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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                Review Article

Formulation and Evaluation of Floating Oral In-Situ Gel of Etodolac: A Comprehensive Review

Rupesh Kumar Sahu ³, Niharika Sahu ², Ruchi Gupta ¹, Dharmendra Sahu ¹, Rahul Dev ¹, Shiv Kumar Bhardwaj ^3*

¹ Gracious College of Pharmacy, Village-Belbhata, Abhanpur, Raipur-493661, Chhattisgarh, India

² Columbia College of Pharmacy, Columbia Professional University, Tekari, Near Vidhansabha Road, Raipur-493111, Chhattisgarh, India

³ Columbia Institute of Pharmacy, Columbia Professional University, Tekari, Near Vidhansabha Road, Raipur-493111, Chhattisgarh, India

Highlights

• Etodolac floating in-situ gel was proposed for gastroretective delivery.
• Sodium alginate and HPMC support gel formation and sustained release.
• Effervescence-induced buoyancy enables prolonged gastric residence.
• Formulation optimization targets viscosity, gel strength and drug release.
• In-vivo studies are essential to confirm gastroretection and pharmacokinetic benefits.

1. Introduction

The oral route remains one of the most convenient and widely accepted routes for drug administration because of its simplicity, patient acceptability, low cost and ease of administration.¹  However, conventional oral dosage forms may undergo rapid gastric emptying, resulting in relatively short residence at the upper gastrointestinal tract. This can be problematic when prolonged gastric residence, controlled release or improved dissolution under acidic conditions is desirable.²  Gastroretective drug delivery systems (GRDDS) have therefore been investigated to prolong the residence of dosage forms in the stomach and regulate drug release.³  GRDDS include floating, mucoadhesive, expandable, high-density, magnetic and raft-forming systems.⁴  Among these, floating systems are designed to possess a density lower than gastric contents, allowing them to remain buoyant for an extended period. Floating systems may be broadly classified into effervescent and non-effervescent systems. Hydrophilic polymers such as HPMC and sodium alginate can hydrate and form gel barriers that contribute to buoyancy and sustained drug release.⁵   An in-situ gel is administered as a liquid or low-viscosity formulation and undergoes gel formation after exposure to physiological conditions. Gelation can be triggered by pH, temperature, ions or solvent exchange. In gastroretentive systems, ionic or pH-responsive gelation can be combined with gas generation to produce a buoyant gel depot in the stomach. Sodium alginate is particularly attractive because of its gel-forming ability, biocompatibility and suitability for gastroretentive formulations.⁶   Etodolac is an NSAID exhibiting analgesic and anti-inflammatory activity. It is well absorbed orally and does not undergo significant first-pass metabolism. The reported terminal half-life in healthy adults is approximately 6.4 h, while the mean time to peak concentration is approximately 1.4 h. Food does not substantially alter the extent of absorption but can reduce peak concentration and delay the time to peak concentration.⁷ 

Etodolac has a molecular formula of C₁₇H₂₁NO₃, reported pKa of approximately 4.65 and logP of approximately 2.5.⁸  These physicochemical characteristics make polymeric gastroretentive formulations worthy of investigation, particularly when the objective is to modify the release profile rather than simply provide immediate systemic exposure. The present review therefore focuses on the scientific rationale, formulation strategy, polymer selection, preparation, characterization, evaluation and future development of floating oral in-situ gel of etodolac.

