WO2016157136A1 - Crystalline forms of idelalisib - Google Patents

Crystalline forms of idelalisib Download PDF

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Publication number
WO2016157136A1
WO2016157136A1 PCT/IB2016/051865 IB2016051865W WO2016157136A1 WO 2016157136 A1 WO2016157136 A1 WO 2016157136A1 IB 2016051865 W IB2016051865 W IB 2016051865W WO 2016157136 A1 WO2016157136 A1 WO 2016157136A1
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Prior art keywords
idelalisib
crystalline
butyl ether
powder
ray diffraction
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PCT/IB2016/051865
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French (fr)
Inventor
Ramakoteswara Rao Jetti
Anjaneyaraju Indukuri
Amit Singh
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Mylan Laboratories Ltd
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Publication of WO2016157136A1 publication Critical patent/WO2016157136A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to novel crystalline forms of idelalisib designated as Form-Mi and Form-M2 and processes for the preparation thereof.
  • Idelalisib chemically known as 5-fluoro-3-phenyl-2-[(15)- l-(7H-purin-6- ylamino)propyl]-4(3H)-quinazolinone, is represented by Formula I below.
  • Idelalisib is marketed under the tradename ZYDELIG by Gilead Sciences, Inc.
  • ZYDELIG is indicated for the treatment of patients with chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities. It is also indicated for treating patients with relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies and patients with relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies.
  • Idelalisib is disclosed in U.S. Patent No. RE44638. This patent also discloses an ethanol solvate of idelalisib.
  • International Publication No. WO2013134288 discloses crystalline Forms-I, -II, -III, -IV, -V, -VI, and -VII of idelalisib.
  • International Publication No. WO2015014315 discloses Form- IX of idelalisib, which is a 0.7 hydrate form, as well as Forms -II, -III, -IV, and -VIII.
  • crystalline idelalisib Form-Ml may be characterized by a powder X-ray diffraction pattern with significant peaks at 7.45 and 20.23 + 0.2 °2 ⁇ .
  • crystalline idelalisib Form-Ml may be further characterized by a powder X-ray diffraction pattern with significant peaks at 9.6, 10.8, 14.3, 14.8, 15.7, 17.4, 17.8, 18.2, 18.8, and 19.3 + 0.2 °2 ⁇ .
  • the crystalline idelalisib Form-Ml may further be characterized by the powder X- ray diffraction pattern as depicted in Figure 1.
  • the crystalline idelalisib Form-Ml is a methyl-tert-butyl ether solvate.
  • Another aspect of the present invention provides a process for the preparation of crystalline Idelalisib Form-Ml, which may be carried out by the following steps: a. combining idelalisib in an organic solvent to form a mixture;
  • the organic solvent may be, for example, formic acid, acetic acid, tetrahydrofuran, or mixtures thereof.
  • the process disclosed above may further comprise the step of heating the mixture after combining idelalisib with an organic solvent and before adding methyl tert-butyl ether.
  • Another aspect of the present invention provides a process for the preparation of crystalline idelalisib Form-Ml, which may include the following steps: a. combining idelalisib with methyl tert-butyl ether; and
  • the crystalline idelalisib Form-Ml may be isolated by methods well known in the art, for example, by filtration. Another aspect of the present invention provides crystalline idelalisib Form-M2.
  • crystalline idelalisib Form-M2 may be characterized by a powder X-ray diffraction pattern with significant peaks at 9.41, 12.56, and 14.9 + 0.2 °2 ⁇ .
  • crystalline idelalisib Form-M2 may be further characterized by a powder X-ray diffraction pattern with significant peaks at 10.91, 17.52, 17.95, 19.42, 20.33, and 20.75 + 0.2 °2 ⁇ .
  • the crystalline idelalisib Form-M2 may further be characterized by the powder X- ray diffraction pattern as depicted in Figure 2.
  • Another aspect of the present invention provides a process for the preparation of crystalline idelalisib Form-M2, which may be carried out by holding an amount of crystalline idelalisib Form-Ml at an elevated temperature.
  • crystalline idelalisib Form-Ml may be held at about 80 °C to about 110 °C for about 18 hours to 22 hours to yield crystalline idelalisib Form-M2.
  • crystalline idelalisib Form-Mi may be incorporated into a pharmaceutical dosage form.
  • crystalline idelalisib Form-M2 may be incorporated into a pharmaceutical dosage form.
  • oral dosage forms as described above may further contain one or more pharmaceutically acceptable excipients.
