OA17123A - Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one - Google Patents

Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one Download PDF

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OA17123A
OA17123A OA1201400405 OA17123A OA 17123 A OA17123 A OA 17123A OA 1201400405 OA1201400405 OA 1201400405 OA 17123 A OA17123 A OA 17123A
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polymorphie
polymorph
purin
propyl
ylamino
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OA1201400405
Inventor
Ernest Carra
Michael Gerber
Bing Shi
Duong Tran
Keiko Sujino
Fang Wang
Jerry B. Evarts
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Gilead Calistoga Llc
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Abstract

Polymorphs of (S)-2-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, compositions thereof, methods for their preparation, and methods for their use are disclosed.

Description

[0001] This application claims the benefit of U.S. provisional patent application Serial
No. 61/606,870, filed March 5,2012, the disclosure of which is hereby incorporated herein by reference in its entirety.
FIELD [0002] Provided are polymorphs of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one, compositions thereof, methods for their préparation, and methods for their use.
BACKGROUND [0003] Cell signaling via 3’-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity. See Rameh et al., J. Biol. Chem., 274:8347-8350 (1999) for a review. The enzyme responsible for generating these phosphorylated signaling products is phosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally was identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylâtes phosphatidylinositol (PI) and its phosphorylated dérivatives at the 3*hydroxyl ofthe inositol ring. See Panayotou et al., Trends Cell Biol. 2:358-60 (1992).
[0004] PI 3-kinase activation is believed to be involved in a range of cellular responses induding cell growth, différentiation, and apoptosis. See Parker et al., Curr. Biol., 5:577-99 (1995); Yao et al.. Science, 267:2003-05 (1995). PI 3-kinase also appears to be involved in a number of aspects of leukocyte activation. See e.g.. Pages et al., Nature, 369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996); Fraser étal.. Science, 251:313-16 (1991).
]0005] Several compounds hâve been identified as PI 3-kinase inhibitors. For example, compounds capable of inhibiting the biological activity of human PI3K, induding (S)-2-(l(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(377)-one, and their uses are disclosed in U.S. Patent No. 6,518,277, U.S. Patent No. 6,667,300, and U.S. Patent No. 7,932,260. Each of these référencés is hereby incorporated herein by reference in its entirety.
I
BRIEF SUMMARY [0006] (5)-2-( l -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyIquinazo!in-4(3//)-one, has been chosen for further development Consequently, it is desired to produce this compound in a form that is bioavailable and stable. In one aspect, provided herein are polymorphs of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluon>-3-phenylquinazolin-4(3/7)one, a compound having the molecular structure:
Specifically, polymorphie Forms l, II, III, IV, V, VI and VII of (5)-2-( l-(9H-purin-6ylamino)propyI)-5-fluoro-3-phenylquinazoIin-4(3//)-one, and methods of makîng and using 10 these polymorphie forms are provided. Also provided are polymorphie products obtained by the processes (e.g. methods of makîng). Pharmaceutical compositions comprising one or more polymorphie forms of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquînazolin-4(3/Z)-one (any one or more of polymorphie Forms I, II, III, IV, V, VI and VII) and a pharmaceutically acceptable carrier are provided. Articles of manufacture and unit 15 dosage forms comprising any one o f more of the polymorphie forms of (5)-2-( 1 -(9H-purin-6yIamino)propy1)-5-fluoro-3-phenylquinazolin-4(3/7)-one (e.g., any one of more of polymorphie Forms 1, il, III, IV, V, VI and VII) are provided. Kits comprising any one of more of the polymorphie forms (e.g., polymorphie Forms I, II, III, IV, V, VI and VII of (5)-2(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/Z)-one), and instructions 20 for use (e.g, instructions for use in PI3K-mediated disorder, such as cancer) are also provided.
[0007] These polymorphs are characterized by a variety of solid state analytical data, including for example X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
[0008] Provided is a polymorph of (S)-2-(l-(9H-purin-6-ylamîno)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern substantially as shown in FIG. IA.
[0009] Provided is also a polymorph of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-35 phenylquinazolin-4(3//)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern that includes characteristic peaks at about 17.7 degrees 20 and about 24.9 degrees 20. In some embodiments, the X-ray powder diffraction pattern further includes any one or more of characteristic peaks at about 14.3 degrees 20, about 17.2 degrees 20, about 20.9 degrees 20, and about 23.9 degrees 20. In some embodiments, the polymorphie Form I has a melting température of about 254°C to about 256°C. In one variation, polymorphie Form I has an X-ray powder diffraction pattern that includes any one or more characteristic peaks at about I4.3 degrees 20, about 17.2 degrees 20, about 17.7 degrees 20, about 20.9 degrees 20, about 23.9 degrees 20, and about 24.9 degrees 20; and a melting température of about 254°C to about 256°C.
[0010] It should be understood that relative intensifies can vary depending on a number of factors, including sample préparation, mounting, and the instrument and analytîcal procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein (including for polymorphie Form I) are intended to encompass variations of plus or minus 0.2 degrees 20.
[0011] In some embodiments, the polymorphie Form I described herein is obtained by: a) combining (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one with a solvent to form a mixture; b) heating the mixture to form a solution; and c) cooling the heated solution to form the polymorphie Form I. In certain embodiments, the heated solution is cooled to a température of at least about 30°C. In other embodiments, the heated solution is cooled to a température of at least about 35°C, or between about 3 0°C and about 40°C, or between about 30°C and about 35°C, or between about 35°C and about 40°C. In some embodiments, polymorphie Form I is further obtained by isolating the solids, such as polymorphie Form I solids, from the cooled solution. In yet other embodiments, polymorphie Form I is further obtained by washing the isolated solids; and drying the washed isolated solids. In some embodiments, the solvent used to obtain polymorphie Form I includes water, an organic solvent, or a mixture thereof. In certain embodiments, the solvent includes water, an alcohol (e.g., methanol, éthanol), or a mixture thereof. In some embodiments, the solvent includes a mixture of alcohol and water in a ratio between 2 to 1 and 10 to 1, or between 4 to 1 and 5 to I. In certain embodiment, the solvent includes a mixture of alcohol and water in a ratio of 2 to I, or 2.5 to 1, or 3 to 1, or 3.5 to I, or 4 to 1, or 4.5 to 1, or 5 to 1. In certain embodiments, the solvent includes a mixture of methanol and water in a ratio between 2 to 1 and 10 to 1, or between 4 to 1 and 5 to 1. In one embodiment, the solvent includes a mixture of methanol and water in a ratio of2 to 1, or 2.5 to 1, or 3 to I, or 3.5 to 1, or 4 to 1, or 4.5 to I, or 5 to 1.
[0012] It should be understood, however, one or more of the steps described above to obtain polymorphie Form I may be omitted or the order ofthe steps may be varied. For example, in other embodiments, polymorphie Form I may be obtained by heating (5)-2-(1(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one prior to combining with a solvent to form a mixture. In yet other embodiments, polymorphie Form 1 may be obtained by combining (5)-2-(1-(9H-purin-6-y!amino)propyl)-5-fluoro-3-phenylquinazolin4(3//)'0ne with a solvent to form a mixture, and cooling the mixture to obtain polymorphie Form I.
[0013| In other embodiments, the polymorphie Form 1 described herein is obtained by: a) combining a sait of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one and a solvent to form an acidic mixture or solution; b) neutralizing the acidic mixture or solution, wherein the neutralized mixture or solution includes free (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one; c) heating the neutralized mixture or solution; and d) adding water to the heated mixture or solution to convert at least a portion ofthe free (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fIuoro-3-phenylquinazolin-4(37/)one into polymorphie Form I. Optionally, one or more seed crystals of polymorphie Form I may be added to the neutralized mixture or solution before heating. In certain embodiments, the sait of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fIuoro-3-phenylqumazo!in-4(3f/)-one is a hydrochloride sait of (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one. In some embodiments, the solvent includes water, an alcohol, or a mixture thereof. In certain embodiments, the solvent includes water, éthanol, or a mixture thereof. In some embodiments, the acidic mixture or solution is neutralized using an aqueous sodium carbonate solution. In other embodiments, the neutralized mixture or solution is heated to a température between 40°C and 60°C, or to a température of about 50°C.
[0014] It should be understood, however, one or more of the steps described above to obtain polymorphie Form I from the sait of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(37/)_one may be omitted or the order of the steps may be varied. For example, in other embodiments, the sait of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-35 phenylquinazolin-4(3/7)*one niay be combined with a solvent to form an acidic mixture or solution, and the acidic mixture or solution may be heated before neutralization. In yet other embodiments, the sait of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyIquînazolin4(377)-one may be combined with a solvent to form an acidic mixture or solution, the acidic mixture or solution may then be neutralized, and water may be added to the neutralized mixture or solution to convert at least a portion of the free (5)-2-(1 -(9H-purin-6y[amino)propyl)-5-fluoro-3-phenylquinazolin-4(377)one into polymorphie Form I.
[0015] Provided is also a polymorph of (5)-2-( I-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-onc which is bioequivalent to the polymorphie Form I described herein.
[0016] In some embodiments, the polymorphie Form I described herein is isolated, e.g., from a mixture or solution comprising (5)-2-(1-(9H-purin-6-ylamino)propyI)-5-fluoro-3phenylquinazolin-4(3/Z)-one and one or more impuritîes. In some embodiments, the polymorphie Form I described herein is a substantiaily pure polymorph.
[0017] Provided is also a composition including the polymorphie Form I described herein, wherein the composition is substantiaily free of polymorphs other than polymorphie Form I of (5)-2-(1-(9 H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)*°ne· [0018] In other embodiments of the composition, at least about 95% of the (5)-2-(1 -(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one présent in the composition is polymorphie Form I. In yet other embodiments, at least 96%, at least 97%, at least 98%, or at least 99% of the (5)-2-( 1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazoI in4(377)-one présent in the composition is the polymorphie Form 1 described herein.
[0019] In other embodiments of the composition, less than about 5% of the (5)-2-( 1-(9 Hpurin-6-ylamino)propyI)-5-fluoro-3-phenylquinazolin-4(3/7)-one présent in the composition are polymorphs other than polymorphie Form I. In yet other embodiments, less than about
4%, less than about 3%, less than about 2%, or less than about 1 % of the (5)-2-( 1 -(9H-purin5
6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one présent in the composition are polymorphs other than polymorphie Form I.
[0020] Provided is also a pharmaceutical composition inciuding polymorphie Form I described herein and one or more pharmaceutically acceptable carriers or excipients.
[0021] Provided is also a kit inciuding the polymorphie Form I described herein and packaging. Provided is also a kit inciuding the composition of polymorphie Form I described herein and packaging.
[0022] Provided is a method of preparing the polymorphie Form I described herein, by: a) combining (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one with a solvent to form a mixture; b) heating the mixture to form a solution; and c) cooling the heated solution to form the polymorphie Form I described herein. In some embodiments, the solution is cooled to a température of at least about 30°C. In other embodiments, the heated solution is cooled to a température of at least about 35°C, or between about 30°C and about 40°C, or between about 30°C and about 35°C, or between about 35°C and about 40°C. In some embodiments, the method further includes isolating the solids, such as polymorphie Form I solids. In yet other embodiments, the method further includes: washing the isolated solids; and drying the washed isolated solids. In some embodiments, the solvent includes water, an organic solvent, or a mixture thereof. In certain embodiments, the organic solvent is selected from solvent groups such as the alcohols (e.g., methanol, éthanol, propanol, etc.), acétates (e.g., isopropyl acetate, ethyi acetate, etc.), ethers (e.g., methyl t-butyl ether, 2methyl tetrahydrofuran, etc.), ketones (e.g., methyl ethyi ketone, methyl isobutyl ketone, etc.), other polar aprotics (e.g., dimethylsulfoxide, etc.) and nonpolars (e.g., hexane, heptane, etc.) or a mixture thereof.
[0023] It should be understood, however, one or more of the steps of the method to prépare polymorphie Form l may be omitted or the order of the steps may be varied. For example, in other embodiments, the method includes heating (5)-2-(1-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one prior to combining with a solvent to form a mixture. In yet other embodiments, the method includes combining (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one with a solvent to form a mixture, and cooling the mixture to obtain polymorphie Form I.
10024] Provided is also a method of preparing the polymorphie Form I described herein, by: a) combining a sait of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)*one ar*d a solvent to form an acidic mixture or solution; b) neutralizing the acidic mixture or solution, wherein the neutralized mixture or solution inciudes free (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one;
c) heating the neutralized mixture or solution; and d) adding water to the heated mixture to convert at least a portion of the free (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)‘one into polymorphie Form I. Optionally, one or more seed crystals of polymorphie Form I may be added to the neutralized mixture or solution before heating.
