NZ723714B2 - Crystalline solid forms of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, processes for making, and methods of use - Google Patents
Crystalline solid forms of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, processes for making, and methods of use Download PDFInfo
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- NZ723714B2 NZ723714B2 NZ723714A NZ72371415A NZ723714B2 NZ 723714 B2 NZ723714 B2 NZ 723714B2 NZ 723714 A NZ723714 A NZ 723714A NZ 72371415 A NZ72371415 A NZ 72371415A NZ 723714 B2 NZ723714 B2 NZ 723714B2
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Abstract
The invention relates to novel crystalline solid forms of the chemical compound N- {4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl } -N'-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide (Compound 1), and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib. pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.
Description
Crystalline Solid Forms of (6,7-Dimethoxyquinolinyl)oxy]phenyl}-N′-(4-
fluorophenyl) cyclopropane-1,1-dicarboxamide, ses for Making, and Methods of
Priority Claim
This application claims priority to United States Application Serial No.
61/939,985, filed February 14, 2014. The entire contents of the aforementioned ation
are incorporated herein by referenced.
Field of the Invention
The invention relates to novel crystalline solid forms of the chemical compound
(6,7-dimethoxyquinolinyl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-
dicarboxamide, and solvates thereof, including hydrates, that are useful for the treatment of
. Also disclosed are pharmaceutical compositions comprising the crystalline solid
forms and processes for making the crystalline solid forms, as well as methods of using them
for the treatment of cancer, particularly thyroid cancer, prostate cancer, cellular cancer,
renal cancer, and non-small cell lung carcinoma.
Background of the Invention
Commonly assigned PCT Patent Publication No. , incorporated
by reference herein in its entirety, discloses novel inhibitors of multiple receptor tyrosine
kinases (RTKs) implicated in tumor growth and enesis, pathologic bone remodeling,
and metastatic progression of cancer. In particular, the compound N-{4-[(6,7-
dimethoxyquinolinyl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide is
specifically described in as an RTK tor. The chemical ure of
N-{4-[(6,7-dimethoxyquinolinyl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-
dicarboxamide is represented by Compound 1.
Compound 1
Compound 1 was found to have an enzyme Ret IC50 value of about 5.2 nM
(dihydrate) and an enzyme c-Met IC50 value of about 1.3 nM (dihydrate). The assay that was
used to measure this c-Met activity is bed in paragraph [0458] in WO2005/030140.
During initial development experiments, Compound 1 (a free base) was found to
be a BCS class II nd having low solubility and high permeability. Because
Compound 1 was observed to have low solubility in water, it was initially considered
unsuitable for solid oral dosage development, and hence the pharmaceutical development
focused on finding a salt with suitable hygroscopicity, thermal stability, chemical stability,
physical stability, and solubility.
The malate salt of the Compound 1, as described in , the entire
contents of which is incorporated by reference, was subsequently identified as providing an
acceptable combination of crystallinity, solubility, and stability as compared to cabozantinib
free base. On er 29, 2012, the te salt of N-{4-[(6,7-dimethoxyquinolin
yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (also known as
cabozantinib or COMETRIQ®) was ed by the United States Food and Drug
Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).
In December 2013, the European Committee for Medicinal Products for Human Use (CHMP),
issued a positive opinion on the Marketing Authorization Application (MAA), submitted to
the European Medicines Agency, or EMA, for COMETRIQ for the ed indication of
progressive, unresectable, locally advanced, or atic MTC. Cabozantinib is being
evaluated in a broad development program, ing ongoing phase 3 pivotal trials in
metastatic renal cell cancer (RCC), and advanced hepatocellular cancer (HCC).
Besides therapeutic efficacy, the Applicant continues to endeavor to e
suitable form(s) of Compound 1 that have favorable properties related to sing,
manufacturing, storage stability, and/or usefulness as a drug. Accordingly, the discovery of
new lline solid forms of Compound 1 that possesses some or all of these desired
properties s vital to drug development. Thus, disclosed herein are novel crystalline
solid forms of Compound 1 that may be used in pharmaceutical compositions for the
treatment of proliferative diseases such as cancer.
] In this specification where nce has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents, or such sources of information, is not to be
construed as an admission that such documents, or such sources of information, in any
jurisdiction, are prior art, or form part of the common general knowledge in the art.
y of the Invention
These and other needs are met, and/or the public at least provided with a useful
choice, by the present invention, which is directed to novel crystalline solid forms of
Compound 1, as well as ceutical compositions containing, uses of, and processes for
making such crystalline solid forms. Methods for using such crystalline solid forms are
disclosed herein. The crystalline solid forms include free base crystalline solid forms, as well
as solvate, ing hydrate, crystalline solid forms. Among other uses, crystalline solid
forms of Compound 1 are useful for preparing pharmaceutical compositions expected to have
utility in treating cancer. Accordingly, one aspect of the invention pertains to a
pharmaceutical composition comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of a solid form of Compound 1.
[0008a] More specifically, in a first , the present invention provides a crystalline
solid form of Compound 1:
Compound 1
wherein the crystalline solid form is ed from nd 1 Form III and Compound
1 Form , having XRPD peaks (CuKα), wherein all peaks are measured in (º2θ ±
0.2 º2θ), as depicted in the following table:
Compound 1
Form III Form XXVIII
7.0 6.5
7.8 9.5
9.4 11.8
11.1 12.3
12.6 13.0
14.1 15.5
.5 16.9
17.3 17.7
22.3 19.1
Compound 1
Form III Form XXVIII
24.3 21.7
22.3
[0008b] In a second aspect, the present invention provides a pharmaceutical
composition comprising a therapeutically effective dose of a crystalline solid form of
Compound 1 as recited in the first aspect that contains at least 90 weight percent based
on the weight of such solid form; and a pharmaceutically acceptable carrier.
[0008c] In a third aspect, the present invention provides a ceutical composition
comprising a therapeutically effective dose of a mixture of crystalline solid forms of
compound 1 as recited in the first aspect and a pharmaceutically acceptable carrier.
[0008d] In a fourth aspect, the t invention provides a pharmaceutical
ition sing the crystalline solid form of Compound 1 as recited in the first
aspect for use in a method of treating cancer.
[0008e] In a fifth aspect, the present invention provides a pharmaceutical composition
for use in a method of treating diseases or disorders associated with rolled, abnormal,
and/or unwanted cellular activities due to cMET or RET pression, wherein the
pharmaceutical composition comprises at least one solid form of Compound 1 as recited in
the first aspect and a ceutically acceptable carrier, wherein the disease or disorder is
cancer.
[0008f] In a sixth aspect, the present invention provides a pharmaceutical formulation,
comprising:
ient (% w/w)
Compound I Solid Form III or XXVIII 31.68
as recited in the first aspect
Microcrystalline Cellulose 38.85
Lactose anhydrous 19.42
Hydroxypropyl Cellulose 3.00
Croscarmellose Sodium 3.00
Total Intra-granular 95.95
Silicon dioxide, dal 0.30
Croscarmellose Sodium 3.00
Magnesium Stearate 0.75
Total 100.00
[0008g] In a seventh , the present invention provides a pharmaceutical
formulation, comprising:
Ingredient (% w/w)
nd 1 Form III or XXVIII as 25.0-33.3
recited in the first aspect
Microcrystalline Cellulose q.s
Hydroxypropyl Cellulose 3
mer 0-3
Croscarmellose Sodium 6.0
Colloidal Silicon Dioxide 0.5
Magnesium Stearate 0.5-1.0
Total 100
[0008h] In an eighth aspect, the present invention es a pharmaceutical
formulation, comprising:
Ingredient Theoretical Quantity (mg/unit dose)
Compound 1 Form III or XXVIII as 100.0
recited in the first aspect
Microcrystalline Cellulose PH-102 155.4
Lactose Anhydrous 60M 77.7
Hydroxypropyl Cellulose, EXF 12.0
Croscarmellose Sodium 24
dal n Dioxide 1.2
ium Stearate (Non-Bovine) 3.0
Opadry Yellow Film Coating which 16.0
includes:
- HPMC 2910 /Hypromellose
6 cp
- Titanium dioxide
- Triacetin
- Iron Oxide Yellow
Total 416
[0008i] In a ninth aspect, the present invention provides a pharmaceutical formulation,
comprising:
Ingredient % w/w
Compound 1 Form III or XXVIII as recited 31.7
in the first aspect
Microcrystalline Cellulose (Avicel PH-102) 38.9
Lactose Anhydrous (60M) 19.4
Hydroxypropyl Cellulose (EXF) 3.0
Croscarmellose Sodium -Sol) 6.0
Colloidal Silicon Dioxide, 0.3
Magnesium te 0.75
Opadry Yellow Film Coating which 4.00
includes:
- HPMC 2910 /Hypromellose 6 cp
- Titanium dioxide
Ingredient % w/w
- Triacetin
- Iron Oxide Yellow
[0008j] In a tenth aspect, the t invention provides a s for producing
nd 1 Solid Form III as recited in the first aspect, the process comprising:
dissolving Compound 1 Solid Form I in tetrahydrofuran to a starting volume, wherein
Compound 1 Solid Form I is characterized by an x-ray powder diffraction pattern (CuKα)
comprising peaks at 10.1, 11.9, 12.9, 14.4, 16.0, and 23.6 (º2θ ± 0.2 º2θ);
ling about one-half of the starting volume;
adding methanol to e approximately the starting volume;
ing the distilling at least twice; and
collecting the Compound 1 Solid Form III.
[0008k] In an eleventh aspect, the present invention provides a process for producing
nd 1 Solid Form XXVIII as recited in the first aspect, the process comprising:
slurrying amorphous Compound 1 in nitromethane for 11 days;
collecting and drying resulting solids; and
desolvating the solids on a Thermogravimetric Differential Thermal Analyzer to
produce the Compound 1 Solid Form XXVIII.
[0008l] In a twelfth aspect, the present invention provides use of the crystalline solid
form of Compound 1 as recited in the first aspect in the manufacture of a ment for
ng cancer.
[0008m] In a thirteenth aspect, the present invention provides use of the lline
solid form of nd 1 as recited in the first aspect in the manufacture of a
medicament for treating diseases or disorders associated with uncontrolled, abnormal, and/or
unwanted cellular activities due to cMET or RET overexpression.
As indicated previously, Compound 1 inhibits multiple receptor tyrosine kinases
(RTKs) implicated in tumor growth and angiogenesis, pathologic bone remodeling, and
metastatic progression of cancer. Accordingly, crystalline solid forms of the Compound 1 are
useful for treating cancer. Thus, disclosed herein is a method for treating cancer comprising
administering to a subject a therapeutically ive amount of a solid form of nd 1
as disclosed herein. The invention is also directed to processes for ing crystalline solid
forms of Compound 1.
As a further aspect, any of the crystalline solid forms disclosed herein can be used
to make pharmaceutically acceptable salts of N-{4-[(6,7-dimethoxyquinolin
yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, including its S-malate
salt, which is sold as cabozantinib.
[00010a] In the description in this specification reference may be made to subject matter
which is not within the scope of the appended claims. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the invention
as d in the ed .
Brief Description the Drawings
Various aspects of the present invention are illustrated by reference to the
following drawings.
shows the experimental x-ray powder diffraction (XRPD) pattern of
amorphous nd 1 prepared by lyophilisation.
shows the experimental x-ray powder diffraction (XRPD) n for
Compound 1 Form I.
shows the thermogravimetric differential thermal analysis (TG/DTA)
thermogram for Compound 1 Form I, run from 30-300 °C at 10 °C/min.
shows the differential scanning calorimetry (DSC) thermogram for
Compound 1 Form I, run from 30-300 °C at 10 °C/min.
shows the Fourier transfer infrared (FT-IR) spectrum for Compound 1
Form I.
shows the 1H nuclear magnetic resonance (NMR) um for Compound
1 Form I.
shows the experimental x-ray powder diffraction (XRPD) pattern for
Compound 1 Form II.
shows the gravimetric differential thermal analysis (TG/DTA)
thermogram for crystalline Compound 1 Form II, run from 30-300 °C at 10 °C/min.
shows the differential scanning calorimetry (DSC) thermogram for
Compound 1 Form II, run from 30-300 °C at 10 °C/min.
shows the 1H nuclear magnetic resonance (NMR) spectrum for
Compound 1 Form II.
shows the mental x-ray powder diffraction (XRPD) n for
Compound 1 Form III.
shows the thermogravimetric differential thermal analysis A)
thermogram for Compound 1 Form III, run from 30-300 °C at 10 °C/min.
shows the differential ng calorimetry (DSC) thermogram for
Compound 1 Form III, run from 30-300 °C at 10 °C/min.
shows the Fourier transfer infrared ) um for Compound 1
Form III.
shows the 1H nuclear magnetic resonance (NMR) spectrum for
Compound 1 Form III.
shows the experimental x-ray powder diffraction (XRPD) n for
Compound 1 Form XXVIII.
shows the thermogravimetric differential thermal analysis (TG/DTA)
thermogram for Compound 1 Form XXVIII, run from 30-300 °C at 10 °C/min.
shows the differential scanning calorimetry (DSC) thermogram for
Compound 1 Form XXVIII, run from 30-300 °C at 10 °C/min.
