List of Excipients in Branded Drug DIVALPROEX SODIUMDELAYED-RELEASE

Generic Drugs Containing DIVALPROEX SODIUMDELAYED-RELEASE

Company	Ingredient	NDC	Excipient
Aidarex Pharmaceuticals LLC	divalproex sodium	33261-621	D&C RED NO. 27
Aidarex Pharmaceuticals LLC	divalproex sodium	33261-621	FD&C BLUE NO. 2
Aidarex Pharmaceuticals LLC	divalproex sodium	33261-621	FD&C RED NO. 40
Aidarex Pharmaceuticals LLC	divalproex sodium	33261-621	FD&C YELLOW NO. 6
Aidarex Pharmaceuticals LLC	divalproex sodium	33261-621	HYPROMELLOSES
Aidarex Pharmaceuticals LLC	divalproex sodium	33261-621	METHACRYLIC ACID

What are the Most Frequently-Used Excipients in DIVALPROEX SODIUMDELAYED-RELEASE?

# Of NDCs	Excipient
1	D&C RED NO. 27
1	FD&C BLUE NO. 2
1	FD&C RED NO. 40
1	FD&C YELLOW NO. 6
1	HYPROMELLOSES
1	METHACRYLIC ACID

Divalproex Sodium Delayed-Release: Excipient Strategy, Patent Position, and Commercial Opportunities

Last updated: August 6, 2026

Divalproex sodium delayed-release is a mature, multisource oral solid product with limited active-ingredient patent protection and substantial commercial room in formulation execution. The principal opportunity is not API exclusivity. It is reliable enteric performance, low-cost manufacturing, differentiated dose presentation, pediatric usability, and supply-chain quality.

The product combines sodium valproate and valproic acid in a 1:1 molar relationship. Delayed-release tablets and sprinkle capsules use enteric protection to limit release in the stomach. The formulation must balance acid resistance, prompt intestinal release, dose uniformity, mechanical robustness, moisture control, and tolerability [1,2].

What is divalproex sodium delayed-release?

Divalproex sodium delayed-release is an oral dosage form approved for epilepsy, manic episodes associated with bipolar disorder, and migraine prophylaxis. It is not indicated for the acute treatment of migraine headaches [1].

Attribute	Commercial description
Active ingredient	Divalproex sodium
Molecular composition	Sodium valproate and valproic acid in a 1:1 molar relationship
Principal dosage forms	Delayed-release tablets; delayed-release sprinkle capsules
Common strengths	125 mg, 250 mg, and 500 mg tablets; 125 mg sprinkle capsules
Therapeutic areas	Epilepsy, bipolar mania, migraine prophylaxis
Regulatory pathway	NDA-originated product with multiple ANDA-approved generic products
Administration	Oral; tablets generally swallowed whole
Core formulation requirement	Enteric or delayed-release protection
Reference product	Depakote delayed-release products marketed by AbbVie and predecessor companies

Divalproex sodium is distinct from valproic acid and immediate-release sodium valproate products in release profile, dosage form, and labeling. Substitution decisions must account for formulation and release characteristics rather than active moiety alone.

What excipients are used in divalproex sodium delayed-release tablets?

The excipient system typically contains a tablet core, coating layers, and an enteric film. Exact composition varies by manufacturer and strength.

Tablet-core excipients

Common tablet-core excipients include:

• Microcrystalline cellulose for structure and compressibility
• Lactose or another diluent
• Povidone or a comparable binder
• Crospovidone or another disintegrant
• Colloidal silicon dioxide as a glidant
• Magnesium stearate or another lubricant
• Hypromellose in the film-coating system
• Colorants and opacifiers where required

The core must remain mechanically stable during coating and packaging. Excessive disintegrant or lubricant can affect water penetration and dissolution. Excessive compression can create a tablet that passes friability testing but delays intestinal release after the enteric film ruptures.

Delayed-release coating excipients

The enteric layer commonly relies on an acid-insoluble polymer, such as a methacrylic acid copolymer, combined with:

• Plasticizer, often polyethylene glycol or triethyl citrate
• Talc or another anti-tacking agent
• Titanium dioxide or colorant
• Water or hydroalcoholic processing solvent, depending on the coating system

The polymer choice determines the pH threshold for dissolution. A coating that resists gastric fluid but dissolves consistently in intestinal conditions is central to product performance.

