DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Indian provisional patent applications No. 599/CHE/2015 filed on February 6, 2015; 1849/CHE/2015 filed on April 8, 2015 and 2884/CHE/2015 filed on June 9, 2015, which are hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION
The present invention relates generally to the chemical and pharmaceutical arts and more specifically to a process for the preparation of amorphous ibrutinib, polymorphs of ibrutinib, solvates of ibrutinib, premixes of ibrutinib, and processes for the preparation thereof.
2. BACKGROUND OF THE INVENTION
Ibrutinib is chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and is structurally represented in Formula-I below. Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK).

Ibrutinib is currently marketed in the United States as IMBRUVICA® by Janssen Pharmaceuticals for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy, chronic lymphocytic leukemia who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, and Waldenstrom’s macroglobulinemia.
U.S. Patent No. 7,514,444 discloses inhibitors of Bruton’s tyrosine kinase, including ibrutinib.
U.S. Patent Application Publication No. 2014/0336203 discloses crystalline and amorphous forms of ibrutinib.
Preparation of pharmaceutical dosage forms is often procedurally complex, particularly when combining the active ingredient with excipients. For example, workability or stability issues may arise when different components of the pharmaceutical dosage form come into intimate contact with one another. It may, thus, be advantageous to supply the manufacturer of pharmaceutical dosage forms with a pre-combined mixture (pre-mix) of excipients and active pharmaceutical ingredient (API) to facilitate and simplify the final processing of dosages forms.
The present invention provides methods for the preparation of amorphous ibrutinib, a premix of amorphous ibrutinib, as well as methods for the preparation thereof.
SUMMARY OF THE INVENTION
One aspect of the present invention provides a process for preparing amorphous ibrutinib, which may include the following steps:
a. dissolving ibrutinib in a solvent to form a solution;
b. adding the solution to water; and
c. isolating amorphous ibrutinib.
Within the context of this embodiment, the solvent may be polar solvent. Examples of suitable polar solvents include alcohol solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone, 2-butanone; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ether solvents such as dioxane; dimethyl sulfoxide and mixtures thereof.
Another aspect of the present invention provides a process for preparing amorphous ibrutinib, which may include the following steps:
a. dissolving ibrutinib in a solvent to form a solution; and
b. removing the solvent to isolate amorphous ibrutinib.
Within the context of this embodiment, the solvent may be an alcohol solvent, a ketone solvent, a chlorinated solvent, or mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2,2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1-propanol, 1,1-dimethyl-1-propanol, and mixtures thereof. Examples of suitable ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone, and mixtures thereof. Examples of suitable chlorinated solvents include dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
According to this embodiment, the solvent is removed by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.
Another aspect of the present invention provides a premix, comprising amorphous ibrutinib and a pharmaceutically acceptable excipient. In some embodiments of the present invention, the pharmaceutically acceptable excipient is a polysaccharide.
Another aspect of the present invention provides a process for preparing a premix containing amorphous ibrutinib, which may be carried out by the following steps:
a. dissolving ibrutinib in a solvent to form an ibrutinib solution;
b. combining water and one or more pharmaceutically acceptable excipients to form a mixture of water and pharmaceutically acceptable excipients;
c. adding the ibrutinib solution to the mixture of water and pharmaceutically acceptable excipients; and
d. isolating the premix containing amorphous ibrutinib.
Within the context of this embodiment, the solvent may be polar solvent. Examples of suitable polar solvents include alcohol solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone, 2-butanone; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ether solvents such as dioxane; dimethyl sulfoxide and mixtures thereof.
Within the context of this embodiment, examples of suitable pharmaceutical excipient include polysaccharides, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, C1-C6 polyalkylene glycols, and mixtures thereof. The polysaccharide may be, for example, hydroxypropyl methyl cellulose, croscarmellose, carboxymethyl cellulose, a sodium salt of carboxymethyl cellulose, a calcium salt of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, unsubstituted a-cyclodextrins, substituted a-cyclodextrins, unsubstituted ß-cyclodextrins, substituted ß-cyclodextrins, unsubstituted ?-cyclodextrins, substituted ?-cyclodextrins, or mixtures thereof.
Another aspect of the present invention provides an anisole solvate of ibrutinib. Within the context of this embodiment, the anisole solvate of ibrutinib may be characterized by a powder X-ray diffraction pattern having significant peaks at 6.60, 13.11, 17.66, 18.38, 20.10, 21.13, 21.52, and 22.24 ± 0.2° 2-theta. The anisole solvate of ibrutinib may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 5.
Another aspect of the present invention provides a process for preparing an anisole solvate of ibrutinib which may include the following steps:
a. dissolving ibrutinib in anisole to form a solution;
b. cooling the solution; and
c. isolating anisole solvate of ibrutinib.
Another aspect of the present invention provides a process for preparing an anisole solvate of ibrutinib, which may include the following steps:
a. dissolving ibrutinib in anisole to form a solution;
b. adding a second solvent; and
c. isolating anisole solvate of ibrutinib.
Within the context of this embodiment, the second solvent may be heptane, hexane, pentane, cyclohexane, methyl cyclohexane, or mixtures thereof.
Another aspect of the present invention provides an isopropyl acetate solvate of ibrutinib. Within the context of this embodiment, the isopropyl acetate solvate of ibrutinib may be characterized by a powder X-ray diffraction pattern having significant peaks at 18.32, 19.02, 20.69, 21.37, and 22.03 ± 0.2° 2-theta. The isopropyl acetate solvate of ibrutinib may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 9.
Another aspect of the present invention provides a process for preparing an isopropyl acetate solvate of ibrutinib, which may include the following steps:
a. dissolving ibrutinib in isopropyl acetate to form a solution;
b. cooling the solution; and
c. isolating isopropyl acetate solvate of ibrutinib.
Another aspect of the present invention provides a xylene solvate of ibrutinib. Within the context of this embodiment, the xylene solvate of ibrutinib may be characterized by a powder X-ray diffraction pattern having significant peaks at 6.66, 9.68, 10.56, 13.20, 14.44, 16.97, 17.68, 18.47, 19.34, 20.02, 21.10, 21.58, 22.19, 23.34, 24.02, and 25.82 ± 0.2° 2-theta. The xylene solvate of ibrutinib may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 14.