  • Figure 1 shows a powder X-ray diffraction (PXRD) pattern of crystalline idelalisib Form-Mi
  • Figure 2 shows a differential scanning calorimetry (DSC) curve of crystalline idelalisib Form-Mi;
  • FIG. 3 shows a thermogravimetric analysis (TGA) curve of crystalline idelalisib Form-Mi;
  • Figure 4 shows a proton nuclear magnetic resonance (1H NMR) spectrum of crystalline idelalisib Form-M 1 ;
  • Figure 5 shows a PXRD pattern of crystalline idelalisib Form-M2
  • Figure 6 shows a DSC curve of crystalline idelalisib Form-M2
  • Figure 7 shows a TGA curve of crystalline idelalisib Form-M2
  • Figure 8 shows a 1H NMR spectrum of crystalline idelalisib Form-M2.
  • the polymorphs of the present invention may be characterized by their X-ray powder diffraction patterns.
  • the PXRD pattern of crystalline idelalisib Form-Ml and Form M-2 were measured on a BRUKER D-8 Discover powder diffractometer equipped with a goniometer of ⁇ /2 ⁇ configuration and Lynx Eye detector.
  • the Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
  • crystalline idelalisib Form-Ml which was characterized using numerous analytical techniques.
  • crystalline idelalisib Form-Ml may be characterized by a PXRD pattern having peaks at 7.4, 9.6, 10.8, 14.3, 14.8, 15.7, 17.4, 17.8, 18.2, 18.8, 19.3, and 20.2 + 0.2 °2 ⁇ .
  • Crystalline idelalisib Form-Ml may be further characterized by the PXRD pattern in Figure 1. Crystalline idelalisib Form-Ml may be further characterized by differential scanning calorimetry (DSC) and may produce a DSC curve as shown in Figure 2. 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.
  • Crystalline idelalisib Form-Ml may be further characterized by thermogravimetric analysis (TGA) and may produce a TGA curve as depicted in Figure 3. As shown in Figure 3, crystalline idelalisib Form-Ml, the TGA curve indicates a weight loss of 17.25% upon constant heating of the sample, which is attributed to methyl-tert butyl ether (MTBE) solvent loss. TGA 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. Crystalline idelalisib Form-Mi may be further characterized by proton NMR (1H
  • the present invention further provides processes for the preparation of crystalline idelalisib Form-Mi.
  • crystalline idelalisib Form-Mi may be prepared by the following steps: a) combining idelalisib with an organic solvent to form a mixture;
  • idelalisib may be combined with an organic solvent to form a mixture.
  • the idelalisib starting material may be any form, for example, any crystalline polymorphic form or amorphous.
  • the organic solvent may be, for example, formic acid, acetic acid, tetrahydrofuran, or mixtures thereof.
  • the mixture may then be heated.
  • heating of the mixture of idelalisib in organic solvent may facilitate dissolution of idelalisib in the solvent.
  • the mixture may be heated to about 50 °C to about 70 °C. In some embodiments, the mixture is heated to about 60 °C.
  • the mixture may then be cooled and methyl tert-butyl ether may be added.
  • the cooling and adding steps may be done sequentially in any order, or simultaneously.
  • the mixture may be cooled, for example, to about 20 °C to about 30 °C. In some particularly effective embodiments, the mixture is cooled to about 25 °C to about 30 °C.
  • cooling and addition of methyl-tert butyl ether may cause a precipitate to form.
  • the mixture of idelalisib may be subjected to evaporation drying prior to addition of methyl tert-butyl ether.
  • the mixture may be stirred upon addition of methyl tert- butyl ether to promote formation of the precipitate.
  • crystalline idelalisib Form-Mi may be isolated by separating the precipitate from the solvent/s. Isolation of crystalline idelalisib Form-Mi may be carried out by a variety of methods well known to one of skill in the art. For example, the solution may be filtered and the resulting solid may be dried. While not wishing to be bound by theory, it is currently believed that crystalline idelalisib Form-Mi obtained through this method may be a solvate of methyl tert-butyl ether.
  • crystalline idelalisib Form-Mi may be prepared by the following steps: a) combining idelalisib with methyl tert-butyl ether to form a mixture; and b) isolating crystalline idelalisib Form-Mi.
  • idelalisib may be combined with methyl tert-butyl ether to form a mixture.
  • the mixture may then optionally be stirred.
  • the solution may be stirred for from about 30 minutes to 24 hours and stirring may facilitate the transition of the idelalisib starting material into crystalline idelalisib Form-Mi.
