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1. WO2016135755 - AMORPHOUS APREMILAST, PREMIXES THEREOF, AND NOVEL CRYSTALLINE FORMS OF APREMILAST

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[ EN ]

AMORPHOUS APREMILAST, PREMIXES THEREOF, AND NOVEL CRYSTALLINE

FORMS OF APREMILAST

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian provisional patent applications No. 950/CHE/2015 filed on February 27, 2015; 1953/CHE/2015 filed on Aril 15, 2015 and 2789/CHE/2015 filed on June 3, 2015, which are hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The present disclosure generally relates to a process for the preparation of pharmaceutical active ingredients and more specifically to amorphous apremilast. The present disclosure further relates to premixes of amorphous apremilast and processes for the preparation thereof. The present invention further relates to novel crystalline forms of apremilast and processes for the preparation thereof.

BACKGROUND OF THE INVENTION

Apremilast is chemically known as N-[2-[(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide and is shown in Formula-I below. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor and is useful in the treatment of severe plaque psoriasis and psoriatic arthritis.


Formula I

United States Pat. No. 7,427,638 discloses apremilast and process for the preparation of thereof. WO2009/120167 discloses solid forms of apremilast.

WO2014/072259 discloses amorphous apremilast and a melting process for the preparation of an amorphous apremilast composition.

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.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing amorphous apremilast, which may be carried out by the following steps:

a. dissolving apremilast in a solvent;

b. removing the solvent;

c. adding a non-polar solvent; and

d. isolating amorphous apremilast.

According to this embodiment, the solvent may be an alcohol solvent, a ketone solvent, a chlorinated solvent, a polar hydrocarbon solvent, or mixtures thereof. Specific examples of suitable solvents include methanol, ethanol, propanol, isopropanol, n-butanol, sec -butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. The non-polar solvent may be, for example, an ethereal solvent, a non-polar hydrocarbon solvent, or mixtures thereof. Specific examples of non-polar solvent include

heptane, hexane, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.

Within the context of this embodiment, the solvent may be removed by distillation.

Another aspect of the present invention provides a process for preparing amorphous apremilast, which may be carried out by the following steps:

a. dissolving apremilast in a solvent to form a solution;

b. cooling the solution; and

c. isolating amorphous apremilast.

Within the context of this embodiment, the solvent may be an alcohol solvent, for example, methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl- 1-butanol, 2,2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, or mixtures thereof.

Another aspect of the present invention provides a process for preparing a premix containing amorphous apremilast, which may be carried out by the following steps:

a. dissolving apremilast and a pharmaceutical excipient in a solvent;

b. removing the solvent;

c. adding a non-polar solvent;

d. isolating a premix containing amorphous apremilast.

Within the context of this embodiment, the solvent may be, for example, an alcohol solvent, a ketone solvent, a chlorinated solvent, a polar hydrocarbon solvent, or mixtures thereof. Specific examples of suitable solvents include methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-pentanol, 2-methyl-1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

Within the context of this embodiment, the non-polar solvent may be an ethereal solvent, a non-polar hydrocarbon solvent, or mixtures thereof. Specific examples of non-polar solvents include heptane, hexane, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.

Examples of suitable pharmaceutical excipients include polysaccharides, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C6 polyalkylene glycols, and mixtures thereof. Examples of suitable polysaccharides include 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, optionally substituted a-cyclodextrins, optionally substituted β-cyclodextrins, optionally substituted γ-cyclodextrins, and mixtures thereof. In some embodiments, a vinylpyrrolidone-vinyl acetate copolymer comprising N-vinyl-2-pyrrolidone and vinyl acetate in a 60:40 ratio, by mass is used.

Within the context of this embodiment, the solvent may be removed by distillation.

Another aspect of the present invention provides a premix which contains amorphous apremilast and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is a polyvinylpyrrolidone-vinyl acetate copolymer with a ratio of 60:40 polyvinylpyrrolidone to vinyl acetate by mass.

Another aspect of the present invention provides an anisole solvate of apremilast.

Within the context of this embodiment, the anisole solvate may be characterized by a PXRD pattern having significant peaks at 11.89, 16.30, 17.63, 22.34, 25.30, and 26.19 ± 0.2 °2Θ.

The anisole solvate of apremilast may be further characterized by a PXRD pattern as depicted in Figure 3.

