U.S. patent application number 15/203673 was filed with the patent office on 2016-12-08 for solid state forms of vemurafenib hydrochloride.
The applicant listed for this patent is ratiopharm GmbH. Invention is credited to Wolfgang Albrecht, Richard Guserle, Frank Lehmann.
Application Number | 20160354351 15/203673 |
Document ID | / |
Family ID | 50639921 |
Filed Date | 2016-12-08 |
United States Patent
Application |
20160354351 |
Kind Code |
A1 |
Albrecht; Wolfgang ; et
al. |
December 8, 2016 |
SOLID STATE FORMS OF VEMURAFENIB HYDROCHLORIDE
Abstract
Provided herein are solid state forms of Vemurafenib
hydrochloride, processes for preparing the solid state forms, as
well as pharmaceutical compositions and formulations comprising
said solid state forms.
Inventors: |
Albrecht; Wolfgang; (Ulm,
DE) ; Guserle; Richard; (Kotz, DE) ; Lehmann;
Frank; (Ulm, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ratiopharm GmbH |
Jim |
|
DE |
|
|
Family ID: |
50639921 |
Appl. No.: |
15/203673 |
Filed: |
July 6, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14772566 |
Sep 3, 2015 |
9440971 |
|
|
PCT/US2014/023166 |
Mar 11, 2014 |
|
|
|
15203673 |
|
|
|
|
61783651 |
Mar 14, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 43/00 20180101; C07D 471/04 20130101; A61K 31/437
20130101 |
International
Class: |
A61K 31/437 20060101
A61K031/437 |
Claims
1-16. (canceled)
17. A method of treating a subject suffering from cancer comprising
administering to the subject a therapeutically effective amount of
a crystalline form of Vemurafenib hydrochloride salt, designated as
Form II, characterized by one or more of the following: a powder
X-ray diffraction pattern having peaks at 5.0, 9.9, 15.7, 19.8 and
22.1 degrees two theta.+-.0.2 degrees two theta; a powder X-ray
diffraction pattern substantially as depicted in FIG. 1; a
solid-state .sup.13C NMR spectrum having characteristic peaks at
51.0, 114.5, 132.3, 138.0 and 139.5 ppm, .+-.0.2 ppm; a solid state
.sup.13C NMR spectrum having chemical shift differences between
said characteristic peaks and a peak at 120.9 ppm.+-.0.2 ppm of
-69.9, -6.4, 11.4, 17.1 and 18.6.+-.0.1 ppm, respectively; a solid
state .sup.13C NMR spectrum substantially as shown in FIG. 3; or
any combination of these data.
18. The method of claim 17, wherein the cancer is metastatic
melanoma.
19. The method of claim 18, wherein the metastatic melanoma has a
BRAF V600E mutation.
20. A process for preparing a pharmaceutical formulation comprising
a crystalline form of Vemurafenib hydrochloride salt, designated as
Form II, characterized by one or more of the following: a powder
X-ray diffraction pattern having peaks at 5.0, 9.9, 15.7, 19.8 and
22.1 degrees two theta.+-.0.2 degrees two theta; a powder X-ray
diffraction pattern substantially as depicted in FIG. 1; a
solid-state .sup.13C NMR spectrum having characteristic peaks at
51.0, 114.5, 132.3, 138.0 and 139.5 ppm, .+-.0.2 ppm; a solid state
.sup.13C NMR spectrum having chemical shift differences between
said characteristic peaks and a peak at 120.9 ppm.+-.0.2 ppm of
-69.9, -6.4, 11.4, 17.1 and 18.6.+-.0.1 ppm, respectively; a solid
state .sup.13C NMR spectrum substantially as shown in FIG. 3; or
any combination of these data; comprising: combining the
crystalline form of Vemurafenib hydrochloride with at least one
pharmaceutically acceptable excipient.