2. Rationale for developing etodolac floating in-situ gel

The development of a floating in-situ gel of etodolac is based on the need to combine gastroretention with controlled drug release.⁹  Following oral administration, the liquid formulation is expected to reach the stomach, where exposure to the acidic gastric environment promotes polymer hydration and in-situ gel formation. Incorporation of an effervescent agent can generate CO₂, which becomes entrapped within the polymeric network and decreases the apparent density of the formed gel, thereby promoting buoyancy and prolonging gastric residence.¹⁰  The resulting floating gel depot can act as a sustained-release matrix from which etodolac is gradually released by diffusion, polymer relaxation, swelling and/or erosion. Etodolac → Oral administration → Gastric environment → Polymer hydration and in-situ gelation → CO₂ generation and entrapment → Floating gel depot → Prolonged gastric residence → Controlled etodolac release → Sustained drug exposure. The principal advantages expected from this approach include prolonged gastric residence, sustained drug release, reduced fluctuations in plasma drug concentrations, potential reduction in dosing frequency, and improved control over the drug-release profile.¹¹  The formulation also provides flexibility for optimizing polymer type, polymer concentration and polymer combinations to achieve an appropriate balance between viscosity, gel strength, buoyancy and drug diffusion. Thus, the floating in-situ gel approach may provide a useful platform for modifying the release characteristics of etodolac while maintaining the convenience of oral administration. However, prolonged gastric residence does not necessarily result in improved bioavailability or therapeutic efficacy. Gastric retention is influenced by several physiological and formulation-related factors, including the fed or fasted state, gastric motility, gastric emptying rate, dosage-form density, viscosity, gel strength and polymer characteristics.¹²  Therefore, the proposed formulation should be evaluated systematically using in-vitro buoyancy, gelation, rheological, drug-release and stability studies, followed by appropriate in-vivo gastric-retention and pharmacokinetic investigations to establish whether the formulation provides a meaningful pharmaceutical advantage over conventional etodolac dosage forms.

3. Drug profile of etodolac

Table 1: Comprehensive drug profile of etodolac^13–16

4. Floating oral in-situ gel: concept and mechanism

Floating oral in-situ gels combine in-situ gelation with buoyancy to achieve prolonged gastric retention and sustained drug release.¹⁷  The formulation is administered as a liquid and, upon reaching the stomach, physiological conditions trigger polymer hydration, chain relaxation, and gel-network formation. When an effervescent component such as sodium bicarbonate reacts with gastric hydrochloric acid, carbon dioxide is generated:

NaHCO₃ + HCl → NaCl + H₂O + CO₂↑

The generated CO₂ becomes entrapped within the polymeric gel network, thereby reducing the apparent density of the gel and enabling it to float on the gastric fluid.¹⁸  Simultaneously, drug release occurs through diffusion from the hydrated and formed polymeric network, providing sustained drug delivery:

Polymer hydration → Chain relaxation → Gel-network formation → CO₂ entrapment → Reduced apparent density → Buoyancy → Drug diffusion → Sustained drug release

Thus, the overall mechanism involves two interconnected processes: (1) in-situ gel formation and (2) buoyancy generation which together enhance gastric residence time and support sustained drug release. Floating gastroretentive systems based on sodium alginate and other hydrocolloids have been extensively investigated, with alginate being particularly useful because of its excellent gel-forming ability, biocompatibility, and gastroretentive properties.^19,20  Figure 1 illustrates the proposed mechanism of the Etodolac in-situ gel following oral administration. After reaching the acidic gastric environment (pH ~1–3), polymer hydration and gel formation occur. Simultaneously, sodium bicarbonate reacts with gastric hydrochloric acid to generate CO₂, which becomes entrapped within the polymeric gel network. The entrapped CO₂ reduces the apparent density of the formulation, resulting in the formation of a floating gel depot in the stomach. The retained gel gradually releases etodolac through controlled diffusion, thereby providing sustained drug release and prolonged gastric residence.

Figure 1. Mechanism of floating oral in-situ gel

(Schematic representation of gel formation, CO₂ entrapment, buoyancy and controlled release from an etodolac floating oral in-situ gel).

5. Formulation Design

5.1 Selection of polymers

Polymer selection is one of the most critical factors in the development of an effective in-situ gel, as the polymer determines the formulation’s rheological properties, gelation behavior, gastric retention and drug-release profile.²¹  An ideal polymer should provide appropriate viscosity before administration to facilitate easy swallowing and administration, followed by rapid and reproducible gelation under physiological gastric conditions.²²  The formed gel should possess adequate mechanical strength and integrity to withstand gastric motility while maintaining good compatibility with the drug and other formulation components.²³  In addition, the polymer should promote prolonged gastric retention and controlled drug diffusion, thereby supporting sustained drug release. Finally, it should exhibit acceptable physical and chemical stability during storage and use. Ideal polymer requirements:  Appropriate pre-administration viscosity → Rapid & reproducible gelation → Adequate gel strength → Drug compatibility → Prolonged gastric retention → Controlled drug diffusion → Physical stability

