List of Excipients in Branded Drug REMIFENTANIL HYDROCHLORIDE

Generic Drugs Containing REMIFENTANIL HYDROCHLORIDE

Company	Ingredient	NDC	Excipient
Hikma Pharmaceuticals USA Inc	remifentanil hydrochloride	0143-9391	GLYCINE
Hikma Pharmaceuticals USA Inc	remifentanil hydrochloride	0143-9391	HYDROCHLORIC ACID
Fresenius Kabi USA LLC	remifentanil hydrochloride	63323-723	GLYCINE
Fresenius Kabi USA LLC	remifentanil hydrochloride	63323-723	HYDROCHLORIC ACID
Navinta LLC	remifentanil hydrochloride	68475-505	GLYCINE

What are the Most Frequently-Used Excipients in REMIFENTANIL HYDROCHLORIDE?

# Of NDCs	Excipient
4	GLYCINE
4	HYDROCHLORIC ACID

Remifentanil Hydrochloride Excipient Strategy and Commercial Opportunities

Last updated: August 30, 2026

Remifentanil hydrochloride is an established generic intravenous opioid with limited protection at the active-ingredient level and meaningful commercial differentiation available through formulation, packaging, administration, and supply reliability. The strongest opportunities are ready-to-use presentations, lower-concentration products for pediatric and procedural use, premixed infusion bags, and packaging that reduces preparation errors without compromising chemical stability or microbial control.

What is the current FDA status of remifentanil hydrochloride?

Remifentanil hydrochloride is an FDA-approved short-acting opioid administered by continuous intravenous infusion for induction and maintenance of general anesthesia, monitored anesthesia care, and immediate postoperative analgesia where rapid titration is required.[1]

The reference product, Ultiva, was marketed by GlaxoSmithKline and originally supplied as a sterile, preservative-free lyophilized powder for reconstitution. Generic remifentanil hydrochloride products are approved as injectable products under abbreviated new drug applications.

Attribute	Remifentanil hydrochloride
Pharmacologic class	Synthetic opioid analgesic
Primary use	General anesthesia and monitored anesthesia care
Administration	Continuous intravenous infusion
Dosage form	Sterile lyophilized powder for injection
Typical vial strengths	1 mg, 2 mg, and 5 mg
Key excipient in reference formulation	Glycine
Preservatives	None
Metabolism	Rapid hydrolysis by nonspecific blood and tissue esterases
Onset and offset	Rapid, with limited context-sensitive accumulation
FDA pathway for generics	ANDA
Biosimilar pathway	Not applicable
Current protection profile	Mature generic market; core exclusivity expired

Remifentanil has a short duration of action because its ester linkage is rapidly hydrolyzed. That property supports use during procedures requiring rapid adjustment of anesthetic depth but creates formulation and administration requirements that differ from longer-acting opioids.[1,2]

What excipients are used in remifentanil hydrochloride injection?

The reference formulation uses glycine as the principal excipient. The product is supplied as a sterile lyophilized cake that must be reconstituted and diluted before intravenous administration.[1]

Glycine

Glycine performs several formulation functions:

• It supports the lyophilized cake structure.
• It improves reconstitution behavior.
• It contributes to the solids content of the formulation.
• It is compatible with a sterile, preservative-free injectable product.
• It avoids introducing a reactive carbohydrate or complex buffer system.

The use of glycine gives generic manufacturers a relatively clear qualitative target. A formulation that substitutes mannitol, sucrose, trehalose, or another bulking agent may be technically feasible, but the change can affect cake appearance, reconstitution time, residual moisture, osmolality, and bioequivalence risk.

pH control

Remifentanil hydrochloride is formulated as an acidic solution after reconstitution. The labeled product has an approximate pH range of 2.5 to 3.5.[1] The low pH helps maintain chemical stability but can create tolerability and compatibility considerations if the product is administered through small peripheral veins or mixed with alkaline solutions.

A commercial formulation should control:

• Final pH after reconstitution.
• pH drift during storage.
• Degradation under elevated temperature.
• Compatibility with common infusion fluids.
• Local tolerability at the intended concentration.