  • other process may be undertaken to facilitate this transition as well, for example, heating the solution or seeding the solution with crystalline idelalisib Form-Mi.
  • crystalline idelalisib Form-Mi may then be isolated.
  • This isolation may be carried out by methods well known in the art, for example, by filtering the suspension to isolate a solid.
  • the solid may optionally be further treated, for example, by drying, to obtain crystalline idelalisib Form-Mi.
  • Another aspect of the present invention provides crystalline idelalisib Form-M2.
  • crystalline idelalisib Form-M2 may be characterized by a PXRD pattern having peaks at 9.41, 10.91, 14.94, 17.52, 17.95, 19.42, 20.33, and 20.75 + 0.2 °2 ⁇ .
  • crystalline idelalisib Form-M2 may be further characterized by a PXRD pattern having peaks at 7.52, 9.41, 10.91, 11.30, 12.34, 14.94, 17.52, 17.95, 18.60, 19.42, 20.33, and 20.75 + 0.2 °2 ⁇ .
  • Crystalline idelalisib Form-M2 may be further characterized by the PXRD pattern in Figure 5.
  • Crystalline idelalisib Form-M2 may be further characterized by differential scanning calorimetry and may produce a DSC curve as shown in Figure 6.
  • Crystalline idelalisib Form-M2 may be further characterized by thermogravimetric analysis and may produce a TGA curve as depicted in Figure 7. As shown in Figure 7, the TGA curve for crystalline idelalisib Form-Mi indicates a weight loss of 6.972% upon constant heating of the sample, which is attributed to MTBE loss.
  • Crystalline idelalisib Form-M2 may be further characterized by proton NMR (1H NMR) and may produce a 1H NMR curve as depicted in Figure 8.
  • Another aspect of the present invention encompasses methods for preparing crystalline idelalisib Form M-2.
  • crystalline idelalisib Form-M2 may be prepared by subjecting crystalline idelalisib Form-Mi to a temperature of about 80 °C to about 110 °C under vacuum for about 18 hours to about 22 hours. Crystalline idelalisib Form-Mi and Form-M2 may be included in pharmaceutical dosage forms that are useful in the treatment of patients with chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
  • Pharmaceutical dosage forms containing premixes of crystalline idelalisib Form-Mi and Form-M2 may also be used for treating patients with relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies and patients with relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies.
  • Crystalline idelalisib Form-Ml and Form-M2 may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet.
  • the dosage form may include additional excipients, for example, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and mixtures thereof.
  • the dosage form may, in some embodiments, be coated with a shell or film that includes additional excipients, artificial flavorings, artificial colorings, and mixtures thereof.
  • the shell or film may include such excipients as polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide, red iron oxide, and mixtures thereof.
  • dosage forms containing crystalline idelalisib Form-Ml and/or Form-M2 may have between about 100 mg and 150 mg of idelalisib per dose, including 100 mg and 150 mg of idelalisib.
  • crystalline idelalisib Form-Ml and Form-M2 as disclosed herein may exhibit long-term physical and chemical stability.
  • the physical and chemical stability of crystalline idelalisib Form-Ml and Form-M2 may be determined by storing the samples at either 40 °C/75% relative humidity (RH), at 25 °C/60% RH, or at 5 °C + 3 °C for 6 months and analyzing the stored material by PXRD to determine polymorph integrity.
  • RH relative humidity
  • PXRD °C + 3 °C for 6 months
  • crystalline idelalisib Form-Ml and Form-M2 prepared by methods disclosed herein show no change in PXRD pattern when stored for six months at 5 °C + 3 °C, 25 °C/60% RH, or at 40 °C/75% RH conditions.
  • Table 1 below shows the stability data as evidenced by PXRD patterns.
  • Idelalisib (200 mg) was dissolved in formic acid (0.5 mL) at 60 °C. The clear solution was cooled to 25 - 30 °C and the solvent was slowly evaporated at 25 - 30 °C for 3 days. No precipitate was observed. Methyl tert-butyl ether (10 mL) was then added to the solution and the solution was stirred for 18 hours. The solution was filtered and the resulting product was identified as crystalline idelalisib Form-Mi.