Why excipient selection matters

Divalproex sodium has several formulation sensitivities:

1. The drug can produce an unpleasant taste and odor if the dosage form opens prematurely.
2. The enteric coat must withstand gastric conditions across the labeled shelf life.
3. The product requires controlled release of the tablet core after intestinal exposure.
4. Valproate products have narrow tolerability margins, making dose uniformity and content uniformity commercially important.
5. Patients with epilepsy or bipolar disorder may be sensitive to changes in exposure caused by altered release behavior.

Excipient selection is therefore a performance and substitution issue, not simply a cost issue.

How should an excipient strategy be designed for delayed-release divalproex?

A practical excipient strategy has four priorities: coating robustness, manufacturability, stability, and patient use.

1. Use a robust enteric polymer platform

Methacrylic acid copolymers are established choices for delayed-release oral products. The commercial decision is whether to use a conventional aqueous dispersion, an organic-solvent system, or a proprietary polymer blend.

An aqueous coating system can reduce solvent-handling requirements and improve environmental performance. It may require tighter control of drying conditions, spray rate, inlet temperature, and residual moisture.

The coating should be evaluated under:

• Acid-stage dissolution
• Buffer-stage dissolution
• Accelerated stability
• High-humidity storage
• Mechanical stress and tablet abrasion
• Multiple batch-scale coating runs

A formulation that passes initial dissolution but shows increased acid-stage release after storage has limited commercial value.

2. Optimize the coating for scale

The coating is often the highest-risk excipient subsystem. Critical process variables include:

• Polymer solids concentration
• Viscosity
• Spray rate
• Atomization pressure
• Pan speed
• Bed temperature
• Weight gain
• Drying endpoint

Commercial manufacturers should design for a broad operating window. A narrow coating process can create yield loss, color variation, tablet sticking, or dissolution failures.

3. Control moisture and packaging interaction

Moisture can affect coating flexibility, tablet hardness, disintegration, and stability. Packaging options include high-density polyethylene bottles with desiccant, unit-dose packaging, or blister systems with appropriate moisture-barrier properties.

The best packaging strategy depends on:

• Target market
• Expected distribution humidity
• Wholesale and pharmacy handling
• Child-resistance requirements
• Unit-dose demand
• Product shelf life
• Packaging-line speed

Low-cost bottles may be sufficient for a mature generic tablet. Unit-dose or calendar packaging can support institutional and adherence-focused channels but increases packaging cost.

4. Minimize unnecessary excipient complexity

A generic product does not need to replicate every excipient in the reference product. It must meet applicable quality, bioequivalence, dissolution, stability, and labeling requirements. A simpler excipient system can reduce supplier risk and regulatory maintenance.

However, substitutions should be screened for:

• Lactose intolerance or excipient sensitivity
• Colorant restrictions in specific markets
• Nitrosamine or elemental-impurity risk from raw materials
• Animal-derived materials
• Residual solvents
• Peroxide generation
• Supply concentration among excipient vendors

Excipient reduction can be commercially useful when it lowers variability without changing the release profile.

What formulations are protected or commercially differentiated?

The core delayed-release tablet concept is mature and widely available. Commercial differentiation is more likely in dosage form, coating execution, packaging, and patient handling than in the basic composition.

Formulation area	Commercial opportunity	Principal technical barrier
Delayed-release tablet	Low-cost generic supply	Dissolution and coating consistency
Sprinkle capsule	Pediatric and swallowing-related use	Capsule content uniformity, taste, food compatibility
Smaller tablet	Easier swallowing	Dose uniformity and coating surface area
Unit-dose packaging	Hospitals, institutions, adherence programs	Packaging cost and moisture protection
Color or imprint differentiation	Brand recognition and error reduction	Labeling and manufacturing complexity
Modified excipient system	Allergen or supply-chain positioning	Demonstrating equivalent performance
Abuse-deterrent or tamper-evident package	Institutional and controlled-distribution settings	Added cost with limited clinical differentiation
Novel multiparticulate system	Pediatric or flexible dosing	Higher development and regulatory burden

The delayed-release sprinkle capsule is the strongest adjacent opportunity because it addresses administration difficulty without requiring a new active ingredient. Sprinkle products must maintain dose uniformity when opened and mixed with soft food. The product must not be chewed, crushed, or otherwise damaged if the particles depend on enteric protection.