Sodium alginate

Sodium alginate is a natural polysaccharide widely investigated for gastroretentive systems. It can form hydrogels and can be combined with other polymers to modify gel strength and release characteristics.²⁴ 

HPMC

HPMC is a semisynthetic hydrophilic polymer commonly used as a viscosity enhancer and release-retarding polymer. Its hydration produces a viscous gel barrier, which can slow drug diffusion.²⁵

Gellan gum

Gellan gum is an ion-responsive polysaccharide capable of forming gels in the presence of suitable ions. It can therefore be investigated in combination with sodium alginate for improving gel structure.²⁶

Carbopol

Carbopol can increase viscosity and mucoadhesive characteristics. However, excessive polymer concentration can make the formulation difficult to administer and may adversely affect drug release.²⁷

Table 2. Major excipients and their functions

6. Proposed formulation development

The proposed formulation development of Etodolac floating in-situ gel involves the preparation of several experimental batches with varying concentrations and ratios of polymers, particularly sodium alginate and HPMC, while maintaining Etodolac and other excipients at suitable levels.³⁷  Gellan gum may be incorporated as a secondary gelling polymer, whereas sodium bicarbonate and citric acid are used to generate carbon dioxide and impart floating characteristics. The formulations are optimized based on viscosity, gelation capacity, floating lag time, total floating duration, drug content and in-vitro drug-release characteristics.³⁸  The final concentrations of the polymers and excipients are determined through preliminary formulation and optimization studies.

7. Preparation method^39–41

A suitable general preparation procedure is:

Step 1: Polymer dispersion

The required quantity of sodium alginate is dispersed gradually in purified water under continuous stirring to avoid lump formation.

Step 2: Secondary polymer incorporation

HPMC and/or gellan gum is separately hydrated and subsequently incorporated into the alginate dispersion.

Step 3: Drug incorporation

Etodolac is dispersed or solubilized using a suitable pharmaceutical vehicle/co-solvent system, depending on its concentration and formulation characteristics.

Step 4: Addition of excipients

Sodium bicarbonate and other formulation components are incorporated carefully under controlled stirring.

Step 5: Volume adjustment

The formulation is brought to the desired final volume using purified water.

Step 6: Deaeration

Entrapped air is removed because excessive air bubbles can alter viscosity, dose uniformity and apparent buoyancy.

Step 7: Final characterization

The formulation is evaluated for pH, viscosity, gelation, floating characteristics, drug content and dissolution. Figure 2 illustrates the stepwise formulation development of Etodolac floating oral in-situ gel. Sodium alginate is initially hydrated in purified water under continuous stirring, followed by the incorporation of HPMC and/or gellan gum to obtain a uniform polymer dispersion. Etodolac is subsequently added, followed by suitable excipients and an effervescent agent. The formulation volume is adjusted with purified water and the preparation is deaerated to remove entrapped air. The resulting formulation is filled into a suitable container as an Etodolac floating oral in-situ gel and subjected to further physicochemical and performance evaluation.

Figure 2: Formulation development process of etodolac floating oral in-situ gel

(Generalized manufacturing workflow for development of an etodolac floating oral in-situ gel).

8. Evaluation of floating oral in-situ gel

8.1 Appearance

The formulation should be visually examined for colour, clarity/opacity, homogeneity, phase separation, sedimentation and visible particulate matter.⁴²

8.2 pH

The pH should be determined using a calibrated digital pH meter. Measurements should be performed at room temperature, preferably in triplicate.^42,43

8.3 Viscosity

Viscosity is a critical parameter because it influences the pourability, syringe ability, ease of administration, gel formation, drug release and floating behavior of the formulation. Viscosity can be measured using a Brookfield-type viscometer with a suitable spindle and rotational speed.⁴³

8.4 Gelation study

A measured quantity of the formulation is introduced into simulated gastric fluid (SGF) or an acidic medium and the time required for gel formation, nature and integrity of the gel, gel duration and erosion behavior are observed and evaluated.^44,45  