In some embodiments, the method further inciudes isolating the polymorphie Form I. Jn certain embodiments, the sait of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)*one is a hydrochloride sait of (5)-2-(1-(9H-purin-6-ylamino)propyl)-
5-fluoro-3-phenylquinazolin-4(3//)-°ne· In some embodiments, the solvent inciudes water, an alcohol, or a mixture thereof. In certain embodiments, the solvent inciudes water, éthanol, 15 or a mixture thereof. In some embodiments, the acidic mixture or solution is neutralized using an aqueous sodium carbonate solution. In other embodiments, the neutralized mixture or solution is heated to a température between 40°C and 60°C, or about 50°C.
[0025] It should be understood, however, one or more of the steps of the method to préparé polymorphie Form I from the sait of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro20 3-phenylquinazolin-4(3//)-one may be omitted or the order ofthe steps may be varied. For example, in other embodiments, the method inciudes combining the sait of (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-pheny]quinazolin-4(3//)°ne with û solvent to form an acidic mixture or solution, heating the acidic mixture or solution, neutralizing the heated acidic mixture or solution, and adding water to the heated mixture or solution to convert at 25 least a portion of the free (5)-2-(l-(9H-purin-6-ylamino)propy!)-5-fluoro-3-pheny]quinazolin4(3//)-one into polymorphie Form I. In yet other embodiments, the method inciudes combining the sait of (5)-2-(1 -(9H-purin-6-ylamino)propy!)-5-fluoro-3-pheny]quinazolin4(3//)-one with a solvent to form an acidic mixture or solution, neutralizing the acidic mixture or solution, and adding water to the neutralized mixture or solution to convert at least 30 a portion of the free (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one into polymorphie Form I.
|0026] Provided is also a method of treating a patient with a cancer, by administering to the patient a composition comprising the polymorphie Form I described herein and a pharmaceutically acceptable excipient. In some embodiments, the cancer is a hématologie malignancy. In other embodiments, the hématologie malignancy is leukemia, wherein leukemia is non-Hodgkin*s lymphoma (NHL) or chrome lymphocytic leukemia (CLL). In particular embodiments, the hématologie malignancy is leukemia or lymphoma. In spécifie embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom’s macrogtobulinemia (WM), T-celI lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The non15 Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin’s lymphoma (iNHL).
|0027] Provided is a poiymorph of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenytquinazolin-4(3//)-one, wherein the poiymorph is Form II having an X-ray powder diffraction pattern substantially as shown in FIG. 2A.
|0028] Provided is also a poiymorph of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazoIin-4(3//)-one, wherein the poiymorph is Form II having an X-ray powder diffraction pattern that includes a characteristic peak at about 18.6 degrees 20. In some embodiments, the X-ray powder diffraction pattern further includes characteristic peaks at about 24.3 degrees 20 and about 14.0 degrees 20.
{0029] It should be understood that relative intensities can vary depending on a number of factors, including sample préparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein (including for polymorphie Form II described herein) are intended to encompass variations of plus or minus 0.2 degrees 20.
[0030] In certain embodiments, polymorphie Form II described herein is obtained by: a) providing a polymorphie Form I of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one; b) grinding the polymorphie Form I; and c) stirring the ground polymorphie Form I in a solvent to form the polymorphie Form II described herein. In one variation, polymorphie Form II described herein is obtained by grinding the polymorphie Form I of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one; and stirring the ground polymorphie Form I in a solvent to form the polymorphie Form II described herein. In some embodiments, polymorphie Form II is obtained by further heating the ground polymorphie Form I stirred in the solvent to form the polymorphie Form II described herein. In some embodiments, polymorphie Form I is ground to a particle size of between about I microns to about 10 microns. In some embodiments, polymorphie Form II is obtained by further isolating the polymorphie Form II. In certain embodiments, the stirred mixture is heated at a température of less than about 30°C. In one embodiment, the stirred mixture is heated at a température of between about 25°C and about 30°C. In another embodiment, the ground polymorphie Form I is stirred in the solvent at a température of between about 10°C and about 25qC. In some embodiments, the grinding may be performed using any suitable methods or techniques known to one of skill in the art, including for example using a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mil), a bail mill, or a combination of methods or techniques. In one embodiment, the grinding is performed using a bail mill. In some embodiments, the solvent includes an organic solvent. In one embodiment, the solvent includes acetone.
[0031 ] It should be understood, however, one or more of the steps described above to obtain polymorphie Form II from polymorphie Form I may be omitted or the order of the steps may be varied. For example, in other embodiments, polymorphie Form I may be combined with a solvent before grinding to obtain the polymorphie Form II.
[0032] In some embodiments, the polymorphie Form II described herein is obtained by:
a) providing a polymorphie Form 1 of (5)-2-( l-(9H-purin-6-yIamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one; and b) compressing the polymorphie Form I at a pressure of between about 500 psi and about 5000 psi to convert at Ieast a portion of the polymorphie
Form I to the polymorphie Form II described herein. In one embodiment, the polymorphie Form II described herein is obtained by compressing polymorphie Form I at a pressure of between about 500 psi and about 5000 psi to convert at least a portion of the polymorphie
Form I of (5)-2-( l-(9H-purin-6-ylamino)propy])-5-fluoro-3-phenylquinazolin-4(3//)-one to the polymorphie Form II described herein.
[0033] In some embodiments, the compressing is performed using a tablet press or a rotary press. In some embodiments, the polymorphie Form I is compressed at a pressure of between 500 psi and 2000 psi, between I000 psi and 4500 psi, or between 3000 psi and 4500 psi.
[0034] Provided is also a polymorph of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one which is bioequivalent to the polymorphie Form II described herein.
[0035] ln some embodiments, the polymorphie Form II described herein is isolated. In some embodiments, the polymorphie Form II described herein is a substantially pure polymorph.
[0036] Provided is also composition comprising the polymorphie Form II described herein, wherein the composition is substantially free of polymorphs other than polymorphie
Form II of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one.
[0037] In other embodiments, at least about 95% of the (5)-2-(1 -(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one présent in the composition is polymorphie Form II. In yet other embodiments, at least 96%, at least 97%, at least 98%, or at least 99% ofthe (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin20 4(3/7)-one présent in the composition is the polymorphie Form II described herein.
[0038] In other embodiments, less than about 5% of the (5)-2-( I-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one présent in the composition are polymorphs other than polymorphie Form II. In yet other embodiments, less than about 4%, less than about 3%, less than about 2%, less than about 1% of the (5)-2-(1-(9H-purin-625 ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one présent in the composition are polymorphs other than polymorphie Form II.
[0039] Provided is also a pharmaceutical composition including the polymorphie Form II described herein and one or more pharmaceutically acceptable carriers or excipients.
|0040] Provided is also a kit including the polymorphie Form II and packaging. Provided is also a kit including the composition of polymorphie Form II and packaging.
10041 ] Provided is a method of preparing the polymorphie Form II described herein, by:
a) providing a polymorphie Form I of (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one; b) grinding the polymorphie Form I; and c) stirring the ground polymorphie Form I in a solvent to form the polymorphie Form II described herein. In one embodiment, provided is a method for preparing the polymorphie Form II described herein, by grinding the polymorphie Form I of (5)-2-(1-(9 H-purin-6-yIamino)propyI)-5-fluoro-3phenylquinazolin-4(3J/)-one; and stirring the ground polymorphie Form I in a solvent to form the polymorphie Form II described herein. In certain embodiments, the polymorphie Form I is ground to a particlc size ofbetween about 1 microns to about 10 microns. In some embodiments, the method further indudes heating the ground polymorphie Form I stirred in the solvent to form the polymorphie Form II described herein. In some embodiments, the method further indudes isolating the polymorphie Form II. In certain embodiments, the stirred mixture is heated at a température of less than about 30°C. In one embodiment, the stirred mixture is heated at a température of between about 25°C and about 30°C. In other embodiments, the ground polymorphie Form I is stirred in the solvent at a température of between about I0°C and about 25°C. In some embodiments, the grinding may be performed using any suitable methods or techniques known to one of skill in the art, including for example using a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mill, a bail mill, or a combination of methods or techniques. In one embodiment, the grinding is performed using a bail mill. In some embodiments, the solvent indudes an organic solvent. In one embodiment, the solvent indudes acetone.
|00421 It should be understood, however, one or more of the steps of the method to préparé polymorphie Form II from polymorphie Form I may be omitted or the order ofthe steps may be varied. For example, in other embodiments, polymorphie Form 1 may be combined with a solvent before grinding to obtain the polymorphie Form II.
|0043| Provided is also a method of preparing the polymorphie Form H described herein, by: a) providing a polymorphie Form I of (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one; and b) compressing the polymorphie Form I at a pressure of between about 500 psi and 5000 psi to form the polymorphie Form II described herein. In one embodiment, provided is a method of preparing the polymorphie Form II described
II herein, by compressing the polymorphie Form I of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(J/7)-one at a pressure of between about 500 psi and 5000 psi to form the polymorphie Form II described herein. In some embodiments, the compressing is performed using a tablet press or a rotary press. In some embodiments, the polymorphie Form I is compressed at a pressure of between 500 psi and 2000 psi, between 1000 psi and 4500 psi, or between 3000 psi and 4500 psi.
[0044] Provided is also a method of treating a patient with a cancer, by administering to the patient a composition including the polymorphie Form II described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the cancer is a hématologie malignancy. In other embodiments, the hématologie malignancy is leukemia, wherein leukemia is non-Hodgkin’s lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In particular embodiments, the hématologie malignancy is leukemia or lymphoma. In spécifie embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom’s macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (BALL). The non-Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin’s lymphoma (iNHL).
[0045] Provided is also a composition comprising a mixture of polymorphie Form I and Form II of(S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. In some embodiments, the polymorphie Form I has an X-ray powder diffraction pattern comprising characteristic peaks at about 17.7 degrees 20 and about 24.9 degrees 20; and the polymorphie Form II has an X-ray powder diffraction pattern comprising a characteristic peak at about 18.6 degrees 20.
[0046] In certain embodiments of the composition, the X-ray powder diffraction pattern for the polymorphie Form I further comprises one or more characteristic peaks at about 14.3 degrees 20, about 17.2 degrees 20, about 20.9 degrees 20, and about 23.9 degrees 20. In one embodiment of the composition, the X-ray powder diffraction pattern for the polymorphie Form I has one or more characteristic peaks at about 14.3 degrees 20, about 17.2 degrees 20, about 17.7 degrees 20, about 20.9 degrees 20, about 23.9 degrees 20, and about 24.9 degrees 20.
[0047] In some embodiments of the composition, the X-ray powder diffraction pattern for the polymorphie Form II further comprises characteristic peaks at about 24.3 degrees 20 and about 14.0 degrees 20. In one embodiment ofthe composition, the X-ray powder diffraction pattern for the polymorphie Form I has one or more characteristic peaks at about 14.0 degrees 20, about 18.6 degrees 20, and about 24.3 degrees 20. In certain embodiments of the composition, the polymorphie Form I is présent in excess of the polymorphie Form II. In one embodiment of the composition, the polymorphie Form I and polymorphie Form II are présent in a ratio of between 99 to I and 55 to 45, or a ratio of 99 to 1,90 to 10,85 to 15, 80 to 20,75 to 25,70 to 30,65 to 35,60 to 40, or 55 to 45. In one embodiment, the weight ratio of polymorphie Form I to polymorphie Form II is between 90:1 and 99:1.
[0048] Provided is also a composition including a mixture of polymorphie Form I and polymorphie Form II of(S)-2-(I-(9H-purin-6-yIamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one, wherein the polymorphie Form I has an X-ray powder diffraction pattern substantially as shown in FIG. IA, and wherein the polymorphie Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 2A. In certain embodiments, the composition is substantially free of polymorphs other than polymorphie Form I and polymorphie Form II of (S)-2-(I-(9H-purin-6-yIamino)propyl)-5-fluoro-3-phenylquinazolin4(3Â/)-one.
[0049] Provided is also a pharmaceutical composition including the composition of a mixture of polymorphie Form I and polymorphie Form II and one or more pharmaceutical acceptable carriers or excipients. In one embodiment, the pharmaceutical composition is for oral administration. For example, the pharmaceutical composition may be in the form a tablet.
[0050] In some of the foregoing embodiments, the polymorph (e.g. polymorphie Form I, polymorphie Form II, or both) is not hygroscopic. In some ofthe foregoing embodiments, the polymorph (e.g. polymorphie Form I, polymorphie Form II, or both) is anhydrous or noncrystalline.
(0051 [ Provided is a polymorph of (5)-2-(1 -(9H-purin-6-yIamino)propyI)-5-fluoro-3phenylquinazolin-4(3//)-one, wherein the polymorph is Form III having an X-ray powder diffraction pattern substantially as shown in FIG. 10A.
[0052] Provided is a polymorph of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenyIquinazolin-4(3W)-one, wherein the polymorph is Form IV having an X-ray powder diffraction pattern substantially as shown in FIG. 11.
