Crystalline forms of trofinetide
Inventors
Peterson, Matthew • Carlos, Marlon • BOUSMANNE, MARTIN BERNARD CATHERINE • BETTI, CECILIA • JONAITIS, David T. • McCracken, Lisa M. • GROVE, Lisa M.
Assignees
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Publication Number
US-11827600-B2
Publication Date
2023-11-28
Expiration Date
Abstract
This disclosure provides crystalline forms of trofinetide and trofinetide hydrate, pharmaceutical compositions comprising crystalline forms of trofinetide and trofinetide hydrate, methods of making crystalline forms of trofinetide or trofinetide hydrate, and methods of treating a disease, condition, or disorder in a subject comprising administering a composition comprising crystalline forms of trofinetide or trofinetide hydrate to the subject.
Core Innovation
The invention relates to crystalline trofinetide.xH2O, where x is about 2 to about 4. The crystalline material is characterized by one or more specified analytical characterization sets, including powder x-ray diffraction patterns using Cu Kα radiation, FT-Raman spectra, low frequency Raman spectra, 13C solid-state nuclear magnetic resonance spectra, infrared spectra, near-infrared spectra, and melting behavior by differential scanning calorimetry.
For powder x-ray diffraction characterization, the material is defined by peak locations in 2θ ranges and by specified d-spacings. For Raman-based characterization, the material is defined by specific FT-Raman peak positions and low frequency Raman peak positions, each with stated tolerances in cm−1, and for 13C solid-state nuclear magnetic resonance characterization, the material is defined by specified peak positions or by a specified count of peaks with constraints on chemical shift differences.
The invention also includes characterization by melting point determined by differential scanning calorimetry, using an onset temperature and a peak temperature, and characterization by IR and NIR spectra with specified peak positions and stated tolerances. The document also describes trofinetide hydrate Form A as a crystalline polymorphic material.
Claims Coverage
The independent claim defines crystalline trofinetide.xH2O (x about 2 to about 4) that is characterized by satisfying at least one of multiple specified inventive characterization sets. These inventive features cover distinct analytical identification routes including powder X-ray diffraction, FT-Raman, low frequency Raman, 13C solid-state NMR, DSC melting behavior, and IR/NIR spectra, or combinations thereof.
Crystalline trofinetide.xH2O powder x-ray diffraction pattern with specified 2θ peaks
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a powder x-ray diffraction pattern with a peak in the range of 6.6-6.8, a peak in the range of 11.3-11.6, a peak in the range of 12.5-12.7, and a peak in the range of 13.6-13.8 degrees 2θ using Cu Kα radiation, wherein the 2θ values are ±0.2 degrees 2θ.
Crystalline trofinetide.xH2O powder x-ray diffraction pattern with specified d-spacings
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a powder x-ray diffraction pattern with d-spacings at 13.1, 7.7, 7.0, 6.4, and 5.3 Å using Cu Kα radiation.
Crystalline trofinetide.xH2O FT-Raman spectrum with specified peaks
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a FT-Raman spectrum with peaks at 2989, 2934, 2883, 1685, 1637, 1459, and 930 cm−1, wherein the cm−1 values are ±4 cm−1.
Crystalline trofinetide.xH2O low frequency Raman spectrum with specified peaks
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a low frequency (LF) Raman spectrum with peaks at 13, 24, 67, and 77 cm−1, wherein the cm−1 values are ±4 cm−1.
Crystalline trofinetide.xH2O 13C solid-state NMR spectrum with specified peaks
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a 13C solid-state nuclear magnetic resonance spectrum with peaks at 179.7, 177.9, 177.5, 177.2, 177.0, 165.3, 164.9, 164.8, 67.8, 67.4, 58.6, 58.2, 46.8, 40.3, 33.3, 25.3, 23.5, and 21.1 ppm, wherein the ppm values are ±3 pm.
Crystalline trofinetide.xH2O 13C solid-state NMR spectrum with constrained peak distributions
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a 13C solid-state nuclear magnetic resonance spectrum with 18 peaks, wherein the Δ from the furthest downfield peak to the second through seventeenth furthest downfield peaks and the furthest upfield peak are specified by the claim.
Crystalline trofinetide.xH2O melting point defined by DSC onset and peak temperatures
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a melting point with an onset temperature of 71.71° C. and a peak temperature of 72.06° C. based on differential scanning calorimetry.
Crystalline trofinetide.xH2O infrared spectrum with specified peaks
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having an infrared (IR) spectrum with peaks at 1678, 1636, 1589, 1525, 1214, and 1196 cm−1, wherein the cm−1 values are ±4 cm−1.
Crystalline trofinetide.xH2O near-infrared spectrum with specified peaks
Crystalline trofinetide.xH2O (x about 2 to about 4) is characterized as having a near-infrared (NIR) spectrum with peaks at 5145, 4630, and 4423 cm−1, wherein the cm−1 values are ±4 cm−1.
Overall, the claim covers crystalline trofinetide.xH2O (x about 2 to about 4) identified by any one of multiple specified characterization sets, including powder X-ray diffraction peak and d-spacing patterns, FT-Raman or low frequency Raman peak patterns, 13C solid-state NMR peak patterns or distribution constraints, DSC melting onset and peak temperatures, and IR/NIR peak patterns.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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