List of Excipients in Branded Drug DIVALPROEX SODIUM

Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
Sandoz Inc	DIVALPROEX SODIUM	divalproex sodium	0781-2243	D&C RED NO. 28
Sandoz Inc	DIVALPROEX SODIUM	divalproex sodium	0781-2243	FD&C BLUE NO. 1
Sandoz Inc	DIVALPROEX SODIUM	divalproex sodium	0781-2243	FERRIC OXIDE RED
Sandoz Inc	DIVALPROEX SODIUM	divalproex sodium	0781-2243	GELATIN
Sandoz Inc	DIVALPROEX SODIUM	divalproex sodium	0781-2243	MAGNESIUM STEARATE
Sandoz Inc	DIVALPROEX SODIUM	divalproex sodium	0781-2243	SILICON DIOXIDE

Generic Drugs Containing DIVALPROEX SODIUM

Company	Ingredient	NDC	Excipient
Mylan Pharmaceuticals Inc	divalproex sodium	0378-0472	AMMONIA
Mylan Pharmaceuticals Inc	divalproex sodium	0378-0472	CELLULOSE, MICROCRYSTALLINE
Mylan Pharmaceuticals Inc	divalproex sodium	0378-0472	DIBUTYL SEBACATE
Mylan Pharmaceuticals Inc	divalproex sodium	0378-0472	ETHYLCELLULOSE
Mylan Pharmaceuticals Inc	divalproex sodium	0378-0472	HYDROXYETHYL CELLULOSE
Mylan Pharmaceuticals Inc	divalproex sodium	0378-0472	HYPROMELLOSE 2910

What are the Most Frequently-Used Excipients in DIVALPROEX SODIUM?

# Of NDCs	Excipient
1	2-(3-OXAZOLIDINYL)ETHYL METHACRYLATE
1	ACETONE
54	ALCOHOL
90	AMMONIA
1	ANHYDROUS DIBASIC CALCIUM PHOSPHATE
1	BROWN IRON OXIDE

Divalproex Sodium Excipient Strategy and Commercial Opportunities

Last updated: August 22, 2026

Divalproex sodium is a mature, genericized antiepileptic and mood-stabilizing drug with continuing commercial potential in modified-release, sprinkle, liquid, pediatric, geriatric, and excipient-sensitive formulations. The strongest opportunities are formulation-led rather than molecule-led: controlling valproate release, reducing peak-related adverse effects, improving swallowability, masking taste, supporting dose flexibility, and meeting specific dietary or excipient restrictions.

What is the formulation and excipient profile of divalproex sodium?

Divalproex sodium is a 1:1 coordination compound of valproic acid and sodium valproate. It dissociates in the gastrointestinal tract into valproate ions. The active ingredient is available in immediate-release, delayed-release, extended-release, sprinkle, and liquid dosage-form strategies.

The principal formulation challenge is not chemical activation. It is controlling the rate and site of valproate release while maintaining dose uniformity and acceptable gastrointestinal performance.

Dosage form	Primary commercial purpose	Key excipient strategy
Delayed-release tablet	Reduce gastric exposure and delay release until the intestine	Enteric coating using pH-dependent polymers
Extended-release tablet	Permit once-daily dosing and reduce peak-to-trough fluctuation	Hydrophilic matrix, controlled-release polymer, film coating
Sprinkle capsule	Enable administration to soft food for patients unable to swallow tablets	Coated drug particles, capsule shell, flow and moisture-control excipients
Oral solution or syrup	Pediatric and swallowing-sensitive administration	Solubilization, taste masking, viscosity control, preservative system
Orally disintegrating or multiparticulate product	Rapid administration without conventional swallowing	Disintegrants, taste-masking coating, particle engineering
Fixed-dose or combination product	Improve adherence or address comorbid treatment	Compatibility control, dose uniformity, release synchronization

Commercial reference products include Depakote delayed-release tablets, Depakote ER extended-release tablets, and Depakote Sprinkle Capsules. Their labels identify excipient systems that include combinations of lactose, microcrystalline cellulose, hypromellose, povidone, crospovidone, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, talc, titanium dioxide, and coating materials, depending on the dosage form and strength [1-3].

What excipients are used in divalproex sodium products?

Diluent and compression excipients

Lactose and microcrystalline cellulose are commonly used to build tablet mass and support compression. Microcrystalline cellulose can improve compactibility and reduce dependence on higher binder concentrations. Lactose can improve tablet processability but creates an opportunity for lactose-free products aimed at patients with intolerance, dietary restrictions, or institutional procurement requirements.

