List of Excipients in Branded Drug AMLODIPINE AND BENAZEPRIL HYDROCHLORIDE

« Back to Dashboard

Generic Drugs Containing AMLODIPINE AND BENAZEPRIL HYDROCHLORIDE

Company	Ingredient	NDC	Excipient
Heritage Pharmaceuticals Inc d/b/a Avet Pharmaceuticals Inc	amlodipine and benazepril hydrochloride	23155-925	AMMONIA
Heritage Pharmaceuticals Inc d/b/a Avet Pharmaceuticals Inc	amlodipine and benazepril hydrochloride	23155-925	CELLULOSE, MICROCRYSTALLINE
Heritage Pharmaceuticals Inc d/b/a Avet Pharmaceuticals Inc	amlodipine and benazepril hydrochloride	23155-925	FD&C BLUE NO. 2
Heritage Pharmaceuticals Inc d/b/a Avet Pharmaceuticals Inc	amlodipine and benazepril hydrochloride	23155-925	FERROSOFERRIC OXIDE
Heritage Pharmaceuticals Inc d/b/a Avet Pharmaceuticals Inc	amlodipine and benazepril hydrochloride	23155-925	GELATIN

What are the Most Frequently-Used Excipients in AMLODIPINE AND BENAZEPRIL HYDROCHLORIDE?

# Of NDCs	Excipient
2	AMMONIA
3	ANHYDROUS DIBASIC CALCIUM PHOSPHATE
2	ANHYDROUS LACTOSE
43	CELLULOSE, MICROCRYSTALLINE
1	CI 16035

Amlodipine and Benazepril Hydrochloride Excipient Strategy and Commercial Opportunities

Last updated: October 13, 2026

Amlodipine/benazepril is a mature, multisource fixed-dose antihypertensive combination. The branded product, Lotrel, contains amlodipine besylate and benazepril hydrochloride in hard gelatin capsules. Core patent and regulatory exclusivity barriers have expired, leaving formulation performance, manufacturing cost, supply reliability, and market access as the principal commercial levers.

The strongest opportunities are generic capsule platforms, low-cost global supply, differentiated excipient systems, contract manufacturing, and selected line extensions. A new formulation is unlikely to obtain meaningful market protection unless it delivers a clinically relevant benefit supported by a 505(b)(2) or equivalent regulatory pathway.

What is the formulation of amlodipine and benazepril hydrochloride?

Amlodipine/benazepril is an oral fixed-dose combination of a dihydropyridine calcium-channel blocker and an angiotensin-converting enzyme inhibitor.

Attribute	Amlodipine/benazepril
Reference product	Lotrel
Reference sponsor	Novartis, historically marketed through the Lotrel brand
Dosage form	Hard gelatin capsule
Amlodipine component	Amlodipine besylate
ACE-inhibitor component	Benazepril hydrochloride
U.S. regulatory pathway	505(b)(1) reference product; ANDA pathway for generics
Primary indication	Hypertension
U.S. strengths	2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, and 10 mg/20 mg
Administration	Once daily
Commercial status	Mature generic market

The active amlodipine moiety is supplied as amlodipine besylate. Benazepril is supplied as the hydrochloride salt. A formulation must therefore account for the physical and chemical properties of two different salt forms rather than treating the combination as a simple two-API blend.

The reference product labeling identifies conventional capsule excipients, including microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, and capsule-shell components. The precise qualitative and quantitative composition of a generic product may differ, provided the product meets applicable pharmaceutical equivalence, bioequivalence, quality, and labeling requirements. The FDA Inactive Ingredient Database and the current Lotrel label are key sources for selecting precedent excipients and maximum exposure levels (FDA, n.d.-a; FDA, n.d.-b).

What excipient strategy is best for this fixed-dose combination?

A direct-blend capsule is generally the most commercially efficient platform. It minimizes processing steps, lowers equipment requirements, and supports rapid development across multiple strengths.

