Patent Application
20200031769
The present invention relates generally to active pharmaceutical ingredients and more specifically to the hydrochloride salt of (5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide. In particular, an amorphous form, an ethyl acetate solvate form, a methyl n-butyl ketone solvate form, an anisole solvate form, an isobutyl acetate solvate form, a n-butyl acetate solvate form, a toluene solvate form, a 4-methyl-2-pentanol solvate form, a n-propyl acetate solvate form, a xylene solvate form, Form VIII and Form IX of the salt are disclosed. Processes for the preparation of each of the disclosed forms are also provided.
(5-[3-(3-Hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride has a structure depicted below as Compound-A.
Compound-A is a muscarinic antagonist useful for treating allergy or respiratory chronic obstructive pulmonary disease.
Compound-A and pharmaceutically acceptable salts are claimed in U.S. Pat. No. 7,772,223 B2 and one of its non-solvated crystalline forms is claimed in U.S. Pat. No. 8,263,583 B2.
The present disclosure provides a wide range of polymorphic forms of Compound-A such as an amorphous form, an ethyl acetate solvate form, a methyl n-butyl ketone solvate form, an anisole solvate form, an isobutyl acetate solvate form, a n-butyl acetate solvate form, a toluene solvate form, a 4-methyl-2-pentanol solvate form, a n-propyl acetate solvate form, a xylene solvate form, Form VIII and Form IX. Processes for the preparation of each of the disclosed forms are also provided.
In one aspect, the present invention provides an amorphous form of Compound-A. In another aspect, the present invention provides a process for the preparation of the amorphous form of Compound-A. In one embodiment, the amorphous form of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form I of ethyl acetate solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form I of ethyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another embodiment, crystalline Form I of ethyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form II of methyl n-butyl ketone solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form II of methyl n-butyl ketone solvate of Compound-A can be prepared by a process that includes the following steps:
In yet another embodiment, crystalline Form II of methyl n-butyl ketone solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form III of anisole solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form III of anisole solvate of Compound-A can be prepared by a process that includes the following steps:
In another embodiment, crystalline Form III of anisole solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form IV of isobutyl acetate solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form IV of isobutyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another embodiment, crystalline Form IV of isobutyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form V of n-butyl acetate solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form V of n-butyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another embodiment, crystalline Form V of n-butyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form VI of toluene solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form VI of toluene solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form VIII of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form VIII of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form IX of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form IX of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form X of n-propyl acetate solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form X of n-propyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
In another aspect, the present invention provides crystalline Form XI of xylene solvate of Compound-A and a process for the preparation of the same. In one embodiment, crystalline Form XI of xylene solvate of Compound-A can be prepared by a process that includes the following steps:
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying figures wherein:
In one aspect, the present invention provides an amorphous form of Compound-A. In another aspect, the present invention provides solvates of Compound-A. In still another aspect, the present invention provides processes for making the various novel forms of Compound-A disclosed herein.
The PXRD measurements were carried out using a BRUKER D8 Discover powder diffractometer equipped with goniometer of θ/2θ configuration and a Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 40 mA. The experiments were conducted over the 2θ range of 2.0°-50.0°, 0.030° step size and 0.2 seconds step time.
Differential Scanning calorimetry of novel forms were measured on TA Q1000 of TA instruments. The experiment was conducted from 30° C. to 250° C. at a heating rate of 20.0° C./min and nitrogen purging at a flow rate of 50 ml/min Standard aluminum pans covered by lids with pin holes were used.
Differential Scanning calorimetry of an amorphous form was measured on TA Q1000 of TA instruments. The samples were heated from 30° C. to 250° C. at a heating rate of 5.0° C./min with modulation amplitude±1.0° C., modulation period 60 seconds and nitrogen purging at a flow rate of 50 ml/min Standard aluminum pans covered by lids with five pin holes were used. The glass transition temperature (Tg) of the amorphous form was measured using modulated DSC software.
TGA was recorded using on instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0° C./min over a temperature range of 25° C.−300° C. purging with nitrogen at a flow rate of 25 ml/min.
