title: 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.
authors.affiliation: Division of Nanotechnology and Functional Materials, Uppsala University, PO Box 534, SE-751 21 Uppsala, Sweden. johan.forsgren@angstrom.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Forsgren
authors.forename: Mattias
authors.initials: M
authors.lastname: Andersson
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Albert
authors.initials: A
authors.lastname: Mihranyan
mesh_terms: D001682:Biological Availability; D002119:Calcium Carbonate / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D000068579:Celecoxib; D003460:Crystallization; D008855:Microscopy, Electron, Scanning; D009584:Nitrogen / Q000737:chemistry; D044367:Phase Transition; D016062:Porosity; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D012995:Solubility; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D011720:Pyrazoles; D013449:Sulfonamides; D002119:Calcium Carbonate; D000068579:Celecoxib; D009584:Nitrogen
keywords: amorphous drugs; calcium carbonate; celecoxib; drug solubility; mesoporous materials