List of Excipients in Branded Drug GADOBUTROL

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Generic Drugs Containing GADOBUTROL

Company	Ingredient	NDC	Excipient
Viwit Pharmaceutical Co Ltd	gadobutrol	42337-007	CALCOBUTROL SODIUM
Viwit Pharmaceutical Co Ltd	gadobutrol	42337-007	HYDROCHLORIC ACID
Viwit Pharmaceutical Co Ltd	gadobutrol	42337-007	TROMETHAMINE
Viwit Pharmaceutical Co Ltd	gadobutrol	42337-007	WATER
Fresenius Kabi USA LLC	gadobutrol	65219-281	CALCOBUTROL SODIUM

What are the Most Frequently-Used Excipients in GADOBUTROL?

# Of NDCs	Excipient
8	CALCOBUTROL SODIUM
8	HYDROCHLORIC ACID
8	TROMETHAMINE
4	WATER

GADOBUTROL Excipient Strategy, Formulation Patents, and Commercial Opportunities

Last updated: September 24, 2026

Gadobutrol is a high-concentration, nonionic macrocyclic gadolinium-based contrast agent supplied primarily as a ready-to-use intravenous injection. Its commercial formulation contains gadobutrol, calcobutrol sodium, trometamol, hydrochloric acid, and water for injection. The strongest excipient opportunities are in injectable-grade raw materials, formulation optimization, container-closure systems, manufacturing controls, and differentiated presentations rather than in a new active-ingredient patent position. [1]

What is the FDA-approved gadobutrol formulation?

Gadavist, marketed by Bayer, contains gadobutrol at 1.0 mmol/mL, equivalent to 604.72 mg/mL. The product is supplied as a sterile aqueous injection in single-dose vials, prefilled syringes, and pharmacy bulk packages in certain markets. The labeled formulation includes the following components: [1]

Component	Function in the formulation	Commercial relevance
Gadobutrol	Active gadolinium chelate	High-value active pharmaceutical ingredient
Calcobutrol sodium	Calcium-containing formulation component associated with reduction of free gadolinium exposure	Potentially specialized sourcing and quality-control requirement
Trometamol	Buffer and pH-control agent	Injectable-grade supply opportunity
Hydrochloric acid	pH adjustment	Commodity but regulated sterile-manufacturing input
Water for injection	Vehicle	Requires compendial and sterile-manufacturing compliance

The labeled pH is approximately 6.6 to 7.4. The formulation is designed for high gadobutrol concentration while maintaining acceptable osmolality, chemical stability, sterility, and injection performance. [1]

Why is calcobutrol sodium commercially important?

Calcobutrol sodium differentiates the formulation from a simple aqueous solution of gadobutrol. The calcium-containing component is associated with reducing the potential for free gadolinium release and improving the safety profile of the finished product. Its use creates a technical barrier for manufacturers seeking to reproduce the reference formulation with the same inactive ingredients.

A supplier entering this segment would need control over:

• Identity and purity testing.
• Trace-metal limits.
• Calcium-to-chelate stoichiometry.
• Residual solvents and inorganic impurities.
• Stability under sterilization and storage.
• Batch-to-batch consistency at low concentration.
• Compatibility with the primary container and elastomeric closure.

Calcobutrol sodium is therefore more strategically relevant than conventional excipients such as hydrochloric acid or water for injection. It may support a qualified-supplier position even where the active ingredient and finished dosage form are no longer strongly protected by core composition patents.

What excipient strategy is most attractive for gadobutrol?

The highest-value strategy is a formulation platform that supports generic or alternative-source gadobutrol while controlling free-gadolinium risk, particulate formation, extractables, and container interaction.

1. Reference-formulation matching

The lowest regulatory-risk approach is to reproduce the qualitative and quantitative inactive-ingredient profile of the reference product. This strategy can simplify comparative pharmaceutical evaluation and reduce the need to justify a novel excipient system.

The commercial disadvantages are limited differentiation and dependence on the same specialized raw materials. A supplier may still create value through:

• A qualified alternate source of calcobutrol sodium.
• Improved control of trace metals.
• Lower impurity profiles.
• Better supply continuity.
• Smaller minimum order quantities for emerging generic manufacturers.
• Regional manufacturing and distribution.

2. Alternative-buffer formulation

Trometamol is the reference buffer. Alternative buffers could be evaluated, but substitution would require a substantial data package covering pH stability, gadolinium-chelate integrity, osmolality, viscosity, compatibility, and toxicological acceptability for parenteral use.