Another aspect of the present invention provides a process for preparing an anisole solvate of apremilast, which may include the following steps:

a. dissolving apremilast in anisole;

b. adding a solvent; and

c. isolating an anisole solvate of apremilast.

Within the context of this embodiment, the solvent may be, for example, isopropanol, heptane, hexane, methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, or mixtures thereof.

Another aspect of the present invention provides a process for preparing an anisole solvate of apremilast, which may include the following steps:

a. dissolving apremilast in anisole to form a solution;

b. adding the solution to a solvent; and

c. isolating an anisole solvate of apremilast.

Within the context of this embodiment, the solvent may be, for example, isopropanol, heptane, hexane, methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, and mixtures thereof.

Another aspect of the present invention provides a process for preparing an anisole solvate of apremilast, which may include the following steps:

a. adding apremilast to anisole; and

b. isolating an anisole solvate of apremilast.

Another aspect of the present invention provides a methyl ethyl ketone solvate of apremilast.

Within the context of this embodiment, the methyl ethyl ketone solvate of apremilast may be characterized by a PXRD pattern having significant peaks at 7.37, 11.12, 17.61, 22.38, 24.65, and 26.23 ± 0.2 °2Θ.

The methyl ethyl ketone solvate of apremilast may be further characterized by a PXRD pattern as depicted in Figure 5.

Another aspect of the present inventing provides a process for preparing a methyl ethyl ketone solvate of apremilast which may be carried out by the following steps:

a. dissolving apremilast in methyl ethyl ketone to form a solution;

b. cooling the solution; and

c. isolating a methyl ethyl ketone solvate of apremilast.

Within the context of the present invention, the premix of amorphous apremilast disclosed herein may be suitable for incorporation into a pharmaceutical dosage form.

Within the context of the present invention, the anisole solvate of apremilast disclosed herein may be suitable for incorporation into a pharmaceutical dosage form.

Within the context of the present invention, the methyl ethyl ketone solvate of apremilast disclosed herein may be suitable for incorporation into a pharmaceutical dosage form.

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 apremilast;

Figure 2 is a PXRD pattern of a premix of amorphous apremilast with 25% w/w PLASDONE S-630;

Figure 3 is a PXRD pattern of an anisole solvate of apremilast;

Figure 4 is 1H NMR spectrum of an anisole solvate of apremilast;

Figure 5 is a PXRD pattern of a methyl ethyl ketone solvate of apremilast;

Figure 6 is a differential scanning calorimetry (DSC) thermogram of a methyl ethyl ketone solvate of apremilast;

Figure 7 is TGA/DTA of a methyl ethyl ketone solvate of apremilast; and

Figure 8 is 1H NMR spectrum of a methyl ethyl ketone solvate of apremilast.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

One aspect of the present invention provides a process for the preparation of amorphous apremilast.

One embodiment of the present invention provides amorphous apremilast.

The amorphous form of apremilast and premixes thereof disclosed herein may be characterized by its X-ray powder diffraction (PXRD) pattern. Each solvate of apremilast disclosed herein also may be characterized by its PXRD pattern. Thus, the PXRD patterns of amorphous apremilast, premixes thereof, and each apremilast solvate disclosed herein were measured on BRUKER D-8 Discover powder diffractometer equipped with a goniometer of Θ/2Θ 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 2Θ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

The amorphous form of apremilast may be characterized by a PXRD pattern as depicted in Figure 1.

Another aspect of the present invention encompasses processes for the preparation of amorphous apremilast.

One embodiment provides a process for the preparation of amorphous apremilast, which may be carried out by the following steps:

a) dissolving apremilast in a solvent;

b) removing the solvent;

c) adding a non-polar solvent; and

d) isolating amorphous apremilast.

According to the present embodiment, apremilast may be dissolved in a solvent. Within the context of this embodiment, the apremilast starting material may be of a variety of different forms, for example, any polymorph or any solvated form. The solvent may be an alcohol solvent, a ketone solvent, a chlorinated solvent, a polar hydrocarbon 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-l-propanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l-propanol, and mixtures thereof. Examples of suitable ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable polar hydrocarbon solvent include toluene. Examples of suitable chlorinated solvents include dichloromethane, dichloroethane, chloroform, and mixtures thereof. In some embodiments, dichloromethane or acetone are used as a solvent.

