A Review on Formulation and Evaluation of BI- Layered Tablet of Divalproex Sodium

A popular anticonvulsant and mood stabilizer, divalproex sodium is mostly prescribed to treat epilepsy, bipolar disorder, and migraine prevention. Compared to valproic acid alone, this stable coordination combination of sodium valproate and valproic acid in a 1:1 molar ratio provides better gastrointestinal tolerance and longer-lasting therapeutic efficacy. However, repeated dosage is frequently necessary because of its relatively short half-life (6–16 hours), which can result in poor patient adherence and variable plasma drug levels. The creation of bi layered tablets has drawn a lot of interest as a solution to these constraints. Two separate layers usually make up a bi layered tablet system: one for sustained release (SR), which maintains effective drug levels over time, and the other for instant release (IR), which offers a quick start to therapeutic activity. By ensuring both immediate symptom relief and extended therapeutic coverage, this dual-release mechanism lowers the frequency of administration and improves patient compliance. In order to achieve the correct drug release kinetics and tablet integrity, a bi layered tablet formulation requires a careful combination of polymers, excipients, and compression processes. In the sustained layer, a variety of hydrophilic and hydrophobic polymers, including carbopol, hydroxypropyl methylcellulose (HPMC), and ethylcellulose (EC), are frequently used to regulate drug release. In the immediate release layer, superdisintegrants, such as sodium starch glycolate or crospovidone, are used to facilitate quick drug disintegration and absorption. The goal of this review is to present a thorough analysis of the formulation techniques, assessment criteria, and most current developments in the creation of Divalproex Sodium bi layered tablets. The importance of in vitro and in vivo performance testing, manufacturing difficulties, and crucial elements influencing bilayer tablet design are all highlighted.

Benefits of Tablets with Two Layers

1. Bi-layered implementation with a single-layer conversion kit available as an option.

2. It is less expensive than all other oral dose forms.

3. The oral dose form with the highest chemical and microbiological stability.

4. The coating procedure can cover up unpleasant smells and disagreeable flavors.

5. Adaptable idea.

6. They are unit dosage forms that provide the most capabilities for the least amount of content fluctuation and the highest dose precision of any oral dosage form.

7. It is easy to swallow and has a low chance of hanging up.

8. Fit for production on a wide scale.

The drawback of tablets with two layers

1. Because of their low density and amorphous nature, certain medications do not compress into dense compacts.

2. Drugs that taste bitter, have an unpleasant smell, or are oxygen-sensitive can need to be coated or encapsulated.

3. Children and patients who are unconscious may find it difficult to swallow.

The market offers a variety of tablet kinds, including controlled release, sustained release, delayed release, instant release, fast dissolving, and traditional tablets. Tablets that dissolve quickly and release the medication are known as immediate release tablets. Superdisintegrants are an essential part of formulations for quick release. Superdisintegrants are used to increase the solid dose form's effectiveness. This is accomplished by a number of processes, including swelling, capillary action and porosity, heat of wetting, particle repulsion forces, deformation recovery, and an enzyme reaction that breaks the tablets into tiny pieces.

Immediate Release Drug Delivery System Benefits:

1. Increased stability and bioavailability; enhanced compliance Adaptable and compatible with current processing and packaging equipment
2. Cost-effective
3. Suitable for controlled/sustained release actives
4. Permits high drug loading
5. Capable of offering the benefits of liquid medication in the form of solid preparation

Ibuprofen and Diclofenac sodium are examples of analgesic and anti-inflammatory medication categories that are better suited for quick release. Anti-coagulants such dipyridamole and dicoumarol. medications that treat depression, such amoxapiine. Glipizide is an anti-diabetic medication. For immediate release, antihypertensive medications including amlodipine, minoxidil, and nifedipine are the best options. Any medication that lasts for a long time is included in sustained release systems. The system is regarded as a controlled release system if it is able to keep the medication levels in the blood or target tissue steady. It is regarded as a prolonged released system if it is ineffective today but prolongs the duration of action beyond what is possible with traditional delivery.

