Floating Microspheres: A Comprehensive Review on Advanced Drug Delivery Applications

In pharmaceutical technology, the controlled release of drugs remains a cornerstone for improving therapeutic efficacy and patient compliance. Traditional dosage forms often fail to maintain effective plasma concentrations due to rapid transit through the gastrointestinal tract (GIT) and variable gastric emptying times. These limitations have prompted the exploration of novel systems capable of retaining the dosage form at the absorption site for a prolonged period. One such promising approach is the floating microsphere or microballoon system, which provides an effective means of controlled drug delivery via buoyancy mechanisms. Microspheres are typically defined as free-flowing spherical particles with diameters ranging between 1 and 1000 μm (Janjale et al., 2020). They can be composed of natural polymers (e.g., sodium alginate, gelatin, chitosan), synthetic polymers (e.g., Eudragit, polymethyl methacrylate, polylactic acid), or their blends. The floating property of these microspheres is imparted by entrapping air or gas within the matrix or by incorporating effervescent agents that generate CO? when exposed to acidic conditions. This results in a bulk density lower than that of gastric fluid, ensuring the microspheres remain buoyant for extended periods. The floating microsphere system has distinct advantages over conventional single-unit floating tablets. Whereas single-unit systems are subject to unpredictable gastric emptying (the “all-or-none” phenomenon), multi-particulate microspheres distribute uniformly throughout the stomach and small intestine, leading to consistent and reproducible drug release. This feature significantly reduces localized irritation and variability in bioavailability (Ma et al., 2008).

Floating microspheres are particularly beneficial for drugs with:

Narrow absorption windows in the upper GIT (e.g., levodopa, riboflavin).

Instability or poor solubility in alkaline pH (e.g., verapamil, amoxicillin).

Short biological half-life requiring sustained release (e.g., diltiazem hydrochloride).

Local action in the stomach (e.g., antacids, antibiotics for H. pylori eradication).

Over the past decade, researchers have developed microsphere formulations for a wide variety of therapeutic agents. For instance, Eudragit RS100-based microballoons of metformin provided sustained release up to 12 hours (Singh et al., 2022), while alginate–chitosan systems demonstrated enhanced encapsulation efficiency for hydrophilic drugs (Li et al., 2018). Furthermore, hybrid microspheres have been explored for co-delivery of drugs with different solubility profiles, paving the way for fixed-dose combination therapies. Beyond oral delivery, floating microsphere concepts have been extended to pulmonary aerosols (where buoyant microparticles enhance residence time in alveoli) and topical formulations (providing controlled release in dermal layers). These developments demonstrate the flexibility of floating microsphere systems as multifunctional drug delivery platforms. In summary, floating microspheres address the central challenge of maintaining a controlled residence time and predictable drug release profile in diverse biological environments. Their design integrates principles of polymer chemistry, physical pharmaceutics, and biopharmaceutics, offering a bridge between formulation science and therapeutic optimization.

MECHANISM OF FLOATATION

The buoyancy mechanism of floating microspheres is a delicate interplay between formulation density, polymer swelling, and gas entrapment. When introduced into the gastrointestinal fluid, the polymer matrix absorbs water and swells, forming a gel barrier that traps air or generated gas within the microsphere core. This entrapment lowers the overall density below that of gastric fluid (≈1.004 g/cm³), allowing the system to remain afloat. The floatation force (F) acting on a microsphere is derived from Archimedes’ principle:

F = (ρ_f - ρ_s) V g

where ρ_f represents the density of gastric fluid, ρ_s the density of the microsphere, V the volume of displaced fluid, and g the gravitational acceleration. A positive buoyant force keeps the microsphere afloat at the liquid surface, while a negative force causes sinking.

Two fundamental mechanisms support floatation:

2.1 Effervescent Mechanism

In this system, gas-generating agents such as sodium bicarbonate, citric acid, or tartaric acid are incorporated. Upon exposure to acidic gastric fluid, CO? is liberated and entrapped within the hydrated polymer matrix, creating internal pores and decreasing density. The generated CO? bubbles become locked within the gel barrier, sustaining buoyancy for 8–12 hours. For example, Ma et al. (2008) formulated calcium alginate–chitosan microspheres where CO? entrapment enabled floating for over 10 hours without compromising release kinetics.

2.2 Non-Effervescent Mechanism

Non-effervescent microspheres rely solely on the inherent low density and swelling of the polymers used. Polymers such as ethyl cellulose, Eudragit RS, HPMC, and PLA form a matrix that retains air pockets during solidification or solvent evaporation. These air-filled voids maintain buoyancy even without gas-forming additives. Non-effervescent systems often demonstrate superior mechanical stability and more predictable release profiles due to the absence of internal gas evolution.

