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Publication Number
US-10174074-B2
Publication Date
2019-01-08
Expiration Date
Abstract
SCY-078 is a glucan synthase inhibitor with antimicrobial activity. Novel salts and polymorph forms of SCY-078 are disclosed herein. The disclosure also relates to pharmaceutical compositions, methods of use, and methods of preparing the novel salts and polymorphs of SCY-078.
Core Innovation
The invention relates to pharmaceutically acceptable salt forms of compound 1, including salts selected from citrate, hippurate, mesylate, and fumarate, and characterized by water sorption measured by DVS at 25° C and 80% relative humidity. The salts are defined by a water sorption range of from 2% to 7% at 25° C and 80% relative humidity as determined by DVS. The disclosure also characterizes specific citrate crystal forms for a citrate salt of compound 1, including Type A, Type B, Type E, Type F, Type M, Type N, Type O, Type Q, Type R, and Type S citrate crystal forms.
The disclosure establishes quantitative definitions for salts of compound 1 based on resulting compound 1 concentration in a filtered resulting supernatant after processing in specified media. Examples reported include dextrose buffer at pH 5.5, phosphate buffer at pH 6.0, SGF media, and FaSSIF media, where the filtered resulting supernatant contains compound 1 at defined concentration thresholds or ranges. The characterization is tied to defining salt performance outcomes across different media conditions.
The disclosure further supports salt form identification and characterization using solid-state and thermal analytical methods including XRPD, DSC, TGA, and DVS, and reports key thermal events and hygroscopic water uptake. It documents chemical purity measurements and pH of saturated solutions, and reports kinetic and equilibrium solubility across buffers and media including dextrose buffer, phosphate buffer, SGF, FaSSIF, and FeSSIF. In addition, it documents inter-conversion among citrate crystalline types and solvate and freebase forms, including observations of metastability and form changes following DVS and ambient exposure.
Claims Coverage
The provided claim set includes multiple independent claims defining (i) pharmaceutically acceptable salt forms of compound 1 characterized by water sorption measured by DVS, (ii) citrate salts characterized by particular citrate crystal form types, and (iii) pharmaceutically acceptable salts characterized by compound 1 concentration in filtered resulting supernatant under specified media conditions. Across these independent claims, the inventive features are primarily quantitative solid-state and hygroscopic behavior, quantitative concentration outcomes in defined media workflows, and citrate crystal form membership.
Water sorption-defined pharmaceutically acceptable salt selection
A pharmaceutically acceptable salt of compound 1 selected from citrate, hippurate, mesylate, and fumarate, wherein the pharmaceutically acceptable salt has a water sorption of from 2% to 7% at 25° C and 80% relative humidity as determined by DVS.
Citrate salt comprising specified citrate crystal form types
A citrate salt of compound 1 comprising at least one of Type A, Type B, Type E, Type F, Type M, Type N, Type O, Type Q, Type R, and Type S citrate crystal forms.
Filtered supernatant concentration defined for a dextrose buffer workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into a dextrose buffer at pH 5.5 and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of at least 2 mg/mL.
Filtered supernatant concentration range defined for a dextrose buffer workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into a dextrose buffer at pH 5.5 and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of from 2 mg/mL to 9 mg/mL.
Filtered supernatant concentration range defined for a shorter dextrose buffer workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into a dextrose buffer at pH 5.5 and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of from 2 mg/mL to 5 mg/mL.
Filtered supernatant concentration defined for a phosphate buffer workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into a phosphate buffer at pH 6.0 and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of at least 2 mg/mL.
Filtered supernatant concentration range defined for a phosphate buffer workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into a phosphate buffer at pH 6.0 and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of from 2 mg/mL to 5 mg/mL.
Filtered supernatant concentration threshold defined for an SGF workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into SGF media and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of at least 16 mg/mL.
Filtered supernatant concentration range defined for an SGF workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into SGF media and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of from 17 mg/mL to 21 mg/mL.
Filtered supernatant concentration threshold defined for a FaSSIF workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into FaSSIF media and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of at least 17 mg/mL.
Filtered supernatant concentration range defined for a FaSSIF workflow
A pharmaceutically acceptable salt of compound 1 wherein, when placed into FaSSIF media and processed to yield a filtered resulting supernatant, the filtered resulting supernatant contains compound 1 at a concentration of from 17 mg/mL to 22 mg/mL.
Overall, the claim coverage centers on defining pharmaceutically acceptable salt forms of compound 1 by hygroscopic water sorption measured by DVS, defining citrate salts by membership in specified citrate crystal form types, and defining salts by quantitative compound 1 concentration in filtered resulting supernatant under media-specific workflows, with dependent claims tightening the concentration ranges or thresholds.
Stated Advantages
Provides salts with defined water sorption determined by DVS under specified temperature and relative humidity.
Provides defined salt/polymorph identification using XRPD, DSC, and TGA, including crystalline versus amorphous form identification.
Provides measurable performance attributes relevant to formulations, including chemical purity and kinetic solubility/equilibrium solubility across multiple media and pH/buffer conditions.
Provides stability characterization against form change under humidity and temperature.
Documented Applications
No documented applications found
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