Ionic Gelation Approach for Microencapsulation of Efonidipine hydrochloride ethanolate: A Novel drug delivery system

Hypertension and ischemic heart diseases remained among the leading causes of morbidity and mortality worldwide, necessitating effective pharmacological interventions. Efonidipine hydrochloride ethanolate, a dihydropyridine calcium channel blocker with dual L-type and T-type channel inhibitory activity, has demonstrated significant therapeutic potential in the management of hypertension and angina pectoris. Despite its clinical efficacy, the drug suffers from limitations such as poor aqueous solubility, rapid metabolism, and a relatively short biological half-life, which often require frequent dosing and may compromise patient compliance ^[1].

To overcome these challenges, advanced drug delivery systems have been explored to enhance solubility, prolong release, and improve bioavailability. Microencapsulation is one such promising technique, offering controlled release, protection of the drug from degradation, and improved therapeutic outcomes ^{[2, 3]}. Among various encapsulation methods, ionic gelation stands out as a simple, mild, and cost-effective approach that avoids harsh processing conditions, making it suitable for encapsulating sensitive pharmaceutical agents.

In the present study, efonidipine hydrochloride ethanolate (40 mg) was microencapsulated using sodium alginate as a natural polymer and calcium chloride as a cross-linking agent through the ionic gelation method ^[4]. The objective was to develop a sustained-release formulation capable of enhancing drug stability, prolonging therapeutic action, and ultimately improving patient adherence in cardiovascular therapy ^[5]. This work aims to contribute to the growing field of polymer-based drug delivery systems by demonstrating the feasibility and effectiveness of ionic gelation for encapsulating efonidipine hydrochloride ethanolate. ^[6]

Efonidipine Hcl

IUPAC name: (±)-2-[N-benzyl(N-phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate hydrochloride ethanolate

Molecular weight: 667.12 g/mol

Molecular formula: C₃₄H₃₈N₃O₇P·HCl·C₂H₆O

Chemical structure:

 

 

Fig.1. Chemical structure of Efonidipine hydrochloride ethanolate

MATERIALS AND METHODS

MATERIALS:

Efonidipine hydrochloride ethanolate drug sample from (Aventus Lab LLP, Mahape Mumbai), Sodium alginate polymer from (IMCD, Mumbai), Calcium chloride (Merck), Polysorbate grade - 60, 80, Ethanol (Merck), Purified water (HPLC grade), Chitosan, acetic acid, and whatman filter paper 41.

METHODS:

Pharmaceutical drugs or bioactive compounds, can be microencapsulated by various types of methods, like – Coacervation, in situ polymerization, spray drying, extrusion, freeze drying, ionic gelation (Ionotropic gelation) and emulsion solvent evaporation ^{[8, 9]}. While among all these methods ionic gelation method is most commonly used across pharmaceutical industries due to its reproducibility, cost effectiveness, robustness, and encapsulation efficiency is greater than all other methods ^[10]. Ionic gelation or ionotropic gelation method involves dissolving of sodium alginate polymer in water under stirring at 600 RPM, after complete dissolution deaerate the solution for 30 – 45 min. to remove trapped air inside the polymer solution. Then drug dispersion was prepared by dissolving 40 mg EHE drug into 5 ml ethanol. Then drug dispersed solution was added into sodium alginate polymeric solution under stirring, and homogenize at 2000 rpm for 5 min. In next step chelation and microcapsule formation was carried. The calcium chloride 2.5% w/v solution was prepared for chelation. The polymeric solution of sodium alginate along with drug sample into calcium chloride solution 2.5% w/v was extruded using dispo van fitted with 22G syringe under stirring at 300 rpm. After microcapsule formation were kept the beads in hardening solution chitosan 0.5% in 1% acetic acid to strengthen the capsules if require ^{[11, 12]}. The fabricated microcapsules were filtered using Whatman filter paper 41 and washed the capsules 4 to 5 times using HPLC grade water to remove excess calcium chloride solution and sodium alginate (5-6). Then air dried at 25°C or under vacuum to get dried free flowing microsphere. The preparation of microcapsule using sodium alginate polymer, loaded with Efonidipine hydrochloride ethanolate drug via ionic gelation method is summarized in figure2 ^[13].

 

 

Fig 1. Stepwise schematic of sodium alginate microcapsules preparation via Ionic gelationmethod [13]

 

   

 

Fig. 1 Efonidipine hydrochloride ethanolate 40mg            Fig. 2 Efonidipine hydrochloride ethanolate 40mg

Using 1% Na alginate @10_X magnification                      Using 2% Na alginate @10_X magnification

 

 

 

Fig. 3 Efonidipine hydrochloride ethanolate 40mg              Fig. 4 Efonidipine hydrochloride ethanolate 40mg

Using 2.5% Na alginate @10_X magnification                Using 3% Na alginate @10_X magnification

 

 

Fig. In-vitro drug release of efonidipine hydrochloride 40 mg

Encapsulation Efficiency Determination (EE) ^[21-23]

A pestle and mortar were used to precisely weigh and smash 75 mg of microparticles carrying 25 mg of medication. The resulting fine particles were mixed with 50 millilitres of disodium phosphate buffer solution to create a dispersion, sonicated on a sonicator for 30 minutes, and then centrifuge the mixture at high speed 4000 rpm for 10-15 minute, then separate the dissolved polymer and capsule debris. A volume of 1 ml was diluted with 50 ml of phosphate buffer solution. The standard curve was created using the UV Visible Spectrophotometer (IRMACO Germany) and the optimal absorbance measured at 250 nm. EE was calculated using the following equation ^[21-23].              

The actual amount of drug       

% of Encapsulation  Efficiency =                                                    X 100                                            

 Conceptual drug content

Microencapsulation yielded an efficiency of 85%, indicating effective drug entrapment.

Particle Size Distribution

The average particle size was ranging from 98 to 169 µm ± 15 µm, at different concentration of sodium alginate polymer and it is suitable for oral administration and controlled release.

RESULT AND DISCUSSION

The morphology of microspheres was found to be highly dependent on the concentration of sodium alginate used during ionic gelation. At concentrations (2.5% w/v), the microspheres exhibited a nearly spherical shape with smooth surfaces, indicating favorable droplet formation and cross-linking. However, as the polymer concentration increased beyond 2.5% w/v, the viscosity of the solution rose significantly, impairing the ability of droplets to form uniformly. This resulted in irregular shapes, surface roughness, and aggregation of particles. At concentrations of 2% w/v and below, microspheres became irregular, elongated, clumped, or distorted, reflecting poor sphericity and reduced reproducibility. The excessive viscosity at higher alginate levels hindered proper dispersion in the cross-linking medium, leading to non-uniform gelation and loss of discrete microsphere formation. These findings suggest that while sodium alginate is an effective encapsulating polymer, its concentration must be carefully optimized to balance encapsulation efficiency with desirable morphological characteristics. Taken together, these results establish that ionic gelation using sodium alginate at 2.5% w/v provides a robust encapsulation system, ensuring both chemical compatibility and desirable particle morphology. This optimization is essential for achieving high encapsulation efficiency, controlled release, and reproducibility, which are critical parameters for pharmaceutical applications.

ACKNOWLEDGEMENT

Authors’ special thanks to Evonik India Ltd Mumbai, for providing polymer samples, Aventus Labs LLP, Mahape, Navi Mumbai, for providing the drug sample of Efonidipine hydrochloride ethanolate for research purposes and Atul Ltd, Atul, Valsad for characterization support

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