21. A process for preparing Vemurafenib comprising preparing a
crystalline form of Vemurafenib hydrochloride salt, designated as
Form II, characterized by one or more of the following: a powder
X-ray diffraction pattern having peaks at 5.0, 9.9, 15.7, 19.8 and
22.1 degrees two theta.+-.0.2 degrees two theta; a powder X-ray
diffraction pattern substantially as depicted in FIG. 1; a
solid-state .sup.13C NMR spectrum having characteristic peaks at
51.0, 114.5, 132.3, 138.0 and 139.5 ppm, .+-.0.2 ppm; a solid state
.sup.13C NMR spectrum having chemical shift differences between
said characteristic peaks and a peak at 120.9 ppm.+-.0.2 ppm of
-69.9, -6.4, 11.4, 17.1 and 18.6.+-.0.1 ppm, respectively; a solid
state .sup.13C NMR spectrum substantially as shown in FIG. 3; or
any combination of these data; and converting the crystalline form
of Vemurafenib hydrochloride to Vemurafenib.
22. The process according to claim 21, wherein the conversion is
accomplished by a process comprising basifying the crystalline form
of Vemurafenib hydrochloride to obtain the Vemurafenib.
23. A process for preparing a Vemurafenib salt comprising:
preparing a crystalline form of Vemurafenib hydrochloride salt,
designated as Form II, characterized by one or more of the
following: a powder X-ray diffraction pattern having peaks at 5.0,
9.9, 15.7, 19.8 and 22.1 degrees two theta.+-.0.2 degrees two
theta; a powder X-ray diffraction pattern substantially as depicted
in FIG. 1; a solid-state .sup.13C NMR spectrum having
characteristic peaks at 51.0, 114.5, 132.3, 138.0 and 139.5 ppm,
.+-.0.2 ppm; a solid state .sup.13C NMR spectrum having chemical
shift differences between said characteristic peaks and a peak at
120.9 ppm.+-.0.2 ppm of -69.9, -6.4, 11.4, 17.1 and 18.6.+-.0.1
ppm, respectively; a solid state .sup.13C NMR spectrum
substantially as shown in FIG. 3; or any combination of these data;
and converting the crystalline form of Vemurafenib hydrochloride to
the Vemurafenib salt.
24. The process according to claim 23, wherein the conversion is
accomplished by a process comprising basifying the crystalline form
of Vemurafenib hydrochloride to obtain Vemurafenib and adding an
acid or a base to obtain the Vemurafenib salt.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/783,651, filed Mar. 14, 2013, the entirety of
which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to a solid state form of
Vemurafenib hydrochloride, processes for the preparation thereof,
formulations comprising thereof, and the conversion of the solid
state form to Vemurafenib base and/or other Vemurafenib salts.
BACKGROUND OF THE INVENTION
[0003] Vernuraferrib, propane-l-sulfonic acid
{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-
-phenyl}-amide, has the following chemical structure:
##STR00001##
[0004] Vemurafenib is a BRAF kinase inhibitor, which is marketed
under the trade name ZELBORAF.RTM. for the treatment of patients
with metastatic melanoma with the BRAF V600E mutation.
[0005] Vemurafenib is disclosed in U.S. Pat. No. 7,863,288. WO
2010/114928 discloses forms 1 and 2 of Vetnurafenib, and discloses
the mesylate, tosylate, maleate, oxalate, and dichloroacetate
salts. WO 2010/129570 discloses non-crystalline complexes of
Vemurafenib and its L-arginine and L-lysine salts. WO 2014/008270
discloses choline and esylate salts of Vemurafenib; and WO
2012/161776 discloses additional solid forms and salts of
Vemurafenib, including the hydrochloride salt and a crystalline
form thereof.
[0006] Polymorphism, occurrence of different crystal forms, is a
property of some molecules and molecular complexes. A single
molecule, like Vemurafenib or salts thereof, may give rise to a
variety of polymoiphs having distinct crystal structures and
physical properties like melting point, thermal behaviors (e.g.
measured by thermogravirnetric analysis--"TGA", or differential
scanning calorimetry--"DSC"), powder X-ray diffraction (PXRD)
pattern, infrared absorption fingerprint, and solid state NMR
spectrum. One or more of these techniques may be used to
characterize a particular polymorph and to distinguish different
polymorphic forms of a compound.
[0007] Different solid state forms (including solvated forms) of an
active pharmaceutical ingredient may possess different properties.