Recommended platform architecture

Formulation function	Candidate excipient class	Commercial purpose
Diluent	Microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate	Controls fill weight and supports blend uniformity
Disintegrant	Crospovidone, croscarmellose sodium, sodium starch glycolate	Promotes capsule rupture and drug release
Glidant	Colloidal silicon dioxide	Improves flow of low-dose blends
Lubricant	Magnesium stearate, sodium stearyl fumarate	Controls ejection and reduces sticking
Moisture-control aid	Anhydrous diluents, low-moisture capsule shells, desiccant packaging	Reduces hydrolytic and physical stability risk
Capsule shell	Gelatin or hypromellose	Enables conventional or vegetarian positioning
Colorant or opacifier	Titanium dioxide alternatives or approved color systems	Supports product identification and light protection

The preferred initial design is a low-moisture, direct-fill blend using microcrystalline cellulose as the principal diluent, crospovidone as the disintegrant, colloidal silicon dioxide as the glidant, and a tightly controlled lubricant level. Lactose can reduce cost and improve powder density, but compatibility and moisture behavior must be confirmed for the selected API lots and process conditions.

Why low-dose amlodipine creates a content-uniformity issue

The lowest marketed strength contains 2.5 mg of amlodipine, creating a higher segregation and sampling risk than the 10 mg/20 mg strength. A formulation that performs adequately for the highest strength may fail blend-uniformity or assay requirements at the lowest strength.

Risk controls include:

• Ordered addition of the low-dose API through geometric dilution.
• Preblending amlodipine with a portion of the diluent.
• Narrow API and excipient particle-size distributions.
• Controlled transfer and hopper residence time.
• Blend segregation studies at commercial scale.
• In-process capsule-weight and content-uniformity monitoring.
• Separate master formulas for low-dose and high-dose products where proportional scaling is not robust.

A multiparticulate or granulated approach may improve uniformity but adds cost and process complexity. It is commercially justified only if direct blending cannot meet content-uniformity, dissolution, or process-capability targets.

What formulation risks affect amlodipine/benazepril stability?

The principal development risks are moisture exposure, chemical degradation, powder segregation, lubricant sensitivity, and dissolution variability.

Moisture and hydrolysis

Benazepril hydrochloride contains an ester functionality and requires stability assessment under humid conditions. Moisture can affect both chemical stability and powder flow. Amlodipine besylate also requires evaluation for physical and chemical stability under heat, humidity, and light.

The formulation program should include:

• Water activity and loss-on-drying controls for incoming excipients.
• Moisture-barrier packaging studies.
• Stress testing at accelerated and long-term conditions.
• Assay and related-substance testing for both APIs.
• Dissolution profiling after storage.
• Capsule-shell brittleness and cross-linking assessment.
• Excipient peroxide and aldehyde screening where relevant.

Low-peroxide grades of povidone or crospovidone may be appropriate when oxidation pathways are observed. The need for these grades should be based on forced-degradation data rather than assumed from general excipient practice.

Lubrication and dissolution

Over-lubrication with magnesium stearate can reduce wetting and slow dissolution. The risk is more material where the formulation uses hydrophobic excipients, high lubricant concentrations, or extended blending times.

A design-of-experiments program should evaluate:

• Lubricant concentration.
• Lubrication time.
• Blend order.
• API particle size.
• Disintegrant grade.
• Capsule fill density.
• Dissolution across pH conditions.

The target is a robust formulation that matches the reference product's dissolution behavior without requiring an unnecessarily complex process.

Capsule shell selection

Hard gelatin capsules offer the lowest-cost and most established route. Hypromellose capsules may provide commercial differentiation for vegetarian, religious, or supply-chain reasons, but they can alter moisture transfer, brittleness, and dissolution behavior. Shell selection should therefore be treated as a product-quality decision, not only a marketing decision.