Next, the solvent may be removed. This may be carried out by a variety of methods which are well known in the art. For example, in some embodiments, the solvent is removed by distillation.

According to the present embodiment, a non-polar solvent may then be added. Examples of suitable non-polar solvents include ethereal solvents, non-polar hydrocarbon solvents, and mixtures thereof.

Examples of suitable hydrocarbon solvents include heptane, hexane, and mixtures thereof. Examples of suitable ethereal solvents include 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, n-heptane or methyl tert-butyl ether were used as non-polar solvents.

Next, amorphous apremilast may be isolated. This may be carried out by methods well known in the art, for example, by filtering and drying the obtained solid.

Another embodiment of the present invention provides a process for the preparation of amorphous apremilast, which may be carried out by the following steps:

a) dissolving apremilast in a solvent;

b) cooling the solution; and

c) isolating amorphous apremilast.

According to the present embodiment, apremilast may first be dissolved in a solvent. Within the context of this embodiment, the apremilast starting material may be of a variety of different forms, for example, any polymorph or any solvated form. Within the context of this embodiment, the solvent may be an alcohol solvent.

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-l -butanol, 2-methyl-l -propanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, and mixtures thereof. In certain embodiments, propanol, 2-methyl-l -propanol, butanol, methanol, or ethanol are used.

This step may be carried out at an elevated temperature, for example, at a temperature of about 60 °C to about 95 °C. In some embodiments, apremilast is dissolved in a solvent at a temperature of about 85 °C to about 90 °C.

Next, the solution may be cooled. Within the context of this embodiment, the solution may first be cooled to room temperature and then further cooled to about 0 °C to about 15 °C. In some embodiments, the solution is cooled to about 0 °C to about 5 °C. Cooling the solution may, in some embodiments, cause a solid to precipitate from the solution.

Next, amorphous apremilast may be isolated, for example, by filtering the solution to obtain a solid. The solid may then be dried under vacuum to get amorphous apremilast.

The amorphous apremilast disclosed herein may, in some embodiments, exhibit long-term physical and chemical stability. As an example, Table 1 below presents data collected on amorphous apremilast prepared according to the processes of the present invention disclosed herein above. The amorphous apremilast tested shows no significant degradation or change in PXRD pattern (e.g., is stable at 1, 2 and 3 months storage) when stored at 5 ± 3 °C and at 25 °C/60% relative humidity (RH).

As used herein, a compound or pharmaceutical composition is considered "stable" where the HPLC purity of the compound or premix changes by less than about 1 % after being stored under a set of environmental conditions for a period of time. For example, the amorphous apremilast disclosed herein is stable when stored at 5 ± 3 °C and/or at 25 °C/60% relative humidity (RH). In certain embodiments, the compound or premix is stored at 5 ± 3 °C. In other embodiments, the "stable" compound or premix is stored at 25 °C/60% relative humidity (RH).

TABLE 1


The present invention also provides a premix of amorphous apremilast. In certain embodiments, the premix of amorphous apremilast may include, for example, amorphous apremilast and one or more pharmaceutically acceptable excipients. In certain other embodiments, the premix of amorphous apremilast consists essentially of, or consists of, amorphous apremilast and one or more pharmaceutically acceptable excipients.

Within the context of the present invention, a premix of amorphous apremilast may be characterized as such by a PXRD pattern. For example, the PXRD pattern depicted in Figure 2 was obtained for a premix of amorphous apremilast and 25% w/w PLASDONE S-630.

Another aspect of the present invention provides a process for the preparation of a premix of amorphous apremilast. One aspect of the present invention encompasses a process for the preparation of a premix of amorphous apremilast, which may be carried out by the following steps:

a) dissolving apremilast and a pharmaceutical excipient in a solvent;

b) removing the solvent;

c) adding a non-polar solvent; and

d) isolating a premix of amorphous apremilast.

According to the present embodiment, apremilast and a pharmaceutical excipient may be first dissolved in a solvent. Within the context of this embodiment, the apremilast starting material may be of a variety of different forms, for example, any polymorph or any solvated form. Within the context of this embodiment, the solvent may be, for example, an alcohol solvent, a ketone solvent, a chlorinated solvent, a polar hydrocarbon 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-l-propanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, and mixtures thereof. Examples of suitable ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. Examples of suitable hydrocarbon solvent include toluene. Examples of suitable chlorinated solvents include dichlorome thane, dichloroethane, chloroform, and mixtures thereof. In some embodiments, acetone or methanol is used as a solvent.

