Purpose: In order to improve the bioavailability of orally administered drug, solubilization of poorly water soluble drug has been important issue. The transformation of crystalline drug to amorphous form have been studied as an effective method to improve the solubility. It is well known that the solubility of drug in an amorphous form is higher than that of crystalline form. It has been reported that amorphous form could be obtained by dissolving crystals in organic solvents and adsorbing onto the porous material. However, the removing the residual organic solvent should be required. In this study, we attempted to adsorb the sublimable drug onto porous calcium silicate (Florite®, FLR) by heating the sealed container. Ibuprofen (IBU) was used as poorly water soluble and sublimable drug. The physicochemical properties of samples were investigated.
Methods: 1. Materials
Porous calcium silicate (Florite®,FLR) , calcium silicate (CaSiO3) , zirconia beats , Ibuprofen(IBU) , ethanol(analytical reagent grade) were used without refining.
2.1. Adsorb IBU onto FLR
Method: IBU and FLR, were put into ethanol. After stirring for 3 minutes, ethanol was evaporated in rotary evaporator. The white powder that we got was evaporated mixture (EVM).
Method: The physical mixtures (PM) of IBU crystals and FLR, were sealed in the glass container. Then, the sealed heated mixtures (SH) were obtained by heating the PM at 70˚C for 6 hours.
2.2. Evaluation of the Physicochemical Properties of Samples
X-Ray Diffractometry: X-Ray diffraction patterns for the mixtures were determined using a RINT-2000 under the following conditions; Filter Ni, Target Cu, Voltage 30 kV, Current 5 mA, Scanning Speed 5°/min, Receiving Slit 0.15 mm, Count Range 2000 cps, Time Constant 0.5s.
Differential Scanning Calorimetry: DSC measurements of the mixtures were taken with a DSC-60plus under a stream of nitrogen gas(30 mL/min) using a sample of about 2.0 mg at a heating rate of 10℃/min. A liquid pan was used.
IR Absorption Spectroscopy: IR absorption spectroscopy was determined using a Frontier FT-IR Spectrometer. The thickness of samples were 1.0mm and samples were scanned for 4 times.
Dissolution Study: The dissolution behaviors of the IBU from the mixtures were investigated with the JP16 paddle method.50mg IBU or the mixtures which corresponded to 50 mg IBU were added to 500 mL distilled water for the dissolution study.
Results: Crystalline States of IBU in Mixtures: In X-Ray diffraction patterns, the diffraction peaks due to IBU crystals were disappeared in EVMs and SHMs which containing 10~50% IBU. In DSC curves, the endothermic peaks due to IBU crystals were disappeared in EVMs which containing 10~50% IBU and SHMs which containing 10~30%IBU.IBU has become amorphous in EVMs and SHMs.
Molecular States of IBU in Mixtures: The carbonyl stretching vibration band of IBU was observed at 1710 cm-1.In PMs, this peak was also observed while a new peak was observed at 1550 cm-1.In EVMs and SHMs, the peak which was observed at 1550 cm-1 became stronger and the peak which was observed at 1710 cm-1 disappeared in EVMs and SHMs which containing 10~30% IBU. In order to explain previous behavior, we prepared calcium salt of IBU and determined its IR spectrum. The IR spectrum of IBU calcium showed a peak at 1550 cm-1,and didn’t show any peak at 1710 cm-1.It was suggested that IBU calcium generated at the surface of FLR while Adsorbing IBU onto FLR.
Dissolution Behaviors of the IBU from the Mixtures: The EVMs and SHMs which containing 10~70% IBU showed significantly greater dissolution rates comparing to those of IBU crystals.
Conclusion: IBU crystals were adsorbed and amorphized in SH with FLR. The shift of carbonyl stretching vibration band of IBU to higher frequency suggesting the intermolecular interaction between IBU and FLR were observed. In SHMs with FLR, improvement of dissolution were observed, IBU adsorbed FLR showed a greater dissolution rate comparing to those of IBU crystals From these results, SH is considered to be an effective way to adsorb onto FLR without using organic solvents.