What is the Orange Book status of divalproex sodium delayed-release?

Divalproex sodium delayed-release is an established small-molecule product listed in FDA drug databases through multiple approved products. The reference product has historically been Depakote delayed-release tablets, with generic products approved through abbreviated new drug applications [3].

The Orange Book framework distinguishes:

• Active ingredient patents
• Formulation patents
• Method-of-use patents
• Exclusivity periods
• Therapeutic-equivalence codes
• Reference-listed drug status

For a mature product such as delayed-release divalproex sodium, the commercial assessment should focus on current listed patents and exclusivity for the specific reference product and dosage form. Legacy patents covering the original product are generally not expected to block ordinary ANDA entry after expiration, although current listings must be checked for any product-specific claims [3].

When does divalproex sodium delayed-release lose exclusivity?

The principal patent and regulatory exclusivity barriers for the original delayed-release product expired years ago. Generic entry is therefore established, and the market is characterized by multisource competition rather than a pending first generic event.

The commercial distinction is between:

• Patent expiry for the original product
• FDA marketing exclusivity
• Current Orange Book-listed patents
• Product-specific formulation or method-of-use claims
• State substitution and payer formulary access

A generic applicant may seek approval through an ANDA with Paragraph III certification if a relevant patent remains in force, or through Paragraph IV certification if it challenges listed patent validity, enforceability, or infringement. For this mature product, the main commercial risk is usually price erosion and supply disruption rather than a late-stage patent cliff.

Are there Paragraph IV challenges to delayed-release divalproex sodium?

Paragraph IV activity is historically associated with the original generic-entry period and any later product-specific patent listings. Divalproex sodium delayed-release is not generally viewed as a current, high-value Paragraph IV battleground comparable with newly approved specialty drugs.

The relevant questions for a new applicant are:

1. Whether any patent remains listed for the selected strength and dosage form.
2. Whether a formulation claim covers the proposed coating or excipient combination.
3. Whether the applicant can certify that its product does not infringe.
4. Whether the reference sponsor has initiated litigation within the statutory period.
5. Whether a 180-day exclusivity period is available to a first filer.

A Paragraph IV strategy has limited value when several approved generic suppliers already compete and the remaining patent estate does not create a meaningful market entry barrier.

How strong is the patent estate for divalproex sodium delayed-release?

The patent estate is weak for broad composition-of-matter protection and stronger only at the level of specific formulations, manufacturing processes, or delivery systems.

Patent-strength assessment

Patent category	Relative strength	Commercial relevance
Active moiety or basic composition	Low	Original protection is expired
Conventional delayed-release tablet	Low to moderate	Broad concepts are mature and vulnerable to prior art
Specific enteric polymer combination	Moderate	May support narrow formulation claims
Sprinkle or multiparticulate delivery	Moderate	More useful if linked to defined performance parameters
Manufacturing process	Moderate	Can create process-specific barriers but may be designed around
Method of treatment	Low to moderate	Depends on claim scope and jurisdiction
Packaging or adherence system	Low	Usually weak as a standalone barrier
Novel pediatric formulation	Potentially moderate	More relevant if supported by clinical and bioequivalence data

A formulation patent is commercially meaningful only if it covers a product characteristic that competitors cannot readily avoid. Claims directed broadly to common enteric polymers, binders, or tablet excipients may face substantial prior-art and obviousness exposure.

What FDA regulatory issues affect commercial development?

FDA approval requires more than matching the active ingredient. The applicant must demonstrate that the dosage form performs as a delayed-release product and meets applicable quality requirements.

Key regulatory issues include:

• Pharmaceutical equivalence
• Bioequivalence
• In vitro dissolution across multiple pH stages
• Assay and content uniformity
• Degradation-product control
• Stability under long-term and accelerated conditions
• Container-closure integrity
• Manufacturing-process validation
• Comparative performance of strengths
• Labeling consistency with the reference product

For a generic tablet, the formulation should support a defensible biowaiver or bridging strategy where permitted. A sprinkle capsule or other nonidentical dosage form may require a more complex demonstration of equivalence.

FDA labeling also carries important safety information for valproate products, including hepatotoxicity, pancreatitis, fetal risk, thrombocytopenia, hyperammonemia, and drug-interaction considerations [1]. These risks increase the commercial value of dependable dose delivery and reduce the attractiveness of aggressive formulation changes that could alter exposure.