] shows the Fourier transfer infrared (FT-IR) spectrum for Compound 1
Form .
shows the 1H nuclear magnetic resonance (NMR) spectrum for
Compound 1 Form .
shows the experimental x-ray powder diffraction (XRPD) pattern for
Compound 1 Form XXX.
shows the thermogravimetric differential thermal analysis (TG/DTA)
thermogram for Compound 1 Form XXX, run from 30-300 °C at 10 °C/min.
] shows the differential scanning calorimetry (DSC) gram for
Compound 1 Form XXX, run from 30-300 °C at 10 °C/min.
shows the Fourier transfer infrared (FT-IR) spectrum for Compound 1
Form XXX.
shows the 1H nuclear magnetic resonance (NMR) spectrum for
Compound 1 Form XXX.
shows the experimental x-ray powder diffraction (XRPD) pattern for
Compound 1 Form XXXI.
shows the thermogravimetric differential thermal analysis (TG/DTA)
thermogram for Compound 1 Form XXXI, run from 30-300 °C at 10 °C/min
shows the differential scanning calorimetry (DSC) thermogram for
Compound 1 Form XXXI, run from 30-300 °C at 10 °C/min.
shows the Fourier transfer infrared (FT-IR) spectrum for Compound
XXXI, Form I.
shows the 1H nuclear magnetic resonance (NMR) spectrum for
Compound 1 Form XXXI.
Detailed Description of the Invention
Definitions
When describing the compounds, compositions, and processes of the invention,
and methods disclosed herein, the ing terms have the following meanings unless
otherwise indicated.
[00042a] The term ising” as used in this specification and claims means “consisting
at least in part of”. When reting statements in this specification and claims which
include the term “comprising”, other features besides the features prefaced by this term in
each statement can also be present. Related terms such as ise” and “comprises” are to
be interpreted in a similar manner.
The term “solvate” means a complex or aggregate formed by one or more
molecules of a solute, i.e., a crystalline Compound 1, and one or more molecules of a solvent.
Such solvates typically have a substantially fixed molar ratio of solute and t. This term
also includes clathrates, including clathrates with water. Representative solvents include, for
example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is
water, the solvate formed is a hydrate.
“Therapeutically effective amount” means an amount sufficient to effect treatment
when administered to a subject in need of treatment. For e, a therapeutically effective
amount for, as described below. “The amount of a compound of the invention which
constitutes a “therapeutically ive amount” will vary depending on the compound, the
disease state and its severity, the age of the subject to be treated, and the like. The
therapeutically effective amount can be determined routinely by one of ry skill in the
art taking into consideration his own knowledge and to this disclosure. Thus, a
peutically effective ” of Compound 1 refers to an amount sufficient to treat a
t suffering from any of a variety of cancers associated with al cell proliferation
and angiogenesis. A therapeutically effective amount according to this disclosure is an
amount therapeutically useful for the treatment or prevention of the disease states and
disorders discussed herein. Compound 1 (including the solid state forms disclosed herein)
possess therapeutic activity to inhibit, regulate, and/or modulate the signal transduction of
kinases such as described in WO2005-030140.
“Treating” or “treatment” as used herein means the treatment of a disease-state in
a human, which disease-state is characterized by abnormal ar proliferation, and on
and includes at least one of: (i) preventing the disease-state from occurring in a human, in
particular, when such human is predisposed to the disease-state but has not yet been
diagnosed as having it; (ii) inhibiting the e-state, i.e., arresting its development; and (iii)
relieving the disease-state, i.e., causing regression of the e-state.
The term “pharmaceutically acceptable” refers to a material that is not
biologically or otherwise undesirable. For example, the term “pharmaceutically acceptable
carrier” refers to a material that can be incorporated into a composition and administered to a
subject without causing undesirable biological effects or interacting in a rious manner
with other components of the composition. Such pharmaceutically acceptable materials
typically have met the ed standards of toxicological and manufacturing testing and
include those materials fied as suitable inactive ingredients by the U.S. Food and Drug
Administration.
The term “dosage form” refers to a physically discrete unit suitable for dosing a
subject, i.e., each unit containing a predetermined quantity of a compound of the invention
calculated to produce the desired therapeutic effect either alone or in combination with one or
more additional units. For example, such unit dosage forms may be capsules, tablets, pills,
and the like.
As used herein, “amorphous” refers to a solid form of a molecule and/or ion that is
not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern
with sharp maxima.
As used herein, the term “substantially pure” means the solid form of nd
1 referred to contains at least about 90 weight percent based on the weight of such solid form.
The term “at least about 90 weight percent,” while not ing to limit the applicability of
the doctrine of equivalents to the scope of the claims, includes, but is not limited to, for
example, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97,
about 98, about 99, and about 100 weight percent, based on the weight of the solid form
referred to. The remainder of the solid form of nd 1 may comprise other solid )
of Compound 1 and/or reaction ties and/or processing impurities that arise, for
e, when the crystalline form is ed. The presence of reaction impurities and/or
processing impurities may be determined by analytical techniques known in the art, such as,
for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy,
and/or infrared spectroscopy.
Embodiments
This disclosure relates to solid e forms of Compound 1, as well as
unsolvated (otherwise known as “anhydrous” or “free base”) crystalline solid forms of
Compound 1. The forms disclosed herein each represent separate aspects of the sure.
gh the crystalline solid forms are described herein, the invention also relates to novel
compositions containing the disclosed lline solid forms. Therapeutic uses of the
crystalline solid forms described as well as therapeutic compositions containing them
represent separate aspects of the disclosure. The techniques used to characterize the
crystalline solid forms are described in the examples below. These ques, alone or in
combination, may be used to characterize the crystalline forms disclosed herein. The
crystalline solid forms may be also characterized by reference to the disclosed figures.
Crystalline solid forms of Compound 1
This sure relates to crystalline solid forms of Compound 1. The crystalline
solid forms include:
• A lline dihydrate form of Compound designated as Compound 1
Form I;
• A crystalline solvate form of Compound designated as Compound 1
Form II;
• A lline anhydrous (“free base”) form of Compound 1 designated
as Compound 1 Form III;
• A lline anhydrous (“free base”) form of Compound 1 designated
as Compound 1 Form XXVIII;
• A crystalline ous (“free base”) form of Compound 1 designated
as Compound 1 Form XXX; and
• A crystalline dihydrate form of Compound 1 designated as Compound
1 Form XXXI.
The names used herein to characterize a specific form, e.g. “Form I,” etc., are not
to be limited so as to exclude any other substance possessing similar or identical physical and
chemical characteristics, but rather such names are used as mere identifiers that are to be
interpreted in accordance with the characterization information presented herein.
Each form of nd 1 is a separate aspect of the disclosure. es of the
crystalline solid forms of Compound 1 are another aspect of the disclosure. Compound 1
Forms have various desirable properties for development.
Compound 1 Form I may be characterized by at least one of the following:
(i) an x-ray powder ction pattern (CuKα) comprising two or more peaks as
depicted in wherein measurement of the crystalline form is at an
ambient room ature; and
(ii) an x-ray powder diffraction (XRPD) spectrum substantially in accordance
with the pattern shown in
Compound 1 Form I may be terized by an x-ray powder diffraction n
(CuKα) comprising peaks at 10.1, 11.9, 12.9, 14.4, 16.0, 23.0, 23.6, and 24.7 (º2θ ± 0.2 º2θ).
In another embodiment, Compound 1 Form I may be characterized by an x-ray powder
diffraction pattern (CuKα) comprising peaks at 10.1, 11.9, 12.9, 14.4, 16.0, and 23.6 (º2θ ±
0.2 º2θ). In another embodiment, Compound 1 Form I may be characterized by an x-ray
powder diffraction pattern (CuKα) comprising peaks at 10.1 and 12.9 (º2θ ± 0.2 º2θ). In a
further embodiment, Compound 1 Form I may be characterized by an x-ray powder
diffraction pattern (CuKα) comprising peaks at 11.9, 14.4, 16.0, and 23.6 (º2θ ± 0.2 º2θ).
Other solid state properties which may be used to characterize Compound 1 Form
I are shown in the FIGS. (FIGS.3-6) and discussed in the examples below. For example,
thermogravimetric/differential analysis (TG/DTA) of Compound 1 Form I showed weight
loss of 6.5 percent, from 25-80 ºC, corresponding to the loss of 1.92 moles of water,
indicating that Compound 1 Form I is a dihydrate (. The copicity and the
on properties of Compound 1 Form I indicated very small weight gain between 40%
RH and 90% RH, indicating that Compound 1 Form I is stable and non-hygroscopic at higher
humidity.
nd 1 Form I can be prepared by agitating a mixture of Compound 1 Form
I or amorphous Compound 1 and THF at ambient temperature until the Compound 1 is
dissolved. Water is then added portionwise, and the mixture is stirred for a sufficient time.
The solid Compound 1 Form I is collected and dried.
Compound 1 Form II may be characterized by at least one of the following:
(i) an x-ray powder ction n (CuK α) comprising two or more peaks as
depicted in wherein measurement of the crystalline form is at an
ambient room temperature; and
(ii) an x-ray powder diffraction (XRPD) spectrum ntially in accordance
with the pattern shown in
In on embodiment, Compound 1 Form II may be characterized by an x-ray
powder diffraction pattern (CuKα) comprising peaks at 6.4, 11.6, 12.1, 12.6, 12.9, 14.8, 14.9,
18.0, 18.8, and 20.2 (º2θ ± 0.2 º2θ). In another ment, Compound 1 Form II may be
characterized by an x-ray powder ction n (CuKα) comprising peaks at 6.4, 11.6,
12.1, 12.6, 12.9, 14.8, 14.9, and 20.2 (º2θ ± 0.2 º2θ). In another embodiment, Compound 1
Form II may be characterized by an x-ray powder ction pattern (CuKα) sing
peaks at 11.6, 12.1, 12.6, 12.9, and 14.9 (º2θ ± 0.2 º2θ). In a further embodiment, Compound
1 Form II may be characterized by an x-ray powder diffraction pattern (CuKα) comprising
peaks at 6.4, 8.6, 14.9, and 20.2 (º2θ ± 0.2 º2θ).
Other solid state ties which may be used to characterize Compound 1 Form
II are shown in the FIGS. (FIGS.8-10) and discussed in the examples below. For example,
thermogravimetric/differential analysis (TG/DTA) of Compound 1 Form II showed weight
loss of 9.8 percent, attributable to the loss of a mixture of tetrahydrofuran (THF) and water
(.
Compound 1 Form II can be prepared by agitating a mixture of Compound 1 Form
I and THF at ambient temperature until the Compound 1 Form I is ved. Water is then
added portionwise, and the mixture is stirred for a sufficient time. The solid Compound 1
Form II is collected and dried.
] Compound 1 Form III may be characterized by at least one of the following:
(i) an x-ray powder diffraction pattern (CuKα) comprising two or more peaks as
depicted in , wherein measurement of the crystalline form is at an
ambient room temperature; and
(ii) an x-ray powder diffraction (XRPD) spectrum substantially in accordance
with the pattern shown in .
In one embodiment, Compound 1 Form III may be characterized by an x-ray
powder diffraction pattern (CuKα) comprising peaks at 7.0, 7.8, 9.4, 11.1, 12.6, 14.1, 15.5,
17.3 22.3, and 24.3 (º2θ ± 0.2 º2θ). In another embodiment, Compound 1 Form III may be
characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 7.0, 7.8,
9.4, 11.1, 12.6, 14.1, 22.3, and 24.3 (º2θ ± 0.2 º2θ). In another embodiment, Compound 1
Form III may be characterized by an x-ray powder diffraction pattern (CuKα) comprising
peaks at 9.4, 12.6, 22.3, and 24.3 (º2θ ± 0.2 º2θ). In a further ment, Compound 1
Form III may be characterized by an x-ray powder ction pattern (CuKα) comprising
peaks at 7.0, 7.8, 11.1, and 14.1 (º2θ ± 0.2 º2θ).