Such variations in the properties of different solid state forms
and solvates may provide a basis for improving certain aspects of
the API, such as its formulation, for example, by facilitating
better processing or handling characteristics, changing the
dissolution profile in a favorable direction, or improving
stability (polymorph as well as chemical stability) and shelf-life.
These variations in the properties of different solid state forms
may also offer improvements to the final dosage form, for instance,
if they serve to improve bioavailability. Different solid state
forms and. solvates of an active pharmaceutical ingredient may also
give rise to a variety of polymorphs or crystalline forms, which
may in turn provide additional opportunities to assess variations
in the properties and characteristics of a solid active
pharmaceutical ingredient.
[0008] Discovering new polymorphic forms and solvates of a
pharmaceutical product can provide materials having, inter alia,
desirable processing properties, such as ease of handling, ease of
processing, chemical and polymorphic stability upon storage and
processing, and ease of purification or are useful as advantageous
intermediate crystal forms that facilitate conversion to other
solid state forms (including other solvates) of said pharmaceutical
product.
[0009] New polymorphic forms and solvates of a pharmaceutically
useful compound can also provide an opportunity to improve the
performance characteristics of a pharmaceutical product. It
enlarges the repertoire of materials that a formulation scientist
has available for formulation optimization, for example by
providing a product with different properties, e.g., better
processing or handling characteristics, improved dissolution
profile, or improved shelf-life. Lastly, new polymorphic forms may
be prepared with improved reliability and reproducibility compared
to other forms, for example, in terms of crystallinity or
polymorphic purity.
SUMMARY OF THE INVENTION
[0010] The present invention provides a solid state form of
Vemurafenib hydrochloride, processes for the preparation thereof,
and pharmaceutical compositions and formulations comprising the
solid state form of Vemurafenib hydrochloride, and processes for
the preparation of the pharmaceutical compositions and
formulations.
[0011] The present invention also provides the use of said solid
state form of Vemurafenib hydrochloride for the manufacture of
pharmaceutical compositions and formulations. Accordingly, the
present invention further provides a pharmaceutical composition
comprising said solid state form of Vernurafenib hydrochloride of
the present invention. The pharmaceutical composition may
additionally comprise at least one pharmaceutically acceptable
excipient to form a pharmaceutical formulation that can, for
example, be administered to patients in need of such treatment.
[0012] The present invention comprises a process for preparing the
above-mentioned pharmaceutical formulations. The process comprises
combining the solid state form of Vemurafenib hydrochloride with at
least one pharmaceutically acceptable excipient.
[0013] The solid state form as defined herein as well as the
pharmaceutical con wsitions and formulations of Vernurafenib
hydrochloride can be used as medicaments, particularly for the
treatment of cancer. The present invention also provides a method
of treating cancer comprising administering a therapeutically
effective amount of the solid state form of Vernurafenib
hydrochloride of the present invention, or a therapeutically
effective amount of at least one of the pharmaceutical compositions
or formulations of the present invention comprising said solid
state form of Vemurafenib hydrochloride of the present invention to
a patient in need thereof.
[0014] The present invention also provides the use of said solid
state form of Vemurafenib and/or Vernurafenib salt, particularly
Vemurafenib hydrochloride, or at least one of the above
pharmaceutical compositions and/or formulations for the manufacture
of a medicament for treating cancer.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 shows a powder X-ray diffraction pattern ("Powder
XRD" or "PXRD") for crystalline Vemurafenib hydrochloride form
II.
[0016] FIG. 2 shows a Differential Scanning calorimetry ("DSC")
thermogram for crystalline Vemurafcnib hydrochloride form II.
[0017] FIG. 3 shows a solid state .sup.13C NMR spectrum for
crystalline Vemurafenib hydrochloride form II.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention provides a solid state form of
Vetnurafeifib hydrochloride, processes for preparing the solid
state form, as well as pharmaceutical compositions and formulations
comprising said solid state form.
[0019] In accordance with WO 2010/114928 and WO 2010/129570, it was
observed that Vernurafenib has an extremely low solubility which
makes it difficult to formulate and may result in poor
bioavailability.
