Compounds, compositions and methods
Inventors
Mazhari, Reza • Mezaache, Djelila • Paterson, Blake M. • Vornov, James • Garner, Rachel M. • Nelson, Todd
Assignees
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Publication Number
US-10202363-B2
Publication Date
2019-02-12
Expiration Date
Abstract
The disclosed subject matter provides certain polymorphic forms of Compound (I) as well as pharmaceutical compositions comprising Compound (I) or such polymorphic forms, and methods of using or making such compounds and pharmaceutical compositions. It has now been discovered that Compound (I) can exist in multiple crystalline forms (polymorphs). One particular crystalline form, Form II, has been found to be more thermodynamically stable and, thus, likely more suitable for bulk preparation and handling than other polymorphic forms. Efficient and economic methods have been developed to prepare Compound (I) and Form II in high purity on a large scale. In animal studies, Form II has demonstrated safety and efficacy in treating depressive disorders and, when micronized, improved absorption compared to non-micronized Form II.
Core Innovation
The invention relates to crystalline Form II of compound (I) and its solid-state identification. Crystalline Form II is described as an anhydrous form and as thermodynamically stable, and it is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation with a peak at about 5.9° 2-theta and a peak at about 8.8° 2-theta.
Additional characterization of crystalline Form II is described using ultraviolet, infrared, 1H NMR and 13C NMR, together with thermogravimetric analysis and differential scanning calorimetry, as referenced in the figures. Crystalline Form II is also described as comprising at least about 90% purity and as being usable for distinguishing and defining the form.
The invention also covers pharmaceutical compositions and therapeutic methods for suicidal ideation by administering an effective amount of Compound (I) to a patient who has, is suspected of having, or has been diagnosed with suicidal ideation. The described embodiments include patients with a depressive disorder, including major depressive disorder and treatment-resistant major depressive disorder, and treatment of NR2B-antagonist-responsive conditions.
Claims Coverage
The provided independent claims comprise two inventive features: crystalline Form II of compound (I) defined by purity and X-ray powder diffraction criteria, and a method of treating suicidal ideation by administering Compound (I) to a patient with suicidal ideation.
Crystalline form ii defined by x-ray powder diffraction and purity
Crystalline Form II of compound (I), at least about 90% pure, exhibiting an X-ray powder diffraction pattern using copper Kα radiation, comprising a peak of 2-theta angle of about 5.9 degree and a peak at about 8.8 degree.
Treating suicidal ideation by administering compound (I)
A method of treating suicidal ideation, comprising administering an effective amount of Compound (I) to a patient who has, is suspected of having, or has been diagnosed with having suicidal ideation.
Overall, the claim coverage focuses on solid-state definition of crystalline Form II of compound (I) using X-ray powder diffraction and purity requirements, and on therapeutic methods using Compound (I) for suicidal ideation.
Stated Advantages
Crystalline Form II is described as thermodynamically stable.
Documented Applications
Treatment of suicidal ideation in a patient who has, is suspected of having, or has been diagnosed with having suicidal ideation.
Treatment of suicidal ideation in the presence of a depressive disorder, including major depressive disorder and treatment-resistant major depressive disorder.
Treatment of NR2B antagonist-responsive conditions including depressive disorders and suicidal ideation.
Targeting NMDA receptor subunit 2B (GluN2B) expressed on a cell by administering crystalline Form II of compound (I).
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