Pregelatinized starch can provide both binding and disintegration functions. Crospovidone improves tablet breakup after the dosage form reaches the target site.

The commercial tradeoff is straightforward:

• Higher disintegrant loading can improve dissolution from an immediate-release core.
• Excessive compression can slow tablet breakup and create dissolution variability.
• More hydrophilic excipients can increase moisture sensitivity.
• Lubricant overuse, particularly magnesium stearate, can reduce wettability and delay dissolution.

Binder and granulation excipients

Povidone is used as a binder in many oral solid dosage forms. It supports granule strength and content uniformity, but high concentrations can increase tablet hardness and slow disintegration. Wet granulation can improve powder flow and dose uniformity, although it introduces water and drying controls that may affect valproate stability and process reproducibility.

Direct compression is attractive for lower-cost generic manufacturing if the active and excipient particle-size distributions provide adequate flow and blend uniformity. Granulation remains useful where high-dose loading, poor flow, segregation, or low tablet strength creates manufacturing risk.

Coating and enteric-release excipients

Delayed-release products require protection from immediate gastric release. The formulation generally combines a tablet core, seal or subcoat, and pH-dependent enteric layer. Hypromellose may be used in film coating or as a protective polymer. Plasticizers such as triacetin can improve coating flexibility. Talc and titanium dioxide may support coating performance and appearance.

For a new delayed-release product, the key variables are:

1. Enteric polymer selection.
2. Coating weight gain.
3. Film thickness and defect rate.
4. Resistance to gastric fluid.
5. Prompt release at intestinal pH.
6. Mechanical protection during packaging and transport.

A lower-cost enteric system may be commercially viable, but it must reproduce dissolution performance across multiple pH stages. A weak coating can cause premature release. An overly robust coating can delay exposure and alter clinical performance.

Extended-release excipients

Extended-release divalproex sodium products use polymer-based release control. Hydrophilic polymers such as hypromellose can form a hydrated gel layer that controls diffusion and erosion. The release profile also depends on tablet dimensions, compression force, drug loading, polymer viscosity, particle size, and gastrointestinal agitation.

Extended-release products create the clearest formulation differentiation because they can support once-daily dosing and reduce peak concentrations compared with delayed-release dosing. Depakote ER labeling describes once-daily administration and pharmacokinetic distinctions from delayed-release divalproex products [2].

A generic extended-release strategy should focus on:

• Similarity across the full dissolution profile.
• Robustness against fed and fasted conditions.
• Resistance to dose dumping.
• Consistent release across strengths.
• Avoidance of excessive sensitivity to tablet splitting or crushing.
• Manufacturing control of polymer hydration and tablet porosity.

How should an excipient strategy address divalproex sodium stability?

Divalproex sodium development should treat moisture, heat, coating integrity, and packaging as connected variables. The finished product must preserve assay, impurities, dissolution, physical integrity, and dose uniformity through shelf life.

Moisture-control strategy

Moisture can affect powder flow, granule behavior, coating performance, and tablet dissolution. The commercial formulation package may include:

• Low-moisture excipients.
• Controlled-humidity manufacturing.
• High-barrier blister packaging.
• Induction-sealed bottles.
• Desiccants where justified.
• Moisture-sensitive film-coating systems.
• In-process water-activity monitoring.

The packaging decision can create a meaningful cost difference. Bottles are generally efficient for high-volume generic distribution. Unit-dose blister packaging can support adherence, institutional use, and pediatric dose management but increases packaging cost.

Lubricant and flow-agent optimization

Colloidal silicon dioxide can improve flow and reduce segregation. Magnesium stearate supports ejection but can impair wetting if overmixed or used at excessive concentration. A design-of-experiments program should evaluate lubricant concentration, blending time, compression force, and particle-size distribution together rather than optimizing them independently.

Excipient compatibility

Compatibility screening should assess:

• Valproate assay and degradation products.
• Water content.
• Thermal behavior.
• Powder flow.
• Compression performance.
• Dissolution after accelerated storage.
• Coating adhesion.
• Container-closure interaction.

Particular attention is warranted for aldehyde-containing or reactive excipient systems, reducing sugars, peroxide-generating materials, and high-moisture processing conditions. The risk is product-specific and must be demonstrated through stability and compatibility studies rather than inferred from excipient class alone.

What formulation patents protect divalproex sodium products?

Divalproex sodium itself is an established active ingredient with extensive generic availability. The original product and its core composition patents do not provide the main commercial barrier today. Protection has historically concentrated on dosage-form engineering, release profiles, particle coatings, dosing regimens, and manufacturing features.

