Mesoporous Calcium Carbonate as a Phase Stabilizer of Amorphous Celecoxib – An Approach to Increase the Bioavailability of Poorly Soluble Pharmaceutical Substances

Abstract

The bioavailability of crystalline pharmaceutical substances is often limited by their poor aqueous solubility but it can be improved by formulating the active substance in the amorphous state that is featured with a higher apparent solubility. Although the possibility of stabilizing amorphous drugs inside nano-sized pores of carbon nanotubes and ordered mesoporous silica has been shown, no conventional pharmaceutical excipients have so far been shown to possess this property. This study demonstrates the potential of using CaCO3 , a widely used excipient in oral drug formulations, to stabilize the amorphous state of active pharmaceutical ingredients, in particular celecoxib. After incorporation of celecoxib in the vaterite particles, a five to sixfold enhancement in apparent solubility of celecoxib is achieved due to pore-induced amorphization. To eliminate the possibility of uncontrolled phase transitions, the vaterite particles are stored in an inert atmosphere at 5 °C throughout the study. Also, to demonstrate that the amorphization effect is indeed associated with vaterite mesopores, accelerated stress conditions of 100% relative humidity are employed to impose transition from mesoporous vaterite to an essentially non-porous aragonite phase of CaCO3 , which shows only limited amorphization ability. Further, an improvement in solubility is also confirmed for ketoconazole when formulated with the mesoporous vaterite. Synthesis of the carrier particles and the incorporation of the active substances are carried out simultaneously in a one-step procedure, enabling easy fabrication. These results represent a promising approach to achieve enhanced bioavailability in new formulations of Type II BCS drugs.

Nanostructure and pore size control of template-free synthesised mesoporous magnesium carbonate

“…The outer surface area of the carrier particles was negligible compared to the internal surface area and only has a limited ability to interact with the ITZ in order to suppresses the crystallisation of the substance. 26 When the drug loading level increased, crystallisation was no longer completely suppressed, irrespectively to the sample identity (ESI, Fig. S22 and Table S4 †).…”

“…Due to its large variation abilities, mesoporous silica has been evaluated in a number of applications ranging from drug delivery, [21][22][23][24][25][26][27] regeneration of bone tissue 28,29 and as vaccine adjuvants, 30,31 to catalysis and as adsorbents. [32][33][34][35][36] This material can also be functionalised by amine graing, making it potentially suitable as adsorbent for applications such as CO 2 separation.…”

Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying

“…We have reported that pharmaceutical microparticles reduced the tendency for amorphous sucrose to recrystallize and proposed that this change in recrystallization behavior was due to a decrease in molecular mobility of the amorphous phase because of interactions between the amorphous sucrose and the filler particle surface. 3 Other researchers have reported that inert solid particles, either porous [4][5][6][7][8][9] or nonporous nanoparticles 5,10,11 inhibit the recrystallization of amorphous solids and it has been suggested that the inhibition come out of interactions between the filler and the amorphous component, such as hydrogen-bonding 4,5,7 or acid-base reactions. 8,10 Further, amorphous solids in powdered form have been demonstrated to be stabilized by gold or polymer coating of individual particles, suggested to be due to a reduction in mobility of molecules on the surface.…”

Novel Nanostructured Solid Materials for Modulating Oral Drug Delivery from Solid-State Lipid-Based Drug Delivery Systems

“…For oral delivery of poorly water-soluble drugs, few studies have been published. A recent study by Forsgren et al investigated the use of porous vaterite microparticles to encapsulate celecoxib, with drug dissolution enhanced up to 6-fold in comparison to pure drug, and attributed to poreinduced drug amorphization (56). Of major interest, this study highlights the most significant limitation of calcium carbonate microparticles, that is, instability in the presence of water resulting in transformation from vaterite to the nonporous calcite or aragonite polymorphs (Fig.…”

“…Scanning electron microscope images of a freshly synthesized calcium carbonate microparticles loaded with 25% w/w celecoxib, b calcium carbonate microparticles with 25% w/w celecoxib after storage at 100% relative humidity for 7 days, and c pure crystalline celecoxib. Reprinted with permission from Forsgren et al(56) …”