Potential screening candidates include phosphate, citrate, acetate, histidine, and other pharmaceutically accepted buffers. Their commercial viability is limited by risks such as:

• Metal-ion interactions.
• Precipitation or complexation.
• Changes in osmolality.
• Reduced stability during terminal sterilization.
• New extractables or leachables profiles.
• Regulatory scrutiny of a non-reference inactive ingredient.

A buffer-substitution strategy is more suitable for a differentiated product or follow-on development program than for a rapid ANDA strategy.

3. Low-excipient formulation

A lower-excipient formulation could reduce raw-material complexity and simplify the label. It would also remove or reduce the role of calcobutrol sodium, which may create safety, stability, or regulatory concerns.

The main technical challenge is demonstrating that the formulation remains equivalent in:

• Gadolinium chelate stability.
• Free gadolinium levels.
• pH.
• Osmolality.
• Sterility.
• Visible and subvisible particles.
• Container-closure integrity.
• In-use handling.

For a generic product, a low-excipient formulation may increase development cost and regulatory risk despite lowering manufacturing complexity.

What patents protect gadobutrol and its formulation?

Gadobutrol was developed as a macrocyclic, nonionic gadolinium chelate. The earliest composition and use patents were filed decades before the current commercial market. Core patent protection for the active substance is therefore generally expired or near the end of its enforceable life in major jurisdictions.

Patent analysis should separate four categories:

Patent category	Relevance to gadobutrol	Current commercial impact
Active-ingredient composition patents	Protect gadobutrol or related chelates	Core protection is generally expired in major markets
Manufacturing patents	Cover synthesis, purification, or crystallization	May remain relevant where process claims are unexpired or confidential
Formulation patents	Cover calcobutrol sodium, buffers, concentration, or stability systems	Potentially relevant to follow-on products
Method-of-use patents	Cover MRI applications and patient populations	Usually less significant for a product with broad established clinical use

The practical barrier is less likely to be a broad composition patent than the need to produce a sterile, stable, high-concentration injectable with a technically defensible impurity profile.

How strong is the gadobutrol patent estate?

The estate is strongest where claims cover:

• A specific combination of gadobutrol and calcobutrol sodium.
• Defined impurity limits.
• Stabilized aqueous solutions.
• Container-closure combinations.
• Manufacturing processes that improve purity or reduce free gadolinium.
• Specific prefilled syringe or autoinjector presentations.

The estate is weaker for broad claims directed only to gadobutrol as a molecule, particularly in the United States and Europe where early patents have reached expiration.

A freedom-to-operate review should cover the reference product’s Orange Book records, international patent families, continuation applications, manufacturing patents, and patents assigned to Bayer or related entities. The Orange Book is the primary FDA source for listed patents and regulatory exclusivity associated with approved drug products. [2]

What is the Orange Book status of Gadavist?

Gadavist was approved by the FDA under NDA 201277 in 2011. Its approved uses include contrast-enhanced MRI of the central nervous system, breast MRI, magnetic resonance angiography in selected settings, and cardiac MRI indications added through subsequent regulatory actions. Pediatric use has also been included for certain indications. [1,3]

For commercial planning, the relevant status is:

Regulatory issue	Assessment
NDA holder	Bayer HealthCare Pharmaceuticals Inc.
Active ingredient	Gadobutrol
Dosage form	Intravenous injection
Concentration	1.0 mmol/mL
FDA pathway for competitors	Generally ANDA if the product qualifies as therapeutically equivalent
New chemical entity exclusivity	Expired
Core active-ingredient patent position	Largely expired in major markets
Remaining risk	Formulation, process, device, labeling, and jurisdiction-specific patent claims

The live Orange Book record should be reviewed before filing, acquisition, or launch decisions because listed patents and regulatory certifications can change. A Paragraph IV strategy is relevant only if an unexpired listed patent remains associated with the reference product at the time of ANDA submission.

When does gadobutrol lose exclusivity?

Gadobutrol has already passed the principal exclusivity period associated with its original FDA approval. The original NDA approval occurred in 2011, so five-year new chemical entity exclusivity is no longer a commercial constraint. Any remaining U.S. launch barrier would come from unexpired patents, pediatric extensions, litigation-related stays, or regulatory requirements rather than the original approval exclusivity. [1,3]

The commercial timeline is therefore driven by:

1. Completion of pharmaceutical equivalence and bioequivalence-related requirements.
2. Establishment of an injectable manufacturing site.
3. Inspection readiness and process validation.
4. Orange Book patent certifications.
5. Potential Paragraph IV litigation.
6. Commercial supply of gadobutrol and specialized excipients.