8.5 Floating lag time

Floating lag time is the time required for the formulation to begin floating after exposure to simulated gastric conditions. Lower floating lag time generally indicates faster establishment of buoyancy.⁴⁶

8.6 Total floating duration

The duration for which the formed gel remains buoyant should be recorded.^47,48

8.7 Drug-content uniformity

An accurately measured quantity of the formulation is appropriately diluted and analyzed using a validated UV–visible spectrophotometric or chromatographic method to determine the drug content.⁴⁹ 

The drug content is calculated as:

× 100

8.8 Swelling/gel strength

The increase in size or mass of the gel after exposure to simulated gastric medium can be investigated.^50,51

8.9 In-vitro drug-release study

Drug release can be investigated using a USP dissolution apparatus in an appropriate acidic medium at a controlled temperature. Samples are withdrawn at predetermined time intervals, analyzed for drug content and the withdrawn volume is replaced with an equal volume of fresh dissolution medium to maintain constant conditions.⁵²

Table 3. Evaluation parameters

9. Drug-release kinetic analysis^64–68

The dissolution data should be fitted to different mathematical models.

Zero-order model

The zero-order kinetic model is expressed as:

Qₜ = Q₀ + K₀t

where Qₜ is the amount of drug released at time t, Q₀ is the initial amount of drug and K₀ is the zero-order release constant. It is used to evaluate drug release at a constant rate, independent of the drug concentration remaining in the dosage form.

First-order model

The first-order kinetic model is expressed as:

where Qₜ is the amount of drug remaining at time t, Q₀ is the initial amount of drug and K₁ is the first-order release constant. It is used to evaluate concentration-dependent drug release, in which the release rate decreases as the drug concentration decreases.

Higuchi model

The higuchi model is expressed as:

Q = Kₕ√t

where Q is the amount of drug released at time t, Kₕ is the Higuchi dissolution constant and t is the release time. It is used to evaluate diffusion-controlled drug release from a matrix system.

Korsmeyer-peppas model

Used to:
Evaluate drug-release kinetics and estimate the release mechanism. The exponent n provides information about whether release is predominantly diffusion-controlled, swelling-controlled, or governed by anomalous transport, depending on the dosage-form geometry and model assumptions.

= Ktn

Hixson-Crowell Cube-Root Law - Theory

The Hixson-Crowell model describes drug release when the surface area and dimensions of a dosage form change continuously during dissolution.

Equation:

W₀^1/3-W_t^1/3 =K _t

Where:

W₀ = Initial amount of drug in the dosage form

Wₜ = Amount of drug remaining at time t

K = Hixson-crowell release constant

t = Time

Theory:
As the dosage form dissolves, its surface area and dimensions decrease. The Hixson-Crowell model accounts for this changing surface area and is commonly used for dissolution-controlled drug release from tablets and other solid dosage forms.

Table 4. Release models and interpretation

10. Stability studies

The optimized formulation should undergo stability testing in accordance with applicable ICH guidelines to evaluate its physical, chemical and performance stability during storage.⁷⁴  Key parameters should include appearance, pH, viscosity, drug content, gelation behavior, floating lag time, total floating duration and in-vitro drug-release profile. Comparative evaluation of the dissolution/drug-release profile before and after storage can help identify potential formulation changes and confirm the stability and performance of the optimized formulation.⁷⁵  Figure 3 presents the systematic formulation optimization and evaluation strategy for Etodolac floating oral in-situ gel. Preliminary trials are followed by a polymer concentration study to assess the effects on viscosity, gelation and buoyancy. The selected formulations are then evaluated for drug content and in-vitro drug release, followed by release-kinetic analysis. Based on the obtained results, the formulation is optimized and subjected to stability testing. The optimized formulation is subsequently considered for in-vivo gastric-retention and pharmacokinetic assessment.

Figure 3. Flow diagram represents various steps involved in overall evaluation and optimization strategy

(Integrated strategy for formulation optimization and evaluation of etodolac floating oral in-situ gel).