  • Example 5 Preparation of idelalisib Form-Mi
  • Idelalisib (200 mg) was dissolved in tetrahydrofuran (5 mL) at 60 °C. The clear solution was cooled to 25 - 30 °C and the solvent was slowly evaporated off at 25 - 30 °C for 3 days. No precipitate was observed, n-heptane (10 mL) was added to the solution and the solution was stirred for 60 minutes. A gummy mass was observed. Methyl tert- butyl ether was then added and the solution was stirred for 60 minutes. The solution was filtered and the resulting product was identified as crystalline idelalisib Form-Mi .
  • Idelalisib Form-Mi (obtained as above) was dried at 100 °C under vacuum for 20 hours. The resulting product was identified as idelalisib Form-M2.
  • Amorphous idelalisib (200 mg) was suspended in methyl tert-butyl ether (3 mL) and the suspension was stirred for 20 hours at 25 - 30 °C. The suspension was filtered and the obtained solid was suck-dried and identified as crystalline idelalisib Form-Mi.

Abstract

The preparation of a crystalline form of a idelalisib methyl-tert-butyl ether solvate (form M1) is disclosed herein. Drying of this solvate form M1 at elelvated temparature leads to the idelalisib form M2.

Description

CRYSTALLINE FORMS OF IDELALISIB
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 1777/CHE/2015 filed on April 02, 2015.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of idelalisib designated as Form-Mi and Form-M2 and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
Idelalisib, chemically known as 5-fluoro-3-phenyl-2-[(15)- l-(7H-purin-6- ylamino)propyl]-4(3H)-quinazolinone, is represented by Formula I below.
Figure imgf000002_0001
Formula I
Idelalisib is marketed under the tradename ZYDELIG by Gilead Sciences, Inc. ZYDELIG is indicated for the treatment of patients with chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities. It is also indicated for treating patients with relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies and patients with relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. Idelalisib is disclosed in U.S. Patent No. RE44638. This patent also discloses an ethanol solvate of idelalisib.
International Publication No. WO2013134288 discloses crystalline Forms-I, -II, -III, -IV, -V, -VI, and -VII of idelalisib. International Publication No. WO2015014315 discloses Form- IX of idelalisib, which is a 0.7 hydrate form, as well as Forms -II, -III, -IV, and -VIII.
International Publication No. WO2015092810 discloses the amorphous form of idelalisib, processes for the preparation thereof, solid dispersions of idelalisib, as well as process for the preparation thereof. However, there is a need in the art for stable crystalline forms of idelalisib. Thus, the present invention provides novel crystalline polymorphs of idelalisib that are stable and easy to prepare on an industrially viable scale.
SUMMARY OF THE INVENTION
One aspect of the present invention provides crystalline idelalisib Form-Ml. Within the context of this invention, crystalline idelalisib Form-Ml may be characterized by a powder X-ray diffraction pattern with significant peaks at 7.45 and 20.23 + 0.2 °2Θ.
Within the context of this invention, crystalline idelalisib Form-Ml may be further characterized by a powder X-ray diffraction pattern with significant peaks at 9.6, 10.8, 14.3, 14.8, 15.7, 17.4, 17.8, 18.2, 18.8, and 19.3 + 0.2 °2Θ.
The crystalline idelalisib Form-Ml may further be characterized by the powder X- ray diffraction pattern as depicted in Figure 1.
Within the context of the present invention, it is believed that the crystalline idelalisib Form-Ml is a methyl-tert-butyl ether solvate. Another aspect of the present invention provides a process for the preparation of crystalline Idelalisib Form-Ml, which may be carried out by the following steps: a. combining idelalisib in an organic solvent to form a mixture;
b. adding methyl tert-butyl ether to the mixture; and
c. isolating crystalline idelalisib Form-Ml .
Within the context of this embodiment, the organic solvent may be, for example, formic acid, acetic acid, tetrahydrofuran, or mixtures thereof.
The process disclosed above may further comprise the step of heating the mixture after combining idelalisib with an organic solvent and before adding methyl tert-butyl ether.
Another aspect of the present invention provides a process for the preparation of crystalline idelalisib Form-Ml, which may include the following steps: a. combining idelalisib with methyl tert-butyl ether; and
b. isolating crystalline idelalisib Form-Ml.
Within the context of this embodiment, the crystalline idelalisib Form-Ml may be isolated by methods well known in the art, for example, by filtration. Another aspect of the present invention provides crystalline idelalisib Form-M2.
Within the context of this invention, crystalline idelalisib Form-M2 may be characterized by a powder X-ray diffraction pattern with significant peaks at 9.41, 12.56, and 14.9 + 0.2 °2Θ.