The 1HNMR experiments were performed on a Bruker 300 MHz Avance NMR spectrometer equipped with a 5 mm BBO probe in DMSO-d6. The data was collected and processed by Top Spin-NMR software.
In one aspect, the present invention provides an amorphous form of Compound-A.
Within the context of this embodiment, amorphous Compound-A is prepared by the methods disclosed herein and may be characterized as amorphous by the PXRD pattern in
In another aspect, the present invention provides a process for the preparation of the amorphous form of Compound-A.
In one embodiment, the amorphous form of Compound-A can be prepared by a process that includes the following steps:
b) removing the solvent to isolate amorphous form of Compound-A.
Within the context of this embodiment, Compound-A is dissolved in a suitable solvent, for example polar solvents; selected from alcoholic solvent; such as methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, and mixtures thereof.
Next, the solvent may be removed from the solution to isolate an amorphous form of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or combinations thereof. In certain embodiments of the present disclosure, the technique of spray drying is particularly useful for removing the solvent.
In one aspect, the present invention provides crystalline Form I of ethyl acetate solvate of Compound-A.
Within the context of the present invention, crystalline Form I of ethyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum having peaks (±0.2° 2θ) 6.83, 9.58, 10.91, 14.29, 19.71, 20.04, 21.59, 22.14, and 27.65.
The crystalline Form I of ethyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In one embodiment, crystalline Form I of ethyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in ethyl acetate and added a suitable second solvent. In some embodiments, depending on the solvent used, it is useful to dissolve Compound-A in the solvent at an elevated temperature. One of skill in the art will be able to determine the appropriate solvent and temperature conditions needed to dissolve Compound-A in a solvent without undue experimentation. For example, in some particularly useful embodiments, Compound-A is suspended in ethyl acetate at about 55° C. to about 65° C.
The suitable second solvent for addition is a polar solvent. Examples of polar solvents include, but are not limited to, formic acid, acetic acid, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide, N-Methyl-2-pyrrolidone and mixtures thereof. In some particularly useful embodiments, formic acid is used as second solvent.
The above resulted reaction mixture is cooled to 20-35° C.; In some particularly useful embodiments, the solvent may be removed from the solution at 25-30° C. to isolate crystalline form I of ethyl acetate solvate of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation and distillation. In certain embodiments of the present disclosure, slow evaporation of solvent is useful for removing the solvent.
Next, Form I of ethyl acetate solvate of Compound-A may be isolated. For example, the solid obtained above was filtered to yield crystalline Form I of ethyl acetate solvate of Compound-A.
In another embodiment, crystalline Form I of ethyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is dissolved in suitable solvent at 65-80° C. In some particularly useful embodiments of the present disclosure, Compound-A is dissolved at about 70° C. to about 75° C. For example the suitable solvent is a polar solvent. Examples of polar solvents include, but are not limited to, formic acid, acetic acid, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide, N-Methyl-2-pyrrolidone and mixtures thereof. In some particularly useful embodiments, formic acid is used as a solvent.
The obtained reaction mixture is cooled to 20-35° C. (in some particularly useful embodiment's 25-30° C.) and added ethyl acetate solvent. Further, the reaction mixture is optionally seeded with Form I. In some particular embodiment of the present invention, the reaction mixture is seeded with crystalline Form I.
In some embodiments, stirring or agitation may be carried out at a temperature of about 15° C. to about 40° C. In some embodiments, a temperature of about 25° C. to about 30° C. is used. In some embodiments, the stirring or agitation may be carried out for about 2 hours to about 5 days. In some particularly useful embodiments of the present disclosure, stirring the solution is carried out for 3 days.
Next, Form I of ethyl acetate solvate of Compound-A may be isolated. This may be carried out by methods well-known in the art. For example, the suspension may be filtered to isolate solid crystalline Form I of ethyl acetate solvate of Compound-A.
In one aspect, the present invention provides crystalline Form II of methyl n-butyl ketone solvate of Compound-A.
Within the context of the present invention, crystalline Form II of methyl n-butyl ketone solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum having peaks (±0.2° 2θ) 6.61, 20.80, and 26.81.