Another aspect of the present invention provides a process for preparing a xylene solvate of ibrutinib which may include the following steps:
a. dissolving ibrutinib in xylene to form a solution;
b. cooling the solution; and
c. isolating xylene solvate of ibrutinib.
Another aspect of the present invention provides a tert-butyl acetate solvate of ibrutinib. Within the context of this embodiment, the tert-butyl acetate solvate of ibrutinib may be characterized by a powder X-ray diffraction pattern having significant peaks at 8.82, 15.05, 17.97, 18.33, 20.11, 20.99, and 21.34 ± 0.2° 2-theta. The tert-butyl acetate solvate of ibrutinib may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 17.
Another aspect of the present invention provides a process for preparing a tert-butyl acetate solvate of ibrutinib, which may include the following steps:
a. dissolving ibrutinib in tert-butyl acetate to form a solution;
b. cooling the solution; and
c. isolating tert-butyl acetate solvate of ibrutinib.
The amorphous forms of ibrutinib, the premix thereof, as well as the solvates of ibrutinib disclosed herein may be useful in the formulation of oral pharmaceutical dosage forms. These oral pharmaceutical dosage forms may include additional pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
Figure 1 is a powder X-ray diffraction (PXRD) pattern of amorphous ibrutinib;
Figure 2 is a PXRD pattern of the premix of amorphous ibrutinib obtained per the process disclosed in example 23;
Figure 3 is a PXRD pattern of the premix of amorphous ibrutinib obtained per the process disclosed in example 24;
Figure 4 is a PXRD pattern of the premix of amorphous ibrutinib obtained per the process disclosed in example 25;
Figure 5 is a PXRD pattern of an anisole solvate of ibrutinib;
Figure 6 is a DSC thermogram of an anisole solvate of ibrutinib;
Figure 7 is a thermal gravimetric analysis/differential thermal analysis (TGA/DTA) thermogram of an anisole solvate of ibrutinib;
Figure 8 is a 1H NMR spectrum of an anisole solvate of ibrutinib;
Figure 9 is a PXRD pattern of an isopropyl acetate solvate of ibrutinib;
Figure 10 is a DSC thermogram of an isopropyl acetate solvate of ibrutinib;
Figure 11 is a TGA/DTA thermogram of an isopropyl acetate solvate of ibrutinib;
Figure 12 is a 1H NMR spectrum of an isopropyl acetate solvate of ibrutinib;
Figure 13 is a PXRD pattern of a xylene solvate of ibrutinib;
Figure 14 is a DSC thermogram of a xylene solvate of ibrutinib;
Figure 15 is TGA/DTA thermogram of a xylene solvate of ibrutinib;
Figure 16 is a 1H NMR spectrum of a xylene solvate of ibrutinib;
Figure 17 is a PXRD pattern of a tert-butyl acetate solvate of ibrutinib;
Figure 18 is a DSC thermogram of a tert-butyl acetate solvate of ibrutinib;
Figure 19 is a TGA/DTA thermogram of a tert-butyl acetate solvate of ibrutinib; and
Figure 20 is a 1H NMR spectrum of a tert-butyl acetate solvate of ibrutinib.
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention. The detailed description will be provided herein below with reference to the attached drawings.
One embodiment of the present invention provides a process for the preparation of amorphous ibrutinib, which may be carried out using the following steps:
a) dissolving ibrutinib in a solvent to form an ibrutinib solution;
b) adding the ibrutinib solution to water; and
c) isolating an amorphous form of ibrutinib.
According to the present embodiment of the invention, ibrutinib may be first dissolved in a solvent to form an ibrutinib solution. Within the context of this embodiment, the ibrutinib may be of any form, for example, crystalline, a salt, or a solvate. The solvent may be a polar solvent.
Examples of suitable polar solvents include alcohol solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone, 2-butanone; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ether solvents such as dioxane; dimethyl sulfoxide and mixtures thereof.
Next, the solution of ibrutinib may be added to a volume of water, which may cause a precipitate or solid to form. One of skill in the art will be familiar with methods of precipitating a solid out of a solution as well as appropriate conditions for achieving a desirable outcome.
Next, ibrutinib may be isolated. Isolation may be achieved by a number of methods well-known in the art, for example, by filtering the solution and drying the obtained solid. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the final ibrutinib product.
Another embodiment of the present invention provides a process for the preparation of amorphous ibrutinib, which may be carried out by the following steps:
a) dissolving ibrutinib in a solvent to form an ibrutinib solution; and
b) removing the solvent to isolate the amorphous ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in a solvent to form an ibrutinib solution. The solvent may be an alcohol solvent, a ketone solvent, a chlorinated solvent, or a mixture thereof.
Examples of suitable alcohol solvents include methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol, and mixtures thereof. Examples of suitable ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone, and mixtures thereof. Examples of suitable chlorinated solvents include dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
According to the present embodiment of the present invention, the solvent may then be removed from the solution to isolate amorphous ibrutinib. This may be carried out by well-known techniques such as, for example, evaporation, distillation, spray drying, lyophillization, agitated thin film drying, or combinations thereof. In certain embodiments of the present disclosure, spray drying is particularly useful for removing the solvent.
The amorphous form of ibrutinib prepared by methods disclosed herein may be characterized by its X-ray powder diffraction (PXRD) pattern. Thus, the PXRD pattern of the amorphous ibrutinib was measured on BRUKER D-8 Discover powder diffractometer equipped with a goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size, and 0.4 seconds step time.
The amorphous form of ibrutinib may be characterized by a PXRD pattern as depicted in Figure 1.
The amorphous form of ibrutinib disclosed herein may possess several benefits. For example, amorphous ibrutinib is particularly stable and, as described more fully below, may be easily formulated into a premix useful in generating pharmaceutical formulations. Additionally, the amorphous ibrutinib described herein may possess improved workability (e.g., flowability, tackiness), and may permit the use of formulation techniques, such as dry and/or wet granulation with one or more additional pharmaceutically acceptable excipients as described below.
Another aspect of the present invention provides a premix that contains amorphous ibrutinib, as well as a process for the preparation thereof.
In some embodiments of the present invention, the premix of amorphous ibrutinib may include, for example, amorphous ibrutinib and one or more pharmaceutically acceptable excipients. In certain other embodiments, the premix of amorphous ibrutinib may consist essentially of, or consist of, amorphous ibrutinib and one or more pharmaceutically acceptable excipients.