2.3 Role of Polymer Hydration and Cross-Linking

Hydrophilic polymers swell upon hydration, forming a gel network that not only controls drug diffusion but also modulates buoyancy. Cross-linking agents (e.g., calcium chloride, glutaraldehyde) stabilize this gel network, reducing water penetration and prolonging floating duration. Excessive cross-linking, however, can hinder swelling and reduce floating capacity, requiring optimization through experimental design.

2.4 Influence of Surface Topography

Surface porosity also dictates floatation. Microspheres with rugged or porous surfaces trap more air during formation, enhancing buoyancy, while smooth, compact microspheres tend to sink faster. Scanning electron microscopy (SEM) often reveals the structural differences correlating with floating ability.

Figure 1. Schematic representation of floating mechanism. (Shows polymer shell, entrapped CO?, hydrated gel layer, and drug diffusion path.

Source Schematic presentation of the preparation of floating microparticles... | Download Scientific Diagram

3. Polymers Used in Floating Microspheres

The selection of polymers is critical to achieving the desired mechanical strength, buoyancy, biodegradability, and drug release characteristics. Polymers may be natural, semi-synthetic, synthetic, or biodegradable, and often combinations are used to balance hydrophilicity and hydrophobicity.

3.1 Natural Polymers

Natural polymers are preferred for their biocompatibility, biodegradability, and low toxicity. Commonly employed materials include:

Sodium alginate: A natural polysaccharide obtained from brown algae that forms gels in the presence of divalent cations such as calcium. It is highly used in ionotropic gelation.

Chitosan: A deacetylated derivative of chitin, exhibiting cationic nature and excellent mucoadhesion. Chitosan-coated alginate microspheres enhance encapsulation efficiency and drug retention.

Gelatin: Forms thermally reversible gels; often combined with glutaraldehyde or formaldehyde for cross-linking.

Guar gum and pectin: Used for biodegradable floating microspheres targeting colon delivery.

3.2 Semi-Synthetic Polymers

Hydroxypropyl methylcellulose (HPMC) and methylcellulose are widely used for sustained release. Their swelling property enables gel-layer formation, which supports floatation and controls drug diffusion simultaneously.

3.3 Synthetic Polymers

Synthetic polymers provide superior mechanical strength and allow precise control of permeability. Examples include:

Eudragit RS100 and RL100: Ammonium methacrylate copolymers with low and high permeability, respectively.

Ethyl cellulose: Hydrophobic polymer that provides extended release, often used in solvent evaporation techniques.

Polymethyl methacrylate (PMMA): Non-biodegradable, ideal for long-term release applications.

Polylactic acid (PLA) and Poly (lactic-co-glycolic acid) (PLGA): Biodegradable and approved by FDA for parenteral delivery.

3.4 Polymer Combinations

Blends of hydrophilic and hydrophobic polymers can modulate drug release and buoyancy simultaneously. For example, an alginate–Eudragit combination ensures initial floatation via alginate swelling, followed by controlled diffusion through the Eudragit layer.

Table 1. Summary of common polymers used in floating microspheres.

4. Methods of Preparation

The preparation technique directly affects microsphere size, porosity, encapsulation efficiency, and release behavior. Selecting a method depends on the drug’s physicochemical characteristics, polymer type, and desired performance.

4.1 Emulsion–Solvent Evaporation Technique

This is one of the most widely used methods for floating microsphere production. The drug and polymer are dissolved in a volatile organic solvent (e.g., dichloromethane, chloroform, or ethanol). The organic phase is emulsified into an aqueous medium containing a stabilizer such as polyvinyl alcohol (PVA). Continuous stirring forms an oil-in-water emulsion. As the solvent evaporates, the polymer precipitates around the dispersed droplets, forming hollow microspheres. The process parameters—stirring rate, polymer concentration, and solvent ratio—determine particle size and morphology.

Advantages: High encapsulation efficiency and uniform particle size.

Limitations: Risk of residual solvent and thermal stress on heat-sensitive drugs.

Researchers have optimized this process to yield microspheres of 50–300 µm with 80–90% entrapment efficiency. For example, Shinde & Barhate (2019) prepared Eudragit-based metformin microspheres that demonstrated sustained release over 12 hours.

4.2 Emulsion–Solvent Diffusion Technique

A modification of the evaporation process using dual solvents—typically ethanol and dichloromethane—with different solubilities in water. The diffusion of solvent into the aqueous phase leads to polymer precipitation and gas formation, producing a hollow core structure. This technique provides excellent control over floatation time and particle uniformity (Pujara et al., 2012).

4.3 Ionotropic Gelation Technique

Ideal for hydrophilic polymers such as alginate and pectin. The polymer solution containing the drug is dropped into a cross-linking solution (e.g., CaCl?, BaCl?) under mild agitation. Ionic interaction between alginate’s carboxyl groups and calcium ions forms calcium alginate microspheres. Chitosan can be added as a coating to enhance stability and control drug release (Ma et al., 2008). This aqueous-based method is particularly suitable for heat- and solvent-sensitive drugs.