[0053] Provided is a polymorph of (5)-2-(I-(9H-purin-6-ylamino)propyI)-5-fluoro-3phenylquinazolin-4(3//)-one, wherein the polymorph is Form V having an X-ray powder diffraction pattern substantially as shown in FIG. 12.
[0054] Provided is a polymorph of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-315 phenylquinazolin-4(3//)-one, wherein the polymorph is Form VI having an X-ray powder diffraction pattern substantially as shown in FIG. 13.
[0055] Provided is a polymorph of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one, wherein the polymorph is Form VII having an X-ray powder diffraction pattern substantially as shown in FIG. 14A.
[0056] Provided is a polymorphie Form I of (5)-2-( I -(9H-purin-6-ylamino)propyI)-5fluoro-3-phenylquinazolin-4(37/)-one having a unit cell, as determined by crystal X-ray crystallography, ofthe following dimensions: a = 12.6971(7)Â; b = 11.3577(8) Â; c = 15.2065 (10) A; a = 90.00°; β = I04.112°; and γ = 90.00°.
[0057( Provided is a polymorphie Form II of (5)-2-( I-(9H-purin-6-ylamino)propyl)-525 fluoro-3-phenylquinazolin-4(3Â/)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a = 9.1183(3) A; b - 11.3299(3) A; c = 20.7936(5) A; a = 90.00°; β » 98.498°; and γ = 90.00°.
[0058] Provided is a polymorphie Form 111 of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3/7)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a = 8.6133(4) A; b = 11.0763(5) A; c = 14,3996(7) A; a = 99.457°; β = 93.897°; and γ = 107.275°.
[0059] Provided is a polymorphie Form IV of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3/7)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a = 7.9394(5) A; b - 16.9606(11 ) A; c = 17.4405(13) A; a = 90.00°; β = 90.00°; and γ = 90.00°.
[0060] Provided is a polymorphie Form V of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3/7)-one having a unit cell, as determined by crystal X-ray crystallography, of the following dimensions: a = 9.2354(3) A; b = 9.7692(4)A; c = 35.4252(12) A; a = 90.00°; β = 90.00°; and γ = 90.00°.
DESCRIPTION OF THE FIGURES [0061] FIG. IA shows an X-ray powder diffraction pattern (XRPD) pattern of polymorph Form I of (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one. FIG. IB shows a difïerential scanning calorimetry (DSC) and thermographie analysis (TGA) graph of polymorph Form I of (5)-2-( I-(9H-purin-6-yIamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one.
[0062] FIG. 2A shows an XRPD pattern of polymorph Form II of (5)-2-( l-(9H-purin-6ylamino)propyI)-5-fluoro-3-phenylquinazolin-4(3/7)-one. FIG. 2B shows a DSC and TGA graph of polymorph Form II of (5)-2-(1-(9H-purin-6-ylamîno)propyl)-5-fluoro-3phenyIquinazolin-4(3/7)-one.
[0063] FIG. 3 shows XRPD patterns of Form I and Form II after 18 hours and 40 hours, where the Form I solids were bail milled and stirred in acetone at 28°C.
[0064] FIG. 4 shows XRPD patterns of polymorphie forms after wet grinding of Form I in acetone over a period of 1-8 days.
[0065] FIG. 5A shows an XRPD pattern of Form I solids before compression (top) and after compression (bottom). FIG. 5B shows XRPD patterns of compressed Form I solids at various pressures and duration, where from top to bottom the patterns are for the pressures and duration as indicated. FIG. 5C shows an XRPD of Form I compressed at 3000 psi for 60 minutes.
[0066] FIG. 6 shows XRPD patterns of Form I versus Form II at different températures, where from top to bottom the patterns are for the température as indicated.
[0067] FIG. 7 is a graph showing the trend of chord length (related to particle size) distribution during the conversion of bail milled Form I to Form II.
[0068] FIG. 8 is a graph showing Form II and Form I peak ratio (the peaks at 17.8 and
I8.6 degrees) during the conversion of bail milled Form I to Form II at lg and 10 g scales.
[0069] FIGS. 9A and 9B show the moisture content in Form I and II, respectively, over a range of relative humidities.
[0070] FIGS. 10A and 10B show an XRPD pattem and a TGA graph, respectively, of polymorph Form III of (S)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3Z/)-one.
|0071 ] FIG. 11 shows an XRPD pattem of polymorph Form IV of (S)-2-(l-(9H-purin-6ylamino)propyi)-5-fluoro-3-phenylquinazolin-4(3J7)-one.
[0072] FIG. 12 shows an XRPD pattem of polymorph Form V of (S)-2-(l-(9H-purin-615 ylamino)propyl)-5-fluoro-3-phenyIquinazoiin-4(3//)-one.
[0073] FIG. 13 shows an XRPD pattem of polymorph Form V! of (S)-2-(l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenyIquinazolin-4(3//)-one.
[0074] FIGS. 14A and 14B show an XRPD pattem and a TGA graph, respectively, of polymorph Form VII of(S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyIquinazolin20 4(3//)-one.
DETAILED DESCRIPTION [0075] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions ofspécifie devices, techniques, and applications are provided only as examples. Various modifications to the examples 25 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. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.
[0076] Terms used in the singular will also include the plural and vice versa.
|0077] The use of the term “about” includes and describes the value or parameter per se.
For exemple, “about x” includes and describes “x” per se. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/- 5%.
Polymorphs of (5}-2-(l-(9II-purîn-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(377)-one and Compositions Thereof [0078] In some embodiments, the therapeutic use and commercialization of (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/Z)-one involves the development of a crystalline form of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-pheny!quinazolin4(3//)-one that is bioavailable and stable. Development dosage forms, including suitable oral unit dosage forms (such as tablets and capsules), is vital for commercialization of (5)-2-(115 (9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one dosage forms. As one of skill in the art wouid appreciate, variations in the crystal structure of a pharmaceutical drug substance may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently préparé doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product, particularly when formulated in a solid oral dosage form.
[0079| During the formulation process and the development of a commercial scale manufacturing process for (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenyIquinazolin-4(3/7)-one, two distinct crystalline forms, termed polymorph Form 1 and polymorph Form II, were observed. In particular, it was unpredictably observed that Form I partially converts to Form II upon compression, such as in the tableting process.
[0080] Spécifie processes were developed to consistently produce polymorphie Form I and Form II, and allowed the characterization of these polymorphie forms. The processes for the préparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.
[0081J Accordingly, in one aspect, the application discloses particular polymorphie forms o f (5)-2-( 1 -(9H-puri n-6-ylamino)propyl )-5 - fl uoro-3 -phenylqui nazoli n-4(3//)-one, a compound having the molecular structure shown below:
[0082] The compound name provided above is named using ChemBioDraw Ultra 12.0 and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature Systems and symbols. By way of example, the compound may be named or identified with common names, systematic or nonsystematic names, The nomenclature Systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Accordingly, the compound structure provided above may also be named or identified as 5-fluoro-3-phenyl-2-[(lS)-l(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one under IUPAC and 5-fl uoro-3-phenyl-2[(lS)-l-(9H-purin-6-ylamino)propyl]-4(3H)-quinazo!inone under CAS.
[0083] In one aspect is provided polymorphie Form I of (5)-2-(1 -(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3À/)-one, wherein the polymorph exhibits an X-ray powder diffraction pattern substantiaily as shown in FIG. IA. In other embodiments, polymorphie Form I exhibits a differential scanning calorimetry pattern substantiaily as shown in FIG. IB.
[0084] In some embodiments, the term “substantiaily as shown in” when referring to an X-ray powder diffraction pattern or a differential scanning calorimetry pattern means that a pattern that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or déviations, when considered by one of ordinary skill in the art.
[0085] In other embodiments, polymorphie Form I is characterized as having a melting température onset as determined by differential scanning calorimetry at about 254°C. In yet other embodiments, polymorphie Form I is characterized as an anhydrous, crystalline solid.
In yet other embodiments, polymorph Form I is substantially free of water, substantially free of solvent, or a combination thereof.
J0086] In some embodiments of polymorphie Form I, at least one, at least two, at least three, at least four, or ail of the following (a)-(f) apply: (a) polymorphie Form I is anhydrous;
(b) polymorphie Form I is crystalline; (c) polymorphie Form I has an X-ray powder diffraction pattern substantially as shown in FIG. IA; (d) polymorphie Form I has a differential scanning calorimetry thermogram substantially as shown in FIG. IB; (e) a melting température onset as determined by differential scanning calorimetry at about 254°C; and (f) polymorph Form I absorbs less than 1 wt% moisture at 90% relative humidity at 25°C.
[0087] In some embodiments, polymorphie Form I comprises at least one, at least two, or ail of the following properties:
(a) having an X-ray powder diffraction pattern substantially as shown in FIG. 1 A;
(b) having a differential scanning calorimetry thermogram substantially as shown in FIG. IB; and (c) a melting température onset as determined by differential scanning calorimetry at about 254°C.
[0088] In some embodiments, the polymorphie Form I has an X-ray powder diffraction pattern displaying at least two of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. IA. In some embodiments, the polymorphie Form I has an Xray powder diffraction pattern displaying at least three of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1 A. In some embodiments, the polymorphie Form I has an X-ray powder diffraction pattern displaying at least four of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1 A. In some embodiments, the polymorphie Form I has an X-ray powder diffraction pattern displaying at least fîve of the largest peaks as the X-ray powder diffraction pattern substantially as shown in FIG. 1 A. In some embodiments, the polymorphie Form I has an Xray powder diffraction pattern displaying at least six of the largest peaks as the X-ray powder diffraction pattem substantially as shown in FIG. IA.
[0089] In certain embodiments, the polymorphie Form I has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles expressed in degrees 20 of about 14.3, about 17.2, about 17.7, about 20.9, about 23.9 and about 24.9. In one embodiment, the polymorphie Form I has an X-ray powder diffraction pattern having a characteristic peak at a diffraction angle expressed in degrees 20 of about 17.7 degrees 20. In another embodiment, the polymorphie Form I has an X-ray powder diffraction pattern having a characteristic peak at a diffraction angle expressed in degrees 20 of about 17.7 and about 24.9. In yet another embodiment, the polymorphie Form I has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles expressed in degrees 20 of 14.3, 17.2, 17.7,20.9, 23.9 and 24.9. It should be understood that relative intensifies can vary depending on a number of factors, including sample préparation, mountîng, and the instrument and analytical procedure and settings used to obtain the spectrum. As such, the peak assignments listed herein are intended to encompass variations of plus or minus 0.2 degrees 20.
[0090] In another aspect is provided polymorphie Form II of (5)-2-(1 -(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquÎnazolin-4(3//)-°ne» wherein the polymorph exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 2A. In other embodiments, polymorphie Form II exhibits a differential scanning calorimetry pattern substantially as shown in FIG. 2B. In yet other embodiments, polymorphie Form II is characterized as an anhydrous, crystalline solid. In yet other embodiments, polymorph Form 11 is substantially free of water, substantially free of solvent, or a combination thereof.
|0091] In some embodiments of polymorphie Form II, at least one, at least two, at least three, or ail of the following (a)-(e) apply: (a) polymorphie Form II is anhydrous; (b) polymorphie Form II is crystalline; (c) polymorphie Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 2A; (d) polymorphie Form II has a differential scanning calorimetry thermogram substantially as shown in FIG. 2B; and (e) polymorphie Form II absorbs less than 1 wt% moisture at 90% relative humidity at 25°C.
[0092] In some embodiments, polymorphie Form II comprises at least one or both of the following properties:
(a) having an X-ray powder diffraction pattern substantially as shown in FIG. 2A; and (b) having a differential scanning calorimetry thermogram substantially as shown in FIG. 2 B.
[0093] In some embodiments, polymorphie Form II has a melting température that may be different from the melting température of polymorphie Form I.
[0094] In some embodiments, the polymorphie Form II has an X-ray powder diffraction pattern displaying at least two of the largest peaks as the X-ray powder diffraction pattern substantialiy as shown in FIG. 2A. In some embodiments, the polymorphie Form II has an X-ray powder diffraction pattern displaying at least three of the largest peaks as the X-ray powder diffraction pattern substantialiy as shown in FIG. 2A. In some embodiments, the polymorphie Form II has an X-ray powder diffraction pattern displaying at least four of the largest peaks as the X-ray powder diffraction pattern substantialiy as shown in FIG. 2A.
