Formulation Approaches and Evaluation Parameters in Microencapsulation of Diclofenac Sodium for Sustained Drug Delivery

Diclofenac sodium chemically known as (2-[(2,6 dichlorophenyl)amino]benzene acetic acid) is a modern non-steroidal anti-inflammatory drug (NSAID) that falls under the category of aryl acetic acid derivatives [1,2]. It is commonly used to treat conditions such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, particularly in long-term therapy for chronic musculoskeletal disorders, though it can notably affect the gastrointestinal tract. Due to its low oral bioavailability (around 60%), short plasma half-life (1–2 hours), and relatively low dosage requirement (25–75 mg three times daily), DFS — a potent non-steroidal anti-inflammatory and analgesic agent — is well-suited for development into a sustained-release drug delivery system for effective management of acute and chronic pain as well as traumatic conditions [5,6]. Microencapsulation is a highly promising drug delivery approach involving the coating or enclosing of minute liquid or solid particles with a continuous polymeric film. These microcapsules typically range in size from 1 to 5,000 microns. This technique is primarily employed for masking the unpleasant taste of bitter drugs, developing controlled or sustained release formulations, isolating incompatible substances, and protecting drugs that are sensitive to moisture or light. Overall, microencapsulation continues to be a valuable strategy in enhancing therapeutic efficacy and patient compliance in both oral and parenteral drug delivery systems [7,8]. The selection of a microencapsulation method depends on various factors, including the drug's physicochemical properties, polymer characteristics, desired release profile, and route of administration. Key considerations include drug stability, polymer compatibility, particle size requirements, encapsulation efficiency, and release kinetics. Additionally, factors like scalability, cost, and regulatory compliance influence the method's suitability for industrial application. The chosen technique should ensure optimal drug stability, efficacy, and overall product performance [3,4].

1. 1. MECHANISM

Microencapsulated diclofenac sodium works by inhibiting cyclooxygenase (COX) enzymes, reducing prostaglandin production responsible for pain and inflammation. The microencapsulation technique provides a controlled, sustained drug release, maintaining effective drug levels longer and enhancing therapeutic effects. This approach minimizes peak plasma concentrations, lowering the risk of side effects. It also protects the drug from premature degradation and reduces gastrointestinal irritation by limiting direct stomach contact. Overall, microencapsulation improves bioavailability, prolongs efficacy, and enhances patient compliance compared to standard diclofenac formulations.

1. MATERIALS AND METHODS
   1. MATERIALS

Diclofenac sodium was generously supplied by Natco Pharmaceuticals, Hyderabad. Ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, chloroform, hydrochloric acid, methanol, cellulose acetate phthalate, sodium acetate, acacia, and sulfuric acid were obtained from SD Fine Chemicals Ltd., Mumbai. All reagents were of analytical grade, and double-distilled water was used in all experimental procedures.

1. 2. METHODS

Microencapsulation can be carried out using a variety of techniques, which are generally categorized into three main types: [8-12]

1. Physical methods

2. Physico-chemical methods

3. Chemical methods            

Figure 1: A Typical Microcapsule Structure

1. Physical Methods

• Spray drying and spray congealing

• Fluidized bed technology

• Pan coating

• Centrifugal extrusion

• Spinning disk

• Air suspension coating

2. Physico-Chemical Methods

• Coacervation

• Polymer-polymer incompatibility

• Solvent evaporation

• Polymer encapsulation

• Hydrogel microspheres

3. Chemical Methods

• Interfacial polycondensation

• Interfacial cross-linking

• Interfacial polymerization

• Matrix polymerization

•  Spray drying and spray congealing

Spray drying creates microcapsules by spraying a polymer-drug solution into hot air, causing the solvent to evaporate and form a solid coating, preserving sensitive materials. Spray congealing involves melting the coating, dispersing the core inside, and spraying into cold air to quickly solidify the shell [30].

•  Fluidized bed technology

In fluidized bed technology, solid and liquid materials are absorbed into a porous substrate. Using a jet of air, excess solid material is removed, and a liquid coating is sprayed onto the substrate. Rapid evaporation solidifies the coating, and this cycle is repeated until the desired thickness and weight are achieved [13,30].

•  Pan coating

This physical microencapsulation method is widely used commercially to produce small coated particles. The dry coating material is combined with solid core particles, then heated until the coating melts and adheres closely to the core. Upon cooling, the coating solidifies, forming a stable shell around the core [30].