[0020] Amorphous Vemurafenib may improve solubility, however it is
not stable. WO 2010/129570 also states that other base-addition
salts, such as the sodium and potassium salts are difficult to
isolate and hygroscopic. In addition, it was found that those salts
also contain large amounts of residual solvent. Attempts to develop
stable, solvent-free and robust crystalline form of such salts were
not successful. The Vemurafenib arginine and lysine complexes
described in WO 2010/129570 are stated to be non-crystalline
complexes. However, their PXRD pattern shows some degree of
crystallinity.
[0021] Consistent with the latter, it was found that the conversion
of Venturafinib free base to acid addition or base addition salts
was in many cases not possible, rather leading to precipitation of
the free base, or yielding non-crystalline complexes of the free
base and the respective acid or base. For example, it was observed
that a conversion into a variety of amine salts of vemurafenib
could not be accomplished.
[0022] The present invention offers crystalline Vemurafenib HCl,
which can be in anhydrous form. The highly crystalline Vemurafenib
HCl of the present invention has good solubility and high chemical
and crystalline purities which makes it suitable as a
pharmaceutically acceptable salt. The crystalline Vemurafenib HCl
of the present invention can be directly used to prepare highly
soluble formulations, without the need of a solid dispersion
formulation comprising the active ingredient in amorphous form. The
latter is less economical and burdened with potential
re-crystallization of the active ingredient, making quality control
of solid dispersions more demanding as even a partial
re-crystallization, which may have a substantial impact on
dissolution properties of the drug substance and thus clinical
efficacy, must be controlled.
[0023] Depending on which other solid state form it is compared
with, the solid state form of the present invention may have
advantageous properties selected from at least one of chemical or
polymorphic purity, increased crystallinity, flowability,
solubility, dissolution rate, bioavailability, morphology or
crystal habit, specific surface and pycnometric density, bulk/tap
density, stability such as chemical stability as well as thermal
and mechanical stability with respect to polymorphic conversion,
stability towards dehydration and/or storage stability, a lower
degree of hygroscopicity, low content of residual solvents and
advantageous processing and handling characteristics such as
compressibility, and bulk density.
[0024] Solid state forms of Vemarafenib hydrochloride comprise
crystal forms, or crystalline forms, of Vetnurafenib hydrochloride.
As used herein, solid state forms, crystal forms, crystalline
forms, polymorphs and polymorphic forms are used
interchangeably.
[0025] A crystal form may be referred to herein as being
characterized by graphical data "substantially as depicted in" a
Figure. Such data include, for example, powder X-ray
diffractogra.ms and solid state NMR spectra. The graphical data
potentially provides additional technical information to further
define the respective solid state form which can not necessarily or
easily be described by reference to numerical values for peak
positions and/or relative intensities. In any event, the skilled
person will understand that such graphical representations of data
may be subject to small variations, e.g., in peak relative
intensities and peak positions due to factors such as variations in
instrument response and variations in sample concentration and
purity, which are well known to the skilled person. Nonetheless,
the skilled person would readily be capable of comparing the
graphical data in the Figures herein with graphical data generated
for an unknown crystal form and confirm whether the two sets of
graphical data are characterizing the same crystal form or two
different crystal forms.
[0026] As used herein, the expression "chemical shift difference"
refers to the difference in chemical shifts between a reference
signal and another signal in the same NMR spectrum. These chemical
shift differences serve to provide an additional analytical
measurement for a substance, for example a Vernurafenib
hydrochloride crystal form of he present invention, which will
compensate for a phenomenon that may occur in NMR spectroscopy
wherein a shift in the solid-state NMR "fingerprint" is observed.
Such a shift in the NMR peaks may occur, for example, as a result
of variations in the instrumentation, the temperature, or the
calibration method Used in the NMR analysis. This shift in the
solid-state NMR "fingerprint", having chemical shift resonances at
a certain positions, is such that even though the individual
chemical shifts of signals have moved, all the peaks in the
spectrum are moved be the same amount, such that the difference
between chemical shifts of each signal and another is retained.
Thus, this shift may be used as a reliable characterization of the
material being analyzed.
[0027] In the present patent application the chemical shift
differences were calculated by subtracting the chemical shift value
of the signal exhibiting the lowest chemical shift (reference
signal) in the solid state .sup.13C NMR spectrum in the range of 0
to 180 ppm from the chemical shift value of another (observed)
signal in the same .sup.13CNMR spectrum in the range of 100 to 180
ppm.
