Process for producing crystals of a diazabicyclooctane derivative
Inventors
Ogawa, Takaya • Yokoyama, Takuya • FURUYAMA, Shusuke • ICHIKI, Masato • Fushihara, Kenichi
Assignees
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Publication Number
US-11117895-B2
Publication Date
2021-09-14
Expiration Date
Abstract
A process for producing crystals of a compound represented by the following formula (I): by crystallizing the compound from an aqueous solution containing the compound and an inorganic salt, such as sodium chloride. Such crystals can be subjected to lyophilization to provide a lyophilized composition having a desirable storage stability.
Core Innovation
The invention relates to producing crystals of a diazabicyclooctane derivative (Compound (I)), which is a β-lactamase inhibitor. Crystalline form I is obtained by crystallizing Compound (I) from an aqueous solution that contains Compound (I) and an inorganic salt. The crystallinity is characterized by powder X-ray diffraction, with crystalline form I defined by characteristic peaks at specific lattice spacings (d).
The process includes crystallizing from a salt-containing aqueous solution and obtaining a crystalline lyophilized composition by lyophilization of the salt-containing aqueous solution. This approach is described as producing a crystalline, single-form, stable form I lyophilized composition. It is stated that this crystalline lyophilized composition has improved storage stability compared with amorphous material.
The description also addresses productivity by enabling crystalline lyophilization without heat-treatment/refreezing steps, while noting that such steps can optionally be included. Comparative examples are used to contrast outcomes when a salt-containing aqueous solution is not used, where lyophilization yields an amorphous product. Characterization, including powder XRD, and stability evaluation are reported to show crystalline form I predominance and lower increases in related substances for the crystalline lyophilized samples.
Claims Coverage
The independent claims cover three inventive features for producing crystals of Compound (I) from a salt-containing aqueous solution without previous purification with a column, and require formation of crystalline form I defined by a specific powder X-ray diffraction peak set.
Crystallizing from an aqueous solution containing an inorganic salt without prior column purification to produce crystalline form I
A process crystallizing a compound represented by formula (I) from an aqueous solution containing the compound and an inorganic salt, without previous purification with a column, wherein crystalline form I is produced, having characteristic peaks in a powder X-ray diffraction pattern at lattice spacings (d) of 7.34, 5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28, 4.06, 3.68, 3.62, 3.47, 3.36, 3.30, 3.16, 3.11, 3.03, 2.99 and 2.50 Å.
Preparing the salt-containing aqueous solution by dissolving together or sequentially dissolving the compound and the inorganic salt
A process wherein the aqueous solution containing the compound and an inorganic salt is obtained by dissolving the compound and the inorganic salt together in water, or by dissolving either of the compound or the inorganic salt in water and then dissolving the other, and wherein crystalline form I having the specified powder X-ray diffraction characteristic peaks at the listed lattice spacings (d) is produced.
Crystallizing by adding a poor solvent to the salt-containing aqueous solution
A process wherein the compound is crystallized by adding a poor solvent to the aqueous solution containing the compound and the inorganic salt, and wherein crystalline form I having the specified powder X-ray diffraction characteristic peaks at the listed lattice spacings (d) is produced.
Across the independent claims, the core claim coverage requires crystallizing Compound (I) from a salt-containing aqueous solution without previous column purification to obtain crystalline form I defined by a specific powder X-ray diffraction peak set, with further limitations on how the salt-containing aqueous solution is prepared and on using poor solvent addition for crystallization.
Stated Advantages
Improved storage stability for a crystalline lyophilized composition compared with amorphous material.
Enables crystalline lyophilization without heat-treatment/refreezing steps, though such steps can optionally be included.
Documented Applications
Production of crystalline form I of Compound (I), a β-lactamase inhibitor, including crystalline lyophilized compositions.
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