•  Centrifugal extrusion

Special nozzles allow two different solutions—core and shell materials—to be pumped simultaneously while spinning. A metal rod inside the nozzle helps break the solutions into mainly spherical droplets. The properties of the shell material determine how these droplets transform into microcapsules [14,30].

•  Spinning disk

This method is highly efficient due to its speed, low cost, and simplicity. The core material solution is poured onto a spinning disk, which forms a membrane shell around it. Excess particles are removed by centrifugal force, and as the temperature drops, the coating solidifies firmly around the core [30].

•  Air suspension coating

Professor Dale E. Wurster developed a method where solid drug particles are coated in a chamber using an air stream. The process relies on controlled airflow and temperature to separate and coat particles efficiently. Repeating the cycle builds a strong, well-dried coating layer [15].

•  Coacervation

Coacervation involves either desolvation or polymer interaction methods to form microcapsules. Complex coacervation uses oppositely charged polymers to coat core materials and is accelerated by environmental changes, with stabilization achieved by cross-linking. It’s widely used for encapsulating oils, flavors, and dyes [31].

•  Polymer-polymer incompatibility

Polymer-polymer incompatibility involves two immiscible polymers, with one forming the capsule shell and the other acting as a separator. The shell is hardened by cross-linking agents. This method works in both aqueous and non-aqueous environments, often needing organic solvents initially [31].

•  Solvent evaporation

This widely used microencapsulation method emulsifies the active drug and polymer in a medium that doesn’t dissolve during processing. Microsphere properties depend on factors like dispersing agent, polymer ratio, solubility, and stirring speed. The drug’s hydrophilic or hydrophobic nature guides the encapsulation technique, with oil-in-water used mainly for hydrophobic drugs [24,25].

•  Polymer encapsulation

Supercritical fluids like carbon dioxide and nitrous oxide combine liquid and gas properties, with temperature and pressure affecting their density. Under high pressure, active materials and coatings dissolve, then form a shell around the core as pressure is released. This technique encapsulates ingredients such as flavors, vitamins, and pigments. Paraffin wax and polyethylene glycol are common shell materials, which must be soluble in the supercritical fluid [16,17].

•  Hydrogel microspheres

Microspheres are made from gel-type polymers dissolved in water, with the active ingredient separated from the mix. A precise device forms and hardens the droplets through stirring. These are then placed in a calcium chloride hardening bath. The process removes residual materials and solidifies the microspheres [18].

•  Interfacial polycondensation

A fast-interfacial reaction, often involving the Schotten-Baumann method, occurs between acid chlorides and hydrogen-containing compounds. Common materials include polyesters, polyurethanes, amines, and polyureas. Aqueous solutions with amines and isocyanates form thin membranes at droplet interfaces. A base is added to balance pH, resulting in a condensed capsule shell [19].

•  Interfacial cross-linking

This cross-linking method, based on interfacial polycondensation, helps reduce the toxicity of diamines. It’s commonly used in pharmaceuticals and cosmetics. Natural polymers like proteins replace small monomers due to their reactive hydrogen groups. The membrane shell forms at the emulsion surface through a reaction between protein groups and acid chlorides [20,21].

•  Interfacial polymerization

A polymer shell forms around an active core through polymerization of multifunctional monomers dispersed in an aqueous phase. Reactions like isocyanate with amine or hydroxyl yield polyurea, polyamide, or polyurethane shells. Interfacial polymerization encapsulates DAHP in polyurethane-urea microcapsules. The resulting powder contains 62% DAHP, forming 22% microcapsules with particle sizes averaging 13.35 µm to 30.1 µm [31].

•  Matrix polymerization

During particle formation, the core material becomes embedded within the polymer matrix. The spray-drying process speeds up solvent evaporation from the matrix. Changes in the chemical environment help solidify the matrix structure more effectively [22].

2.3 Preparation of DS microcapsules

Diclofenac sodium (DS) microcapsules were developed using the emulsion solvent evaporation method. Ethyl cellulose served as the coating polymer, while solvents such as chloroform, dichloromethane, and ethyl acetate were used, with various core-to-coat ratios (1:1, 2:3, 2:1, and 3:7) tested. Different amounts of polymer (0.5–1.5 g) were dissolved in 25 mL of solvent to form a uniform solution. DS (1–1.4 g) was then incorporated into 10 mL of this polymer solution and mixed thoroughly. This mixture was gradually added to 100 mL of 0.1N HCl containing 0.5% or 1% w/v sodium CMC, and stirred in a 250–450 mL beaker using a Remi medium-duty stirrer (Model RQT 124) at 200–600 rpm to produce fine droplets. Stirring continued for 5–10 minutes for better dispersion. The emulsion was then transferred to a Buchner flask and stirred with a magnetic stirrer. Solvent was removed by evaporation at room temperature (28?°C) under reduced pressure (8 in. Hg Abs), leading to the formation of spherical microcapsules. These were separated by decantation, rinsed with water, and dried at either 40?°C for 4 hours or 60?°C for 1 hour to yield well-defined microcapsules [14,26].