The crystalline Form II of methyl n-butyl ketone solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form II of methyl n-butyl ketone solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in methyl n-butyl ketone. In some embodiments suspending Compound-A is carried at 20-30° C., In some particularly useful embodiment of the present disclosure at 20-25° C. In another embodiment, suspending Compound-A in methyl n-butyl ketone is carried out at 65-80° C. In some particularly useful embodiments, at 70-75° C. Further, the suspension is optionally cooled to −20 to 30° C., in some particularly useful embodiments, 20-25° C. In some particularly useful embodiments, −20° C.
In some embodiments it is useful to maintain the reaction mixture at the same temperature for about 3-5 days. In some particularly useful embodiments of the present disclosure, the temperature is maintained for about 2 days after which Form II of methyl n-butyl ketone solvate of Compound-A may be isolated. For example, the suspension may be filtered to obtain solid crystalline Form II of methyl n-butyl ketone solvate of Compound-A.
Yet another embodiment, crystalline Form II of methyl n-butyl ketone solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in methyl n-butyl ketone. In some embodiments suspending Compound-A is carried out at 20-30° C. In some particularly useful embodiments of the present disclosure it is carried out at 20-25° C. In another embodiment, suspending Compound-A in methyl n-butyl ketone is carried out at 65-80° C. In some particularly useful embodiments it is carried out at 70-75° C. The second solvent is added to the suspension. For example the suitable second solvent is a polar solvent. Examples of polar solvents include, but are not limited to, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, formic acid and acetic acid, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide, N-Methyl-2-pyrrolidone and mixtures thereof. In some particularly useful embodiments, methanol is used as a solvent.
Within the context of the above embodiment, the reaction mixture is cooled to −20 to 30° C., in some useful embodiments to 20-25° C. and, in some particularly useful embodiments, to −20° C. In some embodiments it is useful to maintain the reaction mixture at the same temperature for about 3-5 days. In some particularly useful embodiments the temperature is maintained for about 2 days.
Next, Form II of methyl n-butyl ketone solvate of Compound-A may be isolated. For example, the suspension may be filtered to isolate solid crystalline Form II of methyl n-butyl ketone solvate of Compound-A.
In one aspect, the present invention provides crystalline Form III of anisole solvate of Compound-A.
Within the context of the present invention, crystalline Form III of anisole solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum having peaks (±0.2° 2θ) 6.86, 19.7 and 22.36.
The crystalline Form III of anisole solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form III of anisole solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is dissolved in suitable solvent at 65-80° C., in some particularly useful embodiments at 70-75° C. Preferably, the suitable second solvent is a polar solvent. Examples of polar solvents include, but are not limited to, formic acid, acetic acid, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide, N-Methyl-2-pyrrolidone and mixtures thereof. In some particularly useful embodiments, formic acid is used as a solvent.
Within the context of the above embodiment, the obtained reaction mixture is cooled to 20-35° C., in some particularly useful embodiments at 25-30° C. The solvent may be removed from the solution to isolate crystalline Form III of anisole solvate of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure, slow evaporation is useful for removing the solvent.
Next, Form III of methyl n-butyl ketone solvate of Compound-A may be isolated. For example, the suspension may be filtered to isolate solid crystalline Form III of anisole solvate of Compound-A.
In another embodiment, crystalline Form III of anisole solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in anisole. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days. In some particularly useful embodiments it is found useful to maintain the reaction for about 1-3 days. In certain embodiments of the present disclosure, it is useful to maintain the reaction for 16 to 24 hours.
Next, the solvent is removed from the suspension of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent to isolate crystalline Form III of anisole solvate of Compound-A.
In some embodiment of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form III of anisole solvate of Compound-A.
In one aspect, the present invention provides crystalline Form IV of isobutyl acetate solvate of Compound-A.
Within the context of the present invention, crystalline Form IV of isobutyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum and having peaks (±0.2° 2θ) 6.68, 8.92, 11.01, 13.32, 13.83, 15.80, 18.60, 19.26, 19.56, 20.11, 20.37, 22.10, 23.76, 25.16, 25.96, 26.94, and 28.00.
