A review article on : Anti- anxiety activity

Stress is the body’s natural response to demands or threats, but when it becomes chronic, it disrupts nearly every system from the heart and immune response to mood and sleep. Hans Selye famously described it as the “nonspecific response of the body to any demand.” Today, stress contributes to a wide range of issues, including hypertension, anxiety disorders, depression, and weakened immunity. The scale of the problem is staggering. According to the World Health Organization, over one billion people worldwide live with mental health conditions, with anxiety and depression among the most common. Women are often disproportionately affected, and factors like urbanization, work pressure, social media, and economic uncertainty continue to drive prevalence higher. Stress manifests in different forms: acute (short-term, like facing a deadline), chronic (ongoing, like financial strain), and episodic acute. While some stress (eustress) motivates us, distress harms health by overactivating the hypothalamic-pituitary-adrenal (HPA) axis, flooding the body with cortisol and promoting inflammation and oxidative damage.

Conventional anti-stress drugs can cause drowsiness, dependency, or cognitive fog. This has fueled interest in herbal adaptogens. Ashwagandha, often called “Indian ginseng,” has centuries of traditional use and growing modern clinical support for safely reducing stress and improving resilience. Oral dispersible tablets address practical barriers of conventional tablets such as the need for water and swallowing difficulties while offering rapid onset, making them especially suitable for stress-related conditions where quick relief and ease matter most.

1.1. Types of Stress

Stress can be classified into the following categories:

1.1.1 Acute Stress

Acute stress is a short-term response triggered by immediate threats or demanding situations. It is characterized by temporary activation of the sympathetic nervous system.

1.1.2. Chronic Stress

Chronic stress occurs when exposure to stressors becomes prolonged. It may result in hypertension, depression, anxiety disorders, insomnia, cardiovascular diseases, and immune dysfunction.

1.1.3. Episodic Acute Stress

This type involves repeated episodes of acute stress and is often associated with irritability, tension headaches, and persistent anxiety.

1.1.4. Eustress and Distress

Eustress is considered beneficial stress that motivates individuals, whereas distress is harmful and negatively affects physical and mental health.

1.2. Physiological Effects of Stress

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and stimulates secretion of cortisol and catecholamines. Persistent activation leads to oxidative stress, neuronal damage, endocrine disturbances, and impaired cognitive functions.

The major physiological effects include:

• Increased cortisol secretion
• Elevated blood pressure
• Sleep disturbances
• Reduced immunity
• Gastrointestinal dysfunction
• Neurotransmitter imbalance
• Anxiety and depression

1.3. Need for Herbal Anti-Stress Formulations

Synthetic anti-anxiety and antidepressant drugs are associated with adverse effects such as sedation, dependency, withdrawal syndrome, and cognitive impairment. Herbal medicines offer safer alternatives due to their natural origin, lower toxicity, and multitarget therapeutic actions.

Ayurvedic medicinal plants have been extensively investigated for adaptogenic and anxiolytic activities. Among them, Ashwagandha has shown remarkable efficacy in reducing cortisol levels, improving cognitive performance, and enhancing stress tolerance.

1.4. Oral Dispersible Tablets

Oral dispersible tablets are solid dosage forms designed to disintegrate rapidly in saliva within seconds without water. ODTs improve patient convenience and compliance, especially among pediatric, geriatric, bedridden, psychiatric, and dysphagic patients.

1.5. Advantages of ODTs

• Rapid onset of action
• Improved patient compliance
• Ease of administration
• No requirement of water
• Better bioavailability
• Suitable for dysphagic patients
• Enhanced convenience during travel
• Improved taste masking

1.6. Limitations of Conventional Tablets

Conventional tablets may exhibit delayed disintegration and swallowing difficulties. Patients experiencing stress-related disorders may suffer from dry mouth, poor compliance, and difficulty swallowing, necessitating alternative dosage forms.

1.7. Herbal Drug Delivery Systems

Herbal drug delivery systems combine traditional herbal medicines with advanced pharmaceutical technologies to improve therapeutic efficacy and patient acceptability. ODTs provide an excellent platform for delivering herbal extracts due to rapid disintegration and faster absorption.

1.8. Ashwagandha in Ayurveda

Ashwagandha (Withania somnifera) is one of the most important Rasayana herbs described in Ayurveda. It is traditionally used for rejuvenation, enhancement of vitality, memory improvement, stress reduction, and promotion of longevity.

Ancient Ayurvedic texts describe Ashwagandha as a potent adaptogen capable of strengthening the nervous system and improving resistance against stress.

2. ASHWAGANDHA PROFILE

Biological Source

Ashwagandha consists of dried roots and leaves of Withania somnifera belonging to the family Solanaceae.

Synonyms

• Indian Ginseng
• Winter Cherry
• Asgandh
• Vajigandha

Family

Solanaceae

Geographical Source

Ashwagandha is widely cultivated in India, Pakistan, Sri Lanka, Middle Eastern countries, and parts of Africa.