Examples of suitable pharmaceutical excipients include polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-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), optionally substituted a-cyclodextrins, optionally substituted β-cyclodextrins (e.g., hydroxypropyl β-cyclodextrin), optionally substituted γ-cyclodextrins (e.g., hydroxypropyl γ-cyclodextrin) and mixtures thereof. As used herein, the term "substituted" with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, or other Ci-C6 alkyl and Ci-C6 hydroxyalkyl groups.

In particularly useful embodiments of the present disclosure, copovidone polymer (e.g., PLASDONE S-630) with a 60:40 (by mass) ratio of N-vinyl-2-pyrrolidone to vinyl acetate may be utilized as the pharmaceutically acceptable excipient.

Within the context of this embodiment of the present disclosure, the pharmaceutically acceptable excipient may be combined with the solution of apremilast such that the final w/w % of pharmaceutically acceptable excipient to total composition mass is 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, combining the 40:60 (by mass) N-vinyl-2-pyrrolidone to vinyl acetate copovidone copolymer at concentrations recited above, including from about 10% to 50% w/w, with apremilast may be found to be useful.

According to the present embodiment, the solvent may next be removed by techniques well-known in the art, for example, by evaporation, distillation, or agitated thin film drying. In some embodiments, the solvent is removed by distillation. Within the context of this embodiment, removal of the solvent may result in formation of a solid.

According to the present embodiment, a non-polar solvent may then be added. Examples of suitable non-polar solvents include ethereal solvents, non-polar hydrocarbon solvents, and mixtures thereof. Within the context of this embodiment, addition of a non-polar solvent may result in a suspension of the premix of amorphous apremilast in the solvent. In some embodiments, addition of the non-polar solvent may facilitate subsequent steps in the preparation of the premix of amorphous apremilast, for example, the isolation step.

Examples of suitable non-polar hydrocarbon solvents include heptane, hexane, and mixtures thereof. Examples of suitable ethereal solvents include 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof. In some embodiments, methyl tert-butyl ether is used as a non-polar solvent.

Next, a premix of amorphous apremilast may be isolated, for example, by filtering the solution to obtain a solid. The solid may then be dried under vacuum to get amorphous apremilast.

Within the context of the present disclosure, a premix of apremilast, when prepared by methods disclosed herein, may exhibit long-term physical and chemical stability. As an example, Table 2 below is data collected on a premix of apremilast with PLASDONE S-630 prepared according to the processes disclosed in the present disclosure. According to data collected, each premix of amorphous apremilast is no significant degradation or change in PXRD pattern (e.g., is stable at 15 days, 1, 2, 3, and 6 months) when stored at 5 ± 3 °C and at 25 °C/60%, 40 °C/75% RH relative humidity (RH).

TABLE 2

Another aspect of the present invention encompasses novel crystalline forms of apremilast and processes for the preparation of the same. One embodiment of the present invention provides a process for the preparation of an anisole solvate of apremilast, which may be carried out by the following steps:

a) dissolving apremilast in anisole;

b) adding a solvent; and

c) isolating an anisole solvate of apremilast.

According to the present embodiment, apremilast may first be dissolved in anisole. Within the context of this embodiment, the apremilast starting material may be of a variety of different forms, for example, any polymorph or any solvated form. Next, a solvent may be added. The solvent may be, for example, isopropanol, heptane, hexane, methyl tert-butyl ether, ethyl tert- butyl ether, diisopropyl ether, or mixtures thereof. In some embodiments, n-heptane, isopropanol, or methyl tert-butyl ether is used as the solvent. Within the context of the present embodiment, addition of the solvent may cause precipitation of a solid.

Next, an anisole solvate of apremilast may be isolated, for example, by filtering the solution to isolate the solid. The solid may then be dried under vacuum to get an anisole solvate of apremilast. It is believed that the anisole form of apremilast formed by this embodiment is a hemisolvate.

Another embodiment of the present invention provides a process for the preparation of an anisole solvate of apremilast, which may be carried out by the following steps:

a) dissolving apremilast in anisole;

b) adding the solution to a solvent; and

c) isolating an anisole solvate of apremilast.