The crystalline Form IV of isobutyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form IV of isobutyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is dissolved in suitable solvent at 65-80° C., in some particularly useful embodiments, at 70-75° C. Preferably, the suitable second solvent is a polar solvent. Examples of polar solvents include, but are not limited to, formic acid, acetic acid, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide, N-Methyl-2-pyrrolidone and mixtures thereof. In some particularly useful embodiments, formic acid is used as a solvent.
Isobutyl acetate solvent is added to the above reaction mixture. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days. In some particularly useful embodiments the reaction is maintained for 1-3 days and in certain embodiments of the present disclosure, it is useful to maintain the reaction for 3 days.
Further, the solvent may be removed from the solution. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure, slow evaporation is useful for removing the solvent to isolate solid Form IV of isobutyl acetate solvate of Compound-A.
Next, Form IV of isobutyl acetate solvate of Compound-A may be isolated. This may be carried out by methods well-known in the art. For example, the suspension may be filtered to isolate solid Form IV of isobutyl acetate solvate of Compound-A.
In another embodiment, crystalline Form IV of isobutyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in isobutyl acetate solvent. In some embodiments, it is useful to maintain the reaction for about 2 hours to about 5 days. In some particularly useful embodiments the reaction is maintained for 1-3 days and, in certain embodiments of the present disclosure, it is useful to maintain the reaction for 16 to 24 hours.
Next, the solvent is removed from the suspension of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent to isolate crystalline Form IV of isobutyl acetate solvate of Compound-A.
In some embodiment of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form IV of isobutyl acetate solvate of Compound-A.
In one aspect, the present invention provides crystalline Form V of n-butyl acetate solvate of Compound-A.
Within the context of the present invention, crystalline Form V of n-butyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum depicted in
The crystalline Form V of n-butyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form V of n-butyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is dissolved in a suitable solvent at 65-80° C., in some particularly useful embodiments, at 70-75° C. Preferably, the suitable second solvent is a polar solvent. Examples of polar solvents include, but are not limited to, formic acid, acetic acid, methanol, ethanol, isopropanol, 1-propanol, n-butanol, 2-butanol, isobutanol, t-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide, N-Methyl-2-pyrrolidone and mixtures thereof. In some particularly useful embodiments, formic acid is used as a solvent.
N-butyl acetate solvent is added to above reaction mixture and the solvent may be removed from the solution to isolate Form V of n-butyl acetate solvate of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure, slow evaporation is useful for removing the solvent to isolate crystalline Form V of n-butyl acetate solvate of Compound-A.
In some embodiments of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form V of n-butyl acetate solvate of Compound-A.
In another embodiment, crystalline Form V of n-butyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in n-butyl acetate solvent. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days, in some particularly useful embodiments, about 1-3 days and, in certain embodiments of the present disclosure, it is useful to maintain for 16 to 24 hours.
Next, the solvent is removed to isolate crystalline Form V of n-butyl acetate solvate of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent. In some embodiments of the present disclosure, the resulting solid is filtered to isolate Form V of n-butyl acetate solvate of Compound-A.
In one aspect, the present invention provides crystalline Form VI of toluene solvate of Compound-A.
Within the context of the present invention, crystalline Form VI of toluene solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum and having peaks (±0.2° 2θ) 6.66, 9.25, 10.01, 10.43, 10.85, 13.71, 13.96, 14.82, 15.99, 18.54, 19.10, 19.48, 20.05, 20.56, 21.36, 22.25, 23.54, 26.02, 27.33, and 28.04.
The crystalline Form VI of toluene solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form VI of toluene solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in toluene. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days, in some particularly useful embodiments about 1-3 days and in certain embodiments of the present disclosure, it is useful to maintain the reaction for 16 to 24 hours.
Next, the solvent is removed to isolate crystalline Form VI of toluene solvate of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent to isolate crystalline Form VI of toluene solvate of Compound-A.
In some embodiment of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form VI of toluene solvate of Compound-A.
In one aspect, the present invention provides crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A.