Other solid state properties which may be used to characterize Compound 1 Form
III are shown in the FIGS. (FIGS.12-15) and discussed in the es below. For example,
no weight loss was observed in the TG/DTA analysis of nd 1 Form III, indicating
that Compound 1 Form III is an anhydrous al (). The hygroscopicity and the
sorption properties of Compound 1 Form III indicated very small weight gain between 0%
RH and 80% RH, indicating that Compound 1 Form III is non-hygroscopic according to the
European Pharmacopeia classification.
Compound 1 Form III can be prepared by agitating a mixture of Compound 1
Form I and THF at ambient temperature until Compound 1 Form I is dissolved. The mixture
is then heated to a temperature of at least 40 °C and the pressure is reduced to approximately
100 torr. After approximately one-half of the volume of THF was removed by distillation,
methanol was added to the flask to achieve the approximate starting volume. This distillation
was repeated at least two times, and the mixture was returned to ambient temperature and
pressure. The resulting solids were collected and dried.
Compound 1 Form XXVIII may be characterized by at least one of the following:
(i) an x-ray powder diffraction n (CuKα) comprising two or more peaks as
depicted in , wherein measurement of the crystalline form is at an
ambient room temperature; and
(ii) an x-ray powder diffraction (XRPD) spectrum substantially in accordance
with the pattern shown in .
] In one embodiment, Compound 1 Form XXVIII may be terized by an x-ray
powder diffraction pattern (CuKα) comprising peaks at 6.5, 9.5, 11.8, 12.3, 13.04, 15.5, 16.9,
17.7, 19.1, 21.7 and 22.3 (º2θ ± 0.2 º2θ). In another embodiment, Compound 1 Form XXV III
may be characterized by an x-ray powder diffraction n (CuKα) sing peaks at 6.5,
9.5, 11.8, 12.3, 13.0, 17.7, 19.1, and 22.3 (º2θ ± 0.2 º2θ). In another embodiment, Compound
1 Form XXVIII may be terized by an x-ray powder diffraction pattern (CuKα)
comprising peaks at 9.5, 11.8, 13.0, and 22.3 (º2θ ± 0.2 º2θ). In a further embodiment,
Compound 1 Form XXVIII may be characterized by an x-ray powder diffraction n
(CuKα) comprising peaks at 6.5, 12.3, 17.7, 19.1 (º2θ ± 0.2 º2θ).
Other solid state properties which may be used to characterize Compound 1 Form
XXVIII are shown in the FIGS. (FIGS.17-20) and discussed in the examples below. For
example, no weight loss was observed in the TG/DTA analysis of Compound 1 Form XXVIII,
indicating that Compound 1 Form XXVIII is an anhydrous al (). The
hygroscopicity and the sorption properties indicated very small weight gain between 0% RH
and 80% RH, indicating that Compound 1 Form XXVIII is non-hygroscopic.
Compound 1 Form XXVIII can be prepared by combining Compound 1 Form I
and nol at low temperature (e.g., 0-10 ºC) for several days. The solid Compound 1
Form XXVIII was recovered by filtration and air dried. In an alternative procedure,
amorphous Compound 1 can be ed in nitromethane for several days at room temperature.
The resulting solid Compound 1 Form XXVIII are then collected, dried, and desolvated on a
TG/DTA at 110 °C for 15 minutes.
] Compound 1 Form XXX may be characterized by at least one of the following:
(i) an x-ray powder diffraction pattern (CuKα) comprising two or more
peaks as depicted in , wherein measurement of the lline
form is at an ambient room temperature; and
(ii) an x-ray powder ction (XRPD) spectrum substantially in
accordance with the pattern shown in .
In one embodiment, Compound 1 Form XXX may be characterized by an
x-ray powder diffraction pattern (CuKα) comprising peaks at 7.2, 7.5, 10.0, 12.0, 12.4,
13.5, 15.8, and 19.8 (º2θ ± 0.2 º2θ). In another ment, Compound 1 Form XXX
may be characterized by an x-ray powder ction pattern (CuKα) comprising
peaks at 7.2, 7.5, 10.0, 12.0, 12.4, 13.5, and 19.8 (º2θ ± 0.2 º2θ). In another
embodiment, Compound 1 Form XXX may be characterized by an x-ray powder
diffraction pattern (CuKα) comprising peaks at 10.0, 12.0, and 12.4 (º2θ ± 0.2 º2θ). In
a further embodiment, Compound 1 Form XXX may be characterized by an x-ray
powder diffraction pattern (CuKα) comprising peaks at 7.2, 7.5, 13.5, and 19.8 (º2θ ±
0.2 º2θ).
Other solid state properties which may be used to characterize Compound 1 Form
XXX are shown in the FIGS. (FIGS.21-25) and discussed in the examples below. For
example, no weight loss was observed in the TG/DTA analysis of Compound 1 Form XXX,
indicating that Compound 1 Form XXX is an anhydrous material 2). The
hygroscopicity and the on properties of Compound 1 Form XXX indicated that
Compound 1 Form XXX is hygroscopic according to the European Pharmacopeia
classification.
Compound 1 Form XXX can be prepared by adding amorphous Compound 1 to a
container. The container is placed unsealed inside a larger container that contains acetone.
After several days, the material can be ated on a TG/DTA at 105 °C for 25 minutes
followed by desolvation at 100 °C for 40 minutes to yield Compound 1 Form XXX.
Compound 1 Form XXXI may be characterized by at least one of the following:
(i) an x-ray powder ction pattern (CuKα) comprising two or more
peaks as depicted in , wherein measurement of the crystalline
form is at an ambient room temperature; and
(ii) an x-ray powder diffraction (XRPD) spectrum substantially in
accordance with the pattern shown in .
In one embodiment, Compound 1 Form XXXI may be characterized by
an x-ray powder diffraction pattern (CuKα) comprising peaks at 5.0, 10.0, 11.9, 13.0,
14.4, 16.1, 19.9, 21.4, and 23.8 (º2θ ± 0.2 º2θ). In another embodiment, Compound 1
Form XXXI may be characterized by an x-ray powder ction pattern (CuKα)
comprising peaks at 5.0, 10.0, 11.9, and 13.0 (º2θ ± 0.2 º2θ). In a further embodiment,
Compound 1 Form XXXI may be characterized by an x-ray powder diffraction
n (CuKα) comprising peaks at 14.4, 16.1, 19.9, and 23.8 (º2θ ± 0.2 º2θ).
Other solid state properties which may be used to characterize Compound 1 Form
XXXI are shown in the FIGS. (FIGS.27-30) and discussed in the examples below. For
example, 6.61 percent weight loss was observed in the TG/DTA analysis of Compound 1
Form XXXI, ting that Compound 1 Form XXXI is a dihydrate ().
Compound 1 Form XXXI can be prepared by stirring a mixture of Compound 1
Form III in 2-methyltetrahydrofuran at 0-10 °C for at least two weeks to allow for saturation.
Compound 1 Form I and Compound 1 Form XXXI were added, and the mixture was d
for several days to allow for complete conversion to Compound 1 Form XXXI. The solid
was recovered by vacuum filtration and dried on the filter.
In an embodiment, the disclosure relates to a solid form of Compound 1, as
described herein in any of the aspects and/or embodiments, which is substantially pure
Compound 1 Form I.
In another embodiment, the disclosure s to a solid form of Compound 1, as
described herein in any of the aspects and/or embodiments, which is ntially pure
Compound 1 Form II.
In r embodiment, the disclosure relates to a solid form of nd 1, as
described herein in any of the aspects and/or embodiments, which is ntially pure
Compound 1 Form III.
In another ment, the disclosure relates to a solid form of Compound 1, as
bed herein in any of the s and/or embodiments, which is substantially pure
Compound 1 Form XXVIII.
In another embodiment, the disclosure relates to a solid form of Compound 1, as
described herein in any of the aspects and/or embodiments, which is substantially pure
Compound 1 Form XXX.
In another embodiment, the disclosure s to a solid form of Compound 1, as
described herein in any of the aspects and/or embodiments, which is substantially pure
Compound 1 Form XXXI.
A further aspect of the disclosure relates to mixtures of the crystalline solid forms
of Compound 1 as described herein in any of the aspects and/or embodiments.
Each of the crystalline solid forms of Compound 1 described herein has unique
characteristics that can distinguish them one from another. These characteristics can be
understood by comparing the physical properties of the solid state forms which are ted
in the Examples below.
] In another embodiment, the invention is directed to, or disclosed herein is,
Compound 1 crystalline solid Form I, II, III, XXVIII, XXX, or XXXI with an XRPD
pattern selected from the group consisting of:
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
.1 6.4 7.0 6.5 7.2 5.0
11.9 11.6 7.8 9.5 7.5 10.0
12.9 12.1 9.4 11.8 10.0 11.9
14.4 12.6 11.1 12.3 12.0 13.0
16.0 12.9 12.6 13.0 12.4 14.4
23.0 14.8 14.1 15.5 13.5 16.1
23.6 14.9 15.5 16.9 15.8 19.9
24.7 18.0 17.3 17.7 19.8 21.4
18.8 22.3 19.1 23.8
.2 24.3 21.7
22.3
In another embodiment, the invention is directed to, or disclosed herein is,
Compound 1 crystalline solid Form I, II, II, XXVIII, XXX, or XXXI with an XRPD
pattern selected from the group consisting of:
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
.1 6.4 7.0 6.5 7.2 5.0
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
11.9 8.6 7.8 9.5 7.5 10.0
12.9 12.1 9.4 11.8 10.0 11.9
14.4 12.6 11.1 12.3 12.0 13.0
16.0 12.9 12.6 13.0 12.4 14.3
23.6 14.8 14.1 17.7 13.5 14.4
14.9 22.3 19.1 19.8 16.1
.2 24.3 22.3 19.9
23.8
In another embodiment, the invention is directed to, or disclosed herein is,
Compound 1 lline solid Form I, II, III, , XXX, or XXXI with an XRPD
pattern selected from the group ting of:
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
11.9 6.4 7.0 6.5 7.2 14.4
14.4 8.6 7.8 12.3 7.5 16.1
16.0 14.9 11.1 17.7 13.5 19.9
23.6 20.2 14.1 19.1 19.8 23.8
In another embodiment, the invention is directed to, or disclosed herein is,
Compound 1 crystalline solid Form I, II, III, , XXX, or XXXI with an XRPD
pattern selected from the group consisting of:
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
.1 11.6 9.4 9.5 10.0 5.0
12.9 12.1 11.5 11.8 12.0 10.0
12.6 12.6 13.0 12.4 11.9
12.9 22.3 22.3 13.0
14.9 24.3 14.3
In another embodiment, the invention is directed to, or disclosed herein is, a
crystalline solid form of compound 1 of claims 1-5 having an XRPD patterns as
represented by:
Compound 1
Form I Form III Form XXVIII Form XXX Form XXXI
Fig. 2 Fig. 11 Fig. 16 Fig. 21 Fig. 26
As indicated above the disclosed herein can be used to form the L-malate salt of
cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoloneyloxy)-phenyl]-amide
(4-fluoro–phenyl)-amide (cabozantinib). For example, L-malic acid can be added to a
solution of , cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoloneyloxy)-
phenyl]-amide (4-fluoro–phenyl)-amide free base in l, maintaining a temperature of
approximately 25°C. Carbon (0.5 kg) and thiol silica (0.1 kg) are then added, and the
resulting mixture is heated to approximately 78 °C, at which point water (6.0 kg) is added.
The reaction e is then filtered, followed by the addition of isopropanol (38.0 kg), and is
allowed to cool to approximately 25°C. The product is recovered by filtration and washed
with isopropanol (20.0 kg) and dried at approximately 65°C to afford the L-malate salt of
cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy- oneyloxy)-phenyl]-amide
(4-fluoro–phenyl)-amide.
Pharmaceutical Compositions and Methods of Treatment
Another aspect of this disclosure relates to a pharmaceutical composition
comprising at least one crystalline solid form of Compound 1 as described herein in any of
the aspects and/or embodiments, or combinations thereof, and a pharmaceutically acceptable
excipient. Pharmaceutical compositions of Compound 1 have been disclosed in, for example,
commonly assigned PCT Patent Publication Nos. , WO 09722, and
WO 09510, each of which is incorporated by nce herein in its entirety.