A low-buffer or buffer-free strategy may reduce incompatibility risk. A strong buffer may improve pH control but can increase excipient burden, alter osmolality, and create compatibility problems with other drugs used in the operating room.

Water for injection and reconstitution media

The powder is reconstituted with an appropriate sterile diluent and then further diluted before infusion. The product labeling identifies compatible intravenous fluids, including sodium chloride injection and dextrose-containing solutions, subject to the labeled concentration and handling conditions.[1]

A manufacturer seeking commercial differentiation can supply:

• A vial plus a dedicated reconstitution syringe.
• A dual-chamber container.
• A ready-to-use diluted infusion bag.
• A pharmacy-prepared bulk solution with validated in-use stability.
• A low-volume presentation for syringe pumps.

The principal technical issue is not simply reconstitution. It is maintaining potency, clarity, sterility, and concentration accuracy through the full preparation and administration period.

What formulation patents could protect remifentanil hydrochloride products?

The original remifentanil compound and basic injectable formulation are mature technologies. Core composition-of-matter and early product protections are generally expired, and current commercial value is unlikely to depend on a new patent covering remifentanil itself.

Potentially protectable subject matter includes:

Patent area	Commercial relevance	Likely patent position
Ready-to-use remifentanil solution	Reduces pharmacy preparation	Potentially patentable if stability and packaging are non-obvious
Premixed infusion bag	Supports operating-room workflow	Potentially protectable through formulation and container claims
Dual-chamber delivery system	Separates drug and diluent until use	Protectable primarily through device and combination claims
Low-concentration solution	Supports pediatric or procedural dosing	Requires evidence of stability and clinical utility
Adsorption-control system	Addresses loss to tubing or containers	Potentially protectable if tied to specific materials or excipients
Lyophilization cycle	Improves cake quality and residual moisture	Usually vulnerable to obviousness unless linked to unexpected performance
Ready-to-administer syringe	Reduces dosing steps	More likely protected through container, device, or method claims
Premixed combination anesthetic	May simplify anesthesia protocols	Higher regulatory and compatibility burden

Patent claims directed only to routine substitution of a known bulking agent or conventional pH adjustment would face meaningful obviousness risk. Stronger claims would require comparative data showing unexpected stability, reduced adsorption, lower preparation error, or a clinically meaningful improvement in administration.

How should an excipient strategy address remifentanil stability?

The formulation strategy should prioritize chemical stability, sterility, low adsorption, and operational simplicity. Remifentanil's rapid enzymatic degradation after administration is clinically useful but does not by itself guarantee long-term product stability in a container.

Lyophilized powder strategy

A lyophilized presentation remains the lowest-risk platform for a generic product. It separates the active ingredient from the aqueous environment during storage and aligns with the established reference product.

Development priorities include:

1. Matching reconstitution time and solution appearance.
2. Controlling residual moisture.
3. Protecting against oxidation and hydrolysis.
4. Demonstrating container-closure integrity.
5. Establishing stability after reconstitution and dilution.
6. Validating compatibility with infusion bags, syringes, and tubing.

Glycine-based formulations can be optimized through cake structure, fill volume, vial size, and lyophilization cycle design. These changes may improve manufacturing yield without materially changing the clinical product.

Ready-to-use liquid strategy

A ready-to-use liquid could offer a larger commercial advantage but has a higher technical burden. The liquid must remain stable throughout shelf life and must preserve concentration after contact with the container and administration set.

A development program should assess:

• pH and buffer selection.
• Oxygen exposure and headspace control.
• Light sensitivity.
• Extractables and leachables.
• Sorption to polyvinyl chloride and other tubing materials.
• Stability in polypropylene syringes and polyolefin bags.
• Precipitation after dilution.
• Microbial control without preservatives.
• In-use stability under operating-room conditions.

Preservatives are generally unattractive for an intravenous anesthetic intended for rapid administration. A preservative-free, terminally sterilized or aseptically filled product would better align with the existing safety profile, although the manufacturing process must support sterility assurance.

Adsorption and container compatibility

Low-dose infusions can be vulnerable to losses from adsorption to tubing, syringes, and infusion bags. The risk depends on concentration, surface area, contact time, polymer type, flow rate, and prior conditioning of the administration set.