Within the context of this invention, crystalline idelalisib Form-M2 may be further characterized by a powder X-ray diffraction pattern with significant peaks at 10.91, 17.52, 17.95, 19.42, 20.33, and 20.75 + 0.2 °2Θ.
The crystalline idelalisib Form-M2 may further be characterized by the powder X- ray diffraction pattern as depicted in Figure 2.
Another aspect of the present invention provides a process for the preparation of crystalline idelalisib Form-M2, which may be carried out by holding an amount of crystalline idelalisib Form-Ml at an elevated temperature. Within the context of this embodiment, crystalline idelalisib Form-Ml may be held at about 80 °C to about 110 °C for about 18 hours to 22 hours to yield crystalline idelalisib Form-M2.
Within the context of the invention, crystalline idelalisib Form-Mi may be incorporated into a pharmaceutical dosage form.
Within the context of the invention, crystalline idelalisib Form-M2 may be incorporated into a pharmaceutical dosage form.
The oral dosage forms as described above may further contain one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE FIGURES
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 shows a powder X-ray diffraction (PXRD) pattern of crystalline idelalisib Form-Mi; Figure 2 shows a differential scanning calorimetry (DSC) curve of crystalline idelalisib Form-Mi;
Figure 3 shows a thermogravimetric analysis (TGA) curve of crystalline idelalisib Form-Mi;
Figure 4 shows a proton nuclear magnetic resonance (1H NMR) spectrum of crystalline idelalisib Form-M 1 ;
Figure 5 shows a PXRD pattern of crystalline idelalisib Form-M2;
Figure 6 shows a DSC curve of crystalline idelalisib Form-M2;
Figure 7 shows a TGA curve of crystalline idelalisib Form-M2; and
Figure 8 shows a 1H NMR spectrum of crystalline idelalisib Form-M2. 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. The present invention provides two crystalline forms of idelalisib designated as
Form-Ml and Form-M2.
The polymorphs of the present invention may be characterized by their X-ray powder diffraction patterns. Thus, the PXRD pattern of crystalline idelalisib Form-Ml and Form M-2 were measured on a 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.
One aspect of the present invention encompasses crystalline idelalisib Form-Ml, which was characterized using numerous analytical techniques. Within the context of the invention, crystalline idelalisib Form-Ml may be characterized by a PXRD pattern having peaks at 7.4, 9.6, 10.8, 14.3, 14.8, 15.7, 17.4, 17.8, 18.2, 18.8, 19.3, and 20.2 + 0.2 °2Θ.
Crystalline idelalisib Form-Ml may be further characterized by the PXRD pattern in Figure 1. Crystalline idelalisib Form-Ml may be further characterized by differential scanning calorimetry (DSC) and may produce a DSC curve as shown in Figure 2. 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.
Crystalline idelalisib Form-Ml may be further characterized by thermogravimetric analysis (TGA) and may produce a TGA curve as depicted in Figure 3. As shown in Figure 3, crystalline idelalisib Form-Ml, the TGA curve indicates a weight loss of 17.25% upon constant heating of the sample, which is attributed to methyl-tert butyl ether (MTBE) solvent loss. TGA 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. Crystalline idelalisib Form-Mi may be further characterized by proton NMR (1H
NMR) and may produce a 1H NMR curve as depicted in Figure 4. The 1H NMR data were measured on Bruker 300MHz Avance NMR spectrometer equipped with 5 mm BBO probe in DMSO-d6. The data were collected and processed by XWIN-NMR software.
The present invention further provides processes for the preparation of crystalline idelalisib Form-Mi.
In one embodiment of the methods of the present invention, crystalline idelalisib Form-Mi may be prepared by the following steps: a) combining idelalisib with an organic solvent to form a mixture;
b) adding methyl tert-butyl ether; and
c) isolating crystalline idelalisib Form-Mi .
According to this embodiment, idelalisib may be combined with an organic solvent to form a mixture. Within the context of this embodiment, the idelalisib starting material may be any form, for example, any crystalline polymorphic form or amorphous. The organic solvent may be, for example, formic acid, acetic acid, tetrahydrofuran, or mixtures thereof.
The mixture may then be heated. Within the context of the present invention, heating of the mixture of idelalisib in organic solvent may facilitate dissolution of idelalisib in the solvent. Within the context of this embodiment, the mixture may be heated to about 50 °C to about 70 °C. In some embodiments, the mixture is heated to about 60 °C.
