WO2016088074A1

WO2016088074A1 - Process for the preparation of amorphous ibrutinib

Info

Publication number: WO2016088074A1
Application number: PCT/IB2015/059321
Authority: WO
Inventors: Vishweshwar Peddy; Dharma Jagannadha Rao Velaga; Srinivas RANGINENI
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2014-12-03
Filing date: 2015-12-03
Publication date: 2016-06-09

Abstract

Process for the preparation of amorphous Ibrutinib and solid dispersions of Ibrutinib.

Description

PROCESS FOR THE PREPARATION OF AMORPHOUS IBRUTINIB

INTRODUCTION

The present invention provides process for the preparation of amorphous Ibrutinib and amorphous solid dispersion of Ibrutinib.

BACKGROUND OF THE INVENTION

The drug compound having the adopted name "Ibrutinib" has a chemical name I- ((fl)-3-(4-amino-3-(4^henoxyphenyl)-l/-/^yrazo^^

2-en-l-one, and is structurally represented below.

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) and is approved in US for the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy.

US patent 7,514,444 discloses process for the preparation of Ibrutinib. US '444 discloses isolation of Ibrutinib by flash chromatography using dichloromethane and methanol as eluents.

WO 2013/184572A1 application discloses crystalline, solvates and amorphous form of Ibrutinib. In particular, the application discloses polymorphic Forms A, B, C, D, E and F characterized by PXRD, IR, DSC and TGA. WO '572 application discloses process for the preparation of amorphous form of Ibrutinib by dissolving Form A in dichloromethane. The solvent dichloromethane was removed under rotary evaporation to provide amorphous Ibrutinib.

CN103694241 A discloses crystal form A of Ibrutinib characterized by PXRD.

CN103923084A discloses crystal forms II, III, IV, V, VI, VII and VIII of Ibrutinib, characterized by PXRD pattern.

A single compound may give rise to a variety of solids having distinct physical properties. The variation in the physical properties frequently results in differences in bioavailability, stability, etc. Since polymorphic forms can vary in their physical properties, regulatory authorities require that efforts be made to identify all polymorphic forms, e.g., crystalline, amorphous, and pseudo polymorphic forms, e.g. solvates, etc., of new drug substances.

Some polymorphs of drug substances suffer from the drawbacks of conversion to other crystalline forms on storage resulting in concomitant change, not only in the physical form and shape of the drug crystals, but also the associated changes in distinct physical properties. Generally, the molecules will revert to a more thermodynamically stable form, often a form with lower solubility. Such a thermodynamically stable form may sometimes result in a reduced or suboptimal bioavailability, especially for oral administration.

Towards this end, it has been the endeavor of pharmaceutical scientists to provide enriched, substantially pure or pure amorphous or amorphous solid dispersion (with pharmaceutically acceptable carriers) of the drug substances, more specifically, thermodynamically stable forms of drug substances, which would have the strengths of the crystalline forms, viz. thermodynamic stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.

There remains a continuing need, not only for the amorphous form of Ibrutinib or its solid dispersion that are stable, but also for the process of preparation, which are amenable to scale up for the larger production quantities and may yield both formulation and therapeutic benefits. SUMMARY

In a first aspect, the present invention provides a process for the preparation of amorphous form of Ibrutinib, comprising: a) providing a solution of ibrutinib in a solvent; and b) isolating amorphous form of Ibrutinib.

In a second aspect, the present invention provides amorphous solid dispersion comprising Ibrutinib, together with one or more pharmaceutically acceptable carriers.

In a third aspect, the present invention provides a process for preparing a solid dispersion of amorphous Ibrutinib together with one or more pharmaceutically acceptable carriers, comprising: a) providing a solution of Ibrutinib in combination with one or more pharmaceutically acceptable carriers, in a suitable solvent or mixture of solvents; and b) isolating amorphous solid dispersion comprising Ibrutinib and one or more pharmaceutically acceptable carriers.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates the PXRD pattern of amorphous Ibrutinib, obtained by the procedure of Example 1 .

Fig. 2 illustrates the PXRD pattern of amorphous solid dispersion of Ibrutinib with PVP- K30, obtained by the procedure of Example 2.

Fig. 3 illustrates the PXRD pattern of amorphous solid dispersion of Ibrutinib with HPC, obtained by the procedure of Example 3.

Fig. 4 illustrates the PXRD pattern of amorphous solid dispersion of Ibrutinib with HPMC, obtained by the procedure of Example 4.