Chemical Constituents

The major active constituents of Ashwagandha include:

• Withanolides
• Alkaloids
• Sitoindosides
• Steroidal lactones
• Flavonoids
• Saponins
• Iron

Withanolides

Withanolides are steroidal lactones responsible for most pharmacological activities of Ashwagandha.

Important withanolides include:

• Withaferin A
• Withanolide A
• Withanoside IV
• Withanoside V

2.1. Pharmacological Activities

2.1.1. Anti-Stress Activity

Ashwagandha regulates cortisol secretion and improves stress tolerance by modulating the HPA axis.

2.1.2. Adaptogenic Activity

Adaptogens enhance the body's resistance to physical, emotional, and environmental stress.

2.1.3. Neuroprotective Activity

Ashwagandha protects neuronal cells against oxidative damage and neurodegeneration.

2.1.4. Antioxidant Activity

The herb increases endogenous antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase.

2.1.5. Immunomodulatory Activity

Ashwagandha stimulates immune responses and improves resistance to infections.

2.1.6. Anti-inflammatory Activity

Withanolides inhibit inflammatory mediators and reduce tissue inflammation.

2.2. Mechanism of Anti-Stress Action

Ashwagandha exerts anti-stress effects through multiple pathways:

1. Regulation of cortisol secretion
2. Modulation of GABAergic signaling
3. Reduction of oxidative stress
4. Neurotransmitter balance restoration
5. Improvement in mitochondrial function
6. Reduction in inflammatory cytokines

2.3. Clinical Evidence: Multiple randomized, double-blind, placebo-controlled trials confirm benefits. Doses of 240–600 mg/day of standardized extract often reduce Perceived Stress Scale scores, anxiety ratings, and serum cortisol while improving sleep quality and well-being. Recent studies (2025–2026) further support its safety and efficacy in stressed adults, with significant improvements in psychological parameters and minimal side effects.

3. ORAL DISPERSIBLE TABLETS (ODTs)

Oral dispersible tablets (ODTs), also known as orodispersible tablets or fast-dissolving tablets, are solid dosage forms designed to disintegrate or dissolve rapidly in the oral cavity within seconds when placed on the tongue, without the need for water or chewing. The released drug is then swallowed with saliva, enabling pregastric absorption in some cases and leading to faster onset of action.

Table 1: Advantages vs. Disadvantages of Oral Dispersible Tablets

3.1. Ideal Characteristics of ODTs

For an ODT to be successful in terms of manufacturing, patient acceptability, and therapeutic performance, it must possess several key attributes:

• Rapid Disintegration: Should disintegrate within 30–60 seconds (preferably ≤30 seconds as per FDA guidance) in a small volume of saliva to ensure quick release and convenience.
• Mechanical Strength: Adequate hardness, typically in the range of 3–5 kg/cm² (or 30–50 N), so the tablet can withstand handling, packaging, and transportation without breaking.
• Low Friability: Less than 1% weight loss to ensure durability during manufacturing and distribution.
• Uniform Drug Content: High content uniformity (usually 85–115% of the labeled amount) to guarantee dose accuracy, especially important for potent herbal extracts.
• Pleasant Mouthfeel and Acceptable Taste: Smooth texture with no grittiness; effective taste masking is essential for bitter herbal ingredients like Ashwagandha extract. Sweeteners (e.g., mannitol, aspartame) and flavors help achieve a cooling, palatable sensation.
• Low Hygroscopicity and Good Stability: Resistance to moisture uptake to maintain integrity during shelf life; special moisture-proof packaging (e.g., aluminum blisters) is often required.
• High Drug Loading Capacity: Ability to incorporate sufficient active ingredient (e.g., 250 mg Ashwagandha extract in a 500 mg tablet) without compromising disintegration or mechanical properties.
• Good Flow and Compressibility: For ease of manufacturing, especially via direct compression.
• Cost-Effectiveness: Economical production and packaging processes.

These characteristics ensure high patient compliance, particularly among pediatric, geriatric, dysphagic, and psychiatric patients, as well as travelers or those with busy lifestyles.

3.2. Superdisintegrants in ODTs

Superdisintegrants are specialized excipients added in small quantities (typically 2–8% w/w) that promote rapid tablet breakup in limited saliva volume. They are far more efficient than conventional disintegrants.

3.3. Common Super disintegrants and Their Mechanisms:

Table 2. Overview of Common Superdisintegrants and Their Mechanisms

3.4. Additional Insights:

• Crospovidone is frequently chosen in herbal ODTs like those with Ashwagandha because it works effectively without excessive gelling, preserving rapid drug release.
• Multiple mechanisms (wicking, swelling, deformation recovery, and heat of wetting) often work together. Selection depends on the active ingredient’s properties and desired disintegration time.

3.5. Preparation Methods for ODTs

Several techniques are available for manufacturing ODTs. The choice depends on the drug’s stability, dose, and desired characteristics.

3.5.1. Direct Compression (Most Preferred for Herbal Extracts) This is the simplest, most economical, and widely used method. Ingredients are blended and compressed directly into tablets without granulation or heat.