What patents protect amlodipine and benazepril hydrochloride?

The original compound, formulation, and fixed-combination patent barriers for Lotrel are expired. Amlodipine and benazepril were approved as separate antihypertensive products before the combination entered the market, and the fixed-dose combination has been available generically for many years.

IP category	Commercial status
Amlodipine compound patents	Expired
Benazepril compound patents	Expired
Lotrel fixed-combination patents	Expired
Original capsule formulation patents	Expired or no longer commercially blocking
Method-of-use patents for hypertension	Expired or nonblocking for routine generic entry
Manufacturing patents	May exist in isolated jurisdictions but are unlikely to block standard U.S. ANDA entry without relevant claims
Current Orange Book blocking patent estate	No material active estate is expected to prevent conventional generic entry

The FDA Orange Book remains the controlling source for current listed patents, exclusivity, dosage-form information, and reference-product status. Patent clearance must still cover jurisdiction-specific formulation, process, packaging, and labeling claims because an expired core combination patent does not eliminate every possible third-party patent risk (FDA, n.d.-a).

When did amlodipine/benazepril lose exclusivity?

U.S. exclusivity loss occurred years ago. The market is now dominated by generic products rather than by regulatory exclusivity attached to Lotrel.

Exclusivity type	Status
New chemical entity exclusivity	Expired
Original NDA exclusivity	Expired
Fixed-combination exclusivity	Expired
Pediatric exclusivity	No current commercial barrier
Orphan exclusivity	Not applicable
Biologic exclusivity	Not applicable
Data exclusivity for a new generic formulation	Not generally available through an ANDA

Because this is a small-molecule combination, biosimilar risk is irrelevant. Competition occurs through ANDAs, authorized generics, national generic registrations, and local fixed-dose combination products.

What is the Orange Book and Paragraph IV status?

A conventional generic applicant would normally rely on the reference product through an ANDA and certify against any listed patents. For a mature product with expired or absent blocking patents, the principal filing position would generally be Paragraph III or Paragraph IV depending on the status of listed patents.

Question	Assessment
Is an ANDA the likely U.S. route?	Yes
Is a 505(b)(2) route required for a standard capsule?	No
Are active composition-of-matter patents expected?	No
Is a Paragraph IV challenge likely to create major value?	Low
Is patent litigation a material base-case risk?	Low
Is labeling carve-out litigation likely?	Low for the established hypertension indication

A Paragraph IV certification can still arise if a listed patent remains active or if a new formulation patent is listed. The commercial value of such a challenge is limited where multiple approved generics already compete and the reference product has little remaining branded share.

What commercial opportunities exist for excipient suppliers?

The largest opportunity is not a proprietary excipient patent. It is a qualified, reproducible excipient system that reduces development time and manufacturing failures.

Opportunity 1: Low-moisture direct-fill platform

An excipient package designed for direct capsule filling can combine:

• A high-flow diluent.
• A low-peroxide disintegrant.
• A controlled-surface-area glidant.
• A low-level lubricant.
• Moisture-barrier capsule packaging.

The value proposition is reduced process development, fewer granulation steps, and improved scale-up. Suppliers can provide premixed or co-processed systems, but the mixture must not compromise the applicant's ability to establish pharmaceutical equivalence and control critical material attributes.

Opportunity 2: Co-processed excipients

Co-processed microcrystalline cellulose and colloidal silica, or a diluent-disintegrant platform, may improve flow and reduce segregation at the 2.5 mg amlodipine strength. The commercial case depends on measurable improvements in:

• Blend uniformity.
• Capsule-weight variability.
• Dissolution robustness.
• Compressibility, if a tablet alternative is pursued.
• Equipment throughput.
• Rejection rates.

Opportunity 3: Vegetarian and regional capsule systems

Hypromellose capsules can support procurement and marketing requirements in markets where gelatin is restricted or less desirable. The opportunity is strongest in India, the Middle East, Southeast Asia, and selected institutional channels. The supplier must demonstrate comparable stability and dissolution rather than relying only on capsule-shell substitution.