[0095] In certain embodiments, the polymorphie Form II has an X-ray powder diffraction pattern having one or more characteristic peaks at diffraction angles expressed in degrees 20 ofabout 14.0, about 18.6 and about 24.3. In one embodiment ofpolymorphie Form II, the Xray powder diffraction pattern has a characteristic peak at about 18.6 degrees 20. In another embodiment of polymorphie Form II, the pattern has characteristic peaks at about 18.6 degrees 20 and 14.0 degrees 20. In yet another embodiment of polymorphie Form II, the pattern has characteristic peaks at about 18.6 degrees 20 and 24.3 degrees 20. In yet another embodiment of polymorphie Form II, the pattern has characteristic peaks at about 14.0 degrees 20 and 24.3 degrees 20. In one embodiment, the polymorphie Form II has an X-ray powder diffraction pattern having one or more characteristic peaks at diffraction angles expressed in degrees 20 of 14.0, 18.6 and 24.3.
[0096] In another aspect, provided are compositions comprising the polymorphe (e.g., polymorphie Form I, polymorphie Form II, or both) as described herein. In some embodiments, the composition comprises polymorphie Form I, polymorphie Form II, or a combination thereof. In some embodiments, the composition incorporâtes polymorphie Form I. In other embodiments, the composition incorporâtes polymorphie Form 11.
[0097] In some embodiments are provided compositions incorporating the polymorphie
Form I as described herein, wherein the (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenyIquinazolin-4(3/7)-one within the composition is a substantialiy pure polymorphie
Form I. In particular embodiments of compositions incorporating the polymorphie Form I, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about
99% of the (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one présent in the composition is polymorphie Form I.
[0098[ In other embodiments of compositions incorporating the polymorphie Form I, the composition is substantially free of polymorphie Form II. In certain embodiments of compositions incorporating the polymorphie Form I, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (5)-2-(1-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one présent in the composition is polymorphie Form II.
[0099] In some embodiments of the compositions comprising polymorphie Form I, the composition is substantially free of amorphous or non-crystalline (5)-2-( l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazoIin-4(3//)*°ne. For example, in certain embodiments, the composition comprising the polymorphie Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one.
|0100] In other embodiments of the compositions comprising polymorphie Form I, the composition is substantially free of salts of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one. In one embodiment of the compositions comprising polymorphie Form I, the composition is substantially free of an HCl sait of (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. For example, in certain embodiments, the composition comprising the polymorphie Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of a sait of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. In one embodiment, the composition comprising the polymorphie Form I has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of an HCl sait of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one.
|0101 ] In some embodiments, the term “substantially pure” or “substantially free” with respect to a particular polymorphie form of a compound means that the polymorphie form contains about less than 30%, about less than 20%, about less than 15%, about less than 10%, about less than 5%, or about less than 1% by weight of impurities. In other embodiments, “substantially pure” or “substantially free of* refers to a substance free of impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, dégradation products, other polymorphie forms, water, and solvents.
[0102] In some embodiments of compositions incorporating the polymorphie Form I, the composition is substantially free of polymorphs other than polymorphie Form I. In other embodiments, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one présent in the composition are polymorphs other than polymorphie Form I. In yet other embodiments of compositions incorporating the polymorphie Form I, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the polymorphie Form 1 présent. Impurities may, for example, include by-products from synthesizing (5)-2-(I-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one, contaminants, dégradation products, other polymorphie forms, water, and solvents.
[0103] In some embodiments are provided compositions incorporating the polymorphie
Form II as described herein, wherein (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one within the composition is a substantially pure polymorphie Form II. In certain embodiments of compositions incorporating the polymorphie Form II, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about
99% of the (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one présent in the composition is polymorphie Form II.
[0104] In other embodiments of compositions incorporating the polymorphie Form II, the composition is substantially free of polymorphie Form I. In certain embodiments of compositions incorporating the polymorphie Form II, less than about 5%, less than about 4%, 25 less than about 3%, less than about 2% or less than about I% of the (5)-2-( 1 -(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one présent in the composition is polymorphie Form I.
[0105] In some embodiments of compositions incorporating the polymorphie Form 11, the composition is substantially free of polymorphs other than polymorphie Form IL In other embodiments, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-323 phenylquinazolin-4(377)-one présent in the composition are polymorphe other than polymorphie Form II.
[0106] In some embodiments of the compositions comprising polymorphie Form II, the composition is substantially free of amorphous or non-crystalline ($)-2-( l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(377)-one. For example, in certain embodiments, the composition comprising the polymorphie Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline ($)-2-( I-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenyl quînazol in-4 (3//)-one.
[0107] In other embodiments of the compositions comprising polymorphie Form H, the composition is substantially free of salts of ($)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(377)-one. In one embodiment of the compositions comprising polymorphie Form II, the composition is substantially free of an HCl sait of ($)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one. For example, in certain embodiments, the composition comprising the polymorphie Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight ofa sait of($)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/Z)-one. In one embodiment, the composition comprising the polymorphie Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of an HCl sait of ($)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4 (3H)-one.
[0108] In yet other embodiments of compositions incorporating the polymorphie Form II, impurities make up less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% ofthe total mass relative to the mass of the polymorphie Form II présent. Impurities may, for example, include by-products from synthesizing ($)-2(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/f)-one, contaminants, dégradation products, other polymorphie forms, water, and solvents.
[0109] In another aspect, provided are compositions comprising a mixture of two or more ofthe polymorphie forms described herein. In certain embodiments, provided is a composition comprising a mixture of polymorphie Form I and Form II as described herein. In some embodiments, the composition consists essentially of polymorphie Form 1 and 5%,
4%, 3%, 2%, 1%, or less than 1% of Form II. In other embodiments, the composition consists essentially of polymorphie Form II and 5%, 4%, 3%, 2%, 1%, or less than 1% of Form I.
[0110] In some embodiments ofthe compositions comprising a mixture of polymorphie
Form I and polymorphie Form II, the composition is substantially free of amorphous or noncrystalline (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. For example, in certain embodiments, the composition comprising a mixture of polymorphie Form I and polymorphie Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of amorphous or non-crystalline (5)10 2-( I -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(37/)-one.
[0111] In other embodiments of the compositions comprising a mixture of polymorphie
Form I and polymorphie Form II, the composition is substantially free of salts of (5)-2-(1 (9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyIquinazolin-4(3//)-one. In one embodiment of the compositions comprising a mixture of polymorphie Form I and polymorphie Form II, the 15 composition is substantially free of an HCl sait of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3//)-one. For example, in certain embodiments, the composition comprising a mixture of polymorphie Form I and polymorphie Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of a sait of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3*phenylquinazolin20 4(3/7)-one. In one embodiment, the composition comprising a mixture of polymorphie Form
I and polymorphie Form II has less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of an HCl sait of (5)-2-( l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolîn-4(3//)-one.
[0112] In another embodiment of the composition comprising a mixture of polymorphie 25 Form I and polymorphie Form II, the polymorphie Form I in the composition is présent in excess of polymorphie Form II. For example, in one embodiment of the composition comprising a mixture of polymorphie Form I and polymorphie Form II, the weight ratio of polymorphie Form I to polymorphie Form II in the composition is between 99 to 1 and 55 to 45, or about 60 to 40, about 70 to 30, about 75 to 25, about 80 to 20, about 85 to 15, about 90 30 to 10, about 95 to 5, or about 99 to 1. In one embodiment, the weight ratio of polymorphie
Form 1 to polymorphie Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphie Form II in the composition is présent in excess of polymorphie Form I. For example, the weight ratio of polymorphie Form II to polymorphie Form I in the composition is between 99 to 1 and 55 to 45, or about 60 to 40, about 70 to 30, about 75 to 25, about 80 to 20, about 85 to 15, about 90 to 10, about 95 to 5, or about 99 to 1. ln yet another embodiment, polymorphie Form I and polymorphie Form 11 are présent in approximately the same amounts in the composition.
[0113] In another embodiment, provided is a polymorph of (5)-2-( l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(JZ/)-one, wherein the polymorph is Form 111 having an X-ray powder diffraction pattern substantiaily as shown in FIG. 10. In yet another embodiment, provided is a polymorph of (5)-2-(1 -(9H-purin-6-y!amino)propyl)-5-fluoro-3phenylquinazolin-4(3f/)-one, wherein the polymorph is Form IV having an X-ray powder diffraction pattern substantiaily as shown in FIG. 11. ln yet another embodiment, provided is a polymorph of (5)-2-(1-(9H-purin-6-y4amino)propy!)-5-fluoro-3-pheny!quinazolin-4(3f/)one, wherein the polymorph is Form V having an X-ray powder diffraction pattern substantiaily as shown in FIG. 12. In yet another embodiment, provided is a polymorph of (5)-2-( 1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenj4quinazolin-4(3Z/)-one, wherein the polymorph is Form VI having an X-ray powder diffraction pattern substantiaily as shown in FIG. 13. ln yet another embodiment, provided is a polymorph of(5)-2-(1-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3f/)one» wherein the polymorph is Form VII having an X-ray powder diffraction pattern substantiaily as shown in FIG. 14. Provided are also compositions that include any of polymorphie Form ΠΙ, IV, V, VI or VII as described herein.
Préparation of the Polymorphe [0114] One method of synthesizing (5)-2-(1 -(9H-purin-6-ylamino)prop yl)-5-fluoro-3phenylquinazolin-4(J//)-one has been previously described in U.S. Patent No. 7,932,260. This reference is hereby incorporated herein by reference in its entirety, and specificaliy with respect to the synthesis of (5)-2-(1 -(9H-purin-6-ylamino)propyI)-5-fluoro-3phenjdquinazolin-4(3Z/)-one. The methods for preparing the polymorphe (including polymorphie Form I and Form II) may yield quantity and quality différences compared to the methods for preparing (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one produced on laboratory scale.
[0115] Polymorphie forms of (5)-2-( 1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3 phenylquinazolin-4(37/)-one hâve been discovered. The choice ofa particular température may affect the formation favoring one polymorphie form of (5)-2-(1 -(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one over another. In one aspect, polymorphie Form I described herein may be prepared by dissolving crude (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one in a solvent or solvent combination (e.g., by heating under reflux), followed by cooling the solution to a température of at least about 30°C. In certain embodiments, cooling the solution to a température between about 30°C and about 40°C, or more specifically between about 30°C and about 35°C or between about 35°C and about 40°C, may favor producing the polymorphie Form I over the polymorphie Form IL Suitable solvents may include, for example, water or an organic solvent (e.g., methanol, éthanol, propanol, isopropyl acetate, methyl t-butyl ether, dimethylsulfoxide, ethyl acetate, 2-methyl tetrahydrofuran, methyl ethyl ketone, and methyl isobutyl ketone, hexane, heptane), or a mixture thereof. In yet other embodiments, the method further includes isolating the solids, such as polymorphie Form I solids; washing the isolated solids; and drying the washed isolated solids to obtain substantially pure polymorphie Form I.
[0116] In other embodiments, polymorphie Form 1 may be obtained from a sait of (5)-2(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one, such as, for example, a hydrochloride sait of (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylqumazolin-4(3//)-one. In one embodiment, the hydrochloride sait of(5)-2-(1 -(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3À/)-one may be combined with a solvent or solvent combination to form an acidic mixture or solution. The solvent or solvent combination may be, for example, water and/or an organic solvent. In one embodiment, the solvent includes water, éthanol, or a mixture thereof. The acidic mixture or solution is then neutralized to form free (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one, and heated to convert at least a portion ofthe free (5)-2-( l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3Â/)-one to polymorphie Form I. In certain embodiments, polymorphie Form I crystals may be added to the neutralized mixture or solution before heating. The neutralized mixture or solution may be heated at a température of at least about 30°C, and more specifically between 40°C and 60°C, or about 50°C.
[0117] In another aspect, polymorphie Form II described herein can be prepared by converting a polymorphie Form I of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3Z/)-one to polymorphie Form II. Polymorphie Form I can be converted into polymorphie Form II by grinding or compression.
[0118] ln some embodiments, the method to préparé polymorphie Form II includes grinding the polymorphie Form [ to a micron particle size (e.g., between about 1 micron to about 10 microns); and stirringthe ground polymorphie Form [ in a solvent at a température of less than about 30°C to form the polymorphie Form II. In certain embodiments, the ground polymorphie Form I is stirred at a température of between about 25°C and about 30°C to form the polymorphie Form Π.
[0119] Certain solvents or solvent combinations used in the grinding method described above to préparé polymorphie Form II may favor the rate of formation of polymorphie Form II over the rate of formation of polymorphie Form I. For example, in certain embodiments, the use of acetone may increase rate of formation of polymorphie Form II over polymorphie
Form I. In one variation of the methods to préparé polymorphie Form II, polymorphie Form I of (S)-2-( 1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one is suspended in an acetone at a température less than about 30°C, or between about 25°C and about 30°C.
[0120] The grinding in the method described above to prépare polymorphie Form II may 20 be performed using any suitable methods or techniques known to one of skîll in the art, including for example, a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mill, a bail mill, or a combination thereof. In certain embodiments, the grinding is performed using a bail mill. Furthermore, as discussed above, stirring the suspension of polymorphie Form I in the solvent or solvent combinations described above at a température of between about 25°C and about 30°C may unexpectedly favor the production of the polymorphie Form II over polymorphie Form I.
