	Sodium benzoate	Microbial control	Pediatric exposure and preservative sensitivity
Buffer	Citric acid, sodium citrate	pH control and stability	Taste, active-ingredient stability
Flavor	Cherry, berry, menthol and proprietary flavors	Palatability	Patient acceptance and flavor-substance compatibility
Colorant	Synthetic dyes	Product identification and appearance	Dye-free demand and hypersensitivity concerns
Vehicle	Purified water	Dosage-form carrier	Microbial and physical stability

Promethazine and dextromethorphan create a formulation challenge because the product must balance solubility, chemical stability, preservative performance, and acceptable taste. Promethazine is intensely bitter, while dextromethorphan can produce a strong, lingering taste. A high-sugar syrup can mask both actives but narrows the product’s suitability for some patients.

Product-specific inactive ingredients should not be inferred from another manufacturer’s label. FDA labeling databases show that otherwise equivalent promethazine/dextromethorphan products can use different sweeteners, flavors, colors, preservatives, and solvent systems (FDA, 2024b).

Which excipient strategies offer the strongest commercial opportunities?

The most practical opportunities are not new active ingredients. They are targeted reformulations that remove recognized barriers to use while retaining the familiar oral-solution presentation.

1. Alcohol-free formulation

Alcohol-free Promethazine DM has the broadest commercial rationale. Ethanol can create concerns for pediatric use, patients avoiding alcohol, institutional formularies, religious populations, and consumers taking other sedating medicines.

An alcohol-free system may use a combination of glycerin, propylene glycol, sorbitol, polyethylene glycol, or a surfactant system. The formulation must demonstrate:

• Complete and consistent solubilization of both active ingredients
• Acceptable viscosity and pourability
• Chemical stability over shelf life
• Preservative effectiveness
• No precipitation after temperature cycling
• Acceptable taste and mouthfeel

Alcohol removal alone may be commercially useful but may not create strong patent protection. A patent position is more defensible if the solvent system produces an unexpected stability, taste, or bioavailability result.

2. Sugar-free formulation

A sugar-free product can target patients with diabetes, caregivers seeking lower-sugar medicines, and health-system formularies. Polyols such as sorbitol can provide body and sweetness, while high-intensity sweeteners such as sucralose or acesulfame potassium can reduce sugar load.

The main technical risks are:

• Excessive sweetness or aftertaste
• Gastrointestinal effects from polyols
• Increased viscosity
• Crystallization or precipitation
• Interaction between flavors and sweeteners
• Differences in dosing acceptability among children and adults

A sugar-free formulation should not rely on a one-for-one replacement of sucrose. The product may require a multi-component taste-masking system combining bulk sweetener, high-intensity sweetener, flavor, acidulant, and bitterness blocker.

3. Dye-free formulation

Dye-free Promethazine DM can address parents, pharmacists, and institutions seeking to reduce unnecessary colorants. This is a relatively low-cost product extension, but it is also easy to copy. The commercial benefit is strongest when combined with a broader clean-label position, such as alcohol-free, sugar-free, and preservative-reduced formulation.

4. Improved taste masking

Taste masking is a central value driver. Potential approaches include:

• Ion-pairing or complexation
• Polymer-based taste-masking systems
• Encapsulation of one or both active ingredients
• Bitterness blockers
• Optimized acidulant and flavor systems
• Controlled-release or multiparticulate delivery
• Rapidly dispersible unit-dose formats

A taste-masking patent must distinguish between a routine flavor substitution and a technically demonstrated reduction in bitterness. Sensory data, trained-panel results, electronic-tongue data, dissolution data, and stability results can strengthen the inventive-step argument.

5. Unit-dose packaging and dose-control systems

Promethazine DM is commonly supplied in multidose bottles. Unit-dose cups, oral syringes, sachets, or premeasured stick packs could reduce dosing errors and improve adherence.

The strongest product design would combine:

• A child-resistant and tamper-evident package
• A calibrated oral syringe
• A formulation that remains stable in single-use containers
• Clear differentiation between adult and pediatric dosing
• Packaging that minimizes caregiver confusion

Packaging patents may protect the delivery system even when the formulation itself is difficult to patent. They are more valuable when integrated with a distinctive dose-control mechanism.

What formulations are most attractive for generic and 505(b)(2) development?

Product concept	Likely regulatory route	Commercial attractiveness	Patent potential
Conventional equivalent syrup	ANDA	Moderate	Low
Alcohol-free oral solution	ANDA or 505(b)(2), depending on differences	High	Moderate
Sugar-free oral solution	ANDA or 505(b)(2)	High	Low to moderate
Dye-free solution	ANDA	Moderate	Low
Enhanced taste-masked solution	505(b)(2) more likely if clinically or technically differentiated	High	Moderate to high
Unit-dose oral solution	ANDA if equivalence requirements are met; otherwise 505(b)(2)	Moderate to high	Moderate
Extended-release dextromethorphan/promethazine product	505(b)(2)	Uncertain	High but technically complex
Pediatric-oriented delivery system	505(b)(2) or ANDA depending on design	Moderate	Moderate

An ANDA sponsor must demonstrate pharmaceutical equivalence and bioequivalence to the referenced product. Inactive ingredients may differ, but the proposed formulation must satisfy FDA requirements for safety, quality, performance, and suitability. A formulation that changes release characteristics, absorption, dosing frequency, or clinical use may fall outside a straightforward ANDA strategy (FDA, 2024c).