The amount of the crystalline nd 1 solid form or combinations thereof in
the pharmaceutical composition can be a eutically effective amount. The crystalline
solid forms of Compound 1 may individually be present in the pharmaceutical composition or
as combinations. The crystalline solid forms as disclosed herein include Compound 1 Form I,
Compound 1 Form II, Compound 1 Form III, Compound 1 Form XXVIII, nd 1 Form
XXX, and Compound 1 Form XXXI. Accordingly, another aspect of this disclosure relates
to a solid or dispersion pharmaceutical composition comprising at least one of a
therapeutically effective amount of a solid form of Compound 1, as described herein in any of
the aspects and/or ments, or combinations thereof, and a pharmaceutically acceptable
excipient.
A pharmaceutical composition such as disclosed herein may be any
pharmaceutical form which contains an active crystalline nd 1 solid form. The
pharmaceutical composition may be, for e, a tablet, capsule, liquid suspension,
injectable, topical, or transdermal. The pharmaceutical itions generally contain about
1% to about 99% by weight of the active compound(s), or a solid form of the active
nd(s), and 99% to 1% by weight of a suitable pharmaceutical excipient. In one
example, the composition will be between about 5% and about 75% by weight of active
nd, with the rest being le pharmaceutical excipients or other adjuvants, as
discussed below.
The actual amount required for treatment of any particular subject will depend
upon a variety of factors including the disease state being treated and its severity; the specific
pharmaceutical composition employed; the age, body weight, l health, sex, and diet of
the subject; the mode of administration; the time of administration; the route of
stration; and the rate of excretion of the active compound(s), or a solid form of the
active compound(s), according to this disclosure; the duration of the treatment; any drugs
used in ation or coincidental with the ic compound employed; and other such
factors well known in the medical arts. These factors are discussed in Goodman and
’s “The cological Basis of Therapeutics,” Tenth Edition, A. Gilman,
J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is orated
herein by reference. The active compound(s), or a solid form of active compound(s),
according to this disclosure and pharmaceutical compositions comprising them, may be used
in combination with anticancer or other agents that are generally administered to a subject
being treated for cancer. They may also be co-formulated with one or more of such agents in
a single pharmaceutical composition.
Depending on the type of ceutical composition, the pharmaceutically
acceptable carrier may be chosen from any one or a combination of carriers known in the art.
The choice of the pharmaceutically acceptable carrier depends partly upon the desired
method of administration to be used. For a pharmaceutical composition of this disclosure,
that is, one of the active compound(s), or a solid form of the active compound(s), of this
disclosure, a carrier should be chosen so as to substantially maintain the particular form of the
active compound(s), whether it would be solid or not. In other words, the carrier should not
substantially alter the form of the active compound(s). Nor should the r be otherwise
atible with the form of the active compound(s), such as by producing any undesirable
biological effect or otherwise interacting in a deleterious manner with any other component(s)
of the pharmaceutical composition.
The pharmaceutical compositions of this disclosure may be ed by methods
know in the pharmaceutical formulation art, for example, see Remington’s Pharmaceutical
Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). In solid dosage forms,
Compound 1 Form I, II, III, XXVIII, or XXX, or combinations thereof, is admixed with at
least one pharmaceutically acceptable excipient such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose,
mannitol, and c acid, (b) binders, as for example, cellulose derivatives, starch, alginates,
gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example,
glycerol, (d) disintegrating agents, as for example, agar-agar, calcium ate, potato or
tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate,
I solution ers, as for example paraffin, (f) absorption accelerators, as for example,
quaternary ammonium compounds, (g) g agents, as for example, cetyl alcohol, and
glycerol monostearate, magnesium stearate, and the like (h) adsorbents, as for e,
kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, ium
stearate, solid hylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of
capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Pharmaceutically able nts known in the pharmaceutical formulation
art may also be used in the pharmaceutical compositions of this disclosure. These include,
but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming,
emulsifying, and dispensing agents. Prevention of the action of microorganisms can be
ensured by various cterial and antifungal agents, for example, parabens, chlorobutanol,
phenol, sorbic acid, and the like. It may also be desirable to include ic agents, for
example sugars, sodium chloride, and the like. If desired, a pharmaceutical composition of
this disclosure may also contain minor amounts of auxiliary substances such as wetting or
emulsifying agents, pH buffering agents, and antioxidants, such as, for e, citric acid,
sorbitan monolaurate, triethanolamine oleate, and butylated hydroxytoluene.
In some instances, the pharmaceutical dosage form may be a solid dispersion.
The term “solid dispersion” refers to a system in a solid state comprising at least two
components, wherein one component is dispersed throughout the other component or
components. For example, the can be an amorphous solid dispersion. The term “amorphous
solid dispersion” as used herein, refers to stable solid sions comprising amorphous drug
substance (Compound 1) and a izing polymer. By “amorphous drug substance,” it is
meant that the amorphous solid dispersion contains drug substance in a substantially
amorphous solid state form, that is at least 80% of the drug substance in the dispersion is in
an amorphous form. More preferably, at least 90% and most preferably at least 95% of the
drug substance in the dispersion is in amorphous form. The term “stabilizing polymer” any
r known to the d practitioner that is used to stabilize an ous drug
substance in a solid dispersion such as are described, for instance, in Remington’s
Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).
Processes for making such solid dispersions are also available to the skilled
practitioner and include, for instance, spray drying, melt extrusion, freeze drying, rotary
evaporation, drum drying, or other solvent removal processes. In the spray drying process,
the amorphous dispersion is formed by dispersing or dissolving the drug substance and the
stabilizing polymer in a suitable solvent to form a feed solution, pumping the feed solution
through an atomizer into a drying chamber, and removing the solvent to form the amorphous
solid sion powder in the drying chamber. A drying chamber uses hot gases, such as
forced air, nitrogen, nitrogen-enriched air, or argon to dry particles. The feed solution can be
atomized by conventional means well known in the art, such as a two-fluid sonicating nozzle
and a two-fluid nicating nozzle.
Solid dosage forms as described above can be ed with coatings and shells,
such as enteric coatings and others well known in the art. They may contain pacifying agents,
and can also be of such composition that they release the active compound or nds in a
certain part of the intestinal tract in a delayed manner. Examples of ed compositions
that can be used are polymeric substances and waxes. The active compounds can also be in
microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Suspensions, in addition to the active compounds, may n suspending ,
as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or
mixtures of these substances, and the like.
Compositions for rectal administrations are, for example, suppositories that can be
prepared by mixing the active compound(s), or a solid form of the active compound(s), with,
for example, suitable non-irritating ents or carriers such as cocoa butter,
polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid
at body temperature and therefore melt while in a suitable body cavity and release the active
component therein.
Solid dosage forms are red for the pharmaceutical composition of this
disclosure. Solid dosage forms for oral administration, which includes es, s, pills,
powders, and granules, are ularly preferred. In such solid dosage forms, the active
nd(s) mixed with at least one inert, pharmaceutically able ent (also
known as a pharmaceutically acceptable carrier). Administration of the active compound(s),
or a solid form of the active compound(s), in pure form or in an appropriate pharmaceutical
composition, can be carried out via any of the accepted modes of stration or agents for
serving similar utilities. Thus, administration can be, for example, orally, nasally,
parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally,
intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid,
lyophilized powder, or liquid dosage forms, such as for e, tablets, suppositories, pills,
soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like,
preferably in unit dosage forms suitable for simple administration of precise dosages. One
preferable route of administration is oral administration, using a ient dosage regimen
that can be adjusted according to the degree of severity of the disease-state to be treated.
Thus, in one embodiment, Compound 1 Form I, II, III, XXVIII, XXX, or XXXI is
administered as a ceutical formulation additionally comprising a pharmaceutically
acceptable r and excipient. In some embodiments, the Compound 1 crystalline solid
form is administered as a tablet. In other embodiments, compound 1 is administered as a
capsule.
In another embodiment, the invention is directed to, or disclosed herein is, a
pharmaceutical dosage form comprising 20 mg, 40 mg, 60 mg, 80 m6, 100 mg, 120 mg, or
140 mg of Compound 1 Form I, II, III, XXVIII, XXX, or XXXI or a ceutical
composition sing Compound 1 Form I, II, III, XXVIII, XXX, or XXXI and a
pharmaceutically acceptable carrier. The dosage form can be administered orally with g
once daily as a tablet or capsule. In some embodiments, the dosage form is a . In other
ments, the dosage form is a capsule.
The desired dosage of Compound 1 Form I, II, III, XXVIII, XXX, or XXXI can
be achieved using a combination of tablets or capsules as needed. For example to achieve a
target dose of 20 mg would require administration of one 20 mg tablet or capsule. To achieve
a target dose of 100 mg would e administration of one 80 mg capsule or tablet and one
mg capsule or tablet. To achieve a target dose of 80 mg would require administration of
one 80 mg capsule or tablet. To achieve a target dose of 60 mg would require administration
of three 20 mg capsules or tablets.
For example, in one embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII,
XXX, or XXXI is administered once daily to a patient with cancer in need of treatment. To
achieve a dose of 60 mg of nd 1, a patient is administered three 20 mg tablets. The
three 20 mg tablets can be taken at the same time or sequentially. In a further ment,
compound 1 is orally administered with fasting (that is, without ) for approximately
two hours before and 1 hour after administration. Compound 1 as one of the crystalline solid
forms disclosed herein is preferably administered with a glass of water ximately 8
ounces/240mL).
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered once daily to a patient with cancer in need of treatment. To achieve a
dose of 40 mg of compound 1, a patient is administered two 20 mg tablets. The two 20 mg
tablets can be taken at the same time or sequentially. In a further embodiment, compound 1
is orally administered with fasting (that is, without eating) for approximately two hours
before and 1 hour after administration. Compound 1 as one of the crystalline solid forms
disclosed herein is preferably administered with a glass of water (approximately 8
ounces/240mL).
In one embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered once daily to a t with cancer in need of treatment. To achieve a
dose of 20 mg of nd 1, a patient is administered one 20 mg tablet. In a further
embodiment, Compound 1 Form I, II, III, XXVIII, XXX, or XXXI is orally administered
with fasting (that is, without eating) for approximately two hours before and 1 hour after
administration. Compound 1 Form I, II, III, XXVIII, XXX, or XXXI is preferably
administered with a glass of water (approximately 8 ounces/240mL).
In r ment, the once-daily tablet or capsule formulation ses:
Ingredient (% w/w)
nd 1 Form I, II, III, XXVIII, 31.68
XXX, or XXXI
Microcrystalline Cellulose 38.85
Lactose anhydrous 19.42
Hydroxypropyl Cellulose 3.00
Croscarmellose Sodium 3.00
Total Intra-granular 95.95
n dioxide, Colloidal 0.30
Croscarmellose Sodium 3.00
Magnesium Stearate 0.75
Total 100.00
In r embodiment, the once-daily tablet or capsule formulation comprises:
Ingredient (% w/w)
Compound 1 Form I, II, III, XXVIII, 25.0-33.3
XXX, or XXXI
Microcrystalline Cellulose q.s
Hydroxypropyl Cellulose 3
Poloxamer 0-3
rmellose Sodium 6.0
Colloidal Silicon Dioxide 0.5
Magnesium Stearate 0.5-1.0
Total 100
In another embodiment, the once-daily tablet or capsule ation comprises:
Ingredient Theoretical Quantity (mg/unit dose)
Compound 1 Form I, II, III, XXVIII, 100.0
XXX, or XXXI
rystalline Cellulose PH-102 155.4
Lactose Anhydrous 60M 77.7
Hydroxypropyl Cellulose, EXF 12.0
Croscarmellose Sodium 24
Colloidal n Dioxide 1.2
Magnesium Stearate (Non-Bovine) 3.0
Opadry Yellow 16.0
Total 416
In another embodiment, the once-daily tablet or capsule formulation ses:
Ingredient on % w/w
nd 1 Form I, II, III, XXVIII, XXX, or Active Ingredient 31.7
XXXI
rystalline Cellulose (Avicel PH-102) Filler 38.9
Lactose Anhydrous (60M) Filler 19.4
ypropyl Cellulose (EXF) Binder 3.0
Croscarmellose Sodium (Ac-Di-Sol) Disintegrant 6.0
Colloidal n Dioxide, t 0.3
Magnesium Stearate Lubricant 0.75
Opadry Yellow Film Coating which includes: Film Coating 4.00
- HPMC 2910 /Hypromellose 6 cp
- Titanium dioxide
- Triacetin
- Iron Oxide Yellow
Any of the tablet or capsule formulations provided above can be adjusted
according to the dose of the crystalline solid form of compound 1 desired. Thus, the amount
of each of the formulation ingredients can be proportionally adjusted to provide a table
formulation containing various amounts of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI as provided in the previous paragraphs. In another embodiment, the formulations can
contain 20, 40, 60, or 80 mg of Compound 1 Form I, II, III, XXVIII, XXX, or XXXI.