[0121] In other embodiments, polymorphie Form II described herein can be prepared by compressing polymorphie Form I at a pressure of between about 500 psi and about 5000 psi to convert at least a portion of polymorphie Form I to polymorphie Form II. In certain embodiments, the polymorphie Form I is compressed at a pressure of between 1000 psi and about 4500 psi. Any suitable methods known in the art may be used to compress polymorphie Form I, including for example a tablet press or a rotary press. It should be understood that the compression duration may vary depending on the type of press used. For example, in some embodiments where a tablet press is used, the polymorphie Form 1 may be compressed for about 30 seconds, about I minute, or up to about 5 minutes to produce polymorphie Form II. In other embodiments where a rotary press is used, the polymorphie Form I may be compressed in less than about 1 second, or between about 1 second to about 30 seconds to produce polymorphie Form II.
[01221 Compressing polymorphie Form I of (S)-2-( l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3//)-one unexpectedly converts at least a portion of polymorphie Form I into polymorphie Form II.
[0123| The other polymorphie forms described herein that are solvatés (e.g., Forms III, IV, V, VI and VII) can be prepared by converting polymorphie Form I into the other forms in the presence of one or more solvents. In some embodiments, polymorphie Form III can be prepared by mixing polymorphie Form I with water and isopropyl alcohol (IPA). In other embodiments, polymorphie Form IV can be prepared by mixing polymorphie Form I with dimethylformamide (DMF). In yet other embodiments, polymorphie Form V can be prepared by mixing polymorphie Form I with dimethylformamide (DMF). In yet other embodiments, polymorphie Form VI can be prepared by mixing polymorphie Form I with dichloromethane (DCM). In yet other embodiments, polymorphie Form V can be prepared by mixing polymorphie Form I with dimethylsulfoxide (DMSO). In yet other embodiments, polymorphie Form VII can be prepared by mixing polymorphie Form I with water and éthanol. In some of the foregoing embodiments to convert polymorphie Form I into one of polymorphie Forms III, IV, V, VI and VII, polymorphie Form I can be mixed with the one or more solvents at room température.
Pharmaceutical Compositions [0124| The polymorphie forms described herein can be administered as the neat chemical, but it is typical, and préférable, to admînister the compound in the form of a pharmaceutical composition or formulation. Accordingly, provided are pharmaceutical compositions that include the polymorphie forms described herein (e.g., Form I and/or Form II) and a biocompatible pharmaceutical carrier, excipient, adjuvant, or vehicle. The composition can include the polymorphie forms described herein either as the sole active agent or in combination with other agents, such as oligo- or polynucleotîdes, oligo- or polypeptides, drugs, or hormones mixed with one or more pharmaceuticafly acceptable carriers or excipients. Carriers, excipients, and other ingrédients can be deemed pharmaceutically acceptable insofar as they are compatible with other ingrédients of the formulation and not deleterious to the récipient thereof.
[0125] For example, in some embodiments, provided herein is a pharmaceutical composition comprising polymorphie Form I of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3//)-one, and a pharmaceutical acceptable carrier or excipient. In other embodiments, provided herein is a pharmaceutical composition comprising polymorphie Form II of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one, and a pharmaceutical acceptable carrier or excipient. In yet other embodiments, provided herein is a pharmaceutical composition comprising a mixture of polymorphie Form I and polymorphie Form II of (5)-2-( l-(9H-purin-6-y!amino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one, and a pharmaceutical acceptable carrier or excipient.
[0126] In one embodiment of the pharmaceutical composition, the polymorphie Form I in the composition is présent in excess of polymorphie Form II. For example, the weight ratio of polymorphie Form I to polymorphie Form Π in the pharmaceutical composition may be between 99 to I and 55 to 45, or may be 60 to 40,70 to 30, 75 to 25, 80 to 20, 85 to 15,90 to 10,95 to 5, or 99 to I. In one embodiment, the weight ratio of polymorphie Form I to polymorphie Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphie Form II in the pharmaceutical composition is présent in excess of polymorphie Form I. For example, the weight ratio of polymorphie Form II to polymorphie Form I in the pharmaceutical composition may be between 99 to I and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25,80 to 20,85 to 15,90 to 10,95 to 5, or 99 to 1. In yet another embodiment, polymorphie Form I and polymorphie Form II are présent in approximately the same amounts in the pharmaceutical composition.
(0127[ Techniques for formulation and administration of pharmaceutical compositions can be found in Remington ’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co, Easton, Pa., 1990. The pharmaceutical compositions described herein can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Depending on the condition being treated, these pharmaceutical compositions can be formulated and administered systemically or locally.
[0128] The pharmaceutical compositions can be formulated to contain suitable pharmaceutically acceptable carriers, and optionally can comprise excipients and auxiliaries that facilitate processing of the polymorphie forms described herein into préparations that can be used pharmaceutically. The mode of administration generally détermines the nature of the carrier. For example, formulations for parentéral administration can include aqueous solutions of the active compounds in water-soluble form. Carriers suitable for parentéral administration can be selected from among saline, bufiered saline, dextrose, water, and other physiologically compatible solutions. Preferred carriers for parentéral administration are physiologically compatible buffers such as Hanks's solution, Rtnger’s solution, or physiologically buffered saline. For tissue or cellular administration, pénétrants appropriate to the particular barrier to be permeated are used in the formulation. Such pénétrants are generally known in the art. For préparations including proteins, the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
[0129] Altematively, formulations for parentéral use can include dispersions or suspensions of polymorphie forms described herein prepared as appropriate oily injection suspensions. Suitable lipophilie solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycérides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, dextran, and mixtures thereof. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the préparation of highly concentrated solutions. Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT™ sériés available from Rohm America Inc. (Piscataway, N.J.). Emulsions, e.g,, oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants). Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonîte, agaragar, gum tragacanth, and mixtures thereof.
[0130J Liposomes containing the polymorphie forms described herein also can be employed for parentéral administration. Liposomes generally are derived from phospholipids or other lipid substances. The compositions in liposome form also can contain other ingrédients, such as stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both naturel and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology, Vol. XIV, p. 33, Academie Press, New York (1976).
[0131] In some embodiments, the polymorph or composition thereof disclosed herein is formulated for oral administration using pharmaceutically acceptable carriers well known in the art. Préparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, élixirs, suspensions, or powders. To illustrate, pharmaceutical préparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Oral formulations can employ liquid carriers similar in type to those described for parentéral use, e.g., buffered aqueous solutions, suspensions, and the like.
[0132] Preferred oral formulations include tablets, dragees, and gelatin capsules. These préparations can contain one or more excipients, which include, without limitation:
a) diluents, such as microcrystalline cellulose and sugars, including lactose, dextrose, sucrose, mannitol, or sorbitol;
b) binders, such as sodium starch glycol ate, croscarmellose sodium, magnésium aluminum silicate, starch from com, wheat, rice, potato, etc.;
c) cellulose materials, such as methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such as gum arabic and gum tragacanth, and proteins, such as gelatin and collagen;
d) disintegrating or solubilizing agents such as cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or a sait thereof, such as sodium alginate, or effervescent compositions;
e) lubricants, such as silica, talc, stearic acid or its magnésium or calcium sait, and polyethylene glycol;
f) flavorants and sweeteners;
g) colorants or pigments, e.g., to identify the product or to characterize the quantity (dosage) of active compound; and
h) other ingrédients, such as preservatives, stabliizers, swelling agents, emulsifying agents, solution promoters, salts for regulating osmotic pressure, and buffers.
10133( For example, provided is a tablet comprising one or more of the polymorphie forms described herein (e.g., Form I and/or Form II), and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the tablet comprises substantialiy pure polymorphie Form I of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4 (3//)-0 ne, and one or more pharmaceutically acceptable carriers or excipients. In other embodiments, the tablet comprises substantialiy pure polymorphie Form II of (5)-2-( I-(9 Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one, and one or more pharmaceutically acceptable carriers or excipients. In yet other embodiments, the tablet comprises a mixture of polymorphie Form I and polymorphie Form II of (5)-2-(1-(9H-purin6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3f/)‘°ne» andone or more pharmaceutically acceptable carriers or excipients.
|0134] In one embodiment of the tablet, the polymorphie Form I in the composition is présent in excess of polymorphie Form IL For example, the weight ratio of polymorphie Form I to polymorphie Form II in the tablet is between 99 to I and 55 to 45, or may be 60 to 40,70 to 30, 75 to 25,80 to 20,85 to 15,90 to 10,95 to 5, or 99 to I. In one embodiment, the weight ratio of polymorphie Form I to polymorphie Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphie Form II in the tablet is présent in excess of polymorphie Form I. For example, the weight ratio of polymorphie Form II to polymorphie Form I in the tablet is between 99 to I and 55 to 45, or may be 60 to 40,70 to 30, 75 to 25, to 20, 85 to 15,90 to 10,95 to 5, or 99 to 1. In yet another embodiment, polymorphie
Form I and polymorphie Form II are present in approximately the same amounts in the tablet.
[0135[ In any of the foregoing tablets, in one variation, the tablet is substantially free of amorphous or non-crystalline (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one. In any of the foregoing tablets, in one variation, the unit dosage form is substantially free of a sait of (5)-2-(I-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one (e.g;, an HCl sait of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3//)-one).
[0136] Provided herein are also methods of preparing a tablet comprising polymorphie Form I and polymorphie Form II of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one, wherein the method comprises compressing polymorphie Form I of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one under conditions suitable to produce polymorphie Form II of (5)-2-( l-(9H-purin-6-yIamino)propyl)5-fluoro-3-phenylquinazolin-4(3f/)-one. Suitable conditions may include, for example, applyïng a force of between about 500 psi and about 5000 psi, or between 1000 psi and about 4500 psi, during the tableting process.
[0137] Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc. In soft capsules, the active compounds can be dissoived or suspended in suitable fluids, such as fatty oils, liquid parafïin, or liquid polyethylene glycol with or without stabilizers.
[0138] Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
[0139] The compositions are preferably formuiated in a unit dosage form. The term “unit dosage forms” refers to physically discrète units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The polymorphs described herein are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the polymorph actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the âge, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
[0140] The tablets or pills described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tabiet or pii! can comprise an inner dosage and an outer dosage element, the latter being in the form of an envelope over the former. The two éléments can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner element to pass intact into the duodénum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymorphie acids and mixtures of polymorphie acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
]01411 For example, provided is a unit dosage comprising one or more of the polymorphie forms described herein (e.g., Form I and/or Form II). In one embodiment, the unit dosage comprises substantially pure polymorphie Form I of (5)-2-(1 -(9H-purin-6ylamino)propyl)-5-fIuoro-3-phenylquinazolin-4(3//)-one. In other embodiments, the unit dosage comprises substantially pure polymorphie Form II of (5)-2-( I-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. In yet other embodiments, the unit dosage comprises a mixture of polymorphie Form I and polymorphie Form II of (5)-2-(1(9H-purin-6-ylamino)propyl)-5-fIuoro-3-phenylquinazolin-4(3//)-one.
[0142] ln one embodiment of the unit dosage, the polymorphie Form I in the composition is présent in excess of polymorphie Form II. For example, the weight ratio of polymorphie Form I to polymorphie Form II in the unit dosage is between 99 to I and 55 to 45, or may be 60 to 40,70 to 30, 75 to 25,80 to 20,85 to 15,90 to 10,95 to 5, or 99 to I. In one embodiment, the weight ratio of polymorphie Form I to polymorphie Form II is between 90:1 and 99:1. In yet another embodiment, the polymorphie Form II in the unit dosage is présent in excess of polymorphie Form I. For example, the weight ratio of polymorphie Form II to polymorphie Form I in the unit dosage is between 99 to I and 55 to 45, or may be 60 to 40, 70 to 30, 75 to 25,80 to 20,85 to 15,90 to 10,95 to 5, or 99 to 1. In yet another embodiment, polymorphie Form I and polymorphie Form II are présent in approximately the same amounts in the unit dosage.
[0143| In any of the foregoing unit dosage forms, in one variation, the unit dosage form is substantially free of amorphous or non-crystalline (5)-2-(l-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3Z/)-one. In any of the foregoing unit dosage forms, in one variation, the unit dosage form is substantially free of a sait of (5)-2-( l-(9H-purin-65 ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one (e.g., an HCl sait of (5)-2-( 1-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one). In one embodiment, unit dosage form is a tablet comprising polymorphie Form I and polymorphie Form II of (5)-2-(1(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3Z/)-one, wherein the polymorphie Form II is produced upon applying a force to polymorphie Form I during the tableting process.