Unlike oral generics, injectable contrast-agent products may require a higher level of manufacturing and quality-system investment. Shortages, facility observations, or sterile-fill capacity can delay entry even without a blocking patent.

What formulations are protected by gadobutrol patents?

Potentially relevant formulation claims include:

• High-concentration aqueous gadobutrol solutions.
• Gadobutrol combined with calcobutrol sodium.
• Defined pH ranges.
• Specific buffer concentrations.
• Reduced free-gadolinium formulations.
• Sterile products in prefilled syringes.
• Container systems that limit adsorption or leaching.
• Formulations with controlled osmolality and viscosity.

A formulation patent is commercially stronger when it links composition to measurable performance, such as improved stability, reduced free gadolinium, lower particulate burden, or extended shelf life. Broad claims covering ordinary aqueous formulation components are more vulnerable to validity challenges based on routine formulation practice and prior art.

What generic entry risks exist for gadobutrol?

A generic gadobutrol entrant faces four principal risks.

Regulatory risk

The product must demonstrate pharmaceutical equivalence and acceptable quality for a sterile injectable. FDA review will focus on the active ingredient, strength, route, dosage form, inactive ingredients, sterility assurance, particulate matter, and container-closure system. [4]

Manufacturing risk

Gadobutrol is a high-concentration injectable. The manufacturing process must control:

• Mixing uniformity.
• Metal contamination.
• Bioburden.
• Endotoxin.
• Particulates.
• Fill-volume accuracy.
• Container-closure integrity.
• Sterilization impact on the chelate and excipients.

Supply-chain risk

Calcobutrol sodium or equivalent specialized materials may have fewer qualified suppliers than common buffers. A single-source position can create launch and continuity risk.

Litigation risk

A Paragraph IV certification can trigger patent litigation and a statutory stay of FDA approval for up to 30 months under the Hatch-Waxman framework, subject to the specific litigation posture and patent involved. [5] The litigation value depends on whether any asserted patent covers the proposed formulation or process rather than the expired active substance.

Which companies are positioned to challenge gadobutrol?

Competition can arise from four groups:

Competitor type	Product strategy	Principal advantage
Generic injectable manufacturers	Copy or closely match Gadavist	Lower development risk
Radiology-focused pharmaceutical companies	Develop alternative gadolinium formulations	Clinical and distribution expertise
Contract development and manufacturing organizations	Supply drug substance, excipients, or sterile fill	Manufacturing infrastructure
Excipient and specialty-chemical suppliers	Supply calcobutrol sodium, buffers, or packaging components	Qualified raw-material position

The most credible entrants will have established sterile injectable capacity, experience with contrast agents, and access to high-purity chelation chemistry. Finished-product competition is more likely to emerge from manufacturers already active in injectable generics than from conventional excipient companies alone.

How does gadobutrol compare with competing gadolinium contrast agents?

Gadobutrol competes with gadoterate meglumine, gadoteridol, gadobenate dimeglumine, gadopentetate dimeglumine, and other gadolinium-based contrast agents. Macrocyclic agents such as gadobutrol, gadoterate, and gadoteridol are generally positioned around greater kinetic stability than linear agents. [6]

Product	Active chelate type	Typical commercial positioning	Excipient opportunity
Gadavist	Macrocyclic, nonionic gadobutrol	High-concentration, broad MRI use	Calcobutrol sourcing, syringe and vial systems
Dotarem	Macrocyclic, ionic gadoterate meglumine	Established macrocyclic alternative	Ionic formulation and osmolarity control
ProHance	Macrocyclic, nonionic gadoteridol	CNS and MRI applications	Alternative chelate supply and sterile presentation
MultiHance	Linear, ionic gadobenate	MRI and hepatobiliary-related positioning	More complex formulation and indication strategy

Gadobutrol’s 1.0 mmol/mL concentration supports lower injection volumes than products supplied at 0.5 mmol/mL. That concentration advantage increases the importance of viscosity, syringeability, fill accuracy, and container compatibility.

What commercial opportunities exist in gadobutrol excipients?

The most actionable opportunities are:

Qualified calcobutrol sodium supply

A reliable, pharmacopeial-quality source could command value because manufacturers may prefer an alternate supplier to reduce dependence on the reference-product supply chain.

Injectable-grade trometamol

Trometamol is less differentiated, but a supplier can compete through low endotoxin, tight trace-metal limits, regional inventory, and validated supply for sterile products.