6] Another aspect of this sure relates to a method of treating cancer comprising
administering to a subject in need thereof at least one of solid form of Compound 1 as
described herein in any of the aspects and/or embodiments, or combinations thereof.
Methods of treatment comprising administering Compound 1 have been disclosed in, for
example, commonly assigned PCT Patent Publication Nos. , WO 2011,
017639, , , , , WO
2013/070890, , and WO2013/066296, and US Patent Application
Publication Nos. US 2012/0070368 and US 2012/0252840, each of which is incorporated by
reference herein in its entirety. The amount of the Compound 1 solid form or ations
thereof administered can be a therapeutically effective amount.
Another aspect of this disclosure relates to a method of treating diseases or
disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities
associated with RTK overexpression, ularly cMET of RET overexpression, comprising
administering to a subject in need of such treatment a therapeutically effective amount of at
least one solid form of nd 1 as described herein in any of the aspects and/or
embodiments, or combinations thereof, such as discussed above.
Another aspect of this sure relates to a use of solid Compound 1 according
to any of the above embodiments for the manufacture of a medicament for the treatment of a
disease or disorder sed above. When dissolved, a solid or ous form according
to this disclosure loses its solid state structure, and is therefore referred to as a solution of, for
example, Compound 1. At least one solid form disclosed herein may be used to prepare at
least one liquid formulation in which at least one solid form according to the sure is
dissolved and/or suspended.
sed herein is a method of treating cancer, comprising: administering a
pharmaceutical dosage form comprising Compound 1 Form I, II, III, XXVIII, XXX, or XXXI
or a pharmaceutical composition sing nd 1 Form I, II, III, XXVIII, XXX, or
XXXI and a pharmaceutically able carrier.
Disclosed herein is a method of treating cancer, comprising administering to a
patient in need of such treatment a pharmaceutical dosage form comprising 140 mg, 120 mg,
100 mg, 80 mg, 60 mg, 40 mg, or 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI or a pharmaceutical composition comprising Compound 1 Form I, II, III, XXVIII,
XXX, or XXXI and a pharmaceutically acceptable carrier. In some embodiments, the dosage
form is administered orally with fasting orally once daily as a tablet or capsule. In some
embodiments, Compound 1 Form I, II, III, XXVIII, XXX, or XXXI or a pharmaceutical
composition comprising Compound 1 Form I, II, III, XXVIII, XXX, or XXXI is administered
as a tablet. In other embodiments, Compound 1 Form I, II, III, XXVIII, XXX, or XXXI or a
pharmaceutical composition comprising Compound 1 Form I, II, III, XXVIII, XXX, or XXXI
is administered as a e.
Any of the tablet or capsule formulations provided above can be ed
ing to the dose of compound 1 desired. Thus, the amount of each of the formulation
ients can be proportionally adjusted to provide a table formulation containing various
amounts of compound 1 as provided in the previous aphs. In another embodiment, the
formulations can contain 20, 40, 60, or 80 mg of Compound 1 Form I, II, III, XXVIII, XXX,
or XXXI.
In this method, the desired dosage of Compound 1 crystalline solid form can be
achieved using a ation of tablets or capsules as needed. For example to achieve a
target dose of 20 mg would require administration of one 20 mg tablet or capsule. To achieve
a target dose of 100 mg would require administration of one 80 mg tablet or capsule and one
mg tablet or capsule. To e a target dose of 80 mg would require administration of
one 80 mg tablet or capsule. To achieve a target dose of 60 mg would require administration
of three 20 mg tablets or capsules.
In r embodiment of this method, 60 mg of compound 1 is administered
once daily to a patient with cancer in need of treatment. To achieve a dose of 60 mg of
compound 1, a patient is administered three 20 mg tablets. The three 20 mg s can be
taken at the same time or sequentially. In a further embodiment, compound 1 is orally
administered with fasting (that is, without eating) for approximately two hours before and 1
hour after administration. Compound 1 is preferably administered with a glass of water
(approximately 8 ounces/240mL).
In another embodiment of this method, 40 mg of compound 1 is administered
once daily to a patient with cancer in need of ent. To achieve a dose of 40 mg of
compound 1, a patient is administered two 20 mg s. The two 20 mg s can be taken
at the same time or sequentially. In a further embodiment, compound 1 1 as one of the
crystalline solid forms disclosed herein (that is, nd 1 Forms I, III, XXVIII, XXX, or
XXXI) is orally administered with fasting (that is, without eating) for approximately two
hours before and 1 hour after administration. Compound 1 is preferably administered with a
glass of water (approximately 8 ounces/240mL).
In another embodiment of this method, 20 mg of compound 1 is administered
once daily to a patient with cancer in need of treatment. To achieve a dose of 20 mg of
compound 1, a patient is administered one 20 mg tablet. In a r embodiment, compound
1 is orally administered with fasting (that is, without ) for approximately two hours
before and 1 hour after administration. Compound 1 is preferably administered with a glass
of water (approximately 8 ounces/240mL).
In another embodiment, the method comprises administering Compound 1 Form I,
II, III, XXVIII, XXX, or XXXI orally once daily as a tablet or capsule as ed in the
following table.
Ingredient (% w/w)
Compound 1 Form I, II, III, XXVIII, 31.68
XXX, or XXXI
rystalline Cellulose 38.85
Lactose anhydrous 19.42
Hydroxypropyl Cellulose 3.00
Croscarmellose Sodium 3.00
Total Intra-granular 95.95
Silicon dioxide, Colloidal 0.30
Croscarmellose Sodium 3.00
Magnesium Stearate 0.75
Total 100.00
In some embodiments, the pharmaceutical dosage form is administered as a tablet. In other
embodiments, the pharmaceutical dosage form is administered as a capsule.
In r embodiment, the method comprises administering compound 1 orally
as one of the crystalline solid forms sed herein (that is, Compound 1 Forms I, II, III,
XXVIII, XXX, or XXXI) orally once daily as a tablet or capsule as provided in the following
table.
Ingredient (% w/w)
Compound 1 Form I, II, III, XXVIII, 25.0-33.3
XXX, or XXXI
Microcrystalline Cellulose q.s
ypropyl Cellulose 3
mer 0-3
Croscarmellose Sodium 6.0
Colloidal Silicon Dioxide 0.5
Magnesium Stearate 0.5-1.0
Total 100
In some embodiments, the pharmaceutical dosage form is administered as a tablet. In other
embodiments, the pharmaceutical dosage form is administered as a capsule.
In another embodiment, the method comprises administering compound 1 orally
as one of the crystalline solid forms disclosed herein (that is, Compound 1 Forms I, II, III,
, XXX, or XXXI) orally once daily as a tablet or capsule as provided in the following
table.
Ingredient tical Quantity (mg/unit dose)
Compound 1 Form I, II, III, XXVIII, 100.0
XXX, or XXXI
rystalline Cellulose PH-102 155.4
Lactose Anhydrous 60M 77.7
Hydroxypropyl Cellulose, EXF 12.0
Croscarmellose Sodium 24
Colloidal Silicon Dioxide 1.2
Magnesium Stearate (Non-Bovine) 3.0
Opadry Yellow 16.0
Total 416
In some ments, the pharmaceutical dosage form is stered as a tablet. In other
ments, the ceutical dosage form is administered as a capsule.
In another embodiment, the method comprises administering Compound 1 Form I,
II, III, XXVIII, XXX, or XXXI orally once daily as a tablet or capsule as provided in the
following table.
Ingredient Function % w/w
nd 1 Form I, II, III, XXVIII, XXX, or
Active Ingredient 31.7
XXXI
Microcrystalline Cellulose (Avicel PH-102) Filler 38.9
Lactose Anhydrous (60M) Filler 19.4
Hydroxypropyl Cellulose (EXF) Binder 3.0
Croscarmellose Sodium (Ac-Di-Sol) Disinteegrant 6.0
Colloidal n Dioxide, Glidant 0.3
Magnesium Stearate Lubricant 0.75
Opadry Yellow Film Coating which includes:
- HPMC 2910 /Hypromellose 6 cp
- Titanium dioxide Film Coating 4.00
- Triacetin
- Iron Oxide Yellow
In some embodiments, the pharmaceutical dosage form is administered as a tablet. In other
embodiments, the pharmaceutical dosage form is stered as a capsule.
In some embodiments, the cancer to be treated is thyroid cancer, liver cancer,
gastrointestinal cancer, pancreatic cancer, bone cancer, logic cancer, skin cancer,
kidney , breast cancer, colon cancer, fallopian tube cancer, ovarian cancer, brain cancer,
lung cancer or prostate cancer.
In one embodiment, the cancer is thyroid cancer.
More particularly, the thyroid cancer is medullary thyroid cancer.
In one ment, the cancer in liver cancer.
More particularly, the liver cancer is hepatocellular carcinoma,
cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hemagioma.
] In one embodiment, the cancer is gastrointestinal cancer.
More particularly, the gastrointestinal cancer is cancer of the esophagous which is
squamous cell carcinoma, adenocarcinoma, or leiomyosarcoma; cancer of the stomach which
is carcinoma, or lymphoma; cancer of the pancreas, which is ductal adenocarcinoma,
insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma; cancer of the small
bowel, which is adenocarcinoma, ma, carcinoid tumors, Karposi’s sarcoma,
leiomyoma, hemagioma, ; or cancer of the large bowel, which is adenocarcinoma,
tubular adenoma, villous adenoma, hamartoma, or leiomyoma.
7] In one embodiment, the cancer is cancer of the pancreas.
More particularly, the cancer of the pancreas is ductal adenocarcinoma,
insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma.
In one ment, the cancer is bone cancer.
0] More ularly, the bone cancer is arcoma, fibrosarcoma, malignant
fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant reticulum cell sarcoma,
malignant giant cell tumor chordoma, artiliginous exostoses, chondroblastoma,
chondromyofibroma, or osteoid osteoma.
In one ment, the cancer is hematologic cancer.
More particularly, the hematologic cancer is myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple
myeloma, or myelodysplastic syndrome.
In one embodiment, the cancer is skin cancer.
More particularly, the skin cancer is malignant melanoma, basal cell carcinoma,
squamous cell carcinoma, or Karposi’s sarcoma.
In one embodiment, the cancer is renal cancer.
More particularly, the renal cancer is a renal tumor.
In one embodiment, the cancer is breast cancer.
More particularly, the breast cancer is a breast tumor.
In one embodiment, the cancer is colon cancer.
More particularly, the colon cancer is a colon cancer tumor.
In one embodiment, the cancer is fallopian tube cancer.
More particularly, the fallopian tube cancer is fallopian tube carcinoma.
3] In one embodiment, the cancer is ovarian cancer.
More particularly, the ovarian cancer is ovarian carcinoma [serous
cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified oma],
granulosa-thecal cell tumors, Sertoli Leydig cell , minoma, malignant teratoma),
vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, or
melanoma.
In another embodiment, the cancer is prostate cancer.
More ularly, the prostate cancer is adenocarcinoma or sarcoma.
In another embodiment, the prostate cancer is tion resistant prostate cancer
(CRPC).
In another embodiment, the cancer is lung cancer.
More particularly, the lung cancer is bronchogenic carcinoma (squamous cell,
undifferentiated small cell, erentiated large cell, arcinoma), alveolar
(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous
hanlartoma, or inesothelioma.
The antitumor effect of the dosage form of the invention is measured using
serological and/or radiographic methods available to the skilled practitioner. For serological
methods, the relative tration of a cancer biomarker is measured before and after
administration of Compound 1 Form I, II, III, XXVIII, XXX, or XXXI. A positive response
means that there is a lower gical tration of the ker after treatment as
compared to the concentration before treatment. As an example, for patients being treated for
prostate cancer, particularly castration-resistant prostate cancer, the serological concentration
of the biomarker PSA will be determined before, during, and after treatment. Patients can be
assigned a PSA response according to the following criteria:
• Complete Serological Response: PSA level less than 0.2 ng/mL measured for 2
consecutive measurements at least 4 weeks apart.
• Serological Partial Response (PR): decline of PSA value, referenced to the prestudy
level, by greater than or equal to 50% for 2 consecutive measurements at least 2
weeks apart.