Opportunity 4: Excipient and packaging combination offers

A supplier that combines low-moisture excipients with high-barrier blister or bottle packaging can address both formulation and shelf-life risks. This is more commercially defensible than selling an undifferentiated commodity diluent.

What commercial opportunities exist for generic manufacturers?

U.S. generic entry

The U.S. market is mature and price competitive. A new entrant needs a low-cost, reliable supply chain and broad strength coverage. The most commercially important products are the 5 mg/10 mg and 5 mg/20 mg strengths, while the 2.5 mg/10 mg strength may have greater technical value because of its low-dose uniformity challenge.

The preferred launch package includes all four reference strengths where feasible. A partial-strength launch can reduce development cost but weakens pharmacy substitution and payer coverage.

International markets

The fixed-dose combination has stronger opportunity where:

• Hypertension treatment guidelines support combination therapy.
• Generic substitution is established.
• Local production receives procurement preference.
• Physicians use ACE inhibitor/calcium-channel blocker combinations.
• Regulatory authorities accept biowaivers or streamlined generic procedures where scientifically justified.

Country-specific issues include salt nomenclature, bioequivalence requirements, capsule-shell restrictions, serialization, and local patent examination standards.

Contract manufacturing and licensing

Licensing opportunities are more likely to involve manufacturing rights, technology transfer, or regional distribution than a novel active pharmaceutical ingredient. Potential deal structures include:

• Regional commercialization licenses.
• Finished-dose supply agreements.
• API-plus-finished-product packages.
• Authorized generic arrangements.
• Private-label supply for hospital and tender markets.
• Co-development of a differentiated capsule platform.

No current blockbuster-scale licensing opportunity is inherent in the active combination itself. Value depends on geographic access, manufacturing economics, and regulatory execution.

How does amlodipine/benazepril compare with competing antihypertensive combinations?

Combination	Main commercial distinction	Generic competition
Amlodipine/benazepril	Calcium-channel blocker plus ACE inhibitor	High
Amlodipine/benazepril	Established Lotrel reference and broad clinical familiarity	High
Amlodipine/valsartan	Calcium-channel blocker plus ARB	High
Amlodipine/lisinopril	Calcium-channel blocker plus ACE inhibitor	High
Amlodipine/losartan	Calcium-channel blocker plus ARB	High
Amlodipine/hydrochlorothiazide	Calcium-channel blocker plus diuretic	High

Amlodipine/benazepril has a commercial disadvantage where physicians prefer ARB combinations because of ACE-inhibitor cough or angioedema concerns. Its advantage is established clinical use, once-daily dosing, and a familiar two-mechanism regimen.

What generic launch risks exist?

The base-case launch risk is commercial rather than patent-based.

Key risks include:

1. Price erosion from multiple ANDA holders.
2. Failure to achieve content uniformity at the 2.5 mg strength.
3. Dissolution mismatch after scale-up.
4. Stability loss under high humidity.
5. API supply interruptions affecting either salt.
6. Capsule-shell changes that alter dissolution or moisture behavior.
7. Limited payer or pharmacy differentiation.
8. Weak economics for low-volume strengths.
9. Regional regulatory variation.
10. Litigation over a later formulation or process patent rather than the original combination.

Revenue exposure for a new entrant cannot be inferred from the product's historical branded sales. The relevant metrics are current generic prescription volume, wholesaler acquisition cost, tender pricing, number of approved suppliers, reimbursement status, and manufacturing cost per capsule.

How strong is the patent estate for amlodipine/benazepril?

The patent estate is weak for standard generic products and stronger only for genuinely differentiated delivery or manufacturing systems.