Figure 1: A Hypothetical Plasma Concentration Vs Time Profile

Advantages of sustained release dosage forms:

• The frequency of drug administration is reduced.
• Patient compliance can be improved.
• The blood level oscillation characteristic of multiple dosing of conventional dosage forms is reduced.
• Better control of drug absorption can be attained.
• The characteristic blood variation due to multiple dosing of conventional dosage forms can be reduced.
• The total amount of drug administered can be reduced thus: o Maximizing availability with dose.

• Minimize or eliminate local side effects.
• Minimize or eliminate systemic side effects.
• Minimize drug accumulation with chronic dosing.

• Safety margin of high potency drugs can be increased and the incidence of both local and systemic adverse side effects can be reduced and sensitive patients.
•  Improve efficiency in treatment.

Disadvantages of sustained release formulation

• Administration of sustained release medication does not permit the prompt termination of therapy.
• Flexibility in adjustment of dosage regimen is limited.
• Controlled release forms are designed for normal population; i.e., on the basis of average drug biological half-lives.
• Economic factors must also be assessed, since more costly process and equipment are involved in manufacturing of many controlled release dosage forms.

Factors Influencing Design of Sustained Release Dosage Forms

Various circumstances that the drug molecule encounters during its distribution route may change the medicine's efficacy or the quantity of the drug that reaches the receptor site.

1. Pharmaceutical factor

This is the process of creating an effective delivery mechanism that maximizes the drug's physiological stability and bioavailability.

2. Biopharmaceutics / pharmacokinetics factor

This entails examining the drug's distribution, metabolism, excretion, and absorption both before and after it reaches the intended location, as well as assessing the connection between the delivery method and therapeutic outcome.

3. Pharmacodynamics/ Clinical Pharmacological factor

It is the study of a drug's clinical effectiveness and mode of action in terms of the onset, severity, and duration of pharmacological activity when taken in dose form.

Drug properties influencing the design of sustained or sustained release drug delivery system ate classified as:

• The drug's physicochemical characteristics, such as its molecular size, drug stability, protein binding, water solubility, dosage size, and partition coefficients.
• Absorption, distribution, metabolism, duration of action, margin of safety, pharmacological adverse effects, illness status, and circadian rhythm are examples of biological parameters.

Matrix erosion

Degradation of the polymer surface results in the release of the medication.

Figure 2: Schematic illustration of surface and bulk erosion

In order to improve patient convenience and compliance, the pharmaceutical industry has been more interested in creating a single dose form that combines two or more active pharmaceutical ingredients (API) during the past ten years. In order to prevent chemical incompatibilities across APIs through physical separation and to facilitate the creation of distinct drug release patterns, bi-layered tablets may be the best choice.

Figure 3: Bi-layered tablet

Types of Bi-layered tablet press

1. Single sided tablet press.
2. Double sided tablet press.
3. Bi-layered tablet press with displacement monitoring.

Drug Profile:

Divalproex Sodium

Chemical structure:

Structure of Divalproex sodium:

 Divalproex sodium contains not less than 98% and not more than 102% of available valproic acid, C8H16O2.

Chemical Name: 2-propyl-pentanoic acid sodium salt (2:1). Sodium hydrogen bis (2 propylvalerate) oligomer.

CAS Number: 76584-70-8

Brand name: Depakote, Depakote CP, Depakote ER, Epival, Stavzor. Category: Anticonvulsant.

Molecular Formula: C8H16O2C8H15O2Na

Molecular weight: 310.41.

Description: Odorless, white or off-white crystalline powder.

Melting Point: 222 °C.

Solubility: soluble in ethanol (95%), methanol, Isopropyl alcohol, partially soluble in water, ether.

Storage: Store protected from moisture at a temperature not exceeding 30 °C.