[01441 Provided herein are also methods of preparing a unit dosage comprising polymorphie Form I and polymorphie Form II of (5)-2-( I-(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3//)-one, wherein the method comprises compressing polymorphie Form I of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin15 4(3//)-one under conditions suitable to produce polymorphie Form II of (5)-2-(1 -(9H-purin6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. Suitable conditions may include, for example, applying a force of between about 500 psi and about 5000 psi, or between 1000 psi and about 4500 psi, during the tableting process.
Modes of Administration and Dosages [0145] Pharmaceutical compositions including the polymorphie forms described herein can be administered to the subject by any conventional method, including parenterai and enterai techniques. Parenterai administration modalities include those in which the composition is administered by a route other than through the gastrointestinal tract, for example, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intraarticular, intrathecal, and intraventricular injections. Enterai administration modalities include, for example, oral, buccal, sublingual, and rectal administration. Transepithelial administration modalities include, for example, transmucosal administration and transdermal administration. Transmucosal administration includes, for example, enterai administration as well as nasal, inhalation, and deep lung administration; vaginal administration; and buccal and sublingual administration. Transdermal administration includes passive or active transdermal or transcutaneous modalities, including, for example, patches and iontophoresis devices, as well as topical application of pastes, salves, or ointments. Parenterai administration also can be accomplished using a high-pressure technique, e.g., POWDERJECT™.
[0146] Moreover, the therapeutic index of the compound having the polymorphie forms described herein can be enhanced by modifying or derivatizîng the compound for targeted delivery to cancer cells expressing a marker that identifies the cells as such. For example, the compound can be linked to an antibody that recognizes a marker that is sélective or spécifie for cancer cells, so that the compounds are brought into the vicinity of the cells to exert their effects locally, as previously described. See e.g., Pietersz et al., Immunol. Rev., 129:57 (1992); Trail et al., Science, 261:212 (1993); and Rowlînson-Busza et al., Curr. Opin. Oncol.,
4:1142 (1992). Tumor-directed delivery of the compound can enhance the therapeutic benefit by, inter alla, minimizing potential nonspecific toxicities that can resuit from radiation treatment or chemotherapy. in some embodiments, the compound having a polymorphie form described herein, and radioisotopes or chemotherapeutic agents can be conjugated to the same anti-tumor antibody.
[0147] Pharmacokinetic and pharmacodynamie information about the polymorphie forms described herein and the formulation of the compound having a polymorphie form described herein can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for the compound having a polymorphie form described herein used in the methods described herein, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a désirable circulating concentration range that modulâtes P13KÔ expression or activity. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.
[0148] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animais, e.g., for determining the LDjo (the dose léthal to 50% of the population) and the EDjo (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the “therapeutic index”, which typically is expressed as the ratio
LDîo/ED5o. Compounds that exhibit large therapeutic indices, i.e., the toxic dose is substantiaily higher than the effective dose, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
[0149] It should be understood that any effective administration regimen regulating the timing and sequence of doses can be used. A compound having a polymorphie form 5 described herein and pharmaceutical compositions thereof may include those wherein the active ingrédient is administered in an effective amount to achieve its intended purpose.
[0150] In some embodiments, a “therapeutically effective amount” means an amount sufficient to modulate PI3KÔ expression or activity, and thereby treat an individual suffering an indication, or to alleviate the existing symptoms of the indication. Détermination of a ! 0 therapeutically effective amount is well within the capability of those skilled in the art, especiatty in light of the detailed disdosure provided herein.
[0151] Exemplary dosage levels for a human subject are of the order of from about 0.001 mitligram of active agent per kilogram body weight (mg/kg) to about 1000 mg/kg. Typically, dosage units of the active agent comprise from about 0.01 mg to about 1000 mg, preferably 15 from about 0.1 mg to about 100 mg, depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosage regimen is determined by the attending physicien in view of good medical practice, considering various factors that modify the action of drugs, e.g., the spécifie activity 20 of the compound, the identity and severity of the disease state, the responsiveness of the patient, the âge, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and toterance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations 25 mentioned herein is done routinely by the skilled practitioner without undue expérimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
[0152] The frequency ofdosing dépends on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrète doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent. Short-acting pharmaceutical compositions (i.e,, short half-life) can be administered once a day or more than once a day (e.g., two, three, or four times a day). Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks.
Bioequlvalents of the Polymorphs [0153] Also provided herein are polymorphs that are bioequivalent to the polymorphie Form 1 and the polymorphie Form II described herein.
[0154] In certain embodiments, bioequivalence between two polymorphs refers to polymorphs having substantially similar bioavailability, substantially similar eflicacy, substantially similar safety profiles, or a combination thereof.
[0155] In yet other embodiments, bioequivalence refers to polymorphs that exhibit substantially similar pharmacokinetic profiles or therapeutic effects. Bioequivalence may be demonstrated through several in vivo and in vitro methods. These methods may include, for example, pharmacokinetic, pharmacodynamie, clinical and in vitro studies. In some embodiments, bioequivalence can be demonstrated using any suitable pharmacokinetic measures or combination of pharmacokinetic measures known in the art, including loading dose, steady-state dose, initial or steady-state concentration ofdrug, biological half-life, élimination rate, area under the curve (AUC), clearance, the peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency. In some embodiments, bioequivalence is achieved with similar dosing amounts. In alternative embodiments, bioequivalence is achieved with different dosing amounts.
Therapeutic Use of the Polymorphs and Compositions Thereof [0156] Provided are also a use of the polymorphs or compositions thereof described herein to selectively or specifically inhibiting P13K8 activity therapeutically or prophylactically. The method comprises administering the polymorphs or compositions thereof to an individual in need thereof in an amount suflicient to inhibit PI3K5 activity. The method can be employed to treat humans or animais sufiering from, or subject to, a condition whose symptoms or pathology is mediated by PI3K6 expression or activity.
[0157] In some embodiments, “treating” refers to preventîng a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it; inhibiting the disorder, i.e., arresting its development; relîeving the disorder, i.e., causing its régression; or ameliorating the disorder, i.e., reducing the severity of symptoms associated with the disorder. In some embodiments, “disorder” is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
[0158] The methods disclosed in the application embrace various modes of treating an animal subject, preferably a mammal, more preferably a primate, and still more preferably a human. Among the mammalian animais that can be treated are, for example, humans; companion animais (pets), including dogs and cats; farm animais, including cattle, horses, sheep, pigs, and goats; laboratory animais, including rats, mice, rabbits, guinea pigs, and nonhuman primates; and zoo specimens. Among the non-mammalian animais that can be treated include, for example, birds, fish, reptiles, and amphibians.
[0159] In one aspect, the polymorphs and compositions thereof described herein can be employed in methods of inhiblting the growth or prolifération of cancer cells of hematopoietic origin, such as cancer cells. In some embodiments, the cancer cells are of lymphoid origin, and in spécifie embodiments, the cancer cells are related to or derived from B lymphocytes or B lymphocyte progenitors. Cancers amenable to treatment using the method disclosed in the application include, without limitation, Iymphomas (e.g., malignant neoplasms of lymphoid and réticuloendothélial tissues, such as Burkitt’s lymphoma, Hodgkins’ lymphoma, non-Hodgkins’ Iymphomas, lymphocytic Iymphomas); multiple myetomas; leukemias (e.g., lymphocytic leukemîas, chronic myeloid (myelogenous) teukemias). Other cancercells, ofhematopoietic origin or otherwise, that express pl 106 also can be treated by administration of the polymorphs and compositions thereof described herein.
[0160] In particular embodiments, the cancer is leukemia or lymphoma. In spécifie embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom’s macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The nonHodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin’s lymphoma (iNHL).
[0161] In another aspect, the polymorphe and compositions thereof described herein can be employed in methods of treating a patient with a cancer. In some embodiments, the cancer is a hématologie maügnancy. In spécifie embodiments, the hématologie malignancy is leukemia (e.g., chronic lymphocytic leukemia) or lymphoma (e.g., non-Hodgkin’s lymphoma).
[0162] In yet another aspect, provided are methods of treating an individuai having a PI3K-mediated disorder by administering polymorphie Form I, polymorphie Form II, or a mixture of polymorphie Fonn I and polymorphie Fonn II of (5)-2-( l-(9H-purin-6ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one to the individuai. Provided are also methods of modulating PI3K an individuai by administering polymorphie Form I, polymorphie Fonn II, or a mixture of polymorphie Form I and polymorphie Fonn 11 of (5)-2(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one to the individuai. ln one variation, the polymorphie Fonn I, polymorphie Fonn II, or a mixture of polymorphie Form I and polymorphie Fonn II of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3/7)-one is substantially free of other polymorphie forms. In another variation, the polymorphie Form I, polymorphie Form II, or a mixture of polymorphie Form 1 and polymorphie Fonn II of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one is substantially free of amorphous or non-crystalline (5)-2-(1(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one. In another variation, the polymorphie Fonn I, polymorphie Fonn 11, or a mixture of polymorphie Form I and polymorphie Form 11 of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one is substantially free of amorphous or non-crystalline (5)-2-(1-(9H-purin-641 ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(5//)one substantiaily free of a sait of (5)-2(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/7)-one (e.g., a HCl sait of (5)-2-( 1 -(9H-puri n-6-ylamino)propyl)-5 - fluoro-3 -phenylqui nazol in-4(3//)-one).
[0163] In any of the foregoing methods, the polymorphie form may be administered to the individual as unit dosage, for example in the form of a tablet. Variations in which polymorphie Form II are administered in the form a tablet, the polymorphie Form II is produced upon compression of polymorphie Form I in the tableting process. For example, a force of between about 500 psi and about 5000 psi, between about 500 psi and about 5000 psi, or between 1000 psi and about 4500 psi, may be applied during the tableting process.
Articles of Manufacture and Kits [0164] Compositions comprising the polymorphs disclosed herein and formulated in a pharmaceutically acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, there also is contemplated an article of manufacture, such as a container comprising a dosage form of one or more polymorphie forms of (5)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3//)-one, and a label containing instructions for use ofthe compound.
[0165] In some embodiments, the article of manufacture is a container comprising a dosage form of polymorphie Form I of (5)-2-( I-(9H-purin-6-yIamino)propyI)-5-fluoro-3phenylquinazolin-4(3f/)One, and one or more pharmaceutically acceptable carriers or excipients. In other embodiments, the article of manufacture is a container comprising a dosage form of polymorphie Form II of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(5//)'one» and one or more pharmaceutically acceptable carriers or excipients. In yet other embodiments, the article of manufacture is a container comprising a dosage form of a mixture of polymorphie Form I and polymorphie Form II of (5)-2-(I-(9Hpurin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(5//)One, and one or more pharmaceutically acceptable carriers or excipients. In one embodiment of the articles of manufacture described herein, the dosage form is a tablet.
[0166] Kits also are contemplated. For example, a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition. The instructions for use in the kit may be for treating a PI3K-mediated disorder, including, for example, a hématologie malignancy. In certain embodiments, the instructions for use in the kit may be for treating leukemia. In one embodiment, the instructions for use in the kit may be for treating non-Hodgkin’s lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In certain embodiments, conditions indicated on the label can include, for example, treatment of cancer.
EXAMPLES [0167] The following examples are provided to further aid in understanding the embodiments disclosed in the application, and présupposé an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. The particular matériels and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to
Iimit the reasonable scope thereof.
[0168] The polymorphie forms of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3//)-one were characterized by various analytical techniques, including X-ray powder diffraction pattern (XPPD), differential scanning calorimetry (DSC), and thermographie analysis (TGA) using the procedures described below.
[0169] X-Ray Powder Diffraction'. XR.PD patterns were collected using a PANalytical X’Pert MPD Pro Powder X-Ray Diffractometer configured with réflectance stage with spinning, data acquisition range: 2*40 degrees 20, Copper (Cu) anode; Κα1/Κα2 radiation;
tube current 40 mA; tube tension 45 kV; automatic divergence and anti-scatter slits. Samples 20 were prepared for analysis by distributing solid material as a thin layer on a silicon holder.
Each holder was mounted on a reflectance/transmittance stage and rotated during data acquisition.
[0170] Differential scanning calorimetry: DSC was performed using a TA Instruments Q2000 DSC instrument. The sample was placed into an aluminum DSC pan, and the weight 25 accurately recorded. The pan was covered with a lid, and then either crimped or hermetically sealed. The same cell was equilibrated at 25°C and heated under a nitrogen purge at a rate of 10°C/min, up to a final température of 300°C. Indium was used as the calibration standard.
[0171] Thermogravimetric analysis: TGA was performed using a TA Instruments Q5000
TGA instrument. Each sample was placed in an aluminum sample pan and inserted into the
TG fùmace. The fùmace was first equilibrated at 25°C, and then heated under nitrogen at a rate of 10°C/min, up to a final température of300°C. The TGA fumace was calibrated using the magnetic Curie point method.