Table 5. Critical quality attributes and optimization targets

11. Advantages of the proposed system^86–88

A floating oral in-situ gel of etodolac may provide:

1. Prolonged gastric residence: Buoyancy may delay gastric emptying of the dosage form.
2. Controlled drug release: Hydrated polymer networks can act as diffusion barriers.
3. Reduced dosing frequency: Sustained release may potentially reduce repeated administration.
4. Liquid administration: The formulation can be administered as a liquid before in-situ gel formation.
5. Formulation flexibility: Polymer concentration and polymer combinations can be optimized.
6. Potential improvement in therapeutic consistency: Controlled release may reduce rapid concentration fluctuations.
7. Safety considerations for etodolac

Etodolac belongs to the NSAID class. Gastroretentive delivery should therefore not be interpreted as eliminating the established systemic or gastrointestinal risks associated with NSAIDs. The formulation should be developed with appropriate attention to dose, excipient safety and the approved prescribing information.⁸⁹  Etodolac is highly protein bound (>99%), and its reported terminal half-life in healthy adults is approximately 6.4 h.  For an experimental formulation, dose selection should be based on the intended research protocol and applicable ethical and regulatory requirements rather than simply increasing the dose to achieve prolonged release.^90–93

13. Limitations and challenges

Despite the potential advantages, several challenges must be considered.

13.1 Gastric physiological variability

Gastric emptying varies substantially with fed or fasted state, food composition, gastric motility, age, disease state and individual physiology. Consequently, excellent in-vitro floating performance does not necessarily guarantee prolonged gastric retention in humans, highlighting the importance of appropriate in-vivo evaluation.

13.2 Viscosity-buoyancy relationship

Increasing polymer concentration may improve gel strength and sustained release but can make the formulation excessively viscous.

13.3 Dose loading

The amount of drug that can be incorporated while maintaining acceptable rheological and floating characteristics must be determined experimentally.

13.4 Effervescent stability

Gas-generating agents can be sensitive to moisture. Therefore, manufacturing and packaging conditions are important.

13.5 In-vitro/in-vivo correlation

Dissolution and floating studies alone cannot establish therapeutic superiority. Pharmacokinetic and gastric-retention studies are needed.

14. Future perspectives

The future development of etodolac floating oral in-situ gel can move beyond conventional polymer screening toward systematic formulation optimization.

14.1 Quality-by-Design approach

 A Quality by Design (QbD) strategy can be employed to identify critical material attributes (CMAs) and critical process parameters (CPPs) that influence formulation performance. Potential CMAs include polymer concentration, polymer ratio, drug concentration, gas-generating agent concentration and polymer molecular weight, while potential CPPs include mixing speed, hydration time, addition sequence, temperature and homogenization conditions. Identifying and controlling these factors can improve formulation robustness, reproducibility, and overall product quality.

14.2 Design of experiments

Factorial designs, central composite designs and Box-Behnken designs can be used to identify interactions among formulation variables and optimize multiple responses simultaneously.

14.3 Advanced rheological characterization

Oscillatory rheology can provide detailed information on gel strength, elastic modulus (G′), viscous modulus (G″), gel-network development and structural recovery, thereby helping to characterize the viscoelastic behavior, structural integrity and stability of the gel system.

14.4 In-vivo gastric-retention studies

Future studies should investigate actual gastric residence using appropriate imaging techniques or validated pharmacokinetic approaches. Gastroretention is highly dependent on physiological variables, so in-vivo confirmation is important.

14.5 Pharmacokinetic evaluation

Important pharmacokinetic parameters include Cmax, Tmax, AUC, t½ and mean residence time (MRT). The objective is to determine whether controlled gastroretentive delivery provides a meaningful pharmacokinetic advantage, such as improved drug exposure, prolonged residence, or sustained systemic availability, rather than merely demonstrating prolonged in-vitro drug release.

14.6 Advanced manufacturing

Emerging manufacturing technologies, including 3D printing and other controlled fabrication approaches, may eventually enable personalized gastroretentive dosage forms with programmable drug-release profiles. Recent research has explored advanced manufacturing strategies for gastroretentive systems.

14.7 Mucoadhesive-floating hybrid systems

Combining buoyancy with controlled mucoadhesion could potentially provide an additional mechanism for gastric retention. However, excessive adhesion must be avoided because the system should not interfere with normal gastric physiology.