• PSA Stable e: Patients who do not meet the criteria for response (CR or
PR) or gical progression
• Serological Progression (PD): is observed when the PSA demonstrates an
increase that is more than 50% of nadir, taking as reference the lowest recorded PSA
level since starting therapy. Two consecutive increases must be nted with
each measurement obtained at least 2 weeks apart. On occasions, there may be an
intermediate fluctuant value. In accordance with the Recommendations of the
Prostate Cancer Clinical Trials Working Group this will not restart the evaluation
period so long as the intermediate value was not below the us nadir[18]. The
date of first ed increase (not defeated by a subsequent drop in PSA level to
create a new nadir) will be deemed the date of progression. If a patient achieves a
PSA that is less than 2 ng/mL, progression will only be deemed to have been
med once: (1) There has been an observed rise that is more than 50% of nadir
since starting ADT; AND (2) The confirming increase was to a value that is more
than 2.0 ng/mL (the irmed and second increase may be a value that is less than
2.0 ng/mL but greater than 50% of nadir since starting ADT).
These serological response levels can be modified as needed based on the
ker at issue.
In one embodiment, a te serological se is observed in patients being
treated with the dosage form. In another embodiment, a serological partial response is
observed in patients being treated with the dosage form. In a further embodiment, stable
disease is observed in patients being treated with the dosage form.
With respect to raphic methods, radiographic disease progression is defined
by RECIST 1.1 for soft tissue disease, or the ance of two or more new bone lesions on
bone scan. Progression in the absence of clear symptomatic worsening at the first scheduled
reassessment after commencement of treatment requires a matory scan at later point in
time. Standard imaging procedures available to the skilled practitioner, including technetium
bone scans and CT scans can be used to measure radiographic effect. Other radiographic
methods such as NaF and FDG-PET may also be used to measure radiographic effect.
As ted previously, the amount of Compound 1 Form I, II, III, XXVIII, XXX,
or XXXI that is administered can be adjusted to avoid adverse events. For example, in one
embodiment, a pharmaceutical dosage comprising 60 mg of nd 1 Form I, II, III,
, XXX, or XXXI is administered to a patient that had one or more adverse events at a
dosage greater than 60 mg.
In another embodiments, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is stered to a patient that had one or more adverse events at a pharmaceutical
dosage between 80 mg and 160 mg.
In another ment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 70 mg.
In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 80 mg.
In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse event at a dosage of 90 mg.
In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 100 mg.
0] In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 120 mg.
1] In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 130 mg.
In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 140 mg.
In another embodiment, 60 mg of nd 1 Form I, II, III, , XXX, or
XXXI is administered to a patient that had one or more e events at a dosage of 150 mg.
In another embodiment, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 160 mg.
In other embodiments, 60 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is stered to a patient that had one or more adverse events at a pharmaceutical
dosage of 140 mg or 100 mg.
6] In r embodiment, the pharmaceutical dosage comprising 40 mg of
Compound 1 Form I, II, III, XXVIII, XXX, or XXXI is administered to a patient that had one
or more adverse events at a dosage greater than 40 mg.
In another, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or XXXI is
administered to a t that had one or more adverse events at a pharmaceutical dosage
between 60 mg and 160 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 50 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a t that had one or more adverse events at a dosage of 60 mg.
In another embodiment, 40 mg of nd 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 70 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 80 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 90 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is stered to a patient that had one or more adverse events at a dosage of 100 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 120 mg
of compound 1.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 130 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 140 mg.
In another ment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is stered to a patient that had one or more adverse events at a dosage of 150 mg.
In another ment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a t that had one or more adverse events at a dosage of 160 mg.
In another embodiment, 40 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a pharmaceutical
dosage of 140 mg, 100 mg, or 60 mg.
0] In another embodiment, the pharmaceutical dosage comprising 20 mg of Compound
1 Form I, II, III, XXVIII, XXX, or XXXI is administered to a patient that had one or more
adverse events at a dosage greater than 60 mg.
In another ment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a pharmaceutical
dosage between 40 mg and 160 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a t that had one or more adverse events at a dosage of 30 mg.
In another embodiment, 20 mg of nd 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more e events at a dosage of 40 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 50 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 60 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 70 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 80 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more e events at a dosage of 90 mg.
In another ment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is stered to a patient that had one or more adverse events at a dosage of 100 mg.
In r embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 120 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a t that had one or more adverse events at a dosage of 130 mg.
2] In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 140 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a dosage of 150 mg.
In another embodiment, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is stered to a patient that had one or more adverse events at a dosage of 160 mg.
In other ments, 20 mg of Compound 1 Form I, II, III, XXVIII, XXX, or
XXXI is administered to a patient that had one or more adverse events at a pharmaceutical
dosage of 140 mg, 100 mg, 60 mg, or 40 mg.
In some embodiments, the adverse event is one or more of diarrhea, itis,
palmar-plantar erythrodysesthesia syndrome (PPES), decreased , decreased appetite,
nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain,
constipation, increased AST, sed ALT, lymphopenia, increased alkaline phosphatase,
hypocalcemia, penia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia,
perforations, fistulas, hemorrhage, thromboembolic , wound complications,
osteonecrosis of the jaw, proteinuria, reversible ior leukoencephalopathy syndrome
(RPLS), and embryo-fetal toxicity.
In some embodiments, the adverse event is Grade 1. In some embodiments, the
adverse event is Grade 2. In some embodiments, the adverse event is Grade 3. In some
embodiments, the adverse event is Grade 4. In some embodiments, the adverse event is
Grade 5.
In one embodiment, treatment is temporarily suspended for a patient who had a
Grade 4 adverse event. In another embodiment, upon resolution or ement of the
Grade 4 adverse event, the dose of compound 1 is resumed at the same or a reduced dosage.
In some embodiments, resolution or improvement of the Grade 4 adverse event means
returning to baseline. In other embodiments, resolution or ement of the Grade 4
adverse event means resolution to a Grade 1 adverse event.
In one embodiment, treatment is temporarily suspended for a patient who had a
Grade 3 adverse event. In another embodiment, upon resolution or improvement of the
Grade 3 adverse event, the dose of compound 1 is resumed at the same or a reduced dosage.
In some embodiments, resolution or improvement of the Grade 3 adverse event means
ing to baseline. In other embodiments, resolution or improvement of the Grade 4
adverse event means resolution to a Grade 1 adverse event.
In one embodiment, treatment is temporarily suspended for a patient who had a
Grade 2 adverse event. In another embodiment, upon resolution or improvement of the
Grade 2 adverse event, the dose of compound 1 is resumed at the same or a reduced dosage.
In some embodiments, resolution or improvement of the Grade 2 adverse event means
returning to baseline. In other embodiments, resolution or improvement of the Grade 2
adverse event means resolution to a Grade 1 e event.
In one embodiment, ent is temporarily suspended for a patient who had a
Grade 1 e event. In another embodiment, upon resolution or improvement of the
Grade 4 adverse event, the dose of compound 1 is resumed at the same or a reduced dosage.
In some embodiments, resolution or improvement of the Grade 1 adverse event means
returning to ne.
In some embodiments, the dose is further reduced one or more times following the
first reduction as a result of one or more adverse events. In one embodiment, the dose is
d a first time. In another embodiment, the dose is reduced a first and second time. In
another embodiment, the dose is reduced a first, second, and third time.
General Preparation Methods of Crystalline Solid Forms
Crystalline solid forms may be prepared by a variety of s including, but not
limited to, for example, crystallization or recrystallization from a suitable solvent mixture;
sublimation; growth from a melt; solid state transformation from r phase;
crystallization from a supercritical fluid; and jet spraying. Techniques for crystallization or
recrystallization of crystalline solid forms of a solvent e include, but are not limited to,
for example, evaporation of the solvent; decreasing the temperature of the solvent mixture;
crystal seeding of a supersaturated solvent e of the compound and/or salt thereof;
crystal seeding a supersaturated solvent mixture of the compound and/or a salt from thereof;
freeze drying the solvent mixture; and adding antisolvents (countersolvents) to the solvent
mixture. High hput crystallization ques may be employed to prepare crystalline
solid forms including polymorphs.
Crystals of drugs, including polymorphs, methods of preparation, and
characterization of drug crystals, are discussed in Solid-State try of Drugs, S.R. Byrn,
R.R. Pfeiffer, and J.G. l, 2nd n, SSCI, West Lafayette, Indiana (1999).
] In a crystallization technique in which solvent is employed, the solvent(s) are
typically chosen based on one or more factors including, but not limited to, for e,
solubility of the compound; crystallization technique utilized; and vapor pressure of the
solvent. Combinations of solvents may be employed. For example, the compound may be
solubilized in a first t to afford a solution to which antisolvent is then added to decrease
the solubility of the Compound 1 in the solution and precipitate the formation of crystals. An
lvent is a solvent in which a compound has low solubility.
In one method that can be used in ing crystals, Compound 1 can be
suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to
promote dissolution. The term “slurry,” as used , means a ted solution of the
compound, wherein such solution may contain an additional amount of compound to afford a
heterogeneous mixture of compound and solvent at a given ature.
Seed crystals may be added to any crystallization mixture to promote
crystallization. Seeding may be employed to control growth of a ular polymorph and/or
to control the particle size distribution of the solid product. Accordingly, calculation of the
amount of seeds needed depends on the size of the seed available and the desired size of an
average product particle as described, for e, in Programmed Cooling Batch
Crystallizers,” J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 3690377.
In general, seeds of small size are needed to effectively control the growth of crystals in the
batch. Seeds of small size may be generated by sieving, milling, or micronizing large crystals,
or by microcrystallizing a solution. In the milling or micronizing of crystals, care should be
taken to avoid changing crystallinity from the desired solid form (i.e., changing to an
amorphous or other polymorphic form).
A cooled crystallization mixture may be filtered under vacuum and the isolated
solid product washed with a suitable solvent, such as, for example, cold recrystallization
solvent. After being washed, the t may be dried under a nitrogen purge to afford the
desired solid form. The product may be analyzed by a suitable spectroscopic or analytical
technique including, but not limited to, for example, differential scanning calorimetry (DSC);
x-ray powder diffraction (XRPD); and thermogravimetric analysis (TGA) to assure the solid
form of the compound has been . The resulting solid form may be produced in an
amount greater than about 70 weight percent ed yield, based on the weight of the
compound originally employed in the crystallization procedure, and preferably greater than
about 90 weight percent ed yield. ally, the product may be delumped by being
comilled or passed through mesh screen.
The features and ages of this disclosure may be more readily understood by
those of ordinary skill in the art upon reading the following detailed ption. It is to be
appreciated that n features of the invention that are, for clarity reasons, described above
and below in the context of separate embodiments, may also be combined to form a single
embodiment. Conversely, various features of this disclosure that are, for brevity reasons,
described in the context of a single embodiment, may also be combined so as to form subcombinations
thereof. The disclosure is further illustrated by the following es, which
are not to be construed as limiting the disclosure in scope or spirit to the specific procedures
described in them.
Synthesis
The solid compounds of the invention can be synthesized from readily available
starting materials as described below and in the es. It will be appreciated that while
ic process conditions (i.e., reaction temperatures, times, mole ratios of reactants,
solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise
stated. Generally, the reactions are conducted in a le inert diluent, examples of which
include, but are not limited to, methanol, ethanol, isopropanol, isobutanol, ethyl e,
acetonitrile, dichloromethane, methyl l ether, and the like, and mixtures thereof,
typically containing water. Upon completion of any of the foregoing reactions, the solid
compounds can be isolated from the reaction mixture by any conventional means such as
precipitation, concentration, centrifugation, and the like.
1] The Compound 1 ed in the invention can be readily prepared from
commercially available starting materials and reagents using the ures described in the
Examples, or using the procedures described in , as well as in WO
09510 and , each of which is incorporated by reference in its entirety.
The molar ratios described in the methods of the invention can be readily
determined by various methods ble to those skilled in the art. For example, such molar
ratios can be readily determined by 1H NMR. Alternatively, elemental analysis and HPLC
methods can be used to determine the molar ratio.
Examples
The following examples illustrate the scope of the invention. The examples and
preparations which follow are provided to enable those skilled in the art to more clearly
understand and to practice the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and representative thereof.
Experimental Techniques
X-ray Powder Diffraction (XRPD)
XRPD analyses were performed using a Panalytical Xpert Pro diffractometer
equipped with a Cu X-ray tube and a Pixcel detector system. The isothermal samples were
ed in ission mode and held between low y polyethylene films. The XRPD
analysis program used an analysis range of θ, step size 0.013°, counting time 99
seconds, and an approximate run time of 22 minutes. Variable temperature samples were
loaded into capillaries and ature controlled using an Oxford Cryostream system.