Example 1
Préparation of Form I [0172] 20.6 gof(S)-2-(I-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenyIquinazolin4(3H)-one was suspended in a mixture of 164 mL methanol and 36 mL water. Under stirring, the mixture was heated to reflux (about 66°C) for about 1.5 hours. Upon complété dissolution water was slowly added. The solution température was allowed to reach about 75 °C. When about 100 mL water was added solids were formed and the solution was then slowly cooled to about 30-35°C. Form I was isolated by vacuum filtration at about 35°C, and dried under vacuum at about 40°C. The dried solids were analyzed by XRPD and DSC. FIGS. IA and IB and depict the XRPD and DSC patterns of polymorphie Form I.
Example 2
Préparation of Form II from Form I bv Grinding [0173] Form I was prepared as described in Example I. Form I solids were bail milled in batches for 10 minutes at 30 Hz. Samples were analyzed by XRPD. Table I below summarizes the amount of polymorphie Form II observed from conversion of polymorphie Form I.
Table 1. Bail Milling Experiments
Scale (g) Solvents Temp (°C) Stirring mode Time (days) Form II Product (g)
10 20 vol acetone 28 magnetic 6 6.9
10 20 vol acetone 28 magnetic 5 5
10 20 vol acetone + 20 vol MTBE 28 magnetic 7 6.5
10 acetone 10/28 magnetic 5 6
37 14 vol acetone + 14 vol MTBE 10/28 Half moon blade + magnetic 7 31.3
[0174] Results in Table 1 showed that Form I was successfully converted into Form II using the bail milling technique.
t [0175] Additionally, 1 Og of Form I was bail milled at 30 Hz for 10 minutes and stirred in 300 mL of acetone at 28°C. As seen in FIG. 3, about 50% conversion of Form I into Form II was observed after 18 hours, and about 90% conversion was observed after 40 hours.
Example 3
Comparison of Drv and Wet Grinding in Conversion of Form I into Form II [0176] Form I of (S)-2-( 1 -(9H-purin-6-ylamino)propyl)-5«fluoro-3-phenylquinazolin4(3H)-one was pre-processed using various grinding methods before forming a slurry in either acetone or THF and stirring at either room température, 22oC or 30oC. Table 2 below summarizes the conditions and the resuit ofthe experiment. As used in this Exampie, “enriched” describes a sample that contains substantially more Form II than Form I.
Table 2. Dry and Wet Grinding Experiments
Scale (g) Pre-processlng Slurry Solvent Temp fC) Stirring condition Form II content
0.2 Dry/wet grinding acetone r.t. magnetic Enriched after i day Highly enriched after 2 days
1 Dry/wet grinding acetone r.t. magnetic Trace amount after I week
20 Dry grinding acetone 30 overhead Undetectable after 3 days
5 High shear wet mill acetone 30 overhead Undetectable after 3 days
1 High shear mixer (dry) acetone r.t. magnetic Trace amount after i day
1 High shear mixer (dry) THF r.t. magnetic Trace amount after 1 day
I Jet milled acetone 22 magnetic Small amount after i day Enriched after 4 days
r.t. = room température [0177] The results in Table 2 above show that some Form I was converted into Form II at 15 small scale using dry grinding with mortar and pestle. In addition, Form I was converted into
Form II using jet milling after several days. Additionally, FIG. 4 shows an XRPD comparison of polymorphie forms over a period of 8 days, where Form I solids were suspended in acetone after wet grinding.
Example 4
Préparation of Form ÎI from Form î by Compression [0178] Form I of(S)-2-(!-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one was subjected to high pressure in a hydraulic tablet press (ENERPAC Mode! PI42 hydraulic press; #9166 0.275 inch punch) as shown in Table 3 below. The relaxation time is the time between compressions. A sample of the compressed solids was analyzed by XRPD and DSC. FIGS. 2A and 2B depict the XRPD and DSC patterns ofpolymorphie Form II.
Table 3. Compression conditions and observations
(5>2-(l-(9H-purIn-6ylam!no)propyl)-5fluoro-3phenylqu InazoIIn4(3Z7)-one (mg) Pressure (psi) Duration (min) Relaxation Time (hours) XRPD
NA atm — — Form I & minor II
-150 atm — Form I and II (excess of I)
-160 4500 <0.5 — Form 1 and II (excess of I)
-150 1000 <0.5 24 Form I and II (excess of I)
163 2000 5 72 I & II (-1:1)
167 2000 10 72 I & II (-1:1)
164 3000 5 2 I & II (-1:1)
168 3000 10 2 I & II (-1:1)
171 3000 60 72 I & II(excess of II)
[0179( Results of Table 3 indicated that Form I was partially converted to Form II during compression at the 100-200 mg scale. FIGS. 5A and 5B show XRPD patterns for two lots of Form I solids before and after compression at various pressures, respectively. FIG. 5C shows an XRPD pattern of compressed Form I solids using 3000 psi for 60 minutes. With reference to this figure, conversion of over 50% of Form 1 to Form II was observed under this condition.
Example 5
Effect of Température on Form Conversion in Acetone Suspension [0180] Form I of (S)-2-(I-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one was suspended in acetone at a concentration of 50 mg/mL, and stirred magnetically over a period of 5-6 days. Four experiments at different température were conducted.
[0181] Table 4 summarizes the réaction conditions and the amount of polymorphie forms observed for each of the four experiments. As used in this Example, “Enriched II” described a sample that contains substantially more Form II than Form I.
! 0 Table 4. Form 1 Suspensions in Acetone at température between 27°C and 37°C
(5)-2-( 1 -(9 H-pu rIn-6y Iamlno)propy l)-5-flu oro-3phenylqulnazoiin-4(3//)-one (mg/mL) Temp (°Q Suspens on Time (Days)
5 6
52 37 — Form 1
52 33 —— Form I
50 30 Enriched 11 ——
51 27 Enriched 11 —
[0182] From the results in Table 4 above, it was unexpectedly observed that the rate of conversion from Form 1 to Form II at 27°C and 30°C was higher than the rate of conversion at 33°C and 37°C.
Example 6
Effect of Température on Form Conversion of Solids [0183] DSC indicated close melting points for each polymorph and a solid-solid transition in Form II at about 115°C to produce Form I. To confirm this finding, 200-500 g of Form I of (S)-2-(l-(9H-purin-6-yIamino)propyl)-5-fluoro-3-pheny!quinazoIin-4(3H)-one was 20 heated at 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C and I20°C jacket température using
Destiny for 22 hours. Samples were analyzed by X-ray powder diffraction pattern, which are shown in FIG. 6. With référencé to this figure, conversion from Form I to Form II was observed at around 90°C.
Example 7
Hydrate Screen [0184] About 50 mg of Form I of (S)-2-(l-(9H-purin-6-y1amino)propyl)-5-fluoro-3phenylquinazolin-4(3H)-one was slurried in either (A) a Ι-mL mixture of a isopropyl alcohol (IPA) and water, or (B) a Ι-mL mixture of éthanol and water, for several days at room température. The results of the IPA/water and ethanol/water hydrate screens are summarized in Tables 5 and 6, respectively. As used herein, water activity (aw) in liquid phase corresponds to relative humidity in the atmosphère. For example, 0.5 aw is équivalent to 50% relative humidity.
Table 5. Hydrate screen results in IPA/water system
(5)-2-(1(9H-purInylamino)pro pyl>5fluoro-3phenylquin azolin4(3A0-one (mg) IPA/water aw (1 mL) IPA (mL) Water (mL) 48 Hour Solubility 48 Hour XRPD 15-16 Day Solubility 15-16 Day XRPD
86 0.2 0.16 9,84 24 Form l & Il 20 Form I & II
93 0.3 0.27 9.73 19 Form I & Il 19 Form I & II
85 0.4 0.4 9.60 18 Form I & II 20 Form I & II
113 0.5 0.56 9.44 23 Form i & Il 20 Form I & II
88 0.6 0.76 9.24 23 Form I & Il 24 Form I & Il
125 0.7 1.05 8.95 9.8 Form III 8.7 Form III
138 0.8 1.59 8.41 II Form III 9.5 Form III
121 0.9 6.62 3.38 I Form III 1 Form III
Table 6. Hydrate screen results in ethanol/water system
(5)-2-(l-(9Hpurin-6ylamino)propyl)5-fluoro-3phenylquinazolln4(3Zf)-one (mg) Ethanol/ Water (aw) Form TGA mass loss byI25°C % water (KF) % éthanol (GC) % éthanol (NMR) % éthanol (SCXC)
246 0.7 VII 16.41 14.2 TBD 4.9 TBD
281 0.8 VII 16.45 17.8 TBD 4.0 NA
295 0.9 I & VII NA NA NA NA NA
[0185] Results in Table 5 show that, when water activity in an IPA/water System was below 0.7, Form I was observed to slowly convert to Form II. Also, when water activity in IPA/water system was 0.7 to 0.9, a new crystalline Form III was observed. Form III of (S)-2(I-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazotin-4(3H)-one is a mixed solvate/hydrate.
[0186] In an ethanol/water system, when water activity was from 0.2 to 0.4, Form I was slowly converted to Form II (data not shown in Table 6 above). Additionally, when water activity was 0.5 and 0.6, no conversion was observed (data not shown in Table 6 above). Table 6 shows that, when water activity was 0.7 and 0.8, a new crystalline Form VII was observed. Form VII of (S)-2-(l-(9H-purin-6-ylamino)propyt)-5-fluoro-3-phenylquinazolÎn4(3H)-one was a mixed water/ethanol solvaté.
Example 8
Crystal Structure Analysis [0187] Polymorphie Forms I, III, IV and V of (S)-2-(l -(9H-purin-6-ylamino)propyl)-515 fluoro-3-phenylquinazolin-4(3H)-one were analyzed by single crystal X-ray crystallography. Polymorphie Form II was analyzed by capillary XRPD. Table 7 summarizes crystal structure data for these five polymorphs of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fluoro-3phenylquinazolin-4(3 H)-one.
Table 7. Crystal unit cell parameters
Form Density g/cm3 Unit Cell Dimensions
axis length (A) axis angle (°)
a b c a β γ
I anhydrous 1.297 12.6971 (7) 11.3577 (8) 15.2065 (10) 90.00 104.112 90.00
II anhydrous 1.299 9.1183 (3) 11.3299 (3) 20.7936 (5) 90.00 98.498 90.00
III IPA/water 1.323 8.6133 (4) 11.0763 (5) 14.3996 (7) 99.457 93.897 107.275
IV DMF 1.382 7.9394 (5) 16.9606 (H) 17.4405 (13) 90.00 90.00 90.00
V DMSO 1.350 9.2354 (3) 9.7692 (4) 35.4252 (12) 90.00 90.00 90.00
Example 9
Monitoring of Form Conversion [0188[ Conversion of Form I into Form II of (S)-2-(l-(9H-purin-6-ylamino)propyl)-55 fluoro-3-phenylquinazolin-4(3H)-one was monitored using three techniques: (1 ) a Lasentec Focused Beam Réflectance Measurement (FBRM) probe, (2) microscopy, and (3) XRPD.
Form I solids (lg and 10g) were first bail milled for 10 minutes, and then slurried in 20 volumes of acetone at 28°C.
[0189] FBRM probe: The conversion of Form I into Form II was monitored using a 10 Lasentec FBRM probe. FBRM monitors the particle counts and size during the run. FIG. 7 shows three distinct régions as represented by the three arrows.
Région I : the solids after bail milling broken up and partially dissolved
Région 2: Nucléation of form I (potentially also form II)
Région 3: Conversion of form I to form II
FIG. 7 shows the trend of chord length (related to particle size) distribution during the conversion of bail milled form I to form II.
[0190] Microscopy: After bail milling, the solids were observed to contain a significant amount of amorphous material, in addition to Form I and possibly Form II seed. When slurried in acetone, the amorphous material dissolved and precipitated as Form I (majority) 20 and Form II. At the last stage, Form I converts to Form II although some Form I crystals remain.
[0191] XRPD: The conversion ofForml into Form II was also monitored by XRPD. The XRPD analysis of the slurry in acetone showed that conversion was fast at first and then subsequently slowed down. FIG. 8 shows qualitative changes of solid form versus time, 25 which is in contrast with typical Systems where conversion starts slowly and accelerate ail the way to the end.
Example 10
Anhydrous Forms and Solid-Solid Transitions of Polymorphs [0192] The TGA traces shown in FIGS. 1B and 2B for polymorphie Form I and polymorphie Form H, respectively, support the characterization of anhydrous solids. These figures show minor mass loss below about 125°C.
Example 11
Hygroscopicitv of Form I and Form II [0193] FIGS. 9A and 9B show adsorption and desorption traces for polymorphie Form 1 and polymorphie II, respectively, at constant température over a range of humidities. Both graphs show that the polymorphs absorb less than 1 wt% moisture at 90% relative humidity at 25°C. This Example supports the non-hygroscopic nature of polymorphie Form I and polymorphie Form II.