Patent categories relevant to divalproex sodium

Patent category	Commercial relevance	Typical claim focus
Delayed-release formulation	Protects gastric-resistant delivery	Enteric coating, pH-triggered release, dissolution profile
Extended-release formulation	Supports once-daily administration	Matrix polymer, release kinetics, dosage strength
Sprinkle formulation	Supports pediatric and dysphagia use	Coated particles, food administration, dose uniformity
Method-of-use patent	Extends use in a defined indication or population	Migraine prevention, bipolar disorder, seizure control
Manufacturing patent	Protects production economics or product consistency	Granulation, coating, particle engineering, process controls
Combination patent	Protects coadministration or fixed-dose design	Divalproex plus another active ingredient
Packaging or device patent	Supports adherence or dose administration	Unit-dose systems, dosing accessories, delivery systems

The strongest remaining patent opportunity is usually a narrow formulation or process claim with a clinically relevant performance difference. Broad claims covering ordinary tablets, common binders, or standard enteric coatings are more vulnerable to obviousness and anticipation challenges.

What is the Orange Book status of divalproex sodium?

Divalproex sodium has generic products approved through abbreviated new drug applications, and the principal commercial products have long been exposed to generic competition. The Orange Book is the controlling source for current listed patents, exclusivity, therapeutic-equivalence codes, and reference-listed drug information [4].

For a specific product, an Orange Book review should separate:

• Delayed-release tablets from extended-release tablets.
• Sprinkle capsules from conventional capsules.
• Strength-specific listings.
• Active patents from expired patents.
• Listed patents from enforceable patent rights.
• Product-specific exclusivity from molecule-wide status.

Divalproex sodium does not create a conventional biosimilar pathway issue because it is a small-molecule drug. Competitive entry occurs through ANDAs, not biosimilar applications under the Public Health Service Act.

When does divalproex sodium lose exclusivity?

The core small-molecule exclusivity period has expired, and generic divalproex sodium is commercially established. The relevant commercial question is therefore not loss of basic molecule exclusivity. It is whether a particular modified-release, sprinkle, liquid, combination, or method-of-use product retains enforceable protection.

Generic entry scenarios

Scenario	Entry risk	Main commercial impact
Immediate-release or conventional delayed-release product	High	Price erosion and rapid multisource substitution
Delayed-release tablet with standard enteric coating	High to moderate	Limited differentiation unless device, strength, or formulation is distinct
Extended-release tablet	Moderate to high	Release-profile patents and formulation equivalence can delay or complicate entry
Sprinkle capsule	Moderate	Pediatric and dysphagia positioning may preserve share despite generic competition
Oral liquid	Moderate	Taste, stability, preservative, and dosing-device performance affect substitution
Novel multiparticulate or abuse-deterrent system	Lower initially	Patent and regulatory differentiation may support premium pricing

Paragraph IV litigation is most relevant when a sponsor seeks approval for a modified-release or otherwise differentiated product while listed formulation patents remain active. A generic applicant may certify that listed patents are invalid, unenforceable, or not infringed. Patent litigation can delay approval under the statutory stay, subject to the specific Orange Book listing and litigation posture [5].

No general conclusion about a live Paragraph IV dispute should be drawn from the existence of historical divalproex litigation. Current case status must be checked against the FDA Orange Book, FDA litigation listings, and the relevant court docket.

Which excipient-led commercial opportunities are strongest?

Pediatric and dysphagia products

Sprinkle capsules remain commercially relevant because epilepsy and bipolar disorder populations include children, older adults, and patients with swallowing limitations. A product that can be administered with soft food without compromising release or dose uniformity can compete on usability rather than active-ingredient novelty.

Potential improvements include:

• Smaller coated particles.
• Reduced grittiness.
• Better adhesion to food.
• Neutral or masked taste.
• Lower capsule-opening burden.
• Unit-dose sachets.
• Dosing devices for partial-dose administration.

The critical technical issue is preventing chewing or crushing from destroying the intended release profile.

Taste-masked oral liquids

Valproate products can have strong taste and odor, creating adherence problems in pediatric use. Taste masking can use polymeric coating, ion exchange, complexation, flavor systems, sweeteners, or multiparticulate delivery.

A commercially credible oral liquid must demonstrate:

• Chemical stability over shelf life.
• Preservative efficacy where preservatives are used.
• Accurate dosing at the lowest marketed volume.
• Uniform concentration after shaking.
• Acceptable viscosity.
• Compatibility with oral syringes and feeding tubes.
• Minimal interaction with food and common beverages.