Within the context of the present invention, crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum and having peaks (±0. ° 2θ) 5.21, 6.20, 7.69, 12.50, 13.90, 14.09, 17.33, 19.36, 21.13, 21.71, and 23.04.
The crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in 4-methyl 2-pentanol solvent. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days, in some particularly useful embodiments, about 1-3 days and, in certain embodiments of the present disclosure, it is useful to maintain for 16 to 24 hours.
Next, the solvent is removed from the suspension of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent to isolate crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A.
In some embodiments of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form VII of 4-methyl 2-pentanol solvate of Compound-A.
In one aspect, the present invention provides crystalline Form VIII of Compound-A.
Within the context of the present invention, crystalline Form VIII of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum and having peaks (±0.2° 2θ) 7.51, 19.74, and 21.80.
The crystalline Form VIII of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form VIII of Compound-A can be prepared by a process that includes the following steps:
Within the context of the embodiment, Form I of Compound-a is subjected to drying by using techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying is useful to isolate crystalline Form VIII of Compound-A.
In one aspect, the present invention provides crystalline Form IX of Compound-A.
Within the context of the present invention, crystalline Form IX of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum having peaks (±0.2° 2θ) 6.73, 7.55, 21.00, 21.75, and 26.86.
The crystalline Form IX of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form IX of Compound-A can be prepared by a process that includes the following steps:
In one aspect, the present invention provides crystalline Form X of n-propyl acetate solvate of Compound-A.
Within the context of the present invention, crystalline Form X of n-propyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum having peaks (±0.2° 2θ) 6.73, 9.53, 10.87, 14.20, 15.46, 19.27, 19.50, 19.95, 21.41, 21.77, 23.46, 27.27, and 27.49.
The crystalline Form X of n-propyl acetate solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form X of n-propyl acetate solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in n-propyl acetate. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days, in some particularly useful embodiments, about 1-3 days and, in certain embodiments of the present disclosure, it is useful to maintain for 16 to 24 hours.
Next, the solvent is removed from the suspension of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent to isolate crystalline Form X of n-propyl acetate solvate of Compound-A.
In some embodiment of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form X of n-propyl acetate solvate of Compound-A.
In one aspect, the present invention provides crystalline Form XI of xylene solvate of Compound-A.
Within the context of the present invention, crystalline Form XI of xylene solvate of Compound-A prepared by methods disclosed herein may be characterized by PXRD spectrum having peaks (±0.2° 2θ) 6.84, 9.47, 10.20, 10.69, 11.05, 14.16, 19.24, 19.71, 21.49, 22.37, and 23.72.
The crystalline Form XI of xylene solvate of Compound-A prepared by methods disclosed herein may be characterized by the PXRD pattern in
In another embodiment, crystalline Form XI of xylene solvate of Compound-A can be prepared by a process that includes the following steps:
Within the context of this embodiment, Compound-A is suspended in xylene. In some embodiments, it is found useful to maintain the reaction for about 2 hours to about 5 days, in some particularly useful embodiments, about 1-3 days and, in certain embodiments of the present disclosure, it is useful to maintain for 16 to 24 hours.
Next, the solvent is removed from the suspension of Compound-A. Solvent removal may be carried out by techniques well known in the art, such as evaporation, distillation, vacuum drying or combinations thereof. In certain embodiments of the present disclosure vacuum drying of solvent is useful for removing the solvent to isolate crystalline Form XI of xylene solvate of Compound-A.
In some embodiment of the present disclosure, the solid obtained after removing the solvent may be filtered and further subjected to drying to yield crystalline Form XI of xylene solvate of Compound-A.
In some useful embodiments of the present invention, the Compound-A used to prepare the solid form may be any form including, for example, amorphous form, crystalline form or solvate form.
Compound-A (5 g) was dissolved in methanol (150 ml) at 60-65° C. The solution was filtered at 60-65° C. to remove undissolved particulate and then cooled to 25-30° C. The clear solution of Compound-A was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a 5 ml/min feed rate of the solution and inlet temperature at 75° C. with 100% aspiration to yield an amorphous form of Compound-A.