According to the present embodiment, apremilast may first be dissolved in anisole. Within the context of this embodiment, the apremilast starting material may be of a variety of different forms, for example, any polymorph or any solvated form. Next, a solvent may be added. The solvent may be, for example, isopropanol, heptane, hexane, methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, or mixtures thereof. Within the context of the present embodiment, the solvent may act as an anti-solvent such that its addition causes precipitation of a solid.

Next, an anisole solvate of apremilast may be isolated, for example, by filtering the solution to get a solid. The solid may then be dried under vacuum to produce an anisole solvate of apremilast. It is believed that the anisole solvent of apremilast which is formed by this embodiment is a hemisolvate.

A further embodiment of the present invention provides a process for the preparation of an anisole solvate of apremilast, which may be carried out by the following steps:

a) dissolving apremilast in anisole to form a solution;

b) cooling the solution; and

c) isolating an anisole solvate of apremilast.

According to the present embodiment, apremilast may first be dissolved in anisole. Within the context of this embodiment, the apremilast starting material may be of a variety of different forms, for example, any polymorph or any solvated form. This step may be carried out at an elevated temperature, for example, at a temperature of about 90 °C to about 110 °C. In some embodiments, apremilast is dissolved in anisole at a temperature of about 100 ± 5 °C.

Next, the solution may be cooled. Within the context of this embodiment, the temperature may be decreased to about 20 °C to about 35 °C. In some embodiments, the solution is cooled to 25 ± 5 °C. In some embodiments, it may be particularly useful to stir the solution during cooling for an extended time, for example, from about 15 hours to about 20 hours.

Next, an anisole solvate of apremilast may be isolated, for example, by filtering the solution to get a solid. The solid may then be dried under vacuum to get an anisole solvate of apremilast. It is believed that the anisole solvent of apremilast which is formed by this embodiment is a hemisolvate.

One more embodiment of the present invention provides a process for the preparation of an anisole solvate of apremilast, which may be carried out by the following steps:

a) dissolving apremilast in anisole; and

b) isolating an anisole solvate of apremilast.

According to the present embodiment, apremilast may first be dissolved anisole to form a solution. Within the context of this embodiment, this step may occur at a temperature of about 20 °C to about 35 °C. In some embodiments, this step is carried out 25 ± 5 °C and the solution is stirred for about 15 hours to about 20 hours.

Next, an anisole solvate of apremilast may be isolated, for example, by filtering and drying under vacuum to get an anisole solvate of apremilast. It is believed that the anisole solvent of apremilast which is formed by this embodiment is a hemisolvate.

Another aspect of the present invention provides an anisole solvate of apremilast.

In addition to analysis by PXRD, the solvates disclosed herein may also be characterized by differential scanning calorimetry (DSC). DSC measurements were carried out on a TA Q1000 differential scanning calorimeter (TA Instruments). The 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.

The solvates of the present invention may also be characterized by thermogravimetric analysis (TGA) or differential thermal analysis (DTA). TGA/DTA was 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.

The solvates of the present invention may be further characterized by proton NMR. The 1H NMR data was measured on Bruker 300MHz Avance NMR spectrometer equipped with 5 mm BBI probe in DMSO-d6. The data was collected and processed by Topsin-NMR software.

Within the context of this embodiment, the anisole solvate of apremilast prepared by methods disclosed herein may be characterized by a PXRD pattern having significant peaks at 11.89, 16.30, 17.63, 22.34, 25.30, and 26.19 ± 0.2 °2Θ. The anisole solvate of apremilast may be further characterized by a PXRD pattern having significant peaks at 7.42, 11.25, 15.17, 16.30, 17.63, 20.13, 20.62, 21.32, 22.34, 23.34, 24.68, 25.30, 26.19, 27.40, and 28.86 ± 0.2 °2Θ. The anisole solvate of apremilast may be further characterized by a PXRD pattern as depicted in Figure 3.

The anisole solvate of apremilast may be further characterized by a ΧΗ NMR spectrum as depicted in Figure 4.

The anisole solvate of apremilast may be a hemi anisole solvate of apremilast

The anisole solvate of apremilast disclosed herein may, in some embodiments, exhibit long-term physical and chemical stability. As an example, Table 3 below is data collected on an anisole solvate of apremilast prepared by the processes disclosed herein. The an anisole solvate of apremilast tested is no significant degradation or change in PXRD pattern (e.g., is stable at 1, 2, 3 and 6 months storage) when stored at 5 ± 3 °C and at 25 °C/60%, 40 °C/75% relative humidity (RH).