4.4 Spray Drying Technique

Involves atomization of the polymer-drug solution into a hot drying chamber. The solvent evaporates instantly, forming solid microspheres with hollow interiors. The resulting microspheres are typically small (1–50 µm) with high surface area, allowing rapid floating and controlled release. Spray drying is scalable and cost-effective but may expose thermolabile drugs to elevated temperatures.

4.5 Coacervation/Phase Separation

This complex process involves the separation of a polymer-rich phase (coacervate) from a polymer-poor phase upon addition of a non-solvent or incompatible polymer. The coacervate encapsulates the drug droplets, which are then hardened by cooling or solvent removal. Though labor-intensive, this method yields highly uniform microspheres suitable for parenteral applications.

4.6 Hot-Melt Encapsulation

Involves dispersing the drug in a molten polymer and emulsifying it in a non-miscible phase (e.g., oil). Cooling leads to solidification of microspheres. This solvent-free process avoids toxic residues and is best suited for lipophilic drugs and wax-based polymers

Figure 2: Schematic diagram of the emulsion-solvent evaporation method used for microsphere preparation

Source Schematic representation of emulsion solvent evaporation techniques for... | Download Scientific Diagram

5. Characterization and Evaluation of Floating Microspheres

Comprehensive characterization of floating microspheres is essential to ensure reproducibility, performance, and quality control. Each parameter provides insights into formulation stability, mechanical properties, and drug release behavior.

5.1 Particle Size and Morphology

Particle size significantly affects drug release rate, buoyancy, and surface area. The smaller the particle, the faster the release due to increased surface-to-volume ratio. Particle size analysis is commonly performed using optical microscopy, laser diffraction, or Coulter counter techniques. For morphology, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are employed to visualize surface topology, wall thickness, and the presence of pores or hollow cavities. Smooth, spherical microspheres with uniform size distribution (50–500 µm) generally exhibit consistent floating behavior and drug release.

5.2 Micromeritic Properties

Flowability is crucial during capsule filling or tableting. Parameters such as angle of repose, Carr’s index, and Hausner’s ratio determine powder handling characteristics. Angle of repose below 30° and Carr’s index under 15% are indicative of good flow.

5.3 Buoyancy Test

The buoyancy or floating capacity is determined by dispersing microspheres in simulated gastric fluid (SGF, pH 1.2) maintained at 37 ± 0.5 °C. After a specific time, the fraction of floating microspheres is measured by filtering and drying the floating and settled portions.

\text{Buoyancy (\%)} = \frac{W_f}{W_f + W_s} \times 100

An excellent formulation maintains >90% buoyancy for over 10–12 hours. Studies by Ma et al. (2008) reported that Eudragit RS-based diltiazem microspheres exhibited 92% buoyancy for 12 h, demonstrating effective gas entrapment.

5.4 Drug Loading and Entrapment Efficiency

Drug loading capacity determines therapeutic efficiency and dosage accuracy. Entrapment efficiency is calculated by extracting the drug from a known quantity of microspheres using suitable solvents and measuring absorbance spectrophotometrically.

\text{Entrapment Efficiency (\%)} = \frac{\text{Practical Drug Content}}{\text{Theoretical Drug Content}} \times 100

5.5 In-Vitro Drug Release Studies

Drug release studies are conducted using USP Dissolution Apparatus I (basket type) or Apparatus II (paddle type) in simulated gastric or intestinal fluids. Sampling at regular intervals enables plotting of cumulative drug release versus time. The data are fitted to various kinetic models:

Zero-order model (constant release rate)

First-order model (release proportional to remaining drug)

Higuchi model (diffusion-controlled release)

Korsmeyer–Peppas model (to identify diffusion vs. erosion mechanism)

For example, floating microspheres of metformin HCl displayed Higuchi diffusion-controlled release with an r² value of 0.985 (Shinde & Barhate, 2019).

5.6 Surface Topography and Density Determination

Density measurement (using a pycnometer or solvent displacement method) ensures the system’s buoyancy. The ideal bulk density should be <1.0 g/cm³. SEM analysis reveals hollow core formation, confirming the floatation mechanism.

5.7 Stability Studies

According to ICH Q1A (R2) guidelines, stability studies are conducted under accelerated conditions (40 °C ± 2 °C / 75 ± 5% RH for 6 months). Parameters like drug content, morphology, and release profile are periodically evaluated. Stable microspheres retain >95% drug content with minimal physical changes.

Table 2. Summary of evaluation parameters for floating microspheres.

Figure 3. Schematic representation of morphology, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) are employed to visualize surface topology.