What commercial opportunities exist for excipient suppliers and generic manufacturers?

Low-cost generic tablet platforms

The largest opportunity remains reliable supply at competitive cost. Manufacturers can improve margin through:

• High-throughput compression
• Efficient aqueous film coating
• Common excipient platforms across strengths
• Shared packaging components
• Reduced coating weight without loss of acid resistance
• Dual sourcing of polymers and critical excipients

Because pricing is mature, manufacturing yield and supply continuity have greater impact than premium branding.

Pediatric and swallowing-focused products

The sprinkle capsule provides a practical development path for pediatric and geriatric use. Opportunities include:

• Better particle size control
• Improved palatability
• Reduced capsule-opening complexity
• Clear food-mixing instructions
• Unit-dose sachets
• Dosing flexibility for weight-based therapy

Taste masking must preserve the integrity of the enteric particles. Sweeteners or flavors that contact the patient directly can create stability and regulatory issues.

Excipient-reduced and market-specific products

A product that excludes selected colorants, lactose, or animal-derived ingredients may obtain commercial access in institutional or international markets. This is usually a procurement advantage rather than a patent advantage.

The value depends on whether the change improves formulary acceptance, reduces complaint rates, or supports a differentiated label. A clean-label position without payer or institutional demand is unlikely to justify substantial development expense.

Contract manufacturing and private-label supply

Divalproex sodium delayed-release is suitable for contract manufacturing because the technology is established and demand is recurrent. Buyers will prioritize:

• FDA inspection history
• Reliable API supply
• Coating capacity
• Product-specific dissolution capability
• Recall performance
• Multi-strength manufacturing
• Capacity commitments
• Change-control discipline

The main commercial barrier is operational credibility, not access to a novel technology platform.

Which companies are competing in divalproex sodium delayed-release?

Competition includes the reference-product sponsor and multiple generic manufacturers, contract manufacturers, and private-label distributors. The market may include products marketed under manufacturer names, pharmacy benefit manager labels, and distributor brands.

Competitive differentiation typically rests on:

• Price
• Back-order performance
• Number of available strengths
• Sprinkle-capsule availability
• Bottle and unit-dose formats
• Supply continuity
• Authorized-distributor relationships
• Formulary and institutional contracts

The strongest competitor is often the supplier with the most dependable inventory rather than the supplier with the most differentiated excipient profile.

What generic entry risks exist for divalproex sodium delayed-release?

Generic entry is already established, so the principal risks are commercial and technical.

Commercial risks

• Rapid price erosion from additional suppliers
• Contract loss after a supply interruption
• Distributor consolidation
• Low-margin tender pricing
• Substitution pressure from other valproate formulations
• Declining use in some patient populations because of safety concerns
• Reduced prescribing where alternative antiepileptic or bipolar therapies are preferred

Technical risks

• Failure of acid-stage dissolution
• Delayed intestinal release
• Tablet chipping during coating
• Strength-to-strength variability
• Moisture-driven stability failures
• Sprinkle-particle damage during packaging
• Inconsistent food-mixing performance
• API odor or taste complaints

A formulation that reduces manufacturing cost but increases dissolution variability can create greater liability than its savings justify.

How does divalproex sodium delayed-release compare with other valproate products?

Product type	Release profile	Main commercial advantage	Main limitation
Divalproex delayed-release tablet	Delayed release	Established generic, broad strength range	Must be swallowed whole; coating-sensitive
Divalproex delayed-release sprinkle capsule	Delayed release	Flexible administration	Higher manufacturing and packaging complexity
Divalproex extended-release tablet	Extended release	Once-daily potential in suitable regimens	Different pharmacokinetics and dose conversion issues
Valproic acid capsule or syrup	Immediate release	Familiar and flexible dosing	More frequent dosing and tolerability concerns
Sodium valproate immediate-release product	Immediate release	Established alternative in some markets	Not interchangeable solely by active-moiety quantity

Delayed-release and extended-release divalproex products should not be treated as interchangeable formulations without considering dose conversion, exposure, and labeling. The extended-release segment may offer more formulation differentiation, but it also carries greater development and bioequivalence complexity.

