Method for isolating a cyclohexapeptide
Inventors
De Pater, Robertus Mattheus • Jagesar, Dhiredj Chandre
Assignees
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Publication Number
US-9056897-B2
Publication Date
2015-06-16
Expiration Date
Abstract
The present invention relates to a method for isolating acyclohexapeptide and to a novel crystalline form of caspofungin diacetate thus obtained.
Core Innovation
The invention relates to isolating cyclohexapeptides, including echinocandins such as caspofungin, in crystalline form. The problem addressed is the isolation of cyclohexapeptides from a solution comprising caspofungin and water, while obtaining crystalline caspofungin diacetate with defined solid-state characteristics.
The method contacts a solution comprising caspofungin and water with a resin, removes the liquid phase from the mixture, and elutes the caspofungin by contacting material retained after removal of the liquid phase with an organic solvent. The resin is separated from the resulting mixture, and caspofungin is crystallized from the resin-free solution retained to obtain crystalline caspofungin diacetate in a mixture with the solution.
The crystalline caspofungin diacetate is characterized by XRD powder diffraction data selected from peaks at 2.92±0.2, 5.06±0.2, and 5.88±0.2 degrees 2-theta, an XRD powder diffraction pattern as depicted in FIG. 1, or combinations thereof. A further characterization requires that a ratio between an intensity of the peak at 2.92±0.2 degrees 2-theta and an intensity of any peak in the region 9.0±0.2 degrees 2-theta is at least 10.
Claims Coverage
The document contains two independent claims. The coverage includes a specific resin adsorption/elution plus crystallization method yielding crystalline caspofungin diacetate with defined XRD characterization and intensity ratio, and crystalline caspofungin diacetate defined purely by XRD characterization and intensity ratio.
Resin adsorption/elution followed by crystallization to isolate crystalline caspofungin diacetate
A method for isolating crystalline caspofungin diacetate comprising contacting a solution comprising caspofungin and water with a resin, removing the liquid phase, eluting caspofungin from material retained after removal of the liquid phase by addition of an organic solvent, separating resin, crystallizing caspofungin from the resin-free solution retained, and isolating crystalline caspofungin diacetate from the crystallization mixture.
XRD-defined crystalline caspofungin diacetate with an intensity ratio threshold
The crystalline caspofungin diacetate obtained in the crystallization step is characterized by XRD data selected from an XRD powder diffraction pattern with peaks at 2.92±0.2, 5.06±0.2 and 5.88±0.2 degrees 2-theta, an XRD powder diffraction pattern as depicted in FIG. 1, or combinations thereof, wherein a ratio between the intensity of the peak at 2.92±0.2 degrees 2-theta and the intensity of any peak in the region 9.0±0.2 degrees 2-theta is at least 10.
Crystalline caspofungin diacetate characterized by XRD peaks and intensity ratio
Crystalline caspofungin diacetate is characterized by XRD powder diffraction data selected from peaks at 2.92±0.2, 5.06±0.2 and 5.88±0.2 degrees 2-theta, an XRD powder diffraction pattern as depicted in FIG. 1, or combinations thereof, wherein a ratio between the intensity of the peak at 2.92±0.2 degrees 2-theta and the intensity of any peak in the region 9.0±0.2 degrees 2-theta is at least 10.
Overall, the claim set focuses on producing crystalline caspofungin diacetate using resin adsorption with organic solvent elution and crystallization, and on defining the resulting crystalline material by specified XRD peak locations/pattern, including FIG. 1, and an intensity ratio criterion of at least 10.
Stated Advantages
Increased cyclohexapeptide concentration from step (a) to step (d).
Optional drying to reduce water/impurities.
Replacement of largely aqueous solvent with lower-water eluate.
Crystallization without intermediate concentration.
Documented Applications
Isolation of cyclohexapeptides, including echinocandins such as caspofungin, including crystalline caspofungin diacetate, by resin adsorption/elution followed by crystallization.
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