A commercial product can differentiate through:

• Validated low-sorption container materials.
• Supplied administration sets.
• Concentration ranges that reduce percentage loss.
• Instructions addressing line priming.
• Compatibility data for common anesthesia pumps.
• Packaging that limits unnecessary transfer steps.

Such claims have greater commercial value if they reduce dose variability in low-flow or pediatric infusions.

What dosage forms and delivery systems offer the best commercial opportunity?

The most attractive opportunity is a ready-to-administer presentation for hospitals that value workflow efficiency and medication-error reduction.

Opportunity ranking

Product concept	Technical risk	Commercial potential	Regulatory complexity
Generic lyophilized vial	Low	Moderate	Low
Larger hospital vial	Low to moderate	Moderate	Low
Ready-to-use syringe	Moderate	High in procedural settings	Moderate
Premixed infusion bag	Moderate to high	High in operating rooms and intensive care	Moderate
Dual-chamber vial or bag	High	High if preparation reduction is demonstrated	High
Pediatric low-dose presentation	Moderate	Targeted but defensible	Moderate
Extended-stability pharmacy bulk solution	Moderate	High for institutional buyers	Moderate
Combination with another anesthetic	High	Uncertain	High

A standard vial remains commercially useful where price is the primary purchasing criterion. A ready-to-use syringe or premixed bag can command a premium when it reduces pharmacy labor, preparation time, and medication-selection risk.

When did remifentanil lose exclusivity?

Remifentanil's basic compound and original product protections are historical and expired. The product is therefore exposed to conventional generic competition rather than biosimilar competition.

The relevant exclusivity profile is:

Exclusivity category	Current assessment
Composition-of-matter patent	Expired
Original injectable formulation patent	Expired or no longer commercially blocking
New chemical entity exclusivity	Expired
Orphan-drug exclusivity	Not applicable to the core product
Pediatric exclusivity	No current blocking effect
Reference-product exclusivity	Expired
Biosimilar exclusivity	Not applicable

The FDA Orange Book is the controlling source for listed patents and regulatory exclusivity associated with approved products.[3] Any launch analysis should distinguish expired historical patents from live patents covering a specific reformulated product, delivery device, or method of use.

What is the Orange Book status of remifentanil hydrochloride?

Remifentanil hydrochloride is an established small-molecule injectable listed in FDA drug databases. Its generic competition proceeds through the ANDA pathway, not the 505(b)(2) pathway unless a sponsor seeks a materially different formulation or delivery system.

The main Orange Book implications are:

• Generic applicants can rely on the reference product's safety and efficacy findings.
• A conventional vial formulation has limited opportunity to rely on new clinical differentiation.
• A materially different ready-to-use formulation may require additional bridging, stability, or clinical support.
• Patent certifications under Paragraph III or Paragraph IV depend on any patents listed for the relevant reference product at the time of filing.

Which companies are challenging or competing with remifentanil hydrochloride?

Competition is primarily among generic injectable manufacturers and institutional suppliers. Market participation has included major generic companies such as Hikma, Pfizer's Hospira business, Fresenius Kabi, and other injectable-drug manufacturers, depending on market, supply period, and product availability.

The competitive factors are:

• Contract price.
• Backorder performance.
• Vial strength availability.
• Sterile manufacturing capacity.
• Hospital contracting.
• Bar-code and electronic medication administration compatibility.
• Shelf life.
• Ready-to-use options.
• Regulatory inspection history.
• Ability to supply during anesthesia-drug shortages.

No biosimilar manufacturers are relevant because remifentanil is a chemically synthesized small molecule, not a biologic.

What Paragraph IV and patent litigation risks exist?

Paragraph IV risk for a conventional remifentanil hydrochloride vial is limited because the core patent estate is mature. The greater litigation risk would arise from a newly developed formulation, device, or delivery system that claims a commercial advantage over the generic vial.

Potential disputes could involve:

• Premixed solution stability.
• Specific pH or buffer ranges.
• Container and tubing compatibility.
• Dual-chamber packaging.
• Use of a ready-to-administer concentration.
• Method-of-use claims for procedural sedation or pediatric anesthesia.
• Patentability of lyophilization parameters.

