Abstract
Objective: The purpose of this study was to determine the optimum formula of diltiazem HCl-loaded chitosan nanoparticles due to variations in the speed and duration of stirring and evaluating the release kinetics in vitro using DDSolver.
 Methods: The method used to prepare nanoparticles is ionic gelation. The ionic gelation method involves an ionic cross-linking between cations on the backbone of chitosan and anion, such as sodium tripolyphosphate (Na TPP). 
 Results: Stirring speed of 1200 rpm and stirring time of 2 h produce an optimum response. The optimum formula has an entrapment efficiency of 71.10%, a particle size of 110.2 nm, and a polydispersity index of 0.268. The dry powder of diltiazem HCl nanoparticles produced a drug loading of 66.14±1.71% and a yield of 34.07±0.73%. The FT-IR showed ionic interaction (cross-linking) between ammonium ions from chitosan and phosphate ions from Na TPP. Scanning electron microscopy (SEM) analysis showed a particle size of 150 µm, a spherical shape, and rough surface morphology. In vitro release profiles indicated prolonged release, which follows the Korsmeyer Peppas model. 
 Conclusion: It can be concluded that increasing the speed and duration of stirring will improve drug entrapment and reduce the particles size variation. The dry nanoparticles release mechanism is by diffusion and matrix erosion.
Highlights
Diltiazem HCl has a short half-life (3-4 h) due to rapid elimination from the blood circulation and is available for about 40% [1]
The approach to overcoming the problem of diltiazem HCl is by using a chitosan nanoparticles delivery system
The results show no sharp peak shift in the wavenumber produced in the spectra of diltiazem HCl nanoparticles
Summary
Diltiazem HCl has a short half-life (3-4 h) due to rapid elimination from the blood circulation and is available for about 40% [1]. Formulation of Diltiazem HCl loaded into chitosan nanoparticles will increase the residence time of short half-life drugs at the absorption site, control the drug release rate to maximize the therapeutic effect [3], increase intracellular penetration, and enhancing drug absorption [4]. The ionic gelation technique is a method used to prepare diltiazem-loaded chitosan nanoparticles. Among others methods such as emulsification, coacervation/precipitation, spray-drying, emulsion droplet coalescence method, reverse micellar method, sieving, and ionic gelation methods) the ionic gelation method is simple and could encapsulate a wide range of molecules [6], which occurs through electrostatic interactions between positively charged and negatively charged to form coacervates in nanometer-sized [7]. We use chitosan as the polymer that reacts with Na TPP to form an electrolyte complex
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