One embodiment of the present invention provides a process for the preparation of a premix of amorphous ibrutinib, which may be carried out by the following steps:
a) dissolving ibrutinib in a solvent to form an ibrutinib solution;
b) mixing one or more pharmaceutically acceptable excipients with water to create a mixture of water and pharmaceutically acceptable excipients;
c) adding the ibrutinib solution to the mixture of water and pharmaceutically acceptable excipients; and
d) isolating a premix of amorphous ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in a solvent to form an ibrutinib solution. The ibrutinib starting material may be any polymorphic form or amorphous. The solvent may be a polar solvent.
Examples of suitable polar solvents include alcohol solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone, 2-butanone; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ether solvent such as dioxane; dimethyl sulfoxide and mixtures thereof.
Next, one or more pharmaceutically acceptable excipients may be added to water to create a mixture of water and pharmaceutically acceptable excipients.
Examples of suitable pharmaceutically acceptable excipients include, but are not limited to, polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, C1-C6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename), and mixtures thereof. Suitable polysaccharides include, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), substituted or unsubstituted a-cyclodextrins, substituted or unsubstituted ß-cyclodextrins (e.g., hydroxypropyl ß-cyclodextrin), substituted or unsubstituted ?-cyclodextrins (e.g., hydroxypropyl ?-cyclodextrin), and mixtures thereof. As used herein, the term “substituted” means the addition of side chain groups, for example, hydroxyl, hydroxypropyl, C1-C6 alkyl, and C1-C6 hydroxyalkyl side groups. In particularly useful embodiments of the present disclosure, microcrystalline cellulose may be utilized as a pharmaceutically acceptable excipient.
Within the context of this embodiment of the present disclosure, the pharmaceutically acceptable excipient may be included in the water solution to produce a final % w/w composition pharmaceutically acceptable excipient/total composition mass) from about 10% w/w to about 50% w/w, which may be about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10%-40%, 10%-30%, 10%-20%, 20%-50%, 20%-40%, 20%-30%, 30%-50%, 30%-40%, and 40%-50% w/w. In some embodiments of the present disclosure, including microcrystalline cellulose at concentrations recited above, including from about 10% to 50% w/w, is useful.
Next, the ibrutinib solution may be added to the mixture of water and pharmaceutically acceptable excipients. Within the context of this embodiment of the present invention, adding the ibrutinib solution to the second solution may cause a precipitate to form. One of skill in the art will be familiar with methods of precipitating a solid out of a solution as well as appropriate conditions for achieving a desirable outcome.
Next, a premix of amorphous ibrutinib may be isolated. Isolation may be achieved by a number of methods well-known in the art, for example, by filtering the solution and drying the obtained solid. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the premix of amorphous ibrutinib.
According to the present invention, the premixes of amorphous ibrutinib may be characterized by PXRD. Thus, the PXRD patterns of the premixes disclosed were obtained on BRUKER D-8 Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
For example, a 10% w/w premix of amorphous ibrutinib with AVICEL® PH-101 microcrystalline cellulose may exhibit a PXRD pattern as depicted in Figure 2.
Within the context of the present disclosure, premixes of ibrutinib may exhibit long-term physical and chemical stability. As an example, Table 1 below shows data collected on several embodiments of the present invention. Three premixes of ibrutinib with microcrystalline cellulose were prepared according to the processes disclosed in each of the examples noted at the top of each data column. According to data collected, the premix of amorphous ibrutinib prepared per examples 23, 24 and 25 tested shows no significant degradation or change in PXRD pattern over the periods tested (i.e., is stable at 1, 3 and 6 months) when stored at 5 ± 3 °C and at 25 °C/60% relative humidity (RH).
TABLE 1
Condition\Polymorph Premix with microcrystalline cellulose prepared as per
Example 23 Example 24 Example 25
HPLC purity (%) PXRD HPLC purity (%) PXRD HPLC purity (%) PXRD
at 25°C/60% RH
Initial 99.41 Amorphous premix 99.50 Amorphous premix 99.54 Amorphous premix
1 month 99.44 Stable 99.50 Stable 99.15 Stable
3 months 99.48 Stable 99.47 Stable 99.49 Stable
6 months 99.43 Stable 99.39 Stable 99.31 Stable
at 5±3°C
Initial 99.41 Amorphous premix 99.50 Amorphous premix 99.54 Amorphous premix
1 month 99.60 Stable 99.36 Stable 99.27 Stable
3 months 99.49 Stable 99.49 Stable 99.50 Stable
6 months 99.42 Stable 99.41 Stable 99.43 Stable

The amorphous ibrutinib and premixes of amorphous ibrutinib prepared by the methods disclosed herein may be useful in the treatment of individuals with mantle cell lymphoma who have received at least one prior therapy, chronic lymphocytic leukemia who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, or Waldenstrom’s macroglobulinemia.
The amorphous ibrutinib and premixes disclosed herein may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. The tablet or capsule may include additional pharmaceutically acceptable excipients, for example, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, and mixtures thereof. The tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial flavorings, artificial colorings, and mixtures thereof. For example, the coating may contain gelatin, titanium dioxide, blank ink, or mixtures thereof.
Within the context of the present invention, dosage forms containing the amorphous ibrutinib and premixes of amorphous ibrutinib disclosed herein may have about 140 mg to about 540 mg of ibrutinib per dosage form. In particularly useful embodiments of the present invention, a dosage form contained 140 mg of ibrutinib.
Another aspect of the present invention provides novel of ibrutinib solvates and processes for the preparation thereof.
The present invention provides an anisole solvate, an isopropyl acetate solvate, a xylene solvate, and a tert-butyl acetate solvate of ibrutinib.
Each solvates of ibrutinib disclosed herein may be characterized by their PXRD patterns. Thus, diffraction PXRD pattern of each ibrutinib solvate was measured on BRUKER D-8 Discover powder diffractometer equipped with a goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
Each ibrutinib solvate disclosed herein may also be characterized by differential scanning calorimetry (DSC). The DSC measurements were carried out on a TA Q1000 differential scanning calorimeter (TA Instruments). Each DSC experiment was performed at a heating rate of 10.0 °C/min over a temperature range of 30-250 °C purging with nitrogen at a flow rate of 50 mL/min. Standard aluminum crucibles covered by lids with pin holes were used.