14.8 Patient-centric formulations

Future formulations may focus on improving palatability, providing greater dose flexibility, facilitating easy administration, enhancing physical stability and reducing administration frequency to improve patient convenience, adherence and therapeutic outcomes.

15. Conclusion

Floating oral in-situ gel represents a promising gastroretentive platform for controlled delivery of etodolac. The approach combines liquid administration with rapid in-situ gel formation and buoyancy, potentially prolonging gastric residence and regulating drug release. Sodium alginate, HPMC and other hydrophilic polymers can be systematically investigated to obtain an appropriate balance among viscosity, gel strength, floating ability and drug-release control. Sodium bicarbonate or another suitable gas-generating component can provide buoyancy through CO₂ generation in the acidic gastric environment. Existing literature supports the broader suitability of alginate-based and polymeric gastroretentive systems, but formulation-specific performance must be demonstrated experimentally.  For etodolac specifically, the development should emphasize controlled release rather than simply maximizing gastric residence, because conventional etodolac is already well absorbed orally and has measurable systemic bioavailability. The optimized formulation should therefore be selected using a combination of physicochemical characterization, floating performance, dissolution kinetics, stability testing and, ideally, in-vivo gastric-retention and pharmacokinetic studies. Such an integrated strategy can establish whether the floating in-situ gel provides a genuine pharmaceutical advantage over conventional etodolac dosage forms.

Abbreviations

AUC : Area Under the Curve

API : Active Pharmaceutical Ingredient

Cmax : Maximum Plasma Concentration

CO₂ : Carbon Dioxide

CMA : Critical Material Attribute

CMAs : Critical Material Attributes

CPP : Critical Process Parameter

CPPs : Critical Process Parameters

DoE : Design of Experiments

FDDS : Floating Drug Delivery System

GRDDS : Gastroretentive Drug Delivery System

GI/GIT : Gastrointestinal/Gastrointestinal Tract

HPLC : High-Performance Liquid Chromatography

HPMC : Hydroxypropyl Methylcellulose

HCl : Hydrochloric Acid

ICH : International Council for Harmonisation

MRT : Mean Residence Time

NaHCO₃ : Sodium Bicarbonate

NaCl : Sodium Chloride

NSAID : Non-Steroidal Anti-Inflammatory Drug

pH : Potential of Hydrogen

QbD : Quality by Design

R² : Coefficient of Determination

Tmax : Time to Maximum Plasma Concentration

t½ : Half-Life

UV : Ultraviolet

USP : United States Pharmacopeia

Declaration:

Ethics approval and consent to participate: Ethical approval and informed consent were not applicable to this study because it was a literature-based narrative review and did not involve any original research involving human participants or experimental animals.

Clinical Trial No: Clinical trial registration was not applicable to this manuscript, as it presents a narrative review based exclusively on previously published literature and does not involve any clinical trials.

Consent for publication: Clinical trial registration was not required for this study because the manuscript is a narrative review based entirely on previously published literature and does not include any clinical trial or prospective human intervention.

Availability of data and material: Data availability was not applicable to this study, as the manuscript is a narrative review based solely on previously published literature and does not involve the generation, collection, or analysis of original datasets.

Funding: The authors declare that no specific financial support was received from any government agency, commercial entity, or non-profit organization for the preparation of this review.

Declaration of competing interest: The authors declare that there are no conflicts of interest regarding the publication of this manuscript.

Acknowledgements: The authors sincerely acknowledge the Principals of Columbia Institute of Pharmacy, Columbia Professional University, Raipur, Chhattisgarh, India and Gracious College of Pharmacy, Village Belbhata, Abhanpur, Raipur, Chhattisgarh, India, for their valuable encouragement, support and provision of the necessary infrastructure and library facilities that contributed to the successful

completion of this review.

Authorship contribution statement:

Rupesh Sahu: Writing-review & editing

Niharika Sahu: Visualization and figure design.

Ruchi Gupta: Literature review, data curation and validation.

Dharmendra Sahu: Concept development and critical manuscript review.

Rahul Dev: Manuscript writing, editing and critical revision.

Shiv Kumar Bhardwaj: Writing, methodology, visualization and editing.

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