MECHANISM OF ACTION:

Divalproex sodium is broad-spectrum anticonvulsant. It increases the availability of gamma- amino butyric acid (GABA), an inhibitory neurotransmitter. It has inhibitory action against GABA transaminase which breakdown GABA, it leads to increased concentration of GABA in the synapses Other propose mechanisms of action that account for their anticonvulsant properties is it either enhance the action of GABA or mimic its action at postsynaptic receptor sites. It also blocks voltage gated sodium channels and T-type calcium channels, and cause inhibitory activity in the brain.

Pharmacokinetics Absorption: Rapid absorption from gastrointestinal tract.

Distribution: Protein binding 80-90%

Metabolism: Metabolized almost entirely by the liver.

Excretion: Both bile and urine

Half Life: 9-16 hours

Bioavailability (oral): 84%

Contraindications of Divalproex sodium

1. Hepatic disease or significant hepatic dysfunction
2. Urea cycle disorders
3. Hypersensitivity to the drug

Warnings and Precautions

1. Hepatotoxicity
2. Teratogenic
3. Pancreatitis
4. Thrombocytopenia
5. Hyperammonemia and hyperammonemic encephalopathy

Adverse Effects of Divalproex sodium

1. Nausea, Headache
2. Somnolence
3. Dizziness
4. Vomiting
5. Asthenia
6. Abdominal pain

Drug Interactions

1. Hepatic enzyme-inducing drugs: phenytoin, carbamazepine, primidone, phemobarbital, rifampin can decrease valproate clearance.
2. Aspirin, carbapenem antibiotics
3. Topiramate
4. Amitriptyline, warfarin and zidovudine

MATERIALS AND METHODS:

Preparation of IRL:

IRL of Divalproex sodium (DS) was prepared by wet granulation by using different Superdisintegrants such as SSG and Croscarmellose sodium. PVP K30 solution with containing coloring agent was used as binding solution. As DS was oily in characteristics, MCC was used as adsorbent.

 Manufacturing steps-

• Pass all the ingredients though sieve #80.
• Mix Divalproex sodium with MCC geometrically and then mix with lactose.
• Add Superdisintegrants and mix for 10 to 15 min in mortar and pestle.
• Make wet mass using binding agent PVP K 30 solution containing color.
• Pass the cohesive mass through sieve # 16 to get uniform granules.
• Dry the granules at 50 °C for 15 min in hot air oven.
• Lubricate the granules with lubricating agent and compressed into 250 mg each tablet weight by adjusting hardness.

Preparation of SRL:

Accurately weighed Divalproex sodium and polymer and others ingredients were taken in mortar and pestle and mixed well. The powder were mixed with sufficient quantity for PVP K30 solution until wet mass formed. The cohesive mass obtained was passed though sieve # 16 and the granules were dried in a hot air oven at 50 °C for 20 min. The dried granules again passed through sieve # 22 to break the large lumps. Then granules were mixed with talc and magnesium stearate and compressed into 300 mg each tablet by adjusting hardness.

Preparation of bi-layered tablet

 By the study of disintegration and drug release profile of IRL and SRL, best formulations of each layer were chosen and bi layered tablet were prepared by double compression in single rotatory tableting machine.

Evaluation of prepared formulations

Evaluation of Divalproex sodium IRL, SRL and bi-layered tablet on following parameter

Weight Variation Test 

To study weight variation, 20 tablets of each formulation were weighted using electronic balance and the test was performed according to the official method.

 Hardness

The resistance of tablets to shipping or breakage under condition of storage, transportation and handling before usage depends on its hardness. The hardness of each batch of tablet was checked by using Monsanto hardness tester. The hardness was measured in the terms of kg/cm². 5 tablets were chosen randomly and tested for hardness. The average hardness of 5 determinations was recorded.

Figure no 4: Hardness Tester

generally, refers to loss in weight of tablets in the containers due to removal of fines from the tablet surface. Friability generally reflects poor cohesion of tablet ingredients. 10 tablets were weighed and the initial weight of these tablets was recorded and placed in Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions. Then tablets were removed from the friabilator dusted off the fines and again weighed and the weight was recorded. Percentage friability was calculated by using the formula.

Figure no 5: Friabilator