Each ibrutinib solvate disclosed herein may also be characterized by thermogravimetric analysis (TGA) or differential thermal analysis (DTA). TGA/DTA thermograms were recorded using a TA Q5000 Dynamic Vapor Sorption Instrument (TA Instruments). The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30 °C-300 °C purging with nitrogen at a flow rate of 25 mL/min.
Each ibrutinib solvate disclosed herein may also be characterized by nuclear magnetic resonance spectroscopy (NMR). The 1H NMR experiments were performed on Bruker 300MHz Avance NMR spectrometer equipped with 5mm BBO probe in DMSO-d6. The data collected and processed by XWIN-NMR software.
One aspect of the present invention provides an anisole solvate of ibrutinib and processes for the preparation thereof.
The anisole solvate of ibrutinib may be characterized by a PXRD pattern having significant peaks at 6.60, 13.11, 17.66, 18.38, 20.10, 21.13, 21.52, and 22.24 ± 0.2° 2-theta.
The anisole solvate of ibrutinib may be further characterized by a PXRD pattern having significant peaks at 6.60, 10.56, 13.11, 14.41, 17.29, 17.66, 18.38, 19.46, 20.10, 21.13, 21.52, 22.24, 23.50, 24.03, and 29.01 ± 0.2° 2-theta.
The anisole solvate of ibrutinib may be further characterized by a PXRD pattern as depicted in Figure 5.
The anisole solvate of ibrutinib may be further characterized by a DSC thermogram as depicted in Figure 6.
The anisole solvate of ibrutinib may be further characterized by a TGA/DTA thermogram as depicted in Figure 7.
The anisole solvate of ibrutinib may be further characterized by a 1H NMR spectrum as depicted in Figure 8.
A process for the preparation of the anisole solvate of ibrutinib may be carried out by the following steps:
a) dissolving ibrutinib in anisole to form a solution;
b) cooling the solution; and
c) isolating an anisole solvate of ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in anisole. This step may be carried out at an elevated temperature, for example, at temperature of about 80 °C to about 100 °C. In some embodiments of the present invention, this step is carried out at a temperature of about 85 °C to about 95 °C.
Next, the solution may be cooled, for example, to a temperature of about 20 °C to about 35 °C. In some embodiments of the present invention, the solution is cooled to about 25 °C to about 30 °C. Within the context of this embodiment of the present invention, the aforementioned cooling of the solution may produce a precipitate to form in the solution.
Next, an anisole solvate of ibrutinib may be isolated. This may be carried out using methods well known in the art, for example, by filtering the solution and drying the obtained solid. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the anisole solvate of ibrutinb.
Another embodiment of the present invention provides a process for the preparation of an anisole solvate of ibrutinib, which may be carried out by the following steps:
a) dissolving ibrutinib in anisole to form a solution;
b) adding a solvent; and
c) isolating an anisole solvate of ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in anisole. Next, a solvent may be added. The solvent may be non-polar. In some embodiments of the present invention, the solvent is a substituted or unsubstituted C5-C7 alkane or substituted or unsubstituted C5-C7 cycloalkane. In particularly useful embodiments of the present invention, the solvent may be heptane, hexane, pentane, cyclohexane, methyl cyclohexane, or mixtures thereof.
Next, an anisole solvate of ibrutinib may be isolated. This may be carried out using methods well known in the art, for example, by filtering the solution and drying the obtained solid. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the anisole solvate of ibrutinib.
An additional aspect of the present invention provides an isopropyl acetate solvate of ibrutinib and processes for the preparation thereof.
The isopropyl acetate solvate of ibrutinib may be characterized by a PXRD pattern having significant peaks at 18.32, 19.02, 20.69, 21.37, and 22.03 ± 0.2° 2-theta.
The isopropyl acetate solvate of ibrutinib may be further characterized by a PXRD pattern having significant peaks at 9.09, 15.77, 18.32, 19.02, 20.69, 21.37, 22.03, 22.72, 25.07, and 27.06 ± 0.2° 2-theta.
The isopropyl acetate solvate of ibrutinib may be further characterized by a PXRD pattern as depicted in Figure 9.
The isopropyl acetate solvate of ibrutinib may be further characterized by a DSC thermogram as depicted in Figure 10.
The isopropyl acetate solvate of ibrutinib may be further characterized by a TGA/DTA thermogram as depicted in Figure 11.
The isopropyl acetate solvate of ibrutinib may be further characterized by a 1H NMR spectrum as depicted in Figure 12.
Another embodiment of the present invention provides a process for the preparation of an isopropyl acetate solvate of ibrutinib, which may be carried out by the following steps:
a) dissolving ibrutinib in isopropyl acetate to form a solution;
b) cooling the solution; and
c) isolating an isopropyl acetate solvate of ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in isopropyl acetate. This step may be carried out at an elevated temperature, for example, at a temperature of about 70 °C to about 90 °C. In some embodiments of the present invention, this step is carried out at a temperature of about 75 °C to about 85 °C.
Next, the solution may be cooled, for example, to a temperature of about 20 °C to about 35 °C. In some embodiments of the present invention, the solution was cooled to about 25 °C to about 30 °C. In some embodiments of the present invention, the solution may then be further cooled to about -5 °C to about 5 °C. In some embodiments, the solution is cooled to about 0 °C to about 3 °C. Within the context of this embodiment of the present invention, the aforementioned cooling of the solution may produce a precipitate to form in the solution.
Next the isopropyl acetate solvate of ibrutinib may be isolated. This may be carried out using methods well known in the art, for example, by filtering the solution and drying the solid. In some embodiments, washing the obtained solid before drying with isopropyl acetate was found to be particularly useful at obtaining the isopropyl acetate solvate of ibrutinib. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the isopropyl acetate solvate of ibrutinib.
Another aspect of the present invention provides a xylene solvate of ibrutinib and processes for the preparation thereof.
The xylene solvate of ibrutinib may be characterized by a PXRD pattern having significant peaks at 17.68, 18.47, 20.02, 21.10, 21.58, and 22.19 ± 0.2° 2-theta.