The mixture may then be cooled and methyl tert-butyl ether may be added. The cooling and adding steps may be done sequentially in any order, or simultaneously. In some embodiments, the mixture may be cooled, for example, to about 20 °C to about 30 °C. In some particularly effective embodiments, the mixture is cooled to about 25 °C to about 30 °C. Within the context of this embodiment, cooling and addition of methyl-tert butyl ether may cause a precipitate to form. In some embodiments, the mixture of idelalisib may be subjected to evaporation drying prior to addition of methyl tert-butyl ether. In other embodiments, the mixture may be stirred upon addition of methyl tert- butyl ether to promote formation of the precipitate.
Next, crystalline idelalisib Form-Mi may be isolated by separating the precipitate from the solvent/s. Isolation of crystalline idelalisib Form-Mi may be carried out by a variety of methods well known to one of skill in the art. For example, the solution may be filtered and the resulting solid may be dried. While not wishing to be bound by theory, it is currently believed that crystalline idelalisib Form-Mi obtained through this method may be a solvate of methyl tert-butyl ether.
In another embodiment of the methods of the present invention, crystalline idelalisib Form-Mi may be prepared by the following steps: a) combining idelalisib with methyl tert-butyl ether to form a mixture; and b) isolating crystalline idelalisib Form-Mi.
According to this embodiment, idelalisib may be combined with methyl tert-butyl ether to form a mixture. The mixture may then optionally be stirred. Within the context of this embodiment, the solution may be stirred for from about 30 minutes to 24 hours and stirring may facilitate the transition of the idelalisib starting material into crystalline idelalisib Form-Mi. Optionally, other process may be undertaken to facilitate this transition as well, for example, heating the solution or seeding the solution with crystalline idelalisib Form-Mi.
According to this embodiment, crystalline idelalisib Form-Mi may then be isolated. This isolation may be carried out by methods well known in the art, for example, by filtering the suspension to isolate a solid. The solid may optionally be further treated, for example, by drying, to obtain crystalline idelalisib Form-Mi.
Another aspect of the present invention provides crystalline idelalisib Form-M2.
Within the context of the present invention, crystalline idelalisib Form-M2 may be characterized by a PXRD pattern having peaks at 9.41, 10.91, 14.94, 17.52, 17.95, 19.42, 20.33, and 20.75 + 0.2 °2Θ.
Within the context of the present invention, crystalline idelalisib Form-M2 may be further characterized by a PXRD pattern having peaks at 7.52, 9.41, 10.91, 11.30, 12.34, 14.94, 17.52, 17.95, 18.60, 19.42, 20.33, and 20.75 + 0.2 °2Θ. Crystalline idelalisib Form-M2 may be further characterized by the PXRD pattern in Figure 5.
Crystalline idelalisib Form-M2 may be further characterized by differential scanning calorimetry and may produce a DSC curve as shown in Figure 6.
Crystalline idelalisib Form-M2 may be further characterized by thermogravimetric analysis and may produce a TGA curve as depicted in Figure 7. As shown in Figure 7, the TGA curve for crystalline idelalisib Form-Mi indicates a weight loss of 6.972% upon constant heating of the sample, which is attributed to MTBE loss.
Crystalline idelalisib Form-M2 may be further characterized by proton NMR (1H NMR) and may produce a 1H NMR curve as depicted in Figure 8. Another aspect of the present invention encompasses methods for preparing crystalline idelalisib Form M-2.
In one embodiment of the methods of the present invention, crystalline idelalisib Form-M2 may be prepared by subjecting crystalline idelalisib Form-Mi to a temperature of about 80 °C to about 110 °C under vacuum for about 18 hours to about 22 hours. Crystalline idelalisib Form-Mi and Form-M2 may be included in pharmaceutical dosage forms that are useful in the treatment of patients with chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities. Pharmaceutical dosage forms containing premixes of crystalline idelalisib Form-Mi and Form-M2 may also be used for treating patients with relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies and patients with relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. Crystalline idelalisib Form-Ml and Form-M2 may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. The dosage form may include additional excipients, for example, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and mixtures thereof. The dosage form may, in some embodiments, be coated with a shell or film that includes additional excipients, artificial flavorings, artificial colorings, and mixtures thereof. For example, the shell or film may include such excipients as polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide, red iron oxide, and mixtures thereof. Within the context of the present invention, dosage forms containing crystalline idelalisib Form-Ml and/or Form-M2 may have between about 100 mg and 150 mg of idelalisib per dose, including 100 mg and 150 mg of idelalisib.