Advantages:

• Fewer processing steps → lower cost, time, and labor.
• No moisture or heat involved → ideal for moisture- and heat-sensitive herbal extracts like Ashwagandha.
• Better stability and faster dissolution profile.
• Easy scalability and content uniformity.

Limitations: Requires good flow and compressibility of the powder blend (achieved with proper excipients like mannitol and crospovidone).

3.5.2. Wet Granulation Involves binder solution to form granules, followed by drying and compression. Suitable when direct compression is not feasible due to poor flow, but not ideal for moisture-sensitive herbs.

3.5.3. Freeze Drying (Lyophilization) Produces highly porous tablets that dissolve almost instantly (e.g., Zydis technology). Offers excellent mouthfeel but is expensive and requires special equipment.

3.5.4. Spray Drying Creates porous particles with improved dissolution. Useful for taste masking and bioavailability enhancement.

3.5.5. Other Advanced Methods: Sublimation (using volatile substances to create porosity), melt granulation, phase-transition, and 3D printing (emerging for personalized dosing).

In the present study, direct compression was selected for its simplicity, cost-effectiveness, and suitability for thermolabile herbal extracts.

4. DRUG–EXCIPIENT PROFILE

Table 3. Overview of Drug- Excipients profile

4.1. Detailed Description of Excipients

• Ashwagandha Extract
• Ashwagandha extract serves as the therapeutic agent possessing anti-stress and adaptogenic activities.
• Crospovidone
• Crospovidone is a synthetic superdisintegrant that promotes rapid tablet disintegration through capillary action.
• PVP K-30
• Polyvinyl pyrrolidone acts as a binder improving tablet cohesiveness and mechanical strength.
• Mannitol
• Mannitol provides pleasant mouthfeel and cooling sensation while improving compressibility.
• Magnesium Stearate
• Magnesium stearate reduces friction during tablet compression.
• Talc
• Talc improves powder flow properties and prevents sticking.
• Aspartame
• Aspartame masks the bitter taste of herbal extract.
• Flavoring Agents
• Flavoring agents improve palatability and patient acceptability.

5. FORMULATION TABLE

Table 4. Formulation of Ashwagandha Oral Dispersible Tablet (500 mg)

6. METHOD OF PREPARATION

Direct Compression Method

Step 1: Sieving

All ingredients were passed through sieve no. 60 separately to remove lumps and obtain uniform particle size.

Step 2: Weighing

All ingredients were accurately weighed according to formulation requirements.

Step 3: Blending

Ashwagandha extract, mannitol, crospovidone, and PVP K-30 were blended uniformly using geometric dilution.

Step 4: Lubrication

Talc and magnesium stearate were added to the powder blend and mixed gently.

Step 5: Compression

The final blend was compressed using a rotary tablet compression machine equipped with flat-faced punches.

Step 6: Packaging

Prepared tablets were packed in aluminum blister packs to protect against moisture.

8. PREFORMULATION STUDIES

Preformulation studies were carried out to evaluate the physicochemical characteristics and flow behavior of the powder blend before compression. These studies are essential for ensuring uniformity, compressibility, manufacturability, and stability of oral dispersible tablets.

Table 8.1: Preformulation Parameters and Significance

Table 8.2: Experimental Procedure for Preformulation Studies

Table 8.3: Observed Preformulation Results of Powder Blend

Interpretation of Preformulation Results

The precompression parameters confirmed that the prepared powder blend exhibited satisfactory flowability and compressibility suitable for direct compression technique. The angle of repose below 30° indicated excellent flow characteristics, whereas Carr’s index and Hausner ratio demonstrated acceptable compressibility behavior. Moisture content was within permissible limits, indicating good stability and reduced risk of microbial contamination.

9. EVALUATION PARAMETERS

Evaluation of oral dispersible tablets was performed to determine mechanical strength, disintegration behavior, drug release profile, and overall quality of the prepared formulation according to pharmacopeial standards.

Table 9.1: Evaluation Parameters of Oral Dispersible Tablets

Table 9.2: Detailed Experimental Conditions for Evaluation Studies

10. RESULTS AND DISCUSSION

Table 10.1: Preformulation Study Results of Powder Blend

10.1. Discussion of Preformulation Results

The prepared powder blend exhibited excellent flow and compressibility characteristics suitable for direct compression. The angle of repose value below 30° confirmed free-flowing nature of the blend, which is essential for uniform die filling during tablet compression. Carr’s index and Hausner ratio values indicated low interparticle friction and satisfactory compressibility behavior. Moisture content was found within acceptable limits, suggesting reduced risk of instability and microbial growth.

Table 10.2: Evaluation Results of Ashwagandha Oral Dispersible Tablets

The optimized formulation was subjected to accelerated stability testing under ICH recommended conditions to evaluate physical stability, drug content retention, and dissolution behavior over a period of three months.

Table 10.3: Accelerated Stability Study Results of Optimized Formulation (ICH Guidelines)