The xylene solvate of ibrutinib may be further characterized by a PXRD pattern having significant peaks at 6.66, 9.68, 10.56, 13.20, 14.44, 16.97, 17.68, 18.47, 19.34, 20.02, 21.10, 21.58, 22.19, 23.34, 24.02, and 25.82 ± 0.2° 2-theta.
The xylene solvate of ibrutinib may be further characterized by a PXRD pattern as depicted in Figure 13.
The xylene solvate of ibrutinib may be further characterized by a DSC thermogram as depicted in Figure 14.
The xylene solvate of ibrutinib may be further characterized by a TGA/DTA thermogram as depicted in Figure 15.
The xylene solvate of ibrutinib may be further characterized by a 1H NMR spectrum as depicted in Figure 16.
Another embodiment of the present invention provides a process for the preparation of a xylene solvate of ibrutinib, which may include the following steps:
a) dissolving ibrutinib in xylene to form a solution;
b) cooling the solution; and
c) isolating a xylene solvate of ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in xylene at an elevated temperature, for example at a temperature of about 70 °C to about 90 °C. In some embodiments of the present invention, this step is performed at a temperature of about 75 °C to about 85 °C.
Next, the solution may be cooled, for example, to a temperature of about 20 °C to about 35 °C. In some embodiments of the present invention, the solution is cooled to a temperature of about 25 °C to about 30 °C. The reaction mass may be further cooled, for example, to a temperature of about 0 °C to about 10 °C. In some embodiments of the present invention, the solution is cooled to about 0 °C to about 5 °C. Within the context of this embodiment of the present invention, the aforementioned cooling of the solution may produce a precipitate to form in the solution.
Next the xylene solvate of ibrutinib may be isolated. This may be carried out using methods well known in the art, for example, by filtering the solution and drying the solid. In some embodiments, washing the obtained solid before drying with xylene was found to be particularly useful at obtaining the xylene solvate of ibrutinib. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the xylene solvate of ibrutinib.
Another aspect of the present invention provides a tert-butyl acetate solvate of ibrutinib and processes for the preparation thereof.
The tert-butyl acetate solvate of ibrutinib may be characterized by a PXRD pattern having significant peaks at 8.82, 15.05, 17.97, 18.33, 20.11, 20.99, and 21.34 ± 0.2° 2-theta.
The tert-butyl acetate solvate of ibrutinib may be further characterized by a PXRD pattern having significant peaks at 7.59, 8.82, 9.96, 14.54, 15.05, 17.97, 18.33, 19.85, 20.11, 20.69, 20.99, 21.34, 23.71, and 25.58 ± 0.2° 2-theta.
The tert-butyl acetate solvate of ibrutinib may be further characterized by PXRD pattern as depicted in Figure 17.
The tert-butyl acetate solvate of ibrutinib may be further characterized by a DSC thermogram as depicted in Figure 18.
The tert-butyl acetate solvate of ibrutinib may be further characterized by a TGA/DTA thermogram as depicted in Figure 19.
The tert-butyl acetate solvate of ibrutinib may be further characterized by a 1H NMR spectrum as depicted in Figure 20.
Another embodiment of the present invention provides a process for the preparation of a tert-butyl acetate solvate of ibrutinib, which may include the following steps:
a) dissolving ibrutinib in tertiary butyl acetate to form a solution;
b) cooling the solution; and
c) isolating a tert-butyl acetate solvate of ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in tert-butyl acetate at an elevated temperature, for example at a temperature of about 70 °C to about 90 °C. In some embodiments of the present invention, this step is carried out at a temperature of about 75 °C to about 85 °C.
Next, the solution may be cooled, for example, to a temperature of about 0 °C to about 10 °C. In some embodiments of the present invention, the solution is cooled to a temperature of about 0 °C to about 5 °C. Within the context of this embodiment of the present invention, the aforementioned cooling of the solution may produce a precipitate to form in the solution.
Next the tert-butyl acetate solvate of ibrutinib may be isolated. This may be carried out using methods well known in the art, for example, by filtering the solution and drying the solid. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the tert-butyl acetate solvate of ibrutinib.
Another embodiment of the present invention provides a process for the preparation of a tert-butyl acetate solvate of ibrutinib, which may be carried out by the steps:
a) dissolving ibrutinib in tertiary butyl acetate to form a solution;
b) cooling the solution;
c) seeding the solution with a tert-butyl acetate solvate of ibrutinib; and
d) isolating a tert-butyl acetate solvate of ibrutinib.
According to this embodiment of the present invention, ibrutinib may be dissolved in tert-butyl acetate at an elevated temperature, for example at a temperature of about 70 °C to about 90 °C. In some embodiments of the present invention, this step is carried out at a temperature of about 75 °C to about 85 °C.
Next, the solution may be cooled, for example, to a temperature of about 0 °C to about 10°C. In some embodiments of the present invention, the solution is cooled to a temperature of about 0 °C to about 5 °C. Within the context of this embodiment of the present invention, the aforementioned cooling of the solution may produce a precipitate to form in the solution.
Next, the solution may be seeded with a tert-butyl acetate solvate of ibrutinib by adding some of the tert-butyl solvate of ibrutinib to the solution. Within the context of this embodiment of the present invention, this seeding step may facilitate or expedite the formation of the tert-butyl acetate solvate of ibrutinib in the solution. Within the context of this embodiment of the present invention, the cooling step, the seeding step, or both steps may cause a precipitate to form in the solution.
Next the tert-butyl acetate solvate of ibrutinib may be isolated. This may be carried out using methods well known in the art, for example, by filtering the solution and drying the solid. In some embodiments, the solid obtained by filtering is dried at 40 °C. One of skill in the art will be familiar with a variety of methods and as well as appropriate conditions which may be suitable for isolating the tert-butyl acetate solvate of ibrutinib.
The solvates of ibrutinib prepared by the methods disclosed herein may be useful in the treatment of individuals with mantle cell lymphoma who have received at least one prior therapy, chronic lymphocytic leukemia who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, or Waldenstrom’s macroglobulinemia.
The solvates of ibrutinib disclosed herein may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. The tablet or capsule may include additional pharmaceutically acceptable excipients, for example, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, and mixtures thereof. The tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial flavorings, artificial colorings, and mixtures thereof. For example, the coating may contain gelatin, titanium dioxide, blank ink, or mixtures thereof.