TABLE 3


Another aspect of the present invention encompasses a methyl ethyl ketone solvate of apremilast and processes for the preparation thereof.

The present invention also provides a process for the preparation of a methyl ethyl ketone solvate of apremilast, which may include the following steps:

a) dissolving apremilast in methyl ethyl ketone to get a solution;

b) cooling the solution; and

c) isolating a methyl ethyl ketone solvate of apremilast.

According to the present embodiment, apremilast may first be dissolved in methyl ethyl ketone. This step may be carried out at an elevated temperature, for example, at about 70 °C to about 90 °C. In some embodiments, this step is carried out at about 75 to about 85 °C.

Next, the solution may be cooled to about 20 °C to about 35 °C. In some embodiments, the solution is cooled to about 25 °C to about 30 °C. Within the context of this embodiment, the solution may be further cooled to about -25 °C to about 5 °C. In some embodiments, the solution is further cooled to about -20 °C to about 0 °C. Within the context of this embodiment, cooling the solution may cause precipitation of a solid.

In some embodiments, the reaction temperature may be optionally raised to about to about 20 °C about 35 °C. In some embodiments, this optional increase in temperature may facilitate subsequent steps, such as isolating by filtration. In particularly useful embodiments, the temperature is raised to about 25 °C to about 30 °C. In some embodiments, the solution is also stirred during this step.

Next, a methyl ethyl ketone solvate of apremilast may be isolated. This may be carried out by methods well-known in the art, for example, by filtering the solution and drying the obtained solid to get a methyl ethyl ketone solvate of apremilast.

The present invention also encompasses a methyl ethyl ketone solvate of apremilast. The methyl ethyl ketone solvate of apremilast, prepared by methods disclosed herein, may be characterized by a PXRD pattern having significant peaks at 7.37, 11.12, 17.61, 22.38, 24.65, and 26.23 ± 0.2 °2Θ. The methyl ethyl ketone solvate of apremilast may be further characterized by a PXRD pattern having significant peaks at 7.37, 11.12, 13.90, 15.19, 16.28, 17.61, 19.27, 20.16, 21.26, 22.38, 23.36, 24.65, 25.36, 26.23, 27.41, and 28.85 ± 0.2 °2Θ.

The methyl ethyl ketone solvate of apremilast may be further characterized by a PXRD pattern as depicted in Figure 5.

The methyl ethyl ketone solvate of apremilast may be characterized by a DSC thermogram as depicted in Figure 6.

The methyl ethyl ketone solvate of apremilast may be characterized by a TGA/DTA thermal curve as depicted in Figure 7.

The methyl ethyl ketone solvate of apremilast may be further characterized by an NMR spectrum as shown in Figure 8.

Within the context of the present disclosure, the methyl ethyl ketone solvate of apremilast of the present disclosure may exhibit long-term physical and chemical stability. As an example, Table 4 below presents data collected on a methyl ethyl ketone solvate of apremilast prepared by the processes disclosed herein. The a methyl ethyl ketone solvate of apremilast tested is no significant degradation or change in PXRD pattern (e.g., is stable at 15 days, 2, 3 and 6 months storage) when stored at 5 ± 3 °C and at 25 °C/60%, relative humidity (RH).

TABLE 4

The amorphous apremilast and premixes thereof disclosed herein, as well as the solvates of apremilast disclosed herein may be useful in the treatment of individuals with severe plaque psoriasis who may be candidates for phototherapy or systemic therapy as well as individuals with psoriatic arthritis.

The amorphous apremilast and premixes disclosed herein may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. The solvates of apremilast, including the anisole solvate and methyl ethyl ketone solvent may also be incorporated into oral pharmaceutical dosage forms. The dosage form may include excipients, for example, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, iron oxide yellow, iron oxide black, 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.

Within the context of the present invention, dosage forms containing amorphous apremilast, premixes thereof, or solvates of apremilast may have between about 10 mg to about 30 mg per dose, including dosages of about 10 mg, 20 mg, and 30 mg.

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 apremilast

Apremilast (2 g) was dissolved in dichloromethane (30 mL) at 25 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 30-35 °C. To this, n-heptane (20 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered and washed with n-heptane (4 mL) to get amorphous apremilast.

