Solid forms of an sGC stimulator
Inventors
SETHURAMAN, Vasu • Hashash, Ahmad • Xue, Song • Livingston, Robert C. • Nti-Addae, Kwame Wiredu
Assignees
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Publication Number
US-11572358-B2
Publication Date
2023-02-07
Expiration Date
Abstract
The present disclosure relates to crystalline solid forms of a stimulator of soluble guanylate cyclase (sGC), Compound I: Also provided herein are methods for the preparation of these solid forms. The invention also relates to pharmaceutical formulations and dosage forms comprising these solid forms and their uses thereof, alone or in combination with one or more additional agents, for treating and/or preventing various diseases or disorders; these diseases or disorders are ones that may benefit from sGC stimulation or from an increase in the concentration of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP).
Core Innovation
The document discloses crystalline free forms Form E, Form A, Form D, Form B, Form F, Form G, and Form H of Compound I, and a hydrochloric acid salt (HCl salt). Each crystalline free form is defined by an XRPD spectrum comprising specified peak positions, and the forms are described in relation to preparation from crude Compound I or from another crystalline free form.
The disclosure addresses the importance of polymorphs for stability, solubility, dissolution, and manufacturing consistency of solid forms of Compound I. It also connects sGC/NO/cGMP biology to therapeutic use, while emphasizing that selecting and defining specific crystalline forms and salts is relevant to performance and reproducibility.
The disclosure further provides characterization data including FT-Raman/IR spectra, XRPD peak locations or substantially similar spectra, and HCl salt properties such as melting point and aqueous solubility at pH 1.4. The document includes polymorph interconversion and recrystallization examples yielding different polymorphs together with characterization methods such as XRPD and FTIR.
Claims Coverage
The independent claims cover seven crystalline free forms of Compound I, each defined by an XRPD spectrum with specified peak positions and a corresponding preparation process. The coverage is organized around seven distinct polymorphs and multiple alternative preparation routes for certain forms.
Crystalline free form Form E of Compound I with specified XRPD peaks
Crystalline free form Form E of Compound I is characterized by an XRPD spectrum comprising peaks at 7.4, 18.8-19.3, 21.1, 24.8 and 25.5 2θ, and is prepared by solvent-based crystallization from crude Compound I.
Crystalline free form Form A of Compound I with specified XRPD peaks
Crystalline free form Form A of Compound I is characterized by an XRPD spectrum comprising peaks at 6.0, 18.3, 19.3, 20.2 and 22.0 2θ, and is prepared by multiple alternative process routes.
Crystalline free form Form D of Compound I with specified XRPD peaks
Crystalline free form Form D of Compound I is characterized by an XRPD spectrum comprising peaks at 17.1, 18.1, 18.8 and 25.0 2θ, and is prepared by conversion from selected crystalline free forms or neat heating.
Crystalline free form Form B of Compound I with specified XRPD peaks
Crystalline free form Form B of Compound I is characterized by an XRPD spectrum comprising peaks at 8.8, 16.4, 17.2, 18.8-19.1, 20.1, and 21.1-21.6 2θ, and is prepared from crude Compound I by acetonitrile-based crystallization.
Crystalline free form Form F of Compound I with specified XRPD peaks
Crystalline free form Form F of Compound I is characterized by an XRPD spectrum comprising peaks at 5.3, 8.6, 16.4, and 19.0 2θ, and is prepared by heating crystalline free form Form A neat.
Crystalline free form Form G of Compound I with specified XRPD peaks
Crystalline free form Form G of Compound I is characterized by an XRPD spectrum comprising peaks at 10.7, 13.9, 18.33, and 21.6 2θ, and is prepared from crude Compound I or from crystalline free form Form H in acetone.
Crystalline free form Form H of Compound I with specified XRPD peaks
Crystalline free form Form H of Compound I is characterized by an XRPD spectrum comprising peaks at 5.77, 6.39, 9.1, and 18.5 2θ, and is prepared from crude Compound I in acetone.
The claims collectively define seven crystalline free forms of Compound I by specific XRPD peak positions and associate each form with a defined preparation process.
Stated Advantages
Polymorphs are important for stability, solubility, dissolution, and manufacturing consistency of solid forms of Compound I.
Documented Applications
Therapeutic uses for NO/sGC/cGMP-mediated diseases, with emphasis on cardiovascular and pulmonary indications.
Cardiovascular and pulmonary uses described include pulmonary hypertension, hypertension, heart failure, and stroke.
Other therapeutic uses described include wound healing and bone healing.
Combination therapy and delivery modalities are described, including gels and drug-eluting stents (DES).
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