Within the context of the present invention, dosage forms containing a solvate of ibrutinib as disclosed herein may have about 140 mg to about 540 mg of ibrutinib per dosage form. In particularly useful embodiments of the present invention, a dosage form contained 140 mg of ibrutinib.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES
Example 1: Preparation of amorphous ibrutinib
Ibrutinib (1 g) was dissolved in acetone (15 mL) at 50 °C. The solution was filtered at 50 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear solution of ibrutinib was slowly added into cold water (60 mL), maintained at 0-5 °C for 5-10 min, and stirred at the same temperature for 30-60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 3h to yield an amorphous form of ibrutinib.
Example 2: Preparation of amorphous ibrutinib
Ibrutinib (1 g) was dissolved in acetone (15 mL) at 50 °C. The solution was filtered at 50 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear solution of ibrutinib was slowly added into cold water (45 mL), maintained at 0-5 °C for 5-10 min, and stirred at the same temperature for 30-60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 3 h to yield an amorphous form of ibrutinib.
Example 3: Preparation of amorphous ibrutinib
Ibrutinib (20 g) was dissolved in dichloromethane (300 mL) at 40-45 °C. The solution was filtered through HYFLO and washed dichloromethane (50 mL). The clear filtrate was taken and the solvent was distilled off under vacuum completely using a rotary evaporator at 40 °C to yield an amorphous form of ibrutinib.
Example 4: Preparation of amorphous ibrutinib
Ibrutinib (10 g) was dissolved in methanol (150 mL) at 60 °C. The solution was filtered at 60 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear filtrate was taken and the solvent was distilled off under vacuum completely by using a rotary evaporator at 40 °C to yield an amorphous form of ibrutinib.
Example 5: Preparation of amorphous ibrutinib
Ibrutinib (5g) was dissolved in methanol (100 mL) at 60 °C. The solution was filtered at 60 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear solution was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 5 mL/min and inlet temperature at 70 °C to yield an amorphous form of ibrutinib.
Example 6: Preparation of amorphous ibrutinib
Ibrutinib (10g) was dissolved in acetone (130 mL) at 50-55 ?C. The solution was filtered at 50-55 °C to remove undissolved particulate, washed with acetone (30 mL), and cooled to 25-30 °C. The clear solution of ibrutinib was added to a pre-cooled mixture of water (450 mL) at 0-5 °C in 15-20 min and stirred at the same temperature for 30-60 min. The solid obtained was filtered, washed with cold water (15 mL), and dried at 30 °C under vacuum for 16 hours to yield an amorphous form of ibrutinib.
Example 7: Preparation of amorphous ibrutinib
Ibrutinib (1 g) was dissolved in acetone (15 mL) at 50 °C. The solution was filtered at 50 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear solution of ibrutinib was slowly added into cold water (60 mL) maintained at 0-5 °C for 5-10 min and stirred at the same temperature for 30-60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 3 h to yield an amorphous form of ibrutinib.
Example 8: Preparation of amorphous ibrutinib
Ibrutinib (1 g) was dissolved in acetone (15 mL) at 50 °C. The solution was filtered at 50 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear solution of ibrutinib was slowly added into cold water (45 mL), maintained at 0-5 °C for 5-10 min, and stirred at the same temperature for 30-60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 3 h to yield an amorphous form of ibrutinib.
Example 9: Preparation of amorphous ibrutinib
Ibrutinib (20 g) was dissolved in dichloromethane (300 mL) at 40-45 °C. The solution was filtered through hyflo bed and washed bed with dichloromethane (50 mL). The clear filtrate was taken and the solvent was distilled off under vacuum completely using a rotary evaporator at 40 °C to yield an amorphous form of ibrutinib.
Example 10: Preparation of amorphous ibrutinib
Ibrutinib (10 g) was dissolved in methanol (150 mL) at 60 °C. The solution was filtered at 60 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear filtrate was taken and the solvent was distilled off under vacuum completely using a rotary evaporator at 40 °C to yield an amorphous form of ibrutinib.
Example 11: Preparation of amorphous ibrutinib
Ibrutinib (5g) was dissolved in methanol (100 mL) at 60°C. The solution was filtered at 60 °C to remove undissolved particulate and then cooled to 25-30 °C. The clear solution was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 5 mL/min and inlet temperature at 70 °C to yield an amorphous form of ibrutinib.
Example 12: Preparation of amorphous ibrutinib
Ibrutinib (15 g) was dissolved in methanol (45 mL) at 60 °C and then cooled to 0-5 °C. The solid was washed with methanol (5 mL) and the obtained wet cake was dissolved in dimethyl sulfoxide (30 mL) at 32 °C. The solution was filtered to remove undissolved particulate. The clear solution of ibrutinib was slowly added into water (750 mL) at 25-30 °C for 5-10 min and stirred at the same temperature for 90-120 min. The solid obtained was filtered, washed with water (15 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 13: Preparation of amorphous ibrutinib
Ibrutinib (15 g) was dissolved in dimethyl sulfoxide (30 mL) at 32 °C. The solution was filtered to remove undissolved particulate. The clear solution of ibrutinib was slowly added into water (750 mL) at 25-30 °C for 5-10 min and stirred at the same temperature for 90-120 min. The solid obtained was filtered, washed with water (15 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 14: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in methanol (8 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 15: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in acetone (12 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 16: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in N,N-dimethylformamide (3 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 17: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in N,N-dimethylacetamide (2.5 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 18: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in N-methyl-2-pyrrolidone (3 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 19: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in dimethylsulfoxide (2 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 20: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.5 g) in ethylene glycol (2.5 mL) was slowly added to water (100 mL) under stirring at 25-30 °C and maintained at the same temperature for 60 min. The solid obtained was filtered, washed with water (5 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 21: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.25 g) in dioxane (1.5 mL) was slowly added to water (60 mL) under stirring at 25-30 °C and maintained at the same temperature for 30 min. The solid obtained was filtered, washed with water (2 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 22: Preparation of amorphous ibrutinib
A solution of ibrutinib (0.25 g) in dioxane (1.5 mL) was dumped into water (60 mL) under stirring at 25-30 °C and maintained at the same temperature for 30 min. The solid obtained was filtered, washed with water (2 mL), and dried at 30 °C under vacuum for 15 hours to get an amorphous form of ibrutinib.