Taste masking is more valuable when paired with a differentiated dose-delivery system. Flavor alone is easier to copy and may create pediatric acceptability problems if it is too intense or changes during storage.

Extended-release and adherence products

Once-daily dosing is the most commercially defensible formulation proposition. The excipient system should create a reproducible release curve without excessive food effect or dose dumping.

Commercial value can come from:

• Once-daily administration.
• Lower peak-related tolerability burden.
• Fewer daily administration events.
• Strength combinations that simplify titration.
• More consistent exposure.
• Reduced caregiver administration burden.

The sponsor must avoid positioning that implies clinical superiority without supporting comparative data. A release-profile difference is not automatically a clinical advantage.

Excipient-restricted products

There is a potential niche for:

• Lactose-free products.
• Gluten-free products with documented controls.
• Dye-free products.
• Sugar-free liquid products.
• Low-sodium excipient systems.
• Products without selected animal-derived materials.
• Products with simplified excipient declarations for institutional procurement.

These products can win formulary or pharmacy preference in narrow segments, but they usually require clear patient or procurement value. Excipient substitution must not alter dissolution, bioavailability, stability, or tolerability.

Pediatric and geriatric packaging

Packaging can support commercial differentiation without changing the active ingredient. Relevant options include:

• Unit-dose blister cards.
• Calendar packaging.
• Child-resistant, senior-friendly closures.
• Oral syringes with dose markings.
• Sachets for sprinkle administration.
• Tamper-evident bottles.
• Light- and moisture-protective containers.

Packaging patents may provide supplementary protection, but the commercial benefit usually comes from adherence, medication-error reduction, and institutional workflow rather than exclusivity alone.

How does divalproex sodium compare with valproic acid and valproate sodium?

Divalproex sodium, valproic acid, and valproate sodium produce valproate ion but differ in formulation, tolerability, dosing, and excipient requirements.

Attribute	Divalproex sodium	Valproic acid	Valproate sodium
Chemical form	Valproic acid and sodium valproate coordination compound	Free acid	Sodium salt
Oral dosage forms	Delayed-release, extended-release, sprinkle	Capsules, liquids, other products	Oral and injectable forms depending on product
Formulation focus	Enteric protection, extended release, sprinkle delivery	Taste, liquid stability, capsule tolerability	Solubility, sodium content, parenteral or oral delivery
Main commercial differentiator	Modified release and administration flexibility	Liquid and conventional oral delivery	Hospital and acute-care utility
Excipient opportunity	Polymer coatings, matrix systems, multiparticulates	Taste masking and liquid systems	Sodium-load management and compatibility

A new divalproex product must compete against both generic divalproex and alternative valproate formulations. The reference product is not the only relevant comparator. Prescribers may switch among dosage forms when cost, adherence, swallowing, or dosing frequency changes.

What regulatory strategy supports a new divalproex formulation?

A conventional generic product generally follows the ANDA pathway and must demonstrate pharmaceutical equivalence and bioequivalence to the reference product. A genuinely differentiated formulation may require a different regulatory strategy, including a 505(b)(2) application where permitted.

The regulatory package should align the excipient claim with measurable product performance:

Product proposition	Key regulatory evidence
Delayed release	Multi-stage dissolution, stability, bioequivalence
Extended release	Comparative pharmacokinetics, fed and fasted studies, dissolution
Pediatric sprinkle	Particle-size distribution, food administration, dose recovery, acceptability
Oral liquid	Concentration uniformity, stability, preservative efficacy, device accuracy
Lactose-free or dye-free	Complete excipient qualification and comparative performance
New combination	Drug-drug compatibility, clinical rationale, bioavailability
Novel delivery system	Product-specific CMC, pharmacokinetics, and potentially clinical data

Inactive ingredients must comply with FDA requirements and should be evaluated against the Inactive Ingredient Database, route, dosage form, maximum daily exposure, and concentration [6]. A new excipient that is not adequately supported can increase development time and regulatory risk.

How strong is the patent estate for a new divalproex product?

The patent estate is strongest when the product combines a technically difficult formulation with a clinically meaningful administration advantage. The following ranking reflects general formulation defensibility:

1. Novel multiparticulate extended-release system with demonstrated food robustness.
2. Sprinkle system with protected particles, strong taste masking, and dose-flexible administration.
3. Liquid formulation with differentiated stability and validated dosing-device performance.
4. New combination product with independent clinical and formulation value.
5. Standard enteric-coated tablet using conventional excipients.
6. Simple excipient substitution without a measurable performance benefit.

Patent claims should focus on quantifiable elements such as particle-size ranges, coating composition, polymer ratios, dissolution windows, release-rate parameters, manufacturing steps, and administration conditions. Functional claims without reproducible structural limitations may face validity and infringement challenges.