Fig. 5 illustrates the PXRD pattern of amorphous Ibrutinib, obtained by the procedure of Example 5 Fig. 6 illustrates the PXRD pattern of amorphous Ibrutinib, obtained by the procedure of Example 6

DETAILED DESCRIPTION

In a first aspect, the present invention provides a process for the preparation of amorphous form of Ibrutinib, comprising: a) providing a solution of Ibrutinib in a solvent; and b) isolating amorphous form of Ibrutinib. Providing a solution of Ibrutinib in step a) includes: i) direct use of a reaction mixture containing Ibrutinib that is obtained in the course of its synthesis; or ii) dissolving Ibrutinib in a solvent.

Any physical form of Ibrutinib may be utilized for providing the solution of Ibrutinib in step a). The dissolution temperatures may range from about 0 °C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of Ibrutinib is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization. In embodiments, Ibrutinib can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol, or C1 -C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; or any mixtures of two or more solvents thereof.

The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of ibrutinib in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.

Step b) involves isolating amorphous form of ibrutinib from the solution obtained in step a). Isolation of amorphous form of ibrutinib in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin- film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous form of ibrutinib as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120 °C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

Isolation of amorphous ibrutinib may be effected by combining a suitable anti- solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which ibrutinib is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, Ci to Ci₀ hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.

The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Ibrutinib is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In a third aspect, the present invention provides a process for preparing a solid dispersion of amorphous ibrutinib together with one or more pharmaceutically acceptable carriers, comprising: a) providing a solution of ibrutinib in combination with one or more pharmaceutically acceptable carrier, in a suitable solvent or mixture of solvents; b) isolating amorphous solid dispersion comprising Ibrutinib and one or more pharmaceutically acceptable carriers.

Step a) involves providing a solution of ibrutinib in combination with at least one pharmaceutically acceptable carrier, in a suitable solvent or mixture of solvents;

Step a) may involve forming a solution of ibrutinib together with one or more pharmaceutically acceptable carriers. In embodiments, a carrier enhances stability of the amorphous solid upon removal of solvent.

Providing the solution in step a) includes: i) direct use of a reaction mixture containing ibrutinib that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or ii) dissolution of ibrutinib in a suitable solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.

Any physical form of ibrutinib, such as crystalline, amorphous or their mixtures may be utilized for providing a solution in step a).

Pharmaceutically acceptable carriers that may be used in step a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropylcelluloses(HPC), hydroxymethylcelluloses, hydroxyethylcellulose, hydroxyethylmethylcellulose(HEMC), carboxymethylcellulose(CMC), carboxymethyl hydroxyethylcellulose(CMHEC), hydroxyethylcarboxymethyl cellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropyl methylcelluloses (HPMC), hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

Ibrutinib and the pharmaceutically acceptable carrier may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein includes ibrutinib and the carrier present in weight ratios ranging from about 5:95 to about 95:5. An example of a ratio is about 50:50.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of ibrutinib is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Suitable solvents that may be used in step a) include but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 2-nitroethanol, 2- fluoroethanol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, or C1 -C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; or any mixtures of two or more solvents thereof.

Step b) involves isolating a solid dispersion of amorphous ibrutinib together with one or more pharmaceutically acceptable carriers. Isolation of solid dispersion of amorphous form of ibrutinib in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous form of ibrutinib as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.

In one embodiment, the present invention provides pharmaceutical composition comprising amorphous form of ibrutinib or amorphous solid dispersion of ibrutinib and at least one pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include, but are not limited to, suitable surface modifiers. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants.

Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES

Example 1 : Preparation of amorphous ibrutinib

0.5 g of ibrutinib and 15 mL of methanol were charged into a round bottom flask at 25 °C. The contents were heated to 55-60 °C and filtered. The filtrate was distilled under reduced pressure at 56 °C in rotavapor. The distilled product was dried in rotavapor flask at 56 °C for 90 minutes to afford the title compound.

Example 2: Preparation of solid dispersion of Ibrutinib

0.5 g of ibrutinib and 15 mL of methanol were charged into a round bottom flask at 25 °C. The contents were heated to 55-60 °C and filtered. PVP K-30 (0.5 g) was added to the filtrate and the contents were distilled under reduced pressure at 58 °C. The distilled product was dried in the rotavapor at 58 °C for 90 minutes to afford the title compound.

Example 3: Preparation of solid dispersion of Ibrutinib

0.5 g of ibrutinib and 15 mL of methanol were charged into a round bottom flask at 25 °C. The contents were heated to 55-60 °C and filtered. HPC (0.5 g) was added to the filtrate and the contents were distilled under reduced pressure at 58 °C. The distilled product was dried at 58 °C for 75 minutes to afford the title compound.

