Polymorphic forms of ST-246 and methods of preparation
Inventors
Tyavanagimatt, Shanthakumar R. • ANDERSON, Melialani A.C.L.S. • Weimers, William C. • Nelson, Dylan • Bolken, Tove′ C. • Hruby, Dennis E. • O'Neill, Michael H. • Sweetapple, Gary • McCloughan, Kelley A.
Assignees
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Publication Number
US-10406137-B2
Publication Date
2019-09-10
Expiration Date
Abstract
Polymorph forms of 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide are disclosed as well as their methods of synthesis and pharmaceutical compositions.
Core Innovation
The invention relates to ST-246 crystalline polymorphs, including polymorph Form IV, which is defined by an X-ray powder diffraction pattern having characteristic peaks at specified reflection angles 2θ. ST-246 polymorph forms are characterized using XRPD and FTIR to identify and distinguish the different forms. The crystalline form relationships among hydrate, hemihydrate, and anhydrate are described as part of the characterization of the ST-246 polymorphs.
The disclosure addresses stability and handling attributes of the polymorphs, including Form I showing thermodynamic stability and non-hygroscopic behavior, and moisture uptake differences among the forms. Interconversion behavior is described, including slurry interconversion in water and conversion between forms. Particle-size-dependent dissolution behavior is reported in the context of Form I capsules.
The disclosure further includes performance-related findings for the ST-246 polymorphs in biological and pharmacokinetic contexts. Biological activity is described using vaccinia virus CPE inhibition with associated EC50 values and cytotoxicity with associated CC50 values. Pharmacokinetic and in vivo outcomes are described in non-human primates and other contexts, including NHP/clinical PK and survival in monkeypox, and comparisons between Form I and other forms.
Claims Coverage
The independent claim defines one specific ST-246 polymorph, Form IV, by XRPD characteristic peaks at specified 2θ values. Dependent claims further constrain the polymorph by purity relative to other forms and define pharmaceutical compositions including the polymorph, with refinements for oral administration and hydroxypropyl methylcellulose.
X-ray powder diffraction-defined polymorph Form IV of ST-246
A polymorph Form IV of ST-246 showing an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of 6.97, 9.75, 11.21, 12.13, 13.54, 16.82, 18.17, 18.79, 19.69, 20.51, 23.31, 24.78, 27.24, 30.20, and 33.52 degrees.
Purity threshold excluding other polymorphs
The polymorph is at least about 70% free of other forms.
High purity threshold excluding other polymorphs
The polymorph is at least about 99% free of other forms.
Pharmaceutical composition including polymorph Form IV plus pharmaceutically acceptable ingredients
A pharmaceutical composition comprises the polymorph and one or more pharmaceutically acceptable ingredients selected from carriers, excipients, diluents, additives, fillers, lubricants and binders.
Oral administration of the pharmaceutical composition
The pharmaceutical composition is formulated for oral administration.
Pharmaceutical composition including hydroxypropyl methylcellulose
A pharmaceutical composition comprises the polymorph and hydroxypropyl methylcellulose.
Overall claim coverage is anchored on XRPD-defined polymorph Form IV of ST-246, with dependent claims narrowing the definition by quantitative purity constraints versus other forms, and by pharmaceutical compositions that include the polymorph with specified pharmaceutically acceptable ingredients, including oral administration and hydroxypropyl methylcellulose.
Stated Advantages
Form I is thermodynamically stable and non-hygroscopic.
Different ST-246 forms show different moisture uptake and interconversion behavior.
Biological activity is reported as inhibition of vaccinia CPE, including EC50 and CC50 relationships.
Pharmacokinetic and in vivo outcomes are reported for monkeypox survival and PK comparisons between forms.
Documented Applications
Use of ST-246 polymorphs in biological efficacy studies, including inhibition of vaccinia virus CPE in cell-based contexts.
Use of ST-246 polymorphs in pharmacokinetic and in vivo efficacy contexts in non-human primates and clinical settings, including monkeypox survival and PK comparisons between Form I and Form V.
Use of Form I in capsule formulations with dissolution behavior described in relation to particle size.
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