Example 23: Preparation of a premix of amorphous ibrutinib
Ibrutinib (5 g) was dissolved in acetone (60 mL) at 50-55 °C. The solution was filtered at 50-55 °C to remove undissolved particulate, washed with acetone (15 mL), and cooled to 25-30 °C. The clear solution of ibrutinib was added to pre-cooled mixture of water (225 mL) with microcrystalline cellulose (0.556 g, Grade: AVICEL PH 101) at 0-5 °C in 15-20 min and stirred at the same temperature for 1 h. The solid obtained was filtered, washed with cold water (15 mL), and dried at 30 °C under vacuum for 16 h to get a premix of amorphous ibrutinib with microcrystalline cellulose.
Example 24: Preparation of a premix of amorphous ibrutinib
Ibrutinib (5 g) was dissolved in acetone (60 mL) at 50-55 °C. The solution was filtered at 50-55 °C to remove undissolved particulate, washed with acetone (15 mL), and cooled to 25-30 °C. The clear solution of ibrutinib was added to pre-cooled mixture of water (225 mL) with microcrystalline cellulose (2.142 g, Grade: AVICEL® PH 101) at 0-5 °C in 15-20 min and stirred at the same temperature for 1 h. The solid obtained was filtered, washed with cold water (15 mL), and dried at 30 °C under vacuum for 16 h to get a premix of amorphous ibrutinib with microcrystalline cellulose.
Example 25: Preparation of a premix of amorphous ibrutinib
Ibrutinib (5 g) was dissolved in acetone (60 mL) at 50-55 °C. The solution was filtered at 50-55 °C to remove undissolved particulate, washed with acetone (15 mL), and cooled to 25-30 °C. The clear solution of ibrutinib was added to pre-cooled mixture of water (225 mL) with microcrystalline cellulose (5 g, Grade: AVICEL® PH 101) at 0-5 °C in 15-20 min and stirred at the same temperature for 1 h. The solid obtained was filtered, washed with cold water (15 mL), and dried at 30 °C under vacuum for 16 h to get a premix of amorphous ibrutinib with microcrystalline cellulose.
Example 26: Preparation of a premix of amorphous ibrutinib
Ibrutinib (0.5 g) was dissolved in dimethyl sulfoxide (2.5 mL) at 25-30 °C. The solution was filtered to remove undissolved particulate. The clear solution of ibrutinib was added to pre-cooled mixture of water (15 mL) with microcrystalline cellulose (0.214 mg, Grade: AVICEL® PH 101) at 0-5 °C in 15-30 min and stirred at the same temperature for 3 h. The solid obtained was filtered and dried at 30 °C under vacuum for 24 h to get a premix of amorphous ibrutinib with microcrystalline cellulose.
Example 27: Preparation of an anisole solvate of ibrutinib
Ibrutinib (3 g) was dissolved in anisole (15 mL) at 90 ± 5 °C. The clear solution was cooled to 27 ± 3 °C and maintained under stirring for 1-3 hours at 27 ± 3 °C. The solid obtained was filtered, washed with anisole (5 mL), and dried under vacuum at 40°C for 1-3 hours to get an anisole solvate of ibrutinib.
Example 28: Preparation of an anisole solvate of ibrutinib
Ibrutinib (1 g) was dissolved in anisole (5 mL) at 90 ± 5 °C. The clear solution was cooled to 27 ± 3 °C and maintained under stirring for 15-18 hours at 27 ± 3 °C. The solid obtained was filtered, washed with anisole (2 mL), and dried under vacuum at 40 °C for 1-3 hours to get an anisole solvate of ibrutinib.
Example 29: Preparation of an anisole solvate of ibrutinib
Ibrutinib (0.5 g) was dissolved in anisole (2.5 mL) at 90 ± 5 °C. The clear solution was cooled to 27 ± 3 °C and maintained under stirring for 0.5 hours at 27 ± 3 °C. N-heptane (2.5 mL) was added and the solution was stirred for 24 hours at 27 ± 3 °C. The solid obtained was filtered, washed with n-heptane (1 mL), and dried under vacuum at 40 °C for 1-3 hours to get an anisole solvate of ibrutinib.
Example 30: Preparation of an anisole solvate of ibrutinib
Ibrutinib (0.5 g) was dissolved in anisole (2.5 mL) at 90 ± 5 °C. The clear solution was cooled to 27 ± 3 °C and maintained under stirring for 0.5 hours at 27 ± 3 °C. N-heptane (5 mL) was added and the solution was stirred for 24 hours at 27 ± 3 °C. The solid obtained was filtered, washed with n-heptane (1 mL), and dried under vacuum at 40 °C for 1-3 hours to get an anisole solvate of ibrutinib.
Example 31: Preparation an anisole solvate of ibrutinib
Ibrutinib (10 g) was dissolved in anisole (50 mL) at 85 ± 5 °C. The clear solution was filtered at 50 °C to remove undissolved particulate and slowly cooled to 27 ± 3 °C. N-heptane (100 mL) was then added and the solution was stirred for 18 h at 27 ± 3 °C. The solid obtained was filtered and dried under vacuum for 35 °C for 3 hours to get an anisole solvate of ibrutinib.
Example 32: Preparation of an isopropyl acetate solvate of ibrutinib
Ibrutinib (1 g) was dissolved in isopropyl acetate (30 mL) at 80 ± 5 °C. The clear solution was cooled to 27 ± 3 °C and filtered to remove undissolved particulate at 27±3°C. The resulting clear solution was maintained under stirring for 15-18 hours. The solid obtained was then cooled to 0 ± 2 °C and maintained under stirring for 1-3 hours at 3 ± 2 °C. The product obtained was filtered, washed with isopropyl acetate (2 mL), and dried under vacuum at 40 °C for 1-3 hours to get an isopropyl acetate solvate of ibrutinib.
Example 33: Preparation of an isopropyl acetate solvate of ibrutinib
Ibrutinib (5.0 g) was dissolved in isopropyl acetate (125 mL) at 80 °C. The resulting clear solution was cooled to 40 °C, filtered to remove undissolved particulate. The clear solution was taken into a round bottomed flask at 27 ± 3 °C, seeds of isopropyl acetate solvate (10 mg) were added, and the solution was stirred at the same temperature for 15 h. The solid obtained was further cooled to 0 ± 3 °C and maintained under stirring at the same temperature for 5 h. The resulting solid was filtered, washed with isopropyl acetate (2 mL), and dried under vacuum at 40 °C for 15 hours to get an isopropyl acetate solvate of ibrutinib.