Compound-A (0.5 g) was dissolved in methanol (10 ml) at 60-65° C. The clear solution was distilled to remove the solvent under vacuum completely using laboratory rotary evaporator at 40° C. to yield an amorphous form of Compound-A.
Compound-A (50 mg) was suspended in ethyl acetate (4 ml) and heated to 60° C. Undissolved material was then added formic acid (0.2 ml) at 60° C. to obtain a clear solution. The reaction mixture was cooled to 25-30° C. which allowed for slow solvent evaporation for 2 days without agitation. The solid obtained was filtered and dried under vacuum and identified as crystalline Form I (mono ethyl acetate solvate) of Compound-A.
Compound-A (3 g) was dissolved in formic acid (9.5 ml) at 70-75° C. The clear solution was cooled to 25-30° C. and then ethyl acetate (48 ml) was slowly added for 15-30 min. The reaction mixture was seeded with Form I (1%) and stirred for 3 days at 25-30° C. The resulting solid was filtered, washed with ethyl acetate (2 ml) and dried under vacuum at 30° C. for 15-30 min to obtain crystalline Form 1 (mono ethyl acetate solvate) of Compound-A.
Yield: 2.1 grams.
An amorphous form of Compound-A (100 mg) was suspended in methyl n-butyl ketone (5 ml) and heated to 70-75° C.; further, maintained the same for 15 min under agitation. Material was not dissolved and then cooled the reaction mass to 20-25° C. and kept at the same temperature for 2 days without agitation. The solid obtained was filtered and identified as crystalline Form II (mono methyl n-butyl ketone solvate) of Compound-A.
An amorphous form of Compound-A (100 mg) was suspended in methyl n-butyl ketone (5 ml) at 20-25° C. and agitated for 15 min. Material was not dissolved. The reaction mass was allowed to stand at the same temperature for 2 days without agitation. The solid obtained was filtered and identified as crystalline Form II (mono methyl n-butyl ketone solvate) of Compound-A.
An amorphous form of Compound-A (100 mg) was suspended in methyl n-butyl ketone (5 ml) at 20-25° C. Material was not dissolved. The reaction mass was allowed to stand at −20° C. for 2 days without agitation. The solid obtained was filtered and identified as crystalline Form II (mono methyl n-butyl ketone solvate) of Compound-A.
An amorphous form of Compound-A (100 mg) was suspended in methyl n-butyl ketone (5 ml) at 20-25° C. The reaction mass was heated to 70-75° C. Undissolved material was then added methanol (0.5 ml) at 70-75° C. to obtain a clear solution. The clear solution was allowed to stand at 25-30° C. for 2 days without agitation. The solid obtained was filtered and identified as crystalline Form II (mono methyl n-butyl ketone solvate) of Compound-A.
An amorphous form of Compound-A (3 g) was suspended in methyl n-butyl ketone (30 ml) at 25-30° C. and stirred at the same temperature for 3 days. The solid obtained was filtered, washed with methyl n-butyl ketone (2 ml) and dried under vacuum at 30° C. for 15-30 min to obtain crystalline Form II (mono methyl n-butyl ketone solvate) of Compound-A.
Compound-A (0.1 g) was dissolved in formic acid (0.3 ml) at 75° C. resulting in a clear solution to which anisole (5 ml) was added. The solution was allowed to evaporate slowly for 3 days at 20-25° C. without agitation. The solid obtained was filtered and identified as crystalline Form III of Compound-A.
An amorphous form of Compound-A (50 mg) was suspended in anisole (0.4 ml) at 20-25° C. and the suspension was maintained while shaking at 20° C. for 24 hours. The reaction mass was then kept in a vacuum tray dryer and dried at 30° C. for 24 hours. The resulting solid was identified as crystalline Form III of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in anisole (20 ml) at 20-25° C. and stirred at the same temperature for 16 hours. The reaction mass was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours. The resulting solid was identified as crystalline Form III of Compound-A.
