WO2019195827A1

WO2019195827A1 - Novel form of ibrutinib

Info

Publication number: WO2019195827A1
Application number: PCT/US2019/026299
Authority: WO
Inventors: Padmini Kavuru
Original assignee: Johnson Matthey Public Limited Company
Priority date: 2018-04-06
Filing date: 2019-04-08
Publication date: 2019-10-10

Abstract

The present invention is directed to a crystalline form of ibrutinib, designated herein as Form Z. The present invention is further directed to processes for the preparation of Form Z. The present invention also is directed to pharmaceutical compositions comprising Form Z, and a method for treating disease using Form Z.

Description

NOVEL FORM OF IBRUTINIB

FIELD OF THE DISCLOSURE

The present disclosure relates to a novel form of ibrutinib and processes for the preparation of the form. The present disclosure also relates to pharmaceutical compositions comprising the novel form of ibrutinib and methods for treating disease using the form.

BACKGROUND OF THE DISCLOSURE

Ibrutinib, having the chemical designation l-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one, is an orally bioavailable inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Ibrutinib has the following structure:

Ibrutinib is commercially marketed under the name IMBRUVICA® and is indicated for the treatment of patients with mantel cell lymphoma who have received at least one prior therapy. IMBRUVICA® is also indicated for the treatment of patients with chronic lymphocytic leukemia and Waldenstrom’ s macroglobulinemia.

Forms of ibrutinib are described in United States Patents 9296753 (Forms A-F), 9751889 (Form I), 9884869 (amorphous form, and Forms III-IX), and 9725455 (Forms A-F), United States Patent Applications 20140336203 (Forms A-F), 20160361313 (amorphous form), 20170079981 (dispersion), 20170226114 (Forms G, J, and K), 20170305919 (Forms A-F), 20180028537 (dispersion), and 20180051026 Forms Dl-Dla, D2-D2a, and D3-D13, and, PCT publications W02016/088074 (amorphous form), WO2016/150349 (amorphous form),

WO2016/156127 (co-crystal), W02016/160604 (co-crystal), WO2016/207172 (amorphous), WO2017/029586 (Forms S1-S4, and amorphous form), WO2017/085628 (amorphous form),

WO2017/137446 (amorphous form), WO2017/174044 (Form C), and W02018/000250 (Form III), European Patent EP3243824 Forms a, b, g, d, e and z) and Chinese Publication Nos.

CN103121999, CN 103694241 (Form A solvate), CN 103923084 (II- VIII), and C 104327085 Form A’.

None of the aforesaid references disclose Form Z of ibrutinib

SUMMARY OF THE DISCLOSURE

BRIEF DESCRIPTION OF THE DRAWINGS

Figure I is directed to X-ray Powder Diffraction (“XRPD”) patterns of four batches Form Z of ibrutinib that are prepared according to Examples 2-5. Figure II is a representative Differential Scanning Calorimetry (“DSC”) plot of Form Z and Form A as disclosed in US Patent Application 20170305919.

Figure III is a representative ¾-NME plot of Form Z.

Figure IV(a) and IV(b) are representative respectively of HPLCs of the precipitate and filtrate from an example according to the invention.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure is directed to a novel crystalline form of ibrutinib, designated herein as Form Z; pharmaceutical compositions comprising the form, process for its preparation, and its use for treating a patient with a physiological condition in need of treatment, as herein described in detail.

As used herein and unless otherwise specified, the terms“about” and“approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, e.g., that describing a DSC or TGA thermal event, including, e.g., melting, dehydration, desolvation or glass transition events; a mass change, such as, e.g., a mass change as a function of temperature or humidity; a solvent or water content, in terms of, e.g., mass or a percentage; or a peak position, such as, e.g., in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form.

As used herein and unless otherwise specified, the term“pharmaceutical composition” is intended to encompass the a pharmaceutically effective amount of the amorphous ibrutinib and pharmaceutically acceptable excipient. As used herein, the term“pharmaceutical compositions” includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

As used herein and unless otherwise specified, the term“crystalline” and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, mean that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 2lst edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

As used herein and unless otherwise specified, the term“excipient” refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for the purpose of bulking-up formulations that contain potent active ingredients (thus often referred to as "bulking agents," "fillers," or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life.

As used herein and unless otherwise specified, the term“patient” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Further, a patient may not have exhibited any symptoms of the disorder, disease or condition to be treated and/prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition. As used herein and unless otherwise specified, the terms“polymorph,”“polymorphic form” or related term herein, refer to a crystal form of a molecule, or salt thereof that can exist in two or more forms, as a result different arrangements or conformations of the molecule or salt thereof ions in the crystal lattice of the polymorph.

As used herein and unless otherwise specified, the terms "substantially" or "substantially free/pure" with respect to a polymorph or polymorphic form means that the form contains about less than 30 percent, about less than 20 percent, about less than 15 percent, about less than 10 percent, about less than 5 percent, or about less than 1 percent by weight of impurities.