Example 4: Preparation of solid dispersion of Ibrutinib

0.5 g of ibrutinib and 15 mL of methanol were charged into a round bottom flask at 25 °C. The contents were heated to 55-60 °C and filtered. HPMC (0.5 g) was added to the filtrate and the contents were distilled under reduced pressure at 58 °C in rotavapor. The distilled product was dried at 58 °C to afford the title compound.

Example 5: Preparation of amorphous Ibrutinib

0.5 g of ibrutinib and 2 mL of N, N-dimethyl formamide were charged into a round bottom flask at 25-30 °C. In another flask, 30 mL of demineralized water was taken and cooled to 5-10 °C. To this cooled flask, the above prepared ibrutinib solution was added and maintained for 10-15 minutes. The contents were filtered and washed with 10 mL of demineralized water. The obtained material was sucked dried for 10-15 minutes and dried in vacuum tray drier at 45-55 °C to obtain the title compound. Example 6: Preparation of amorphous Ibrutinib

0.5 g of ibrutinib and 2 mL of dimethyl sulfoxide were charged into a round bottom flask at 25-30 °C. In another flask, 30 mL of demineralized water was taken and cooled to 5- 10 °C. To this cooled flask, the above prepared ibrutinib solution was added and maintained for 10-15 minutes. The contents were filtered and washed with 10 mL of demineralized water. The obtained material was sucked dried for 10-15 minutes and dried in vacuum tray drier at 45-55 °C to obtain the title compound.

Claims

Claims:

1 . A process for the preparation of amorphous form of Ibrutinib, comprising the steps of:

a) providing a solution of Ibrutinib in Ci-₆ alcohol; and

b) isolating amorphous form of Ibrutinib.

2. The process according to claim 1 , wherein the Ci-₆ alcohol is selected from methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2- butanol, iso-butyl alcohol and t-butyl alcohol.

3. A process of claim 1 or 2, wherein isolating amorphous form of ibrutinib is by solvent evaporation technique.

4. A process of claim 3, wherein solvent evaporation technique such as distillation using a rotational evaporator, freeze drying (lyophilization), spray drying and agitated thin film drying (ATFD) are used.

5. An amorphous solid dispersion comprising ibrutinib and one or more pharmaceutically acceptable carriers.

6. The amorphous solid dispersion according to claim 5, wherein pharmaceutically acceptable carriers are selected from polyvinylpyrrolidones (PVP) methylcellulose, ethylcellulose, propylcellulose, hydroxy methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose (HEMC) hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose(CMHEC), hydroxyethyl carboxy methyl cellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP),hydroxypropylmethylcelluloseacetate(HPMCA), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or mixtures thereof.

7. The amorphous solid dispersion according to claim 5, wherein the ratio of ibrutinib and pharmaceutically acceptable carrier is from 5:95 to 95:5 (w/w).

8. The amorphous solid dispersion according to claim 5, wherein the ratio of ibrutinib and pharmaceutically acceptable carrier is 50:50 (w/w)

9. A process for the preparation of amorphous solid dispersion of ibrutinib comprising the steps of: a) providing a solution of ibrutinib in combination with one or more pharmaceutically acceptable carrier in Ci-₆ alcohol ;

b) isolating amorphous solid dispersion comprising Ibrutinib and one or more pharmaceutically acceptable carriers.

10. The process according to claim 9, wherein pharmaceutically acceptable carriers are selected from polyvinylpyrrolidones (PVP), methylcellulose, ethylcellulose, propylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxy propyl cellulose, hydroxyethylmethylcellulose(HEMC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose(CMC), carboxymethylhydroxyethylcellulose (CMHEC),hydroxyethylcarboxymethylcellulose(HECMC), sodium carboxymethyl cellulose, cellulose acetate phthalate(CAP), hydroxypropyl methyl cellulose acetate(HPMCA), hydroxypropylmethylcellulose phthalate(HPMCP), hydroxy propyl methylcellulose acetate succinate (HPMCAS) or mixtures thereof.

1 1 . The process according to claim 9, wherein the Ci-₆ alcohol is selected from methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2- butanol, iso-butyl alcohol and t-butyl alcohol.

12. A process for the preparation of amorphous form of Ibrutinib, comprising the steps of:

a) providing a solution of Ibrutinib in polar aprotic solvent;

b) combining the ibrutinib solution with an antisolvent; and

c) isolating amorphous form of Ibrutinib.

13. The process according to claim 1 2, wherein the polar aprotic solvent is selected from N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethylsulfoxide.

14. The process of claim 12 wherein, the antisolvent is selected from CM O hydrocarbons or water.