Example 2: Preparation of amorphous apremilast

Apremilast (2 g) was dissolved in dichloromethane (30 mL) at 25 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 30-35 °C. To this, methyl tert-butyl ether (20 mL) at 25 ± 5 °C was added and stirred for 1 hour. The reaction mass was filtered and washed with methyl tert-butyl ether (4 mL) to get amorphous apremilast.

Example 3: Preparation of amorphous apremilast

Apremilast (2 g) was dissolved in dichloromethane (30 mL) at 25 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. To this, n-heptane (10 mL) was added and the clear solution was distilled completely under vacuum at 30-35 °C. To this, n-heptane (20 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered and washed with n-heptane (4 mL) to get amorphous apremilast.

Example 4: Preparation of amorphous apremilast

Apremilast (2 g) was dissolved in dichloromethane (30 mL) at 25 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. To this, n-heptane (10 mL) was added and the clear solution was distilled completely under vacuum at 30-35 °C. To this, methyl tert-butyl ether (20 mL) at 25 ± 5 °C was added and stirred for 1 hour. The reaction mass was filtered and washed with methyl tert-butyl ether (4 mL) to get amorphous apremilast.

Example 5: Preparation of amorphous apremilast

Apremilast (5 g) was dissolved in acetone (25 mL) at 55 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, n-heptane (25 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered and washed with n-heptane (5 mL) to get amorphous apremilast.

Example 6: Preparation of amorphous apremilast

Apremilast (0.5 g) was dissolved in n-propanol (6 mL) at 85-90 °C. The resulting clear solution was cooled to 25-30 °C and then to 0-5 °C. The reaction mass was stirred for 3 hours at 0-5 °C. The solid obtained was filtered, washed with chilled n-propanol (4 mL), and dried under vacuum at 40 °C for 15 hours to get amorphous apremilast.

Example 7: Preparation of amorphous apremilast

Apremilast (0.5 g) was dissolved in 2-methyl- 1 -propanol (15 mL) and ethanol (5 mL) at 85-90 °C. The resulting clear solution was cooled to 25-30 °C and then to 0-5 °C. The reaction mass was stirred for 3 hours at 0-5 °C. The solid obtained was filtered and dried under vacuum at 40 °C for 15 hours to get amorphous apremilast.

Example 8: Preparation of amorphous apremilast

Apremilast (1 g) was dissolved in methanol (40 mL) at 62 ± 3 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (10 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get amorphous apremilast.

Example 9: Preparation of a pre mix of amorphous apremilast

Apremilast (4 g) and PLASDONE S-630 (0.444 g) were dissolved in acetone (20 mL) at 55 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (20 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get a premix of amorphous apremilast.

Example 10: Preparation of a premix of amorphous apremilast

Apremilast (4 g) and PLASDONE S-630 (1.333 g) were dissolved in acetone (20 mL) at 55 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (20 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get a premix of amorphous apremilast.

Example 11: Preparation of a premix of amorphous apremilast

Apremilast (3 g) and PLASDONE S-630 (3 g) were dissolved in acetone (20 mL) at 55 ± 5 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (20 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get a premix of amorphous apremilast.

Example 12: Preparation of premix of amorphous apremilast

Apremilast (1 g) and PLASDONE S-630 (0.111 g) were dissolved in methanol (40 mL) at 62 ± 3 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (5 mL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get a premix of amorphous apremilast.

Example 13: Preparation of premix of amorphous apremilast

Apremilast (1 g) and PLASDONE S-630 (0.333g) were dissolved in methanol (40 mL) at 62 ± 3 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (lOmL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get a premix of amorphous apremilast.

Example 14: Preparation of premix of amorphous apremilast

Apremilast (1 g) and PLASDONE S-630 (1 g) were dissolved in methanol (40 mL) at 62 ± 3 °C. The resulting clear solution was filtered through HYFLO to remove any undissolved particulate. The clear solution was distilled completely under vacuum at 40-45 °C. To this, methyl tert-butyl ether (lOmL) was added at 25 ± 5 °C and stirred for 1 hour. The reaction mass was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get a premix of amorphous apremilast.