Within the context of the present disclosure, crystalline idelalisib Form-Ml and Form-M2 as disclosed herein may exhibit long-term physical and chemical stability. Within the context of the present invention, the physical and chemical stability of crystalline idelalisib Form-Ml and Form-M2 may be determined by storing the samples at either 40 °C/75% relative humidity (RH), at 25 °C/60% RH, or at 5 °C + 3 °C for 6 months and analyzing the stored material by PXRD to determine polymorph integrity. As used herein, a compound or pharmaceutical composition is considered "stable" where the HPLC purity of the crystalline idelalisib changes by less than about 1% when stored under testing conditions.
In some embodiments, crystalline idelalisib Form-Ml and Form-M2 prepared by methods disclosed herein show no change in PXRD pattern when stored for six months at 5 °C + 3 °C, 25 °C/60% RH, or at 40 °C/75% RH conditions. Table 1 below shows the stability data as evidenced by PXRD patterns. TABLE 1
Figure imgf000011_0001
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 5 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 idelalisib Form-Mi
Idelalisib (5 g) and formic acid (10 mL) were combined in a round bottom flask at 25 - 30 °C. The reaction mass was heated to 60 °C to get clear solution, then cooled to 25 - 30 °C. Methyl tert-butyl ether (100 mL) was added to the solution and the solution 5 was stirred at the same temperature for 48 hours. The solution was filtered to obtain a solid, which was washed with methyl tert-butyl ether (20 mL) and then dried at 35 °C under vacuum for 2 hours. The resulting product was identified by PXRD as crystalline idelalisib Form-Mi. Yield: 4.7 g; PXRD: Form-Mi.
Example 2: Preparation of idelalisib Form-Mi
Idelalisib (1 g) and formic acid (1 mL) were combined in a round bottom flask at 25 - 30 °C. The reaction mass was heated to 60 °C to get clear solution which was then cooled to 25 - 30 °C. Methyl tert-butyl ether (30 mL) was added to the solution and the solution was stirred at 25 - 30 °C for 48 hours. The solution was filtered to obtain a solid, which was washed with methyl tert-butyl ether (2 mL) then dried at 35 °C under vacuum for 2 hours. The resulting product was identified by PXRD as crystalline idelalisib Form-Mi.
Yield: 0.9 g; PXRD: Form-Mi.
Example 3: Preparation of idelalisib Form-Mi
Idelalisib (1 g) and acetic acid (1 mL) were combined in a round bottom flask at 25 - 30 °C. The reaction mass was heated to 60 °C to get a clear solution, which was then cooled to 25 - 30 °C. Methyl tert-butyl ether (30 mL) was added to the solution and the solution was stirred at 25 - 30 °C for 48 hours. The solution was filtered to obtain a solid, which was then washed with methyl tert-butyl ether (2 mL) and dried at 35 °C under vacuum for 2 hours. The resulting product was identified by PXRD as crystalline idelalisib Form-Mi. Yield: 0.7 g; PXRD: Form-Mi.
Example 4: Preparation of idelalisib Form-Mi
Idelalisib (200 mg) was dissolved in formic acid (0.5 mL) at 60 °C. The clear solution was cooled to 25 - 30 °C and the solvent was slowly evaporated at 25 - 30 °C for 3 days. No precipitate was observed. Methyl tert-butyl ether (10 mL) was then added to the solution and the solution was stirred for 18 hours. The solution was filtered and the resulting product was identified as crystalline idelalisib Form-Mi. Example 5: Preparation of idelalisib Form-Mi
Idelalisib (200 mg) was dissolved in tetrahydrofuran (5 mL) at 60 °C. The clear solution was cooled to 25 - 30 °C and the solvent was slowly evaporated off at 25 - 30 °C for 3 days. No precipitate was observed, n-heptane (10 mL) was added to the solution and the solution was stirred for 60 minutes. A gummy mass was observed. Methyl tert- butyl ether was then added and the solution was stirred for 60 minutes. The solution was filtered and the resulting product was identified as crystalline idelalisib Form-Mi .
Example 6: Preparation of idelalisib Form-M2
Idelalisib Form-Mi (obtained as above) was dried at 100 °C under vacuum for 20 hours. The resulting product was identified as idelalisib Form-M2.
LOD (loss on drying) by TGA— 7%, MTBE by 1H NMR— 33% (0.3 mole);
possibly a hemisolvate.