Ready-to-use formulation packages

A contract supplier could offer a formulation package containing:

• Active-ingredient sourcing.
• Calcobutrol sodium.
• Trometamol.
• Sterile filtration or aseptic processing.
• Vial or syringe filling.
• Stability data.
• Analytical methods.

This model would target small and mid-sized generic developers that lack internal sterile-injectable capabilities.

Container-closure systems

Prefilled syringes and polymer containers can create differentiation through:

• Low extractables and leachables.
• Reduced tungsten or silicone-related particulate risk.
• Better dose accuracy.
• Automated MRI-suite workflow.
• Compatibility with power injectors.

Analytical services

Specialized testing can be commercialized around free gadolinium, chelate integrity, trace metals, osmolality, particle burden, and container interaction. These services may have higher margins than commodity excipient sales.

Are biosimilars relevant to gadobutrol?

No. Gadobutrol is a chemically defined small-molecule gadolinium chelate, not a biologic. Biosimilar approval pathways do not apply. Competition would generally involve generic or follow-on injectable products, subject to FDA requirements for pharmaceutical equivalence, quality, and therapeutic equivalence where applicable. [4]

What licensing deals could support gadobutrol entry?

The most commercially useful licensing structures would involve:

• Access to a validated gadobutrol drug-substance process.
• Rights to specialized excipient manufacturing.
• Technology transfer for calcobutrol sodium.
• Sterile-fill and packaging capacity.
• Regional distribution rights.
• Formulation patents covering an improved shelf-life or container system.
• Co-development of a prefilled syringe or automated injector presentation.

A license focused only on the expired gadobutrol molecule would have limited value. A package combining manufacturing know-how, regulatory documentation, analytical methods, and supply commitments would be more defensible.

Key Takeaways

• Gadobutrol is a 1.0 mmol/mL nonionic macrocyclic gadolinium contrast agent supplied as a sterile aqueous injection.
• The reference formulation uses gadobutrol, calcobutrol sodium, trometamol, hydrochloric acid, and water for injection.
• Core active-ingredient exclusivity has expired; commercial barriers are more likely to arise from formulation, manufacturing, quality, and supply-chain issues.
• Calcobutrol sodium is the most strategically differentiated excipient opportunity.
• Alternative-buffer and low-excipient formulations are technically possible but carry greater regulatory and stability risk.
• Generic entry is more likely through an ANDA and may involve Paragraph IV certification if an unexpired listed patent remains relevant.
• Biosimilar risk does not apply because gadobutrol is a chemically defined small molecule.
• The strongest commercial models combine excipient supply with analytical support, sterile fill-finish, container systems, and regulatory documentation.

FAQs

Is gadobutrol a biologic drug?

No. Gadobutrol is a chemically synthesized small-molecule gadolinium chelate. Generic, not biosimilar, competition is the relevant pathway.

What is the most differentiated gadobutrol excipient?

Calcobutrol sodium is more differentiated than trometamol, hydrochloric acid, or water for injection because it is closely associated with the safety and formulation profile of the reference product.

Can trometamol be replaced in gadobutrol?

Potentially, but replacement would require extensive formulation, stability, compatibility, impurity, and regulatory evaluation. Matching the reference buffer is generally lower risk for a generic product.

Does gadobutrol require a new chemical entity exclusivity analysis?

The original new chemical entity exclusivity period has expired. Current diligence should focus on listed patents, formulation claims, manufacturing patents, and regulatory requirements.

What is the best commercial entry point for an excipient company?

The strongest entry point is a qualified supply and technical-support package for calcobutrol sodium, supported by trace-metal testing, stability data, container compatibility work, and access to sterile fill-finish capacity.

References

1. U.S. Food and Drug Administration. (2024). Gadavist (gadobutrol) injection prescribing information. Bayer HealthCare Pharmaceuticals Inc.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/

3. U.S. Food and Drug Administration. (2011). Gadavist approval letter and regulatory history for NDA 201277. Center for Drug Evaluation and Research.

4. U.S. Food and Drug Administration. (2023). Guidance for industry: ANDAs for certain highly purified synthetic peptides and complex injectable drug products. Center for Drug Evaluation and Research.

5. U.S. Code, 21 U.S.C. § 355(j). Abbreviated applications for new drugs.

6. European Medicines Agency. (2017). Gadolinium-containing contrast agents: referral under Article 31 of Directive 2001/83/EC. EMA.