XRPD patterns were sorted, manipulated, and indexed using HighScore Plus 2.2c software.
ential Scanning Calorimetry (DSC)
DSC analyses were carried out on a Perkin Elmer Jade Differential Scanning
meter. Accurately weighed samples were placed in crimped aluminum pans. Each
sample was heated under nitrogen at a rate of 10°C/minute to a maximum of 300°C. Indium
metal was used as the calibration standard. Temperatures were reported at the tion
onset to the nearest 0.01 degree.
Hyper Differential Scanning Calorimetry (DSC)
Hyper DSC analyses were carried out on a Perkin Elmer d Differential
Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminum pans.
Each sample was heated and cooled under helium over two cycles at a rate of 300°C/minute
using a temperature range of -50 to 300°C. Indium metal was used as the calibration standard.
Hyper DSC allows the measurement of thermal events using very fast scanning
rates. The fast scanning rate results in a much sed heat flow signal and therefore
greatly increases sensitivity. This allows ely low energy transitions, such as the glass
transition temperature (Tg), to be identified and measured much more ively.
Thermogravimetric Differential Thermal Analysis (TG/DTA)
Thermogravimetric analyses were carried out on a Mettler Toledo TGA/DSC1
STARe. The calibration standard was indium. Samples were placed in an aluminum sample
pan, inserted into the TG furnace and accurately weighed. The heat flow signal was stabilized
for one minute at 30°C, prior to heating to a maximum of 300 °C in a stream of nitrogen at a
rate of 10 °C/minute.
1H / 13C Nuclear Magnetic Resonance Spectroscopy (NMR)
NMR is was carried out on either a Bruker 400MHz or 500MHz instrument
in DMSO-d6.
Optical and Hot-Stage copy
Microscopy analysis was carried out on an Olympus BX51 microscope..
Photomicrographs of cabozantinib were ed at objective lens magnifications x10 using a
polarized light source. Hot stage microscopy analyses were performed using a Linkam hot
stage accessory. Solid samples were heated using t temperature programs which
included the ed ramp rate, final temperature, and interval hold times if required for
individual samples.
Dynamic Vapor Sorption (DVS)
Dynamic Vapor Sorption (DVS) was med using a Hiden Analytical
Instruments IGAsorp Vapor Sorption Balance. Approximately 30mg of sample was placed
into a wire-mesh Vapor sorption balance pan, loaded into the IGAsorp Vapor sorption
balance and held at 25 °C ± 0.1 °C. The sample was subjected to a step profile from 0 to
90%RH at 10% increments, followed by desorption from 80%RH to 0%RH at 10%
increments. The equilibrium criterion was set to 99.0% step completion within a minimum of
60 minutes and a maximum of 5 hours for each increment. The weight change during the
sorption cycle was monitored, allowing for the hygroscopic nature of the sample to be
determined. The data collection interval was in seconds.
Fourier Transfer Red (FTIR) Spectroscopy
Fourier Transform Infra-Red (FTIR) was performed using Attenuated Total
Reflectance (ATR) on a Thermonicolet 370 Avatar Infra-Red Spectrometer ed with an
ATR Smart Golden Gate Accessory. A small portion of the sample was placed on the ATR
crystal. The sample spectrum was collected in % ittance in the range of 650cm-1 –
4000cm-1, using a resolution of 4cm-1 and an acquisition of 20 scans.
Experiments
Preparation of Forms
ation of Compound 1 Form I
Compound 1 Form I was prepared by adding Compound 1 Form I (1g) or
amorphous material and THF (12mL) to a flask and agitating at ambient temperature until
dissolved. Water (about 20 mL) was added to the ambient temperature solution over
approximately 2 hours, stirred for about 8 hours, and the solids were collected and dried. The
material was fully characterized.
ation of Compound 1 Form II
Compound 1 Form I (1g) and THF (12 mL) were added to a flask and agitated at
t temperature until dissolved. Water (about 12 mL) was added to the ambient
temperature solution over approximately 2 hours, stirred for about 8 hours, and the solids were
collected and dried. The al was fully characterized.
Preparation of Compound 1 Form III
Compound 1 Form I (1g) and THF (12mL) were added to a flask and agitated at
ambient ature until dissolved. The contents of the flask were heated at a temperature
from 30 to 50 °C and the pressure reduced to approximately 100 torr. After approximately
lf of the volume was removed by distillation, methanol was added to the flask to
achieve the imate starting volume. This distillation was repeated at least two times, and
the contents of the flask returned to ambient temperature and pressure. The resulting solids
were collected, dried, and fully characterized.
ation of Compound 1 Form XXVIII
nd 1 Form I (150mg) and nol (1mL) were added to a vial and stirred
at 5 °C for 7 days. The solids were recovered by filtration, air dried, and characterized. In
another scale-up method, amorphous Compound 1 was slurried in nitromethane for 11 days,
and the solids were ted, dried, and desolvated on a TG/DTA at110 °C ± 30 °C for 15
minutes. The resulting solids were fully characterized.
Preparation of Compound 1 Form XXX
Amorphous Compound 1 (approximately 100mg) was added to a vial which was
placed unsealed inside a larger vial containing acetone. After 5 days, the sample was
desolvated on the TG/DTA at 105 °C for 25 minutes, followed by desolvation at 100 °C ±
°C for 40 minutes to yield pattern XXX material. The material was fully characterized.
Preparation of Compound 1 Form XXXI
Compound 1 Form III (140mg) and EtOH:water (44:56% v/v, 5.6mL) were stirred
in a sealed vial for 3 hours to allow for tion. Compound 1 Form I (50mg) and pattern
XXXI cabozantinib (approximately 1-2mg) were added, and the mixture was stirred for 3
days to allow for complete conversion to Compound 1 Form XXXI. The solid was recovered
by vacuum filtration and dried on the filter with vacuum suction for 30 minutes prior to
analysis by XRPD.
Synthesis of Amorphous Compound 1
Hyper DSC was performed in order to generate amorphous material from fast
cooling of molten forms of Compound 1.
Amorphous Compound 1 was generated by melting Compound 1 followed by fast
cooling. A thermogram taken from the second heating of a heat-cool-heat cycle demonstrates
the presence of a Tg, observed at 99.19 °C (half-height value).
Amorphous Compound 1 was ted by melting Compound 1 Form II
followed by fast cooling. A thermogram taken from the second heating of a ool-heat
cycle demonstrates the presence of a Tg, observed at 103.72 °C (half-height value).
Amorphous Compound 1 was generated by melting Compound 1 Form III
ed by fast g. An expanded thermogram taken from the second g of a heatcool-heat
cycle demonstrated the presence of a Tg, observed at 120.72 °C (half-height value),
higher than was ed with Compound 1 Forms I or II, because in these forms, the solvent
vapor generated plasticizes the amorphous state and lowers the Tg.
Amorphous Compound 1 was also ted on a 200mg scale from Compound
Form I, Compound 1 Form II, or Compound 1 Form III material by freeze-drying a filtered
solution in dioxane. Compound 1 (200mg) was dissolved in e (20mL), filtered
h a 0.2µm filter into a round-bottomed flask containing liquid nitrogen. The flask was
rotated within a Dewar flask containing liquid en, forming frozen droplets inside the
flask. The flask was lyophilized under vacuum (0.08mbar) for 18 hours at 20 °C. XRPD
analysis displayed a halo pattern indicative of X-ray amorphous material (.
Data for Crystalline Solid Forms
X-ray powder diffraction (XRPD) data (CuKα, (º2θ ± 0.2 º2θ) for Compound 1
Forms I, II, III, XXVIII, XXX, and XXXI is summarized in Table 1.
Table 1
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
.1 6.4 7.0 6.5 7.2 5.0
11.9 11.6 7.8 9.5 7.5 10.0
12.9 12.1 9.4 11.8 10.0 11.9
14.4 12.6 11.1 12.3 12.0 13.0
16.0 12.9 12.6 13.0 12.4 14.4
23.0 14.8 14.1 15.5 13.5 16.1
24.7 14.9 15.5 16.9 15.8 19.9
18.0 17.3 17.7 19.8 21.4
18.8 22.3 19.1 23.8
Compound 1
Form I Form II Form III Form XXVIII Form XXX Form XXXI
.2 24.3 21.7
22.3
Compound 1 Form I
The XRPD pattern obtained for Compound 1 Form is shown in
Thermogravimetric/Differential Thermal Analysis (TG/DTA) was performed to determine
the thermal profile and associated % weight changes of Compound 1 Form I. As depicted in
weight loss of approximately 6.5% from 25-80 °C was noted, which ponds to
approximately 1.92 moles of water and confirms that Compound 1 Form I cabozantinib is a
dihydrate. A second weight loss at temperatures r than 200 °C corresponds to the
initiation of decomposition of the material. Two endotherms were observed at onset
temperature approximately 56.6 °C and 116.7 °C. These correspond to the loss of water and
subsequent melting of the dehydrated form respectively.
The DSC thermogram obtained for Compound 1 Form I at 10 °C/min is shown in
The thermogram showed two endotherms, the first one at onset 68.13 °C due to loss
of water, and the second endotherm at onset 112.70 °C, which is the melting endotherm.
This was confirmed visually by age microscopy.
7] The FT-IR um obtained for the material is shown in and includes
stretches at 3445, 3200, 1671, 1561, 1508, 1433, 1431, 1353, 1254, 1223, 826 FTIR (cm-1).
The spectrum was shown to conform to the material structure with all expected functional
groups present. The presence of water is clearly visible (broad, 3200cm-1), and peak shifts
are significantly different to ous Compound 1 Form III. 1H NMR ) conformed
to ure.
Compound 1 Form II
The XRPD pattern obtained for Compound 1 Form II is shown in and is
indicative of a highly crystalline material. Thermogravimetric/Differential Thermal Analysis
A) was med to determine the thermal profile and associated % weight changes
(.
Weight loss of approximately 9.8% was observed, and this was attributed to loss
of a mixture of THF and water. A second weight loss at temperatures above 140 °C may be
due to a mixture solvent loss and decomposition. The first endotherm, at onset 62.7 °C,
corresponds to the loss of solvent and/or water. The second at onset approximately 196.5 °C
corresponds to the melt of an anhydrous form, later confirmed as low crystallinity Compound
1 Form III (see below).
The DSC thermogram ( showed two endotherms, the first at onset 71.47 °C
was a broad peak corresponding to loss of t/water. An exotherm was observed at onset
approximately 119.8 °C, which suggests tallization to another form. A second
endotherm was noted at onset 206.83 °C, which corresponds to the melting point of
Compound 1 Form III.
1] 1H NMR () of Compound 1 Form II conforms to structure and shows the
presence of THF (0.4 mole lents). This implies that 5.5% w/w of weight loss from TGA
can be attributed to THF and the remainder to water (4.3% w/w, or approximately 1.2 mol eq).
Compound 1 Form III
The XRPD pattern for Compound 1 Form III is shown in and is indicative
of a highly crystalline material. Thermogravimetric/Differential Thermal Analysis (TG/DTA)
was performed to determine the thermal profile and associated % weight changes of
Compound 1 Form III ().
No weight loss was observed below 200 °C, ting as Compound 1 Form III
is an anhydrous material. A melting endotherm was observed at onset temperature 220.37 °C.
Weight loss due to decomposition was also observed above this point. The DSC thermogram
obtained for Compound 1 Form III () confirmed the melting onset at 220.59 °C. Hot
stage microscopy showed the onset of melting between 220 °C and 230 °C, with the material
completely molten by 235 °C.
1H NMR d6, ) conformed to structure and showed an absence of
solvent. The FT-IR spectrum obtained for the al is shown in and was shown to
m to the material structure with all expected functional groups present. FTIR (cm-1):
3240, 3061, 1639, 1560, 1504, 1480, 1430, 1213, 1165, 850, 822.
Compound 1 Form XXVIII
The XRPD for Compound 1 Form XXVIII is shown in . The intense
narrow peaks are indicative of a highly lline al. Polarized light microscopy
showed birefringent crystals with particle size generally less than 10µm.
TG/DTA () showed no weight loss from 25 °C to 180 °C, confirming that
the material was an anhydrous form. DSC () showed an l endothermic event at
onset 190.62 °C, a recrystallization exotherm at onset 193.65 °C and another endotherm at
onset 205.83 °C. These results indicate that Compound 1 Form XXVIII melts and
recrystallizes to Compound 1 Form III which uently melts. The melting onset is lower
than that observed for pure Compound 1 Form III (onset 220.59 °C), most likely due to lower
crystallinity.