What patent protection is available for Promethazine DM?

The active-ingredient combination is old and commercially generic. A developer should not assume that composition-of-matter protection remains available for promethazine hydrochloride or dextromethorphan hydrobromide.

Potentially protectable subject matter includes:

1. Specific solvent and co-solvent systems.
2. Taste-masking compositions.
3. Preservative systems with improved stability or reduced concentration.
4. Sugar-free or alcohol-free vehicles.
5. Controlled-release delivery.
6. Unit-dose packaging.
7. Oral syringes or dose-measuring systems.
8. Manufacturing processes that prevent precipitation or degradation.
9. Method-of-use claims for a defined patient population, if supported by new clinical evidence.

How strong is the patent estate for Promethazine DM?

The baseline patent estate is likely weak for an ordinary immediate-release oral solution because the combination, route, and dosage form are established. A new formulation can obtain patent protection, but strength depends on whether the claims cover a narrow, reproducible technical solution rather than a list of conventional excipients.

Claim type	Expected strength for ordinary Promethazine DM	Key vulnerability
Active-ingredient composition	Low	Prior art and expiration history
Basic oral solution	Low	Routine formulation practice
Sugar-free formulation	Low to moderate	Predictable substitution
Alcohol-free formulation	Low to moderate	Known solvent alternatives
Specific taste-masking system	Moderate	Enablement and obviousness
Stability-focused formulation	Moderate	Need comparative data
Controlled-release system	Moderate to high	Technical complexity and prior art
Dose-control packaging	Moderate	Design-around risk
New method of treatment	Variable	Clinical support and obviousness

What is the Orange Book status and exclusivity outlook?

Promethazine DM products are generally prescription products, but commercial status must be assessed at the individual NDA or ANDA level. The Orange Book identifies approved drug products, therapeutic-equivalence evaluations, patent information submitted for listed products, and certain exclusivity periods (FDA, 2024d).

For a conventional generic promethazine/dextromethorphan oral solution:

• No meaningful new-chemical-entity exclusivity is expected.
• Any remaining protection would more likely involve formulation, method-of-use, or product-specific patents.
• Paragraph IV risk depends on the patents listed against the relevant reference product.
• A generic sponsor may file a Paragraph IV certification only when an applicable listed patent exists and the sponsor contests validity, enforceability, or infringement.
• A first-filer advantage is relevant only if the product has qualifying listed patents and statutory exclusivity conditions.

Because the category contains multiple manufacturers and labels, patent analysis must be conducted by reference product, NDA number, dosage form, strength, and listed patent. A category-level statement that "Promethazine DM expires on a single date" would be inaccurate.

What Paragraph IV challenges and litigation affect Promethazine DM?

Promethazine DM does not have the same high-profile Paragraph IV litigation profile associated with newer branded medicines. The primary competitive risk is ordinary generic entry and price competition rather than an imminent patent cliff tied to a dominant branded product.

A company developing a differentiated formulation should review:

• Orange Book patent listings for the selected reference product
• Federal district court filings involving the relevant NDA or ANDA
• Paragraph IV notices
• FDA approval history
• Labeling differences among approved products
• Abbreviated new drug application litigation under the Hatch-Waxman Act

No litigation conclusion should be drawn from the existence of a patent in a public database. The patent must be tied to the specific product, listed use, and proposed commercial formulation.

What generic entry risks exist?

Generic entry risk is high for a standard syrup because the active ingredients are established and multiple manufacturers can compete on price. The main risks to a new entrant are:

• Low barriers to conventional formulation replication
• Retail and wholesaler price pressure
• Limited prescriber loyalty
• Substitution by other cough products
• Product recalls caused by microbial contamination or labeling errors
• Supply interruptions involving active ingredients, bottles, closures, or flavor systems

A differentiated product can reduce direct price competition by targeting an unmet formulation preference. The most defensible commercial package is likely an alcohol-free, sugar-free, dye-free oral solution with calibrated dosing and superior taste, provided the product can maintain acceptable stability and manufacturing cost.

How does Promethazine DM compare with competing cough products?

Product category	Main advantage	Main limitation	Excipient opportunity
Promethazine DM	Antitussive plus antihistamine	Sedation and pediatric warnings	Alcohol-free, sugar-free, taste masking
Dextromethorphan-only products	Lower formulation complexity	No antihistamine component	Long-acting delivery and abuse-deterrent design
Codeine-containing cough products	Strong cough suppression in selected settings	Controlled-substance and respiratory risks	Limited due to regulatory burden
Benzonatate	Non-opioid prescription antitussive	Swallowing and accidental-ingestion concerns	Capsule safety and packaging
OTC antihistamine/cough products	Broad availability	Crowded market and variable efficacy	Pediatric dosing and clean-label vehicles

Promethazine DM’s commercial position is constrained by sedation, respiratory-depression warnings, and the availability of OTC cough medicines. Its strongest niche is a prescription liquid product with better tolerability and usability rather than a premium price based only on the active ingredients.