A sponsor should avoid relying on broad claims that merely restate known remifentanil use. Narrow, data-backed claims tied to a defined composition, container, or administration protocol are more defensible.

What manufacturing and intellectual-property barriers affect remifentanil?

The primary barriers are operational rather than molecular. Sterile injectable manufacturing capacity, controlled-substance handling, validated aseptic processing, and supply reliability can matter more than active-ingredient access.

Key barriers include:

• Controlled-substance security and recordkeeping.
• Sterile fill-finish capacity.
• Low-dose assay accuracy.
• Lyophilization cycle consistency.
• Container-closure integrity.
• Stability after reconstitution.
• Infusion-set compatibility.
• Hospital qualification requirements.
• Short-notice supply demands from operating rooms.
• Procurement concentration among large group purchasing organizations.

A manufacturer with reliable sterile capacity and a differentiated presentation may compete effectively even without an active-ingredient patent.

How large is the revenue opportunity for an excipient-led remifentanil product?

Revenue exposure is concentrated in institutional markets rather than retail pharmacy. The product is administered in operating rooms, intensive care units, procedural suites, and anesthesia services. Public companies generally do not report remifentanil revenue separately from broader injectable portfolios.

The most defensible commercial model is a premium-over-vial strategy:

• Standard vial: price-driven, high generic competition.
• Ready-to-use syringe: premium justified by reduced preparation and waste.
• Premixed bag: premium justified by workflow efficiency and pharmacy outsourcing.
• Specialty pediatric concentration: premium supported by dose precision and reduced dilution steps.
• Emergency-stock presentation: value tied to availability and shelf-life management.

The addressable opportunity is strongest where hospitals incur high labor costs for sterile compounding or face recurrent shortages of short-acting anesthetics. A differentiated product should demonstrate lower total cost of use, not only a higher unit price.

Key Takeaways

• Remifentanil hydrochloride is a mature generic intravenous opioid with expired core exclusivity.
• Glycine-based lyophilized powder remains the lowest-risk formulation strategy.
• Ready-to-use syringes and premixed infusion bags offer the clearest commercial differentiation.
• pH, hydrolytic stability, adsorption, container compatibility, and preservative-free sterility are central development issues.
• Formulation and device patents are more relevant than composition-of-matter patents.
• Paragraph IV risk is limited for a conventional vial but may arise around new delivery systems.
• No biosimilar pathway applies.
• Hospital workflow, sterile supply reliability, and shortage resilience are the main commercial value drivers.

FAQs

Can remifentanil hydrochloride be formulated without glycine?

Yes. Glycine is not the only technically possible excipient, but replacing it can affect cake structure, reconstitution, residual moisture, osmolality, and stability. A substitute must be supported by comparative formulation and regulatory data.

Is a premixed remifentanil infusion bag patentable?

Potentially. Patentability would depend on the specific composition, concentration, container, stability profile, and administration system. A generic premixed solution using conventional ingredients may face obviousness challenges.

Does remifentanil require a preservative?

The established injectable product is preservative-free. A preservative is generally undesirable for an intravenous anesthetic, particularly when the product is intended for rapid administration and single-use handling.[1]

What is the best remifentanil presentation for pediatric anesthesia?

A low-concentration ready-to-use syringe or a small-volume presentation may reduce dilution steps and dosing errors. The product must address adsorption, low-flow delivery, concentration accuracy, and compatibility with pediatric infusion devices.

Can a remifentanil formulation qualify for 505(b)(2) approval?

A materially different formulation or delivery system may fit a 505(b)(2) strategy if the sponsor cannot rely entirely on the reference product through an ANDA. The regulatory route depends on the extent of formulation, device, labeling, and clinical differences.

References

1. U.S. Food and Drug Administration. (2018). Ultiva (remifentanil hydrochloride) for injection prescribing information. GlaxoSmithKline.

2. Egan, T. D. (1995). Pharmacokinetics and pharmacodynamics of remifentanil: An update in the clinical setting. Clinical Pharmacokinetics, 29(Suppl. 1), 92-101.

3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/