Hyper DSC was performed in order to generate amorphous material from fast
g of molten Compound 1 Form XXVIII and ine the temperature of glass
transition (Tg) during the reheat cycle. The thermogram demonstrates the presence of a Tg,
observed during the second heating of a heat-cool-heat cycle at 120.85 °C (half-height value).
The Tg is consistent with Compound 1 Form XXVIII being an anhydrous Form, as it is
similar to the Tg of nd 1 Form III material.
1H NMR () of nd 1 Form XXVIII showed the material to conform
to structure and n no solvent. Infra-red spectroscopy carried out on Compound 1 Form
XXVIII 9) was broadly similar to Compound 1 Form III, except in the 500cm-1
region. Typically associated with carbonyl stretching, this implies ences in the
hydrogen bonding network. FTIR (cm-1): 3038, 1686, 1531, 1504, 1480, 1350, 1213, 994,
856, 831.
Compound 1 Form XXX
The XRPD pattern for Compound 1 Form XXX, shown in , is indicative of
a crystalline material. zed light copy confirms that the material is crystalline
with some aggregation or agglomeration present.
Thermal analysis (TG/DTA) () did not show significant weight loss and
confirmed Compound 1 Form XXX was an anhydrous form. The onset of melting (117.9 °C)
was slightly higher than that observed by DSC (), which showed an initial melt at
onset 110.6 °C, followed by a recrystallization event to Compound 1 Form III at onset
136.25 °C and a final melt at onset 205.64 °C. As was the case for other recrystallization
, the Compound 1 Form III had a lower onset temperature as a result of lower
crystallinity.
1H NMR () of Compound 1 Form XXX showed the material to conform to
structure and contain ~1.1% w/w (0.1 mol eq) of residual acetone. Several attempts to reduce
this solvent level using heat, vacuum drying, and humid drying were unsuccessful and
suggested that some acetone remains trapped within the crystal structure. Infra-red
spectroscopy () differs from Compound 1 Form III and Compound 1 Form XXVIII in
the carbonyl stretch region. The residual acetone carbonyl can be seen at 1717cm-1, which is
comparable to liquid acetone (1715cm-1) and implies that the acetone is not hydrogen
bonded within the crystal structure in Compound 1 Form XXX. FTIR (cm-1): 3250, 1652,
1504, 1480, 1432, 1349, 1211, 1197, 995, 850, 821.
Compound 1 Form XXXI
The XRPD of nd 1 Form XXXI () is indicative of crystalline
material. Thermal analysis (TG/DTA) () showed two endothermic events; the first at
onset 72.7 °C with an associated weight loss of 6.61% (1.97 mol equiv of water) was due to
ation and indicates that Compound 1 Form XXXI is a dihydrate.
The hygroscopicity and the sorption ties of nd 1 Form XXXI were
determined using Dynamic Vapor Sorption (DVS). The program differed from that used for
Compound 1 Form I in that the sample was dried at 0%RH prior to performing sorption and
desorption. The isotherm showed the material lost -7% weight on drying to 0%RH,
consistent with loss of 2 mol eq of water.
The DSC thermogram () obtained for Compound 1 Form XXXI was
complex and showed three endothermic events occurring between -67°C and .
1H NMR () of Compound 1 Form nd 1 XXXI showed the material
to conform to structure. red spectroscopy () conformed to the spectrum of
Compound 1 Form I ( within experimental error. FTIR (cm-1): 3444, 3251, 1672, 1530,
1507, 1483, 1430, 1354, 1256, 1223, 1148, 1000, 856, 843, 826.
nd 1 Amorphous Form
The XRPD for Compound 1 Amorphous Form is shown in The
hygroscopicity and the sorption properties of Compound 1 Amorphous Form were ined
using Dynamic Vapor Sorption (DVS). The sample was dried at 0%RH prior to performing
sorption and desorption. The isotherm showed the material exhibits slow uptake of moisture
from 0%RH to 60%RH. The rate of uptake of moisture increased from 60%RH to 90%RH.
The isotherm showed the total weight gain observed between 0%RH and 80%RH to be 4%
w/w which indicated that the sample was hygroscopic, according to the European
Pharmacopoeia classification. The rate of tion was slower than the rate of sorption, as
hysteresis was observed. All of the moisture adsorbed was lost upon return to 0%RH. XRPD
of the sample post DVS confirmed that no crystallization had occurred (.
The physical stability of amorphous material was assessed under a range of stress
conditions including ature stress, ve humidity (RH), and exposure to selected
organic vapors. Surprisingly, the material was stable to heat stressing at 100 °C for 4 days
(i.e. below Tg of 120 °C). Exposure to relative ty between 23% and 98% for 7-10
days induced no crystallization. From DVS, a water uptake of approximately 5% was
ed at 90%RH and thus the plasticizing effect of water can be estimated from the Fox
equation. This suggests that the amorphous form should have a glass transition of
approximately 87 °C at 90% RH. A Tg over 100 °C coupled with the above stress data
reveal that amorphous Compound 1 contains an exceptional combination of favorable
physical attributes that provide y in a variety of drug product formulations.
Other Embodiments
The foregoing disclosure has been described in some detail by way of illustration
and example, for purposes of y and understanding. The invention has been described
with reference to various specific and red embodiments and ques. However, it
should be understood that many variations and modifications can be made while remaining
within the spirit and scope of the invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the appended claims.
Therefore, it is to be tood that the above description is intended to be illustrative and
not restrictive. The scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be determined with nce to the
following appended claims, along with the full scope of equivalents to which such claims are
entitled.
Claims (29)
1. A crystalline solid form of Compound 1: nd 1 wherein the crystalline solid form is selected from Compound 1 Form III and Compound 1 Form XXVIII, having XRPD peaks (CuKα), wherein all peaks are measured in (º2θ ± 0.2 º2θ), as depicted in the following table: Compound 1 Form III Form XXVIII 7.0 6.5 7.8 9.5 9.4 11.8 11.1 12.3 12.6 13.0 14.1 15.5 15.5 16.9 17.3 17.7 22.3 19.1 24.3 21.7 22.3
2. A pharmaceutical composition comprising a therapeutically effective dose of a crystalline solid form of Compound 1 as recited in claim 1 that contains at least 90 weight percent based on the weight of such solid form; and a pharmaceutically acceptable carrier.
3. A pharmaceutical ition comprising a therapeutically effective dose of a mixture of crystalline solid forms of compound 1 as recited in claim 1 and a pharmaceutically acceptable carrier.
4. A pharmaceutical composition sing the crystalline solid form of Compound 1 as recited in claim 1 for use in a method of ng cancer.
5. A pharmaceutical composition as recited in claim 2 or claim 3 for use in a method of treating .
6. The pharmaceutical composition for use of claim 4 or claim 5, wherein the cancer is selected from thyroid cancer, stomach cancer, esophageal carcinoma, kidney cancer, liver cancer, ovarian carcinoma, cervical carcinoma, large bowel cancer, small bowel cancer, brain cancer, lung cancer, bone cancer, prostate carcinoma, pancreatic carcinoma, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin’s disease, or non-Hodgkin’s ma.
7. A ceutical composition for use in a method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities due to cMET or RET overexpression, wherein the pharmaceutical composition ses at least one solid form of nd 1 as recited in claim 1 and a pharmaceutically acceptable carrier, wherein the disease or disorder is cancer.
8. A pharmaceutical formulation, comprising: Ingredient (% w/w) Compound I Solid Form III or XXVIII 31.68 as recited in claim 1 Microcrystalline Cellulose 38.85 Lactose anhydrous 19.42 Hydroxypropyl Cellulose 3.00 Croscarmellose Sodium 3.00 Total Intra-granular 95.95 Silicon dioxide, Colloidal 0.30 Croscarmellose Sodium 3.00 Magnesium Stearate 0.75 Total 100.00
9. A pharmaceutical formulation, comprising: Ingredient (% w/w) Compound 1 Form III or XXVIII as 25.0-33.3 d in claim 1 Microcrystalline ose q.s Hydroxypropyl Cellulose 3 Poloxamer 0-3 Croscarmellose Sodium 6.0 Colloidal Silicon Dioxide 0.5 Magnesium Stearate 0.5-1.0 Total 100
10. A pharmaceutical formulation, comprising: Ingredient Theoretical Quantity it dose) nd 1 Form III or XXVIII as 100.0 recited in claim 1 Microcrystalline Cellulose PH-102 155.4 e Anhydrous 60M 77.7 Hydroxypropyl Cellulose, EXF 12.0 Croscarmellose Sodium 24 Colloidal Silicon e 1.2 Magnesium Stearate (Non-Bovine) 3.0 Opadry Yellow Film Coating which 16.0 includes: - HPMC 2910 /Hypromellose 6 cp - um dioxide - Triacetin - Iron Oxide Yellow Total 416
11. A pharmaceutical formulation, comprising: Ingredient % w/w Compound 1 Form III or XXVIII as recited 31.7 in claim 1 Microcrystalline Cellulose (Avicel PH-102) 38.9 Lactose Anhydrous (60M) 19.4 Hydroxypropyl Cellulose (EXF) 3.0 Croscarmellose Sodium (Ac-Di-Sol) 6.0 Colloidal Silicon Dioxide, 0.3 Magnesium Stearate 0.75 Opadry Yellow Film Coating which 4.00 includes: - HPMC 2910 /Hypromellose 6 cp - Titanium dioxide - Triacetin - Iron Oxide Yellow
12. A process for producing Compound 1 Solid Form III as recited in claim 1, the s comprising: dissolving Compound 1 Solid Form I in tetrahydrofuran to a starting , wherein Compound 1 Solid Form I is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 10.1, 11.9, 12.9, 14.4, 16.0, and 23.6 (º2θ ± 0.2 º2θ); ling about one-half of the starting volume; adding methanol to achieve approximately the starting volume; repeating the distilling at least twice; and collecting the Compound 1 Solid Form III.
13. The process of claim 12, further comprising g Compound 1 Solid Form I in tetrahydrofuran from about 30 to 50 ºC and reducing the pressure to about 100 Torr before distilling about one-half of the starting volume.
14. A process for ing Compound 1 Solid Form XXVIII as recited in claim 1, the process comprising: slurrying amorphous Compound 1 in nitromethane for 11 days; collecting and drying resulting solids; and ating the solids on a Thermogravimetric ential Thermal Analyzer to produce the Compound 1 Solid Form XXVIII.
15. The process of claim 14, wherein the desolvating the solids on the Thermogravimetric Differential Thermal er is carried out at 110 ºC + 30 ºC for 15 minutes.
16. Use of the crystalline solid form of Compound 1 as recited in claim 1 in the manufacture of a medicament for treating cancer.
17. Use of claim 16, wherein the cancer is selected from thyroid cancer, h cancer, esophageal carcinoma, kidney cancer, liver cancer, ovarian oma, cervical carcinoma, large bowel cancer, small bowel cancer, brain cancer, lung cancer, bone cancer, prostate oma, pancreatic carcinoma, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin’s disease, or dgkin’s lymphoma.
18. Use of claim 17, wherein the thyroid cancer is medullary thyroid cancer.
19. Use of claim 17, wherein the kidney cancer is renal carcinoma.
20. Use of claim 17, wherein the liver cancer is hepatocellular carcinoma
21. Use of claim 17, wherein the brain cancer is astrocytic tumor.
22. Use of claim 21, wherein the astrocytic tumor is selected from glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components.
23. Use of claim 17, wherein the lung cancer is non-small cell lung cancer.
24. Use of claim 17, wherein the prostate carcinoma is castration resistant prostate
25. Use of the crystalline solid form of Compound 1 as recited in claim 1 in the manufacture of a medicament for treating diseases or ers associated with uncontrolled, al, and/or unwanted cellular activities due to cMET or RET overexpression.
26. A crystalline solid form of claim 1, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
27. A pharmaceutical composition of any one of claims 2-11, ntially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
28. A s of any one of claims 12-15, substantially as herein described with reference to any example thereof and with or without reference to the accompanying gs.
29. Use of any one of claims 16-25, substantially as herein described with reference to any example thereof and with or without nce to the accompanying drawings. W0
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201461939985P | 2014-02-14 | 2014-02-14 | |
US61/939,985 | 2014-02-14 | ||
PCT/US2015/016052 WO2015123639A1 (en) | 2014-02-14 | 2015-02-16 | Crystalline solid forms of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, processes for making, and methods of use |
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NZ723714B2 true NZ723714B2 (en) | 2021-06-29 |
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