Compound-A (0.1 g) was dissolved in formic acid (0.3 ml) at 75° C. To this clear solution isobutyl acetate (5 ml) was added. The solution was allowed to slowly evaporate at 20-25° C. for 3 days. The solid obtained was filtered and identified as crystalline Form IV of Compound-A.
An amorphous form of Compound-A (50 mg) was suspended in isobutyl acetate (0.4 ml) at 20-25° C. and, while shaking, the suspension was maintained at 20° C. for 24 hours. The reaction mass was then kept in a vacuum tray dryer at 30° C. for 24 hours. The resulting solid was identified as crystalline Form IV of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in isobutyl acetate (20 ml) at 20-25° C. and stirred at the same temperature for 16 hours. The resulting solid was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours and identified as crystalline Form IV of Compound-A.
Compound-A (0.1 g) was dissolved in formic acid (0.3 ml) at 75° C. To this clear solution n-butyl acetate (5 ml) was added and the solution was allowed to evaporate at 20-25° C. for 3 days.
The solid obtained was filtered and identified as crystalline Form V of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in n-butyl acetate (20 ml) at 20-25° C. and stirred at the same temperature for 16 hours. The product was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours. The resulting solid was identified as crystalline Form V of Compound-A.
An amorphous form of Compound-A (50 mg) was suspended in toluene (0.4 ml) at 20-25° C. and, while shaking, the suspension was maintained at 20° C. for 24 hours. The reaction mass was then kept in a vacuum tray dryer at 30° C. for 24 hours. The resulting solid was identified as crystalline Form VI of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in toluene (20 ml) at 20-25° C. and stirred at the same temperature for 16 hours. The product was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours and the resulting solid was identified as crystalline Form VI of Compound-A.
An amorphous form of Compound-A (50 mg) was suspended in 4-methyl-2-pentanol (0.4 ml) at 20-25° C. and, while shaking, the suspension was maintained at 20° C. for 24 hours. The reaction mass was then kept in a vacuum tray dryer at 30° C. for 24 hours. The resulting solid was identified as crystalline Form VII of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in 4-methyl-2-pentanol (20 ml) at 20-25° C. The suspension was then stirred at the same temperature for 16 hours. The product obtained was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours. The resulting solid was identified as crystalline Form VII of Compound-A.
Form I of Compound-A (200 mg) was placed in a petri-dish and dried in a vacuum tray dryer at 70-100° C. for 15 hours. The resulting solid was identified as crystalline Form VIII of Compound-A.
Form II of Compound-A (200 mg) was placed in a petri-dish and dried in a vacuum tray dryer at 40-70° C. for 15-24 hours. The resulting solid was identified as crystalline Form IX of Compound-A.
An amorphous form of Compound-A (50 mg) was suspended in n-propyl acetate (0.4 ml) at 20-25° C. and, while shaking, the suspension was maintained at 20° C. for 24 hours. The reaction mass was then kept in a vacuum tray dryer at 30° C. for 24 hours. The resulting solid was identified as crystalline Form X of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in n-propyl acetate (20 ml) at 20-25° C. and the suspension was stirred at the same temperature for 16 hours. The product obtained was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours. The resulting solid was identified as crystalline Form X of Compound-A.
An amorphous form of Compound-A (50 mg) was suspended in xylene (0.4 ml) at 20-25° C. and, while shaking, the suspension was maintained at 20° C. for 24 hours. The reaction mass was then kept in a vacuum tray dryer at 30° C. for 24 hours. The resulting solid was identified as crystalline Form XI of Compound-A.
An amorphous form of Compound-A (2.0 g) was suspended in xylene (20 ml) at 20-25° C. and the suspension was stirred at the same temperature for 16 hours. The product obtained was filtered and dried in a vacuum tray dryer at 30° C. for 2 hours. The resulting solid was identified as crystalline Form XI of Compound-A.
Form II of Compound-A (200 mg) obtained as above examples was placed in a petri-dish and dried in a vacuum tray dryer at 100-110° C. for 1-2 days. The resulting solid was identified as the crystalline form of Compound-A disclosed in U.S. Pat. No. 8,263,583.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201741008964 | Mar 2017 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2018/050148 | 3/15/2018 | WO | 00 |