Example 7: Preparation of idelalisib Form-Mi
Idelalisib (10 g) and formic acid (20 mL) were combined in a round bottomed flask at 25 -30 °C. The reaction mass was heated to 60 °C to get a clear solution which was then filtered to remove any undissolved particulate. The solution was distilled at 45 °C to yield a foamy residue which was then cooled to 25 - 30 °C. Methyl tert-butyl ether (200 mL) was added to this residue and the solution was stirred at same temperature for 16 hours. The solution was filtered and the solid obtained was washed with methyl tert-butyl ether (20 mL) and dried at 30 °C under vacuum for 3 hours. The resulting product was identified as crystalline idelalisib Form-Mi.
Example 8: Preparation of idelalisib Form-Mi
Amorphous idelalisib (200 mg) was suspended in methyl tert-butyl ether (3 mL) and the suspension was stirred for 20 hours at 25 - 30 °C. The suspension was filtered and the obtained solid was suck-dried and identified as crystalline idelalisib Form-Mi.

Claims

We claim:
1. Crystalline idelalisib Form-M 1.
2. The crystalline idelalisib Form-Ml according to claim 1, having a powder X-ray diffraction pattern with significant peaks at 7.45 and 20.23 + 0.2 °2Θ.
3. The crystalline idelalisib Form-Ml according to claim 2, further characterized by a powder X-ray diffraction pattern having significant peaks at 9.6, 10.8, 14.3, 14.8, 15.7, 17.4, 17.8, 18.2, 18.8, and 19.3 + 0.2 °2Θ.
4. The crystalline idelalisib Form-Ml according to claim 1, having a powder X-ray diffraction pattern as depicted in Figure 1.
5. The crystalline idelalisib Form-Ml according to claims 1 to 4, wherein said crystalline idelalisib Form-Ml is a methyl-tert-butyl ether solvate.
6. A process for the preparation of crystalline Idelalisib Form Ml, comprising the steps of: a) combining idelalisib with an organic solvent to form a mixture; b) adding methyl tert-butyl ether to the mixture; and
c) isolating crystalline idelalisib Form-Ml .
7. The process according to claim 6, further comprising the step of heating the mixture after the dissolving step and before the adding step.
8. The process according to claim 6, wherein the organic solvent is selected from the group consisting of formic acid, acetic acid, tetrahydrofuran, and mixtures thereof.
9. A process for the preparation of crystalline idelalisib Form-Ml, comprising the steps of:
a) combining idelalisib with methyl tert-butyl ether; and b) isolating crystalline idelalisib Form-Ml.
10. The process according to claim 9, wherein the crystalline idelalisib Form-Ml is isolated by filtration.
11. Crystalline idelalisib Form-M2.
12. The crystalline idelalisib Form-M2 according to claim 11, having a powder X-ray
diffraction pattern with significant peaks at 9.41, 12.56, and 14.9 + 0.2 °2Θ.
13. The crystalline idelalisib Form-M2 according to claim 12, further characterized by a powder X-ray diffraction pattern having significant peaks at 10.91, 17.52, 17.95, 19.42, 20.33, and 20.75 + 0.2 °2Θ.
14. The crystalline idelalisib Form-M2 according to claim 11, having a powder X-ray diffraction pattern as depicted in Figure 2.
15. A process for the preparation of crystalline idelalisib Form-M2, comprising holding an amount of crystalline idelalisib Form-Ml at an elevated temperature.
16. The process according to claim 15, wherein the holding of crystalline idelalisib Form- Ml is carried out for 18 hours to 22 hours.
17. The process according to claim 15, wherein the holding of crystalline idelalisib Form- Ml is carried out at 80 °C to 110 °C.
18. A pharmaceutical dosage form comprising the crystalline idelalisib Form-Ml of claim 1.
19. A pharmaceutical dosage form comprising the crystalline idelalisib Form-M2 of claim 12.
0. The pharmaceutical dosage form of either of claims 17 or 18, further comprising one or more pharmaceutically acceptable excipients.
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CN106632337A (en) * 2016-10-18 2017-05-10 湖北生物医药产业技术研究院有限公司 Idelalisib crystal, pharmaceutical composition comprising idelalisib crystal, and preparation method and application of idelalisib crystal
WO2019178596A1 (en) 2018-03-16 2019-09-19 Johnson Matthey Public Limited Company Pyridine or n,n-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation

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WO2013134288A1 (en) 2012-03-05 2013-09-12 Gilead Calistoga Llc Polymorphic forms of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one
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