Example 34: Preparation of a xylene solvate of ibrutinib
Ibrutinib (1 g) was dissolved in xylene (30 mL) at 80 ± 5°C. The clear solution was cooled to 27 ± 3 °C and filtered to remove undissolved particulate at 27 ± 3 °C. The resulting clear solution was maintained under stirring for 15-18 hours. The solid obtained was then cooled to 3 ± 2 °C and maintained under stirring for 1-3 hours at 3 ± 2 °C. The product obtained was filtered, washed with xylene (2 mL), and dried under vacuum at 40 °C for 1-3 hours to get a xylene solvate of ibrutinib.
Example 35: Preparation of a tert-butyl acetate solvate of ibrutinib
Ibrutinib (1 g) was dissolved in tertiary butyl acetate (30 mL) at 80 ± 5 °C. The resulting clear solution was cooled to 27 ± 3 °C and kept for slow solvent evaporation for 24 hours at 3 ± 2 °C. The solid obtained was filtered and dried under vacuum to get a tert-butyl acetate solvate of ibrutinib.
Example 36: Preparation of a tert-butyl acetate solvate of ibrutinib
Ibrutinib (1 g) was dissolved tertiary butyl acetate (30 mL) and heated to 80 ± 5 °C to get clear solution. The clear solution was cooled to 27 ± 3 °C and filtered to remove undissolved particulate at 27 ± 3 °C. To this a tert-butyl acetate solvate of ibrutinib seeding material (1 mg) was added and maintained under stirring for 15-18 hours at 27 ± 3 °C. The solid obtained was filtered and dried under vacuum at 40 °C for 12-16 hours to get a tert-butyl acetate solvate of ibrutinib.
,CLAIMS:We claim:
1. A process for preparing amorphous ibrutinib, comprising the steps of:
a. dissolving ibrutinib in a solvent to form a solution;
b. adding the solution to water; and
c. isolating amorphous ibrutinib.
2. The process according to claim 1, wherein the polar solvent is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone, 2-butanone; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ether solvents such as dioxane; dimethyl sulfoxide and mixtures thereof.
3. A process for preparing amorphous ibrutinib, comprising the steps of:
a. dissolving ibrutinib in a solvent to form a solution; and
b. removing the solvent to isolate amorphous ibrutinib.
4. The process according to claim 3, wherein the solvent is selected from the group consisting of an alcohol solvent, a ketone solvent, a chlorinated solvent, and mixtures thereof.
5. The process according to claim 4, wherein solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2,2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1-propanol, 1,1-dimethyl-1-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
6. The process according to claim 3, wherein the solvent is removed by evaporation, distillation, spray drying, lyophillization, or agitated thin film drying.
7. A process for preparing a premix containing amorphous ibrutinib, comprising the steps of:
a. dissolving ibrutinib in a solvent to form an ibrutinib solution;
b. combining water and one or more pharmaceutically acceptable excipients to form a mixture of water and pharmaceutically acceptable excipients;
c. adding the ibrutinib solution to the mixture of water and pharmaceutically acceptable excipients; and
d. isolating the premix containing amorphous ibrutinib.
8. The process according to claim 7, wherein the polar solvent is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-1-butanol, 2-2-methyl-2-butanol, 3-methyl-2-butanol, ethylene glycol 2,2-dimethyl-1-propanol, 1,1,dimethyl-1-propanol; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone, 2-butanone; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; ether solvents such as dioxane; dimethyl sulfoxide and mixtures thereof.
9. The process according to claim 7, wherein the pharmaceutical excipient is selected from the group consisting of polysaccharides, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, C1-C6 polyalkylene glycols, and mixtures thereof.
10. A premix, comprising amorphous ibrutinib and a pharmaceutically acceptable excipient.
11. The premix of claim 10, wherein the pharmaceutically acceptable excipient is a polysaccharide.
12. An anisole solvate of ibrutinib characterized by a powder X-ray diffraction pattern having significant peaks at 6.60, 13.11, 17.66, 18.38, 20.10, 21.13, 21.52, and 22.24 ± 0.2° 2-theta.
13. A process for preparing an anisole solvate of ibrutinib, comprising the steps of:
a. dissolving ibrutinib in anisole to form a solution;
b. cooling the solution; and
c. isolating anisole solvate of ibrutinib.
14. A process for preparing an anisole solvate of ibrutinib, comprising the steps of:
a. dissolving ibrutinib in anisole to form a solution;
b. adding a second solvent; and
c. isolating anisole solvate of ibrutinib.
15. An isopropyl acetate solvate of ibrutinib characterized by a powder X-ray diffraction pattern having significant peaks at 18.32, 19.02, 20.69, 21.37, and 22.03 ± 0.2° 2-theta.
16. A process for preparing an isopropyl acetate solvate of ibrutinib, comprising the steps of:
a. dissolving ibrutinib in isopropyl acetate to form a solution;
b. cooling the solution; and
c. isolating isopropyl acetate solvate of ibrutinib.
17. A xylene solvate of ibrutinib characterized by a powder X-ray diffraction pattern having significant peaks at 6.66, 9.68, 10.56, 13.20, 14.44, 16.97, 17.68, 18.47, 19.34, 20.02, 21.10, 21.58, 22.19, 23.34, 24.02, and 25.82 ± 0.2° 2-theta.
18. A process for preparing a xylene solvate of ibrutinib, comprising the steps of:
a. dissolving ibrutinib in xylene to form a solution;
b. cooling the solution; and
c. isolating xylene solvate of ibrutinib.
19. A tert-butyl acetate solvate of ibrutinib characterized by a powder X-ray diffraction pattern having significant peaks at 8.82, 15.05, 17.97, 18.33, 20.11, 20.99, and 21.34 ± 0.2° 2-theta.
20. A process for preparing a tert-butyl acetate solvate of ibrutinib, comprising the steps of:
a. dissolving ibrutinib in tert-butyl acetate to form a solution;
b. cooling the solution; and
c. isolating tert-butyl acetate solvate of ibrutinib.