Examplel5: Preparation of an anisole solvate of apremilast

Apremilast (0.5 g) was dissolved in anisole (5 mL) at 100 ± 5 °C. The resulting clear solution was cooled to 70 ± 5 °C and n-heptane (15 mL) was added. The reaction mass was stirred for 1 hour at 70 ± 5 °C, cooled to 10 ± 5 °C and stirred for 15 hours. The solid obtained was filtered, washed with n-heptane (5 mL), and dried under vacuum to get an anisole solvate of apremilast.

Example 16: Preparation of an anisole solvate of apremilast

Apremilast (0.3 g) was dissolved in anisole (5 mL) at 110 ± 5 °C. The resulting clear solution was cooled to 25 ± 5 °C and added to methyl tert-butyl ether (10 mL) at 25 ± 5 °C. The reaction mass was stirred for 5 hours. The solid obtained was filtered, washed with methyl tert-butyl ether (5 mL), and dried under vacuum to get an anisole solvate of apremilast.

Example 17: Preparation of an anisole solvate of apremilast

Apremilast (0.3 g) was dissolved in anisole (5 mL) at 110 ± 5 °C. The resulting clear solution was cooled to 25 ± 5 °C and added to isopropanol (10 mL) at 25 ± 5 °C. The reaction mass was stirred for 5 hours. The solid obtained was filtered and dried under vacuum to get an anisole solvate of apremilast.

Example 18: Preparation of an anisole solvate of apremilast

Apremilast (5 g) was dissolved in anisole (80 mL) at 110 ± 5 °C. The resulting clear solution was cooled to 70 ± 5 °C and n-heptane (100 mL) was added. The reaction mass was cooled to 25 ± 5 °C and stirred for 15 hours. The solid obtained was filtered, washed with n-heptane (10 mL), and dried under vacuum at 40 °C for 18 hours to get an anisole solvate of apremilast.

Example 19: Preparation of an anisole solvate of apremilast

Apremilast (1 g) was dissolved in anisole (16 mL) at 100 ± 5 °C. The resulting clear solution was cooled to 25 ± 5 °C and stirred for 15 hours. The solid obtained was filtered, dried under vacuum to get an anisole solvate of apremilast.

Example 20: Preparation of a methyl ethyl ketone solvate of apremilast

Apremilast (5 g) was dissolved in methyl ethyl ketone (25 mL) at 80 ± 5 °C. The resulting clear solution was filtered to remove undissolved particulate and cooled to 27 ± 2 °C. The solution was further cooled to -20 °C and maintained under stirring for 5-6 hours. The temperature of the reaction mass was raised to 27 ± 2 °C and maintained under stirring for 1-2 hours. The resulting solid was filtered and dried under vacuum at 40 °C for 15 hours to get a methyl ethyl ketone solvate of apremilast.

Example 21: Preparation of a methyl ethyl ketone solvate of apremilast

Apremilast (1 g) was dissolved in methyl ethyl ketone (5 mL) at 80 ± 5 °C. The resulting clear solution was filtered to remove undissolved particulate and cooled to 27 ± 2 °C. The solution was further cooled to -10 °C and maintained under stirring for 15 hours. The temperature of the reaction mass was raised to 27 ± 2 °C and maintained under stirring for 1-2 hours. The resulting solid was filtered, and dried under vacuum at 40 °C for 15 hours to get a methyl ethyl ketone solvate of apremilast.

Example 22: Preparation of a methyl ethyl ketone solvate of apremilast

Apremilast (1 g) was dissolved in methyl ethyl ketone (5 mL) at 80 ± 5 °C. The resulting clear solution was filtered to remove undissolved particulate and cooled to 27 ± 2 °C. The solution was further cooled to 0 °C and maintained under stirring for 15 hours. The temperature of the reaction mass was raised to 27 ± 2 and maintained under stirring for 1-2 hours. The resulting solid was filtered and dried under vacuum at 40 °C for 15 hours to get a methyl ethyl ketone solvate of apremilast.

Example 23: Preparation of a methyl ethyl ketone solvate of apremilast

Apremilast (1 g) was dissolved in methyl ethyl ketone (5 mL) at 80 ± 5 °C. The resulting clear solution was filtered to remove undissolved particulate and cooled to 27 ± 2 °C. The solution was maintained under stirring at 27 ± 2 °C for 15 hours. The resulting solid was filtered and dried under vacuum at 40 °C for 15 hours to get a methyl ethyl ketone solvate of apremilast.