What licensing and partnering opportunities exist?

Licensing interest is more likely for a finished dosage-form platform than for divalproex sodium itself. Potential transaction structures include:

• Regional licensing of pediatric sprinkle products.
• Co-development of extended-release formulations.
• Contract manufacturing with proprietary coating technology.
• Out-licensing of taste-masking technology.
• Hospital-channel partnerships for liquid or unit-dose products.
• Acquisition of an ANDA with differentiated packaging or dosage delivery.
• Private-label supply agreements for institutional pharmacies.

The asset value depends on approval status, manufacturing scale, bioequivalence package, patent position, supply reliability, and reimbursement. A formulation patent without reliable commercial manufacturing has limited licensing value.

What manufacturing and intellectual-property barriers affect commercial entry?

The main manufacturing barriers are process reproducibility and dissolution control. High-dose tablets can create content-uniformity and compression challenges. Enteric products require consistent coating coverage. Extended-release products require tight control of polymer distribution, tablet porosity, and mechanical strength. Sprinkle products require uniform coating of small drug particles without agglomeration.

The main intellectual-property barriers are:

• Active formulation patents.
• Release-profile patents.
• Particle-coating claims.
• Method-of-use patents.
• Manufacturing-process claims.
• Regulatory exclusivity associated with a new indication or formulation.
• Trade secrets covering coating parameters and process settings.

A successful entry strategy should run patent clearance, Orange Book review, formulation reverse engineering, and regulatory pathway analysis in parallel. Delaying patent review until after formulation selection can force redesign or create avoidable litigation exposure.

Key Takeaways

• Divalproex sodium is a mature genericized drug; the active ingredient itself offers limited exclusivity.
• Commercial opportunities center on dosage-form performance, not molecular novelty.
• Extended-release tablets have the strongest broad-market differentiation potential.
• Sprinkle capsules and taste-masked liquids address pediatric, geriatric, and dysphagia populations.
• Enteric coatings and hydrophilic matrix polymers are the central excipient technologies for delayed- and extended-release products.
• Lactose-free, dye-free, sugar-free, and simplified-excipient products can support targeted procurement and patient segments.
• The principal regulatory routes are ANDA for conventional generics and, where justified, 505(b)(2) for differentiated formulations.
• Patent strength depends on technically specific formulation, process, particle, and release-profile claims.
• Packaging and dosing-device improvements can support adherence and commercial positioning but rarely replace a strong formulation advantage.
• Current patent listings, Paragraph IV cases, and exclusivity status must be evaluated at the product and dosage-form level through FDA records.

FAQs

Can excipients change the therapeutic performance of divalproex sodium?

Yes. Excipients can alter disintegration, gastric resistance, release rate, absorption timing, peak concentration, food sensitivity, and dose uniformity. These effects are especially important in delayed-release and extended-release products.

Is a lactose-free divalproex sodium product commercially attractive?

It can be attractive in targeted markets, particularly where institutional formularies or patients avoid lactose. The opportunity is stronger when lactose removal is combined with a meaningful delivery improvement, such as liquid dosing or sprinkle administration.

Are divalproex sodium extended-release products difficult to develop?

They are more technically demanding than conventional immediate-release tablets because release depends on polymer behavior, compression, tablet geometry, dissolution conditions, and food effects. Bioequivalence and dissolution matching can create substantial development work.

Can a new divalproex liquid receive market exclusivity?

A new liquid may qualify for product-specific patent protection or regulatory exclusivity if it includes a qualifying new formulation, indication, or delivery system. A conventional liquid using known excipients generally has weaker exclusivity potential.

Does divalproex sodium have biosimilar competition?

No. Divalproex sodium is a small-molecule drug and is regulated through generic drug pathways rather than biosimilar pathways. Competition primarily comes from ANDA-approved generic products and differentiated oral formulations.

References

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

2. U.S. Food and Drug Administration. (2023). Depakote ER extended-release tablets: Prescribing information. AbbVie Inc. DailyMed.

3. U.S. Food and Drug Administration. (2023). Depakote Sprinkle Capsules: Prescribing information. AbbVie Inc. DailyMed.

4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th edition. FDA, Center for Drug Evaluation and Research.

5. U.S. Food and Drug Administration. (2024). Hatch-Waxman litigation and 30-month stay provisions. FDA, Center for Drug Evaluation and Research.

6. U.S. Food and Drug Administration. (2024). Inactive Ingredient Database. FDA, Center for Drug Evaluation and Research.