Patent strategy	Strength
Same-dose conventional capsule	Low
New excipient combination without clinical benefit	Low
Improved moisture-stability formulation	Moderate if technically demonstrated
Novel modified-release product	Potentially moderate to strong, but requires clinical and regulatory support
Pediatric liquid or dispersible dosage form	Potentially moderate through 505(b)(2) or equivalent route
New indication	Potentially moderate, subject to clinical evidence and enforceability
Novel manufacturing process	Variable and jurisdiction-specific
Packaging-only claims	Usually weak unless linked to measurable product performance

The most defensible IP would cover a reproducible technical effect, such as improved stability, reduced dose dumping, a clinically useful administration format, or a validated manufacturing process. Merely substituting one conventional excipient for another is unlikely to create durable protection.

What FDA regulatory status applies to a new product?

A standard amlodipine/benazepril capsule is generally suitable for an ANDA if it matches the reference product in active ingredients, dosage form, strength, route, labeling framework, and performance requirements.

The development package should address:

• Pharmaceutical equivalence.
• Comparative dissolution.
• In vitro release across relevant pH conditions.
• Bioequivalence.
• Assay and related substances.
• Content uniformity.
• Impurities and degradation products.
• Container-closure integrity.
• Long-term and accelerated stability.
• Extractables and leachables for packaging.
• Drug Master File and supplier qualification documentation.

A 505(b)(2) strategy becomes relevant for a new dosage form, novel excipient use, modified release, pediatric presentation, or clinically differentiated administration method. It is not the efficient route for an ordinary capsule that can meet ANDA requirements.

Key Takeaways

• Amlodipine/benazepril is a mature generic fixed-dose combination marketed as amlodipine besylate plus benazepril hydrochloride.
• Lotrel's core exclusivity and patent barriers have expired.
• The best initial formulation is usually a low-moisture direct-blend capsule.
• The main technical risk is low-dose amlodipine content uniformity, especially at 2.5 mg.
• Moisture, API degradation, lubrication, and dissolution require focused development work.
• Excipient suppliers can differentiate through co-processed systems, low-peroxide materials, vegetarian capsules, and integrated packaging.
• Generic manufacturers compete primarily on cost, supply reliability, strength coverage, and regulatory execution.
• Biosimilar risk does not apply because both active ingredients are small molecules.
• A new product is more likely to succeed through an ANDA than through a 505(b)(2) program.
• New patent value would require a demonstrated technical or clinical improvement, not a routine excipient substitution.

FAQs

Is amlodipine benazepril a combination product or a single API?

It is a fixed-dose combination containing amlodipine besylate and benazepril hydrochloride in one dosage unit.

Can lactose be used in amlodipine/benazepril capsules?

Lactose can be considered as a diluent if compatibility, moisture behavior, dissolution, and stability data support its use. It is not automatically interchangeable with microcrystalline cellulose.

Is a tablet formulation commercially attractive?

A tablet could reduce capsule-shell cost and support alternative manufacturing, but it would require comparative performance work and may not offer enough commercial differentiation in a crowded generic market.

Does amlodipine/benazepril have biosimilar competition?

No. Biosimilar regulation applies to biological products. Amlodipine and benazepril are small-molecule active ingredients and compete through generic pathways.

What is the most defensible formulation patent opportunity?

The strongest opportunity would generally involve a demonstrated improvement in stability, release, administration, or manufacturing performance that can support a defined patent claim and a suitable regulatory pathway.

References

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

2. U.S. Food and Drug Administration. (n.d.-b). Lotrel prescribing information. DailyMed. https://dailymed.nlm.nih.gov/

3. U.S. Food and Drug Administration. (n.d.-c). Inactive ingredient database. https://www.accessdata.fda.gov/scripts/cder/iig/

4. U.S. Food and Drug Administration. (2015). ANDA submissions: Content and format of abbreviated new drug applications. FDA.

5. United States Pharmacopeial Convention. (2024). United States Pharmacopeia and National Formulary, USP 47-NF 42. USP Convention.