What manufacturing and intellectual-property barriers matter?

Manufacturing control is commercially important because oral solutions are vulnerable to content-uniformity, microbial, precipitation, and stability failures. Key process controls include:

• Order of addition for active ingredients and excipients
• pH adjustment
• Mixing time and shear
• Temperature control
• Deaeration
• Preservative distribution
• Filtration, where appropriate
• Container-closure compatibility
• In-use stability after opening

A process patent may be valuable if it solves a reproducible manufacturing problem, such as preventing precipitation during storage or maintaining uniformity in a low-alcohol vehicle. Trade-secret protection may be more practical for flavor systems, mixing order, and process parameters that are difficult to reverse engineer.

Geographic protection should be planned separately. U.S. formulation patents do not protect sales in Europe, Canada, Japan, or emerging markets. Patent filing decisions should reflect local demand for prescription cough products, pediatric formulations, alcohol-free products, and unit-dose packaging.

What licensing deals and commercial partnerships are relevant?

The most realistic partnership targets are:

• Generic manufacturers with established oral-liquid capacity
• Specialty pharmaceutical companies focused on pediatric products
• Contract development and manufacturing organizations
• Flavor and taste-masking technology providers
• Oral-syringe and unit-dose packaging suppliers
• Regional distributors with institutional-pharmacy access

A licensing agreement is more attractive when the licensor contributes a protected formulation, validated taste-masking platform, regulatory package, or differentiated packaging system. A conventional promethazine/dextromethorphan syrup is unlikely to justify a significant upfront payment unless it has a clear supply, channel, or regulatory advantage.

What is the revenue opportunity for a reformulated Promethazine DM product?

Public revenue estimates should not be assumed for the entire Promethazine DM category because sales are fragmented across multiple generic manufacturers, private-label products, wholesalers, and pharmacy channels. Commercial modeling should separate:

• Prescription retail volume
• Institutional and long-term-care demand
• Pediatric versus adult use
• Bottle versus unit-dose sales
• Branded, authorized-generic, and unbranded pricing
• Gross-to-net deductions
• Formulation-development and packaging costs
• Potential cannibalization of existing products

A premium price is more defensible for an alcohol-free, sugar-free, taste-masked product with strong dosing convenience than for a simple color or flavor change.

Key Takeaways

• Promethazine DM is an established prescription combination with high generic competition.
• Excipient strategy, not active-ingredient novelty, is the principal commercial opportunity.
• Alcohol-free, sugar-free, dye-free, taste-masked, and unit-dose formats have the clearest product rationale.
• Conventional excipient substitutions generally offer weak patent protection.
• Stronger patents require demonstrated technical effects, such as improved stability, reduced bitterness, or controlled release.
• Pediatric safety, sedation, alcohol exposure, and dosing accuracy are central product-development constraints.
• A conventional equivalent is generally an ANDA opportunity; a materially differentiated delivery system may require a 505(b)(2) pathway.
• Orange Book and Paragraph IV analysis must be performed against the specific reference product and listed patents.
• Manufacturing controls for solubility, microbial preservation, pH, and container compatibility are major execution risks.
• Revenue opportunity depends on differentiated positioning and channel access rather than active-ingredient exclusivity.

FAQs

Can Promethazine DM be reformulated without ethanol?

Yes. An alcohol-free formulation is technically feasible, but it requires a validated solvent, preservative, taste, and stability system. Removing ethanol may change solubility and precipitation behavior.

Is a sugar-free Promethazine DM product patentable?

It may be patentable if the formulation contains a non-obvious composition with demonstrated technical benefits. A basic replacement of sucrose with sorbitol or sucralose is vulnerable to obviousness challenges.

Does Promethazine DM have biosimilar risk?

No. Promethazine DM is a small-molecule drug combination, not a biologic. The relevant competitive threat is generic entry, not biosimilar substitution.

Can a company obtain pediatric exclusivity for Promethazine DM?

Potentially, but pediatric exclusivity is tied to an FDA-requested and completed pediatric study program. It is not automatically available for a reformulated generic product.

What is the most commercially attractive Promethazine DM product concept?

An alcohol-free, sugar-free, dye-free oral solution with verified taste masking, a calibrated oral syringe, child-resistant packaging, and strong in-use stability has the clearest differentiated commercial profile.

References

1. U.S. Food and Drug Administration. (2024a). Promethazine hydrochloride and dextromethorphan hydrobromide oral solution: Prescribing information. FDA labeling database.

2. U.S. Food and Drug Administration. (2024b). DailyMed: Promethazine hydrochloride and dextromethorphan hydrobromide oral solution products. National Library of Medicine.

3. U.S. Food and Drug Administration. (2024c). ANDA submissions: Content and format of abbreviated new drug applications. FDA.

4. U.S. Food and Drug Administration. (2024d). Approved drug products with therapeutic equivalence evaluations. FDA.