Impurities may, for example, include other polymorphic forms, water and solvents other than that in the crystalline polymorphic form. As used herein and unless otherwise specified, the terms“treat,”“treating” and

“treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agents, after the onset of symptoms of the particular disease. Ibrutinib is indicated for the treatment of patients with mantel cell lymphoma who have received at least one prior therapy. Ibrutinib is also indicated for the treatment of patients with chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia. IMBRUVICA® is available as 140 mg capsules. The recommended dose of IMBRUVIC A® for mantle cell lymphoma is 560 mg (four 140 mg capsules), orally, once daily. The recommended dose in patients with chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia is 420 mg (three 140 mg capsules), orally, once daily. It is therefore an object of the present disclosure to provide an anhydrous form of ibrutinib that is substantially pure, stable and scalable. It is also an object of the present disclosure to provide an anhydrous form of ibrutinib that is capable of being isolated and handled. It is further an object of the present disclosure to provide a process for the preparation of such anhydrous form of ibrutinib. It is yet another object of the present disclosure to provide a method of use of such anhydrous form of ibrutinib to prepare a pharmaceutical dosage form of ibrutinib.

Form Z is an anhydrous, unique crystalline phase. Form Z is a white solid material.

In one embodiment, crude ibrutinib and isonicotinamide are dissolved in methanol at about 50 °C. Tert-butyl methyl ether is added to the solution. The solution is stirred for about 18- 20 hours at about 5 °C. The solution becomes a slurry that is filtered and dried in the oven under vacuum at about 45 °C to yield Form Z.

In another embodiment, crude ibrutinib and isonicotinamide are dissolved in methanol at about 60 °C. The solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with tert-butyl methyl ether, and then dried in the oven under vacuum at about 45 °C to yield Form Z.

In yet another embodiment, crude ibrutinib and isonicotinamide are dissolved in methanol at about 60 °C. Tert-butyl methyl ether is added to the solution. The solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with tert-butyl methyl ether, and then dried in the oven under vacuum at about 45 °C to yield Form Z. The present disclosure also encompasses pharmaceutical compositions comprising Form

Z. Pharmaceutical compositions containing forms ibrutinib may be prepared according to International Publication Nos. WO2009/147238 and WO2011/003853. The present disclosure provides for a method of treating disease by administering to a patient, in need thereof, pharmaceutical compositions comprising Form Z. Ibrutinib is indicated for the treatment of patients with mantel cell lymphoma who have received at least one prior therapy. Ibrutinib is also indicated for the treatment of patients with chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia.

The dosage of the pharmaceutical compositions may be varied over a wide range.

Optimal dosages and dosage regimens to be administered may be readily determined by those skilled in the art, and will vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient’s sex, age, weight, diet, physical activity, time of administration and concomitant diseases, will result in the need to adjust dosages and/or regimens. Ibrutinib, marketed under the name IMBRUVICA®, is available as 140 mg capsules. The recommended dose of IMBRUVICA® for mantle cell lymphoma is 560 mg (four 140 mg capsules), orally, once daily. The recommended dose in patients with chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia is 420 mg (three 140 mg capsules), orally, once daily.

EXAMPLES

Examples 1-6, which follow herein, provide embodiments of the preparation of Form Z. The Examples are presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are illustrative of the present disclosure and the disclosure is not intended to be limited to the examples described herein and shown. Examples

Analytical Techniques

DSC data are collected using a TA Instruments Q10 DSC. Approximately, samples (2-8 mg) are placed in unsealed but covered hermetic alodined aluminum sample pans and scanned from about 30 to about 300 °C at a rate of about 10 °C/min under a nitrogen purge of about 50 mL/min.

XRPD patterns are obtained using a Bruker D8 Advance equipped with a Cu Ka radiation source (l=1.54 A), a 9-position sample holder and a LYNXEYE super speed detector. Samples are placed on zero-background, silicon plate holders for analysis. One skilled in the art would recognize that the °20 values and the relative intensity values are generated by performing a peak search on the measured data and the r -spacing values are calculated by the instrument from the °20 values using Bragg’s equation. One skilled in the art would further recognize that the relative intensity for the measured peaks may vary as a result of sample preparation, orientation and instrument used, for example. 1H-NMR data are collected using a Bruker Avance 300 MHz NMR equipped with

TopSpin software. Samples are prepared by dissolving the compound in deuterated

dimethylsulfoxide with 0.05% (v/v) tetramethylsilane (TMS). Spectra are collected at ambient temperature.

HPLC

Example 1

Preparation of Form Z

About 100 mg of crude ibrutinib and about 28 mg of isonicotinamide are dissolved in about 0.5 mL of methanol at about 50 °C. About 2.5 mL of tert-butyl methyl ether is added to the solution. A white precipitate is observed after about 2 hours. The slurry is stirred for about 18-20 hours at about 5 °C. The resulting material is filtered and dried under vacuum at about 45 °C.

The dried product is analyzed and identified as Form Z. The isolated Form Z is about 99.6% pure.

Form Z is characterized by its XRPD pattern peaks and/or rZ-spacing values. An average of the XRPD pattern peaks and <7-spacing values for Form Z are listed in Table 1 below. FIG. 1 is a representative XPRD pattern for a representative sample of Form Z made according to Example 1.