What licensing deals and manufacturing-IP barriers matter?

Large licensing opportunities are limited because the underlying product is generic and technically mature. Commercial agreements are more likely to involve:

• Authorized generic distribution
• Regional marketing rights
• Private-label supply
• Contract manufacturing
• API sourcing
• Sprinkle-capsule technology
• Enteric-coating know-how
• Packaging and institutional supply

Manufacturing know-how can still create a practical barrier. A competitor may legally design around a formulation patent but lack the process capability to produce consistent acid-stage and buffer-stage dissolution at commercial scale.

The most defensible know-how typically involves:

• Coating suspension control
• Polymer-plasticizer compatibility
• Drying profiles
• Low-defect tablet handling
• Moisture-resistant packaging
• Scale-up from pilot pan to commercial equipment
• In-process dissolution and weight-gain controls

What is the revenue exposure for divalproex sodium delayed-release?

Revenue exposure is concentrated in mature generic volume rather than exclusivity-driven pricing. Manufacturers should assess the product as a portfolio and supply-chain asset.

A useful commercial model includes:

Revenue driver	Impact
Number of active suppliers	More suppliers generally reduce price
Strength coverage	Three tablet strengths improve contract access
Sprinkle availability	Supports pediatric and swallowing-related demand
Institutional contracts	Can create stable volume but compress margins
API cost	Directly affects low-price products
Coating yield	Strong effect on gross margin
Back-order frequency	Can temporarily improve share and price
Regulatory observations	Can impair market access
Formulary position	Determines substitution volume
Alternative therapies	Limits long-term growth

The product is most attractive to manufacturers with existing oral-solid-dose infrastructure, enteric-coating capability, and a low-cost commercial model. It is less attractive as a standalone premium-development project.

Key Takeaways

• Divalproex sodium delayed-release is a mature generic product with limited remaining broad patent protection.
• The main formulation value lies in enteric-coating reliability, dissolution control, moisture management, and patient usability.
• Common excipient platforms include microcrystalline cellulose, binders, disintegrants, glidants, lubricants, hypromellose, methacrylic acid copolymers, plasticizers, talc, and colorants.
• Sprinkle capsules offer the clearest formulation-led commercial opportunity.
• A Paragraph IV strategy is unlikely to create substantial value unless directed to a current, narrow patent with a meaningful market barrier.
• Manufacturing yield, supply continuity, and multi-strength availability are more important than broad formulation exclusivity.
• The strongest practical IP may be process know-how rather than a broad composition patent.
• Generic entry risk is primarily price erosion, supply competition, and technical failure in delayed-release performance.
• Contract manufacturing, private-label supply, institutional packaging, and pediatric administration are the most credible commercial opportunities.

FAQs

Can divalproex sodium delayed-release tablets use different excipients from Depakote?

Yes. Generic products may use different inactive ingredients if they meet FDA requirements for pharmaceutical equivalence, bioequivalence, quality, stability, and labeling. The delayed-release performance must remain comparable.

Is an enteric coating mandatory for divalproex sodium delayed-release?

A product labeled as delayed release must achieve the required release profile. In practice, this generally requires an enteric or functionally equivalent barrier system that resists gastric conditions and releases the drug after intestinal exposure.

Are divalproex delayed-release sprinkle capsules interchangeable with tablets?

They contain the same active moiety but are different dosage forms. Substitution should follow the applicable FDA-approved labeling, pharmacy rules, and clinical instructions. Sprinkle-particle handling and food administration are product-specific.

Can a new excipient create patent protection for a generic divalproex product?

An excipient combination may support formulation claims if it is novel, nonobvious, adequately described, and linked to patentable performance. Common enteric polymers and standard tablet excipients generally provide weak standalone protection.

Does divalproex sodium delayed-release have biosimilar competition?

No. Divalproex sodium is a small-molecule drug. Competitors enter through generic-drug pathways, primarily ANDAs, rather than the FDA biosimilar pathway.

References

1. U.S. Food and Drug Administration. (2023). Depakote delayed-release tablets: Prescribing information. AbbVie Inc.

2. U.S. Food and Drug Administration. (2023). Depakote sprinkle capsules: Prescribing information. AbbVie Inc.

3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

4. U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.

5. U.S. Food and Drug Administration. (2024). Inactive ingredient database. Center for Drug Evaluation and Research.