Patent Application: US-201213722547-A

Abstract:
the present invention provides gas - induced method for phase - transforming organic solids , such as pharmaceutical crystals . the inventive method subjects the polymorphs of pharmaceutical agents to various pressures of gases to induce phase transform with ease .

Description:
unless otherwise defined , all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . all publications , patent application , patents , and other references mentioned herein are incorporated by reference in their entirety . the invention teaches that simple pressurization of polymorphic forms of an organic solid , such as a pharmaceutical agent , can effect phase transitions among the forms with ease . more specifically , the inventive method comprises the step of subjecting an organic solid to a pressurized gas under low to moderate pressure at room temperature to a mildly elevated temperature for a period of time . the pressurized gas may be co 2 , n 2 o , and ch 4 , and the pressure may start at 1 atm , whereas under slightly elevated pressure , the reaction temperature may be lowered , while the reaction time may be shortened . refer to fig3 , which includes schematic illustrations of the phase transformations between different forms of clarithromycin 1 . as shown in fig3 , different pressure ( 1 to 23 . 8 atm ) and temperature conditions have been experimented , and the inventors found that exposure of form 0 to the 23 . 8 atm ( 350 psi ) co 2 at room temperature for just 4 hours resulted in complete transformation directly to form ii . as expected , desolvated form i can be transformed to form ii with greater ease under analogous conditions . particularly , pressurization of form i under 350 psi co 2 , results in transformation to form ii within just several minutes . different gases including h 2 , he , ch 4 , n 2 , o 2 , air , and n 2 o have been studied , among which n 2 o has similar transformation effect as co 2 . refer to fig4 , which shows the crystal structures , gas adsorption isotherms , and xrpd studies of forms 0 , i , ii of clarithromycin 1 . refer to fig5 , which compares the transformations under different gas pressures ( 350 psi vs . 100 psi ) at different durations . the invention has also studied lansoprazole 2 transformations under co 2 but at higher pressure conditions . as shown in fig6 , while the ethanol hydrate is pressurized with 500 psi of co 2 at room temperature , the transformation to the more thermodynamically stable solvent - free form begins . different gases have also been studied , and it has been found that n 2 o and ch 4 also can affect the transformations . more details of the invention are described in the article titled tian , jian , scott j . dalgarno , and jerry l . atwood . “ a new strategy of transforming pharmaceutical crystal forms .” journal of the american chemical society 133 . 5 ( 2011 ): 1399 - 1404 . which is incorporated hereby in its entirety . while the invention has been described in connection with specific embodiments thereof , it will be understood that the inventive device is capable of further modifications . this patent application is intended to cover any variations , uses , or adaptations of the invention following , in general , the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features herein before set forth . 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