Example 12
Isolation of Form 1 from Reaction Mixture [0194] A reaction vessei was charged with 5-fluoro-3-phenyl-2-(( I S)-1 -((9-(tetrahydro2H-pyran-2-yl)-9H-purin-6-yl)amino)propyl)quinazolin-4(3H)-one (35.1 grams), absolute éthanol (48 mL), water (24 mL), and 12N hydrochloric acid (HCl) (5 mL). The mixture was agitated at about 2i°C and additional I2N HCl was added in small portions to produce a solution. As the reaction progressed, a hydrochloride sait of(S)-2-(I-(9H-purin-620 ylamino)propyl)-5-fluoro-3-phenylquinazotin-4(3H)-one crystallized from solution, forming a suspension. After approximately two hours, the acidic reaction suspension was combined with 50 mL éthanol. The suspension was neutralized with aqueous sodium carbonate solution (5.5 grams in 50 mL water) via slow addition until the pH reached about 7.5. The volume of base used was about 35-40 mL. Form I seeds of (8)-2-(1-(9H-purin-625 ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (187 mg) were added to the reaction mixture. The mixture was agitated, and heated to about 50°C. Water (300 mL) was then added slowty until the éthanol fraction reached about 21% (v/v). Form 1 solids of (S)-2-(l(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one were isolated by filtration without cooling, washed with water, and dried under reduced pressure at about
40°C. The yield of dried Form 1 solids was 16.4 grams.

Claims (52)

  1. What is claimed is:
    1. A polymorph of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fIuoro-3-phenylquinazolin4(3H)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern comprising characteristic peaks, plus or minus 0.2 degrees 20, at 17.7 degrees 20 and 24.9 degrees 20.
  2. 2. The polymorph of claim 1, wherein the X-ray powder diffraction pattern further comprises characteristic peaks, plus or minus 0.2 degrees 20, at 14.3 degrees 20, 17.2 degrees 20,20.9 degrees 20, and 23.9 degrees 20.
  3. 3. A polymorph of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5-fIuoro-3-phenylquinazolin4(3/7)-one, wherein the polymorph is Form I having an X-ray powder diffraction pattern substantialiy as shown in FIG. IA.
  4. 4. A polymorph of (5)-2-( 1 -(9H-purin-6-ylamino)propyl)-5-fIuoro-3-phenylquinazolin4(3H)-one, wherein the polymorph is Form I having a unit cell, as determined by crystal X-ray crystallography, ofthe following dimensions: a = 12.6971(7)Â; b =
    11.3577(8) Â; c = 15.2065 (10) Â; a = 90.00°; β = 104.112°; and γ = 90.00°.
  5. 5. A polymorph of any one of daims 1 to 4 obtained by:
    a) combining (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3phcnylquinazolin-4(3//)-one with a solvent to form a mixture;
    b) heating the mixture to form a solution; and
    c) cooling the heated solution to form the polymorph of any one of daims 1 to 4.
  6. 6. The polymorph of claim 5, wherein the mixture is heated to a température of at least 50°C.
  7. 7. The polymorph of claim 5 or 6, wherein the heated solution is cooled to a température of at least about 30°C.
  8. 8. The polymorph of any one of daims 5 to 7, wherein the solvent comprises water, an organic solvent, or a mixture thereof.
  9. 9. The polymorph of any one of daims 1 to 8, wherein the polymorph is anhydrous.
  10. 10. The poiymorph of any one of claims 1 to 9, wherein the poiymorph is a substantially pure poiymorph.
  11. 11. A poiymorph of (5)-2-( ! -(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3Z/)-one which is bîoequivalent to the poiymorph of any one of claims 1 to 10.
  12. 12. A composition comprising the poiymorph of any one of claims ! to 11, wherein the composition is substantially free of polymorphs other than polymorphie Form I of (5)2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)-one.
  13. 13. A method of preparing the poiymorph of any one of claims 1 to 10 comprising:
    a) combining (5)-2-( 1 -(9H-purin-6-y!amino)propyl)-5-fluoro-3phenylquinazolin-4(37/)-one with a solvent to form a mixture;
    b) heating the mixture to form a solution; and
    c) cooling the heated solution to form the poiymorph of any one of claims 1 to
    10.
  14. 14. The method of claim 13, wherein the mixture is heated to a température of at least about 50°C.
  15. 15. The method of claim 13 or 14, wherein the solution is cooled to a température of at least about 30°C.
  16. 16. The method of any one of claims 13 to 15, further comprising: isolating the poiymorph as solids;
    washing the isolated solids; and drying the washed isolated solids.
  17. 17. The method of any one of claims 13 to 16, wherein the solvent comprises water, an organic solvent, or a mixture thereof.
  18. 18. A poiymorph of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-
    4 (3//)-one, wherein the poiymorph is Form II having an X-ray powder diffraction pattern comprising a characteristic peak, plus or minus 0.2 degrees 20, at 18.6 degrees
    20.
    ί
  19. 19. The polymorph of claim 18, wherein the X-ray powder diffraction pattem further comprises characteristic peaks, plus or minus 0.2 degrees 20, at 24.3 degrees 20 and 14.0 degrees 20.
  20. 20. A polymorph of (S)-2-(l-(9H-purin-6-ytamino)propyl)-5-fluoro-3-phenylquinazolin-
    5 4(3//)-one, wherein the polymorph is Form II having an X-ray powder diffraction pattem substantiaily as shown in FIG. 2A.
  21. 21. A polymorph of (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazotin4(3//)-one, wherein the polymorph is Form II having a unit cell, as determined by crystal X-ray crystallography, of the foliowing dimensions: a = 9.1183(3) A; b =
    10 II .3299(3) A; c = 20.7936(5) A; a = 90.00°; β = 98.498°; and γ = 90.00°.
  22. 22. A polymorph of any one of claims 18 to 21 obtained by:
    a) grinding polymoTphic Form I of (S)-2-(l-(9H-purin-6-ylamino)propyt)-5fluoro-3-phenylquinazolin-4(3//)-one; and
    b) stirring the ground polymorphie Form I in a solvent to form the polymoTph of
    15 any one of claims 18 to 21.
  23. 23. The polymorph of claim 22, wherein the polymorph is obtained by further heating the stirred mixture to form the polymorph of any one of daims 18 to 21.
  24. 24. The polymorph of claim 23, wherein the ground polymorphie Form I is stirred in the solvent at a température of between about 10°C and 30°C.
    20 25. The polymoTph of claim 24, wherein the ground polymorphie Form I is stirred in the solvent at a température of between about 10°C and 25°C.
    26. The polymorph of any one of claims 22 to 25, wherein the grinding is performed using a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mill, a bal! mill, or a combination thereof.
  25. 25 27. The polymoTph of any one of claims 22 to 26, wherein the solvent comprises an organic solvent.
  26. 28. The polymoTph of claim 27, wherein the solvent comprises acetone or isopropyl alcohol.
    z
  27. 29. A polymorph of any one of daims 18 to 21 obtained by compressing polymorphie Form I of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3//)one at a pressure of between about 500 psi and 5000 psi to convert at least a portion of the polymorphie Form I to a polymorph of any one of daims 18 to 21.
  28. 30. The polymorph of any one of daims 18 to 29, wherein the polymorph is anhydrous.
  29. 31. The polymorph of any one of daims 18 to 30, wherein the polymorph is a substantially pure polymorph.
  30. 32. A polymorph of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-
    10 4(3//)-one which is bioequi valent to the polymorph of any one of daims 18 to 31.
  31. 33. A composition comprising the polymorph of any one of daims 18 to 32, wherein the composition is substantially free of polymorphs other than polymorphie Form II of (5)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3/Z)-one.
  32. 34. A method of preparing the polymorph of any one of daims 18 to 21, comprising:
    15 a) grinding polymorphie Form I of (5)-2-(1 -(9H-purin-6-ylamino)propyl)-5fluoro-3-phenylquinazolin-4(3/7)-one; and
    b) stirring the ground polymorphie Form I in a solvent to form the polymorph of any one of daims 18 to 21.
  33. 35. The method of claim 34, further comprising heating the stirred mixture to form the
    20 polymorph of any one of daims 18 to 21.
  34. 36. The method of claim 35, wherein the ground polymorphie Form I is stirred in the solvent at a température of between about 10°C and 30°C.
  35. 37. The method of claim 36, wherein the ground polymorphie Form I is stirred in the solvent at a température of between about 10°C and 25°C.
    25
  36. 38. The method of any one of daims 34 to 37, wherein the grinding is performed using a mortar and pestle, a high shear wet mill, a high shear dry mixer, a jet mil), a bail mill, or a combination thereof.
  37. 39. The method of any one of claims 34 to 38, wherein the solvent comprises an organic solvent.
  38. 40. The method of claim 39, wherein the solvent comprises acetone or isopropyl alcohol.
  39. 41. A method of preparing a polymorph of any one of claims 18 to 21, comprising: compress in g polymorphie Form I of (5)-2-( l-(9H-purin-6-ylamino)propyl)-5-fluoro3-phenylquinazotin-4(3//)-one at a pressure of between about 500 psi and 5000 psi to form a polymorph of any one of claims 18 to 2 L
  40. 42. A composition comprising polymorphie Form I and polymorphie Form II of (5)-2-(1(9H-purin-6-ylamino)propyt)-5-fluoro-3-phenytquinazolin-4(3/7)One, wherein:
    the polymorphie Form 1 has an X-ray powder diffraction pattem comprising characteristic peaks, plus or minus 0.2 degrees 20, at 17.7 degrees 20 and 24.9 degrees 20; and the polymorphie Form 11 has an X-ray powder diffraction pattem comprising a characteristic peak, plus or minus 0.2 degrees 20, at 18.6 degrees 20.
  41. 43. The composition of claim 42, wherein:
    the X-ray powder diffraction pattem for the polymorphie Form 1 further comprises one or more characteristic peaks, plus or minus 0.2 degrees 20, at 14.3 degrees 20,
    17.2 degrees 20,20.9 degrees 20, and 23.9 degrees 20; and the X-ray powder diffraction pattem for the polymorphie Form 11 further comprises one or more characteristic peaks, plus or minus 0.2 degrees 20, at 24.3 degrees 20 and 14.0 degrees 20.
  42. 44. The composition of claim 42 or 43, wherein the weight ratio of polymorphie Form 1 to polymorphie Form 11 is between 90:1 and 99:1.
  43. 45. A composition comprising polymorphie Form 1 and polymorphie Form 11 of (5)-2-(1(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazotin-4(3//)-one, wherein the polymorphie Form I has an X-ray powder diffraction pattem substantially as shown in FIG. IA, wherein the polymorphie Form 11 has an X-ray powder diffraction pattem substantially as shown in FIG. 2A, wherein the composition is substantially free of polymorphs other than polymorphie Form I and polymorphie Form II of (5)-2-( 1-(9Hpuri n-6-ylami no)propyl )-5-fluoro-3-phenylquinazol i n-4(3//)-one.
  44. 46. A pharmaceutical composition comprising the polymorph of any one of daims 1 to
    5 11, and 18 to 32, and one or more pharmaceutically acceptable carriers or excipients.
  45. 47. A kit comprising the polymorph of any one of daims 1 to 11 and 18 to 32, and packaging.
  46. 48. A pharmaceutical composition comprising the composition of any one of daims 12, 33, and 42 to 45, and one or more pharmaceutical acceptable carriers or excipients.
    10
  47. 49. The pharmaceutical composition of daim 46 or 48, wherein the pharmaceutical composition is a tablet.
  48. 50. Use of a composition comprising the polymorph of any one of daims 1 to 11, and 18 to 32, and one or more pharmaceutically acceptable carriers or excipients, in the manufacture of a médicament for treating a patient in need of a cancer treatment.
    15
  49. 51. Use of a composition of any one of daims 12,33, and 42 to 45, or a pharmaceutical composition of any one of daims 46,48 and 49, and one or more pharmaceutically acceptable carriers or excipients, in the manufacture of a médicament for treating a patient with a cancer.
  50. 52. The use of claim 50 or 51, wherein the cancer is a hématologie malignancy.
    20
  51. 53. The used of claim 50 or 51, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin’s lymphoma (iNHL),
    25 refractory iNHL, non-Hodgkin’s lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom’s macroglobulinemia (WM), T-cell lymphoma, Bcell lymphoma, and diffuse large B-cell lymphoma (DLBCL).
  52. 54. The use of claim 50 or 51, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), indolent non-Hodgkin’s lymphoma (iNHL), and refractory iNHL.
OA1201400405 2012-03-05 2013-03-05 Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin4(3H)-one OA17123A (en)

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Application Number Priority Date Filing Date Title
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OA17123A true OA17123A (en) 2016-03-28

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