Co-precipitation of calcium carbonate and curcumin in an ethanol medium as a novel approach for curcumin dissolution enhancement

Abstract

The scope of the present work was to prepare a CaCO₃ based solid dispersion (SD) formulation to enhance dissolution rate of a water insoluble drug curcumin. The formation of SD was carried out in ethanolic CaCl₂ solution by a facile CO₂ diffusion method, proposed to disperse curcumin into CaCO₃ during its crystal nucleation and growth. This pathway enabled gentle interaction between curcumin and CaCO₃, allowing for approximately 100% drug entrapment independent of curcumin concentration. In addition, the drug content of curcumin in as-formed SD was estimated to be parallel to the increased curcumin concentration in ethanol. The SDs were subsequently characterized by various analytical techniques including X-ray diffraction (XRD), zeta potential analysis, and scanning electron microscopy (SEM). Besides, the dissolution study revealed a remarkable enhancement of curcumin dissolution, highlighted with over 90% of loaded curcumin dissolved in 25 min. In addition, the CaCO₃ carrier was shown to preserve antioxidant activity of curcumin during SD preparation and after 6 months storage. Taken together, this novel SD preparation pathway seems to be a promising option for preparing oral administrated formula for water insoluble drugs.

Introduction

Oral delivery is the mostly common route for drug administration due to its reliability, simplicity, and therapeutic efficiency. For outcome optimization, the bioavailability of oral administrated drug is always highlighted in its formulations design, which is determined by three vital factors, dissolution, permeability, and solubility [1]. Unfortunately, around 75% of the drugs under development and 40% of marketed drugs exhibit poor dissolution prolife in body fluid, causing limited bioavailability when orally administrated [2,3]. In order to improve the solubility and dissolution rate of water insoluble drugs, strategies such as solid dispersion (SD), complexation, micro-emulsion, use of surfactant, particle size reduction etc. have been attempted [4]. Among them, SD is now firmly established as a platform technology for the formulation of water insoluble drugs with accelerated increase in the number of FDA-approved drug formula in recent years.

Historically, the term “solid dispersion” was defined as a dispersion of drug in a solid matrix where the matrix was either a small molecule or polymer [5]. To date, several processes have been involved in the SD system, such as melting extrusion [6], solvent evaporation [7], spray drying [8], supercritical anti-solvent process [9], and freeze-drying [10]. With the advance of material science, inorganic materials including silica (SiO₂), magnesium carbonate (MgCO₃), magnesium phosphate (MgP), calcium carbonate (CaCO₃) and hydroxyapatite (HA), have been reported to improve the solubility and dissolution rate of target drugs acting as SD carriers [[11], [12], [13], [14], [15]]. In literature, the drug loading approach used for inorganic carrier is commonly known to be solvent evaporation method, in which drug is slowly diffused into inter-structure of carriers. When the inorganic carrier cannot provide enough sites for drug loading, the solubility and dissolution rate enhancements of water insoluble drug were observed to be frustrated [13].

Inspired by above attempts, here we explored an alternative and novel system to current inorganic SD preparation process via combing the co-precipitation and SD strategies together, allowing immediate drug dispersion into SD carriers during its crystal nucleation (Fig. 1). It is believed such modification can significantly improve the solubility and dissolution rate of target drugs in consequence. For evaluation of above strategy, curcumin, a well-studied traditional natural herbal medicine found in turmeric, was used as a water insoluble drug model (11 ng/mL at pH 5.0) in current work [16,17]. According to the Biopharmaceutics Classification System, curcumin belongs to a class II drug that is poorly water-soluble but highly permeable, suggesting it an ideal candidate for our study [18].

Herein, curcumin-CaCO₃ SDs were synthesized in ethanol medium by a facile CO₂ diffusion method for curcumin dissolution enhancement, in which the selected carrier candidate CaCO₃ is a well-studied additive in oral administrated drug formulas [19,20]. This strategy paves possibility to efficiently prepare SD with 100% drug entrapment and remarkable dissolution enhancement, showing potential applications in the pharmaceutical and biomedical fields.