Polymorphs of phenyl pyrrole aminoguandium salts
Inventors
Boesen, Thomas • JONASSEN, THOMAS ENGELBRECHT NORDKILD • Reece, Hayley Ann • KELK, Natalie Louise • TURNER, Alice Jane • MCLELLAN, Ross
Assignees
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Publication Number
US-12239631-B2
Publication Date
2025-03-04
Expiration Date
Abstract
The present disclosure relates to crystalline forms of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salts having high solubility. The disclosure also relates to use of said crystalline forms in medicine.
Core Innovation
The disclosure provides crystalline polymorphs of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate and related salt polymorph forms, including crystalline Form A. These solid forms are characterized by XRPD powder diffraction patterns measured using Cu Kα radiation, with specified 2-theta values identifying characteristic X-ray lines in the powder diffraction pattern.
The disclosure includes thermal and spectroscopic characterization of the salt polymorphs, including DSC and FT-IR data, and describes differential scanning calorimetry onset temperature constraints for crystalline Form A. It also presents a framework for crystalline forms substantially free of a second crystalline form.
The disclosure further associates the crystalline forms with pharmaceutical and medical use concepts, including formulation, composition, and administration of the crystalline form(s) and/or pharmaceutical formulations. Pharmaceutical compositions are described as including pharmaceutically acceptable excipient.
Claims Coverage
The independent claims center on three inventive features: crystalline Form A defined by characteristic XRPD powder diffraction peaks, crystalline Form A substantially free of any second crystalline form, and a pharmaceutical composition including crystalline Form A and a pharmaceutically acceptable excipient. Additional claim coverage includes a differential scanning calorimetry onset temperature constraint and production and isolation of crystalline Form A.
Crystalline form A defined by characteristic XRPD peaks
A crystalline Form A of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate comprising X-ray lines in a powder diffraction pattern when measured using Cu Kα radiation at 11.5±0.2, 23.5±0.2, and 27.0±0.2 (2-theta values).
Crystalline form A substantially free of a second crystalline form
A crystalline Form A of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate that is substantially free of any second crystalline form of the same compound.
Differential scanning calorimetry onset temperature constraint
Crystalline Form A of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate characterized by a differential scanning calorimetry onset temperature between 185 and 199°C measured using a heating rate of 10°C per minute.
Production and isolation of crystalline form A
Methods for producing N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate of crystalline Form A by mixing specified aminoguanidine or salt precursors with acetic acid or acetate salt in a solvent or by ion-exchanging in acetate, followed by isolating the Form A solid from the resulting mixture or composition.
Pharmaceutical composition with crystalline form A and excipient
A pharmaceutical composition that includes crystalline Form A of N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate and a pharmaceutically acceptable excipient.
Overall, the claims define crystalline Form A of the aminoguanidinium acetate salt using specific Cu Kα XRPD powder diffraction 2-theta peak positions, optionally requiring substantial freedom from a second crystalline form and a specific DSC onset temperature range, and further cover methods for producing and isolating crystalline Form A and pharmaceutical compositions that include it.
Stated Advantages
High solubility at low pH is mentioned as supporting gastric delivery.
Higher solubility at low pH (pH 1.2) for certain crystalline salt forms, including AP1189 acetate and AP1189 succinate.
Documented Applications
Pharmaceutical and medical use concepts, including administration of the crystalline form(s) and/or pharmaceutical formulations for treating disease or disorder.
Gastric delivery concept supported by high solubility at low pH.
Pharmaceutical compositions including crystalline Form A and pharmaceutically acceptable excipient.
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