Table 1 - Average Peak List for Form Z diffractogram

The angle measurements are ± 0.2° 2Q. Key defining peaks for solid-state Form Z of variable methanol solvate of ABC include 6.7 and 18.0, and 15.5° 2Q.

A DSC thermogram of Form Z made according to Example 2 (compared with Pattern A), FIG. 2, shows a thermal event at about 154.98 °C. FIG. 3 is a representative Proton Nuclear Magnetic Resonance ('H-NMR) plot of Form Z made according to Example 1.

Example 2

Preparation of Form Z

About 400 mg of crude ibrutinib and about 120 mg of isonicotinamide are dissolved in about 2.4 mL of methanol at about 60 °C. The clear solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with about 4 mL tert-butyl methyl ether, and dried under vacuum at about 45 °C. The dried product is analyzed and identified as Form Z.

Example 3

Preparation of Form Z About 1000 mg of crude ibrutinib and about 280 mg of isonicotinamide are dissolved in about 3 mL of methanol at about 60 °C. About 3 mL of tert-butyl methyl ether is added slowly. The clear solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with about 4 mL tert-butyl methyl ether, and dried under vacuum at about 45 °C. The dried product is analyzed and identified as Form Z. Example 4

Preparation of Form Z

About 1000 mg of crude ibrutinib and about 280 mg of isonicotinamide are dissolved in about 5 mL of methanol at about 60 °C. The clear solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with about 4 mL tert-butyl methyl ether, and dried under vacuum at about 45 °C. The dried product is analyzed and identified as Form Z. Example 5

Preparation of Form Z

About 630 mg of crude ibrutinib and about 280 mg of isonicotinamide are dissolved in about 2 mL of methanol at about 60 °C. About 2 mL of tert-butyl methyl ether is added slowly. The clear solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with about 4 mL tert-butyl methyl ether, and dried under vacuum at about 45 °C. The dried product is analyzed and identified as Form Z.

Example 6

Preparation of Form Z About 630 mg of crude ibrutinib and about 176 mg of isonicotinamide are dissolved in about 3 mL of methanol at about 60 °C. The clear solution is stirred for about 18-20 hours at about 5 °C. The slurry is filtered, washed with about 4 mL tert-butyl methyl ether, and dried under vacuum at about 45 °C. The dried product is analyzed and identified as Form Z.

The above examples are set forth to aid in the understanding of the disclosure, and are not intended and should not be construed to limit in any way the disclosure set forth in the claims which follow hereafter.

Claims

Claimed:

1. F orm Z of ibrutinib .

2. Form Z, according to claim 1, which is anhydrous.

3. Form Z, according to claim 2, which is characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 6.7, 18.0, and 15.5° 2Q.

4. Form Z, according to claim 2, wherein Form Z is characterized by a thermal event at about 155.0°C, as measured by differential scanning calorimetry.

5. A pharmaceutical composition comprising a pharmaceutically effective amount of Form Z according to claim 1 and pharmaceutically acceptable excipient.

6. A method of treating disease in a patient comprising administering a pharmaceutical formulation according to claim 5 to a patient in need thereof.

7. A method of treating disease according to claim 6, wherein the disease is chronic

lymphocytic leukemia, Waldenstrom's macroglobulinemia, mantle cell lymphoma or marginal zone lymphoma.

8. A process for the preparation of Form Z, according to claim 1, comprising:

(a) dissolving ibrutinib and isonicotinamide in warm methanol to form an

ibrutinib methanol solution;

(b) adding tert-butyl methyl ether to the ibrutinib methanol solution;

(c) stirring the ibrutinib methanol solution for about 18-20 hours with cooling to form a slurry of ibrutinib in the methanol solution;

(d) filtering the slurry of ibrutinib in the methanol solution to yield a precipitate; and

(e) drying the precipitate under vacuum with warming to yield Form Z.

9. A process for the preparation of Form Z, according to claim 1, comprising:

(a) dissolving ibrutinib and isonicotinamide in methanol to yield an ibrutinib methanol solution;

(b) stirring the ibrutinib methanol solution for about 18-20 hours with cooling to form a slurry of ibrutinib in the methanol solution; (c) filtering the slurry of ibrutinib in the methanol solution to yield a precipitate; and;

(d) washing the precipitate with tert-butyl methyl ether; and

(e) drying the washed precipitate under vacuum with warming to yield Form Z.

10. A process for the preparation of Form Z, according to claim 1, comprising:

(a) dissolving ibrutinib and isonicotinamide in warm methanol to form an

ibrutinib methanol solution;

(b) adding tert-butyl methyl ether to the ibrutinib methanol solution;

(d) filtering the slurry of ibrutinib in the methanol solution to yield a precipitate; and;

(e) washing the precipitate with tert-butyl methyl ether; and

(f) drying the washed precipitate under vacuum with warming to yield Form Z.

11. The process according to claim 8, 9 or 10, wherein the step (a) is at about 50 °C to about 60 °C.

12. The process according to claim 8, 9 or 10, wherein the cooling is at about 5 °C.

13. The process according to claim 8, 9 or 10, wherein the drying is under vacuum.

14. The process according to claim 13, wherein the warming is at about 45 °C.