Figure 2: Preparation of DS microcapsules

1. 3. Characterization of DS microcapsules

1. 1. 1. Particle Size Distribution

Microcapsules of varying sizes within a batch were separated using sieve analysis with a series of standard sieves (#10, #22, #44, #52, and #60). The quantity of material retained on each sieve was measured. Based on these measurements, the percentage weight retained on each sieve and the average particle size of the microcapsules were determined [28].

2.3.2 Practical yield

The percentage yield of Diclofenac Sodium (DS) in the prepared microcapsules was calculated using the following formula.                                                            

                                                                       Weight of microcapsules

               Percentage Yield (%) =                                                                               ×100

                                                             Theoretical weight of drug and polymer

2.3.3 Shape and surface morphology

The morphology and surface characteristics of the microcapsules were analyzed using a scanning electron microscope (JSM-T330A, JEOL). The samples were mounted on SEM stubs with double-sided adhesive tape and coated with a thin gold film of about 200 nm thickness under a vacuum pressure of 0.001 mm Hg [29].            

Fig 3. SEM photographs of shape and surface of DS microcapsules

2.3.4 Encapsulation efficiency

The encapsulation efficiency of the microcapsules was determined using the following formula:

                                     % Drug content

% Encapsulation efficiency =                                                            ×100

                                           %Theoretical drug content

2.3.5 Percentage drug content

A precisely weighed amount of microcapsules corresponding to 50 mg of DS was dissolved in 10 ml of chloroform. The obtained solution was filtered, appropriately diluted, and analyzed for drug content at 285 nm using a UV spectrophotometer [30]. Each sample was examined in triplicate, and the percentage drug content of all batches was computed using the following formula.:

                  Actual drug content of microcapsules

% Drug content =                                                                                     ×100

                   Theoretical weight of drug in microcapsules

2.3.6 Drug Release Studies (In vitro)

The in vitro drug release of diclofenac sodium from the prepared microcapsules was evaluated using the USP dissolution apparatus. An accurately weighed quantity of microcapsules equivalent to a specified dose of diclofenac sodium was placed in the dissolution medium maintained at 37 ± 0.5 °C and stirred at a constant speed. The dissolution medium, typically phosphate buffer (pH 7.4), was selected to simulate physiological conditions. At predetermined time intervals, aliquots were withdrawn, filtered, and analyzed spectrophotometrically at 285 nm to determine the amount of drug released. After each sampling, an equal volume of fresh dissolution medium was added to maintain sink conditions. The cumulative percentage of drug released was calculated and plotted as a function of time to evaluate the release profile [1,30].

Figure 6: In vitro drug release profile of diclofenac sodium from microcapsules showing cumulative percentage of drug released versus time

4. RESULTS AND DISCUSSION

Diclofenac sodium (DS) microcapsules formulated with ethyl cellulose, PLGA, and chitosan via the emulsion solvent evaporation method exhibited uniform, spherical morphology with smooth, non-porous surfaces and excellent flow properties. The formulations achieved high practical yields (80–92%) and efficient drug encapsulation, indicating successful polymeric entrapment. Particle size and encapsulation efficiency increased with higher polymer concentrations due to increased solution viscosity and improved coating uniformity. In vitro drug release studies demonstrated sustained release over 10–12 hours, following a biphasic pattern characterized by an initial burst release and a subsequent controlled diffusion phase. The release rate was inversely related to polymer concentration, with ethyl cellulose and PLGA formulations showing slower and more controlled release than chitosan, attributed to their hydrophobicity and reduced polymer erosion. Kinetic analysis revealed that the release followed first-order kinetics and fit well with the Higuchi diffusion model, while the Korsmeyer–Peppas model indicated a non-Fickian diffusion mechanism. These findings confirm that microencapsulation effectively prolongs DS release, offering sustained therapeutic levels, minimized gastrointestinal irritation, and improved patient compliance compared to conventional dosage forms.

Fig 4. SEM Photographs of DS microencapsules

Fig.5. In vitro dissolution profiles comparing immediate release vs sustained release formulations