[0028] A crystal form (or polymorph) may be referred to herein as
substantially free of any other crystalline (or polymorphic) forms.
As used herein in this context, the expression "substantially free
of any other forms" will be understood to mean that the crystalline
form contains 20% or less, 10% or less, 5% or less, 2% or less, or
1% or less of any other forms of the subject compound as measured,
for example, by PXRD. Thus, polymorphs of Venuirafenib
hydrochloride described herein as substantially free of any other
polymorphic forms would be understood to contain m.sup..eater than
80% (w/vv), greater than 90%(w/v), greater than 95% (w/w), greater
than 98% (w/w), or greater than 99% (w/w)of the subject polymorphic
form of Vemurafenib hydrochloride. Accordingly, in some embodiments
of the invention, the described polymorphs of Vemurafenib
hydrochloride may contain from 1% to 20% (w/w), from 5% to 20%
(w/w), or from 5% to 10% (w/w) of one or more other crystal forms
of Vemurafenib or salts thereof.
[0029] The amount of solvent employed in a chemical process, e.g.,
a reaction or a crystallization, may be referred to herein as a
number of "volumes" "vol" or "V." For example, a material may be
referred to as being suspended in 10 volumes (or 10 vol or 10V) of
a solvent. In this context, this expression would be understood to
mean milliliters of the solvent per gram of the material being
suspended, such that suspending a 5 grams of a material in 10
volumes of a solvent means that the solvent is used in an amount of
10 milliliters of the solvent per gram of the material that is
being suspended or, in this example, 50 mL of the solvent. In
another context, the term "v/v" may be used to indicate the number
of volumes of a solvent that are added to a liquid mixture based on
the volume of that mixture. For example, adding MTBE (1.5 v/v) to a
100 ml reaction mixture would indicate that 150 mL of MTBE was
added.
[0030] As used herein, the expression "room temperature" or "RT"
refers to a temperature between about 20.degree. C. and about
30.degree. C. Usually, room temperature ranges from about
20.degree. C. to about 25.degree. C.
[0031] As used herein, the term "overnight" refers to a period of
about 15 and about 20 hours, typically between about 16 to about 20
hours.
[0032] As used herein, the term "reduced pressure" refers to a
pressure of about 10 mbar to about 50 mbar.
[0033] As used herein, the term "isolated" corresponds to product
or solid state form thereof that is physically separated from the
reaction mixture in which it is formed.
[0034] As used herein, unless stated otherwise, XRPD peaks reported
herein are preferably measured using CuK radiation,
.lamda.=1.5418.
[0035] As used herein, the expression "wet crystalline form" refers
to a polymorph as not dried using any conventional techniques to
remove residual solvent. Such conventional techniques include, but
are not limited to, evaporation, vacuum drying, oven drying, drying
under nitrogen flow, etc.
[0036] As used herein, the expression "dry crystalline form" refers
to a polymorph that was dried using any conventional techniques to
remove residual solvent. Such conventional techniques include, but
arc not limited evaporation, vacuum drying, oven drying, drying
under nitrogen flow, etc.
[0037] As used herein, and unless stated otherwise, the term
"anhydrous" in on to crystalline Vemurafenib hydrochloride relates
to a crystalline Vemurafenib hydrochloride which contains no more
than 1% (w/w) of either water or organic solvents as measured by
conventional methods, for example TGA, CC or KF. An anhydrous form
of the solid states of Vemurafenib hydrochloride of the present
invention refers to a form that does not contain crystalline water
(or other solvents) in a defined, stoichiometric amount within the
crystal
[0038] The term "solvate," as used herein and unless indicated
otherwise, refers to a crystal form that incorporates a solvent in
the crystal structure. When the solvent is water, the solvate is
often referred to as a "hydrate." The solvent in a solvate may be
present in either a stoichiometric or in a non-stoichiometric
amount.
[0039] As used herein, and unless indicated otherwise, the term
"polymorphic stability" in relation to the crystalline forms of
Vernurafenib hydrochloride means that there is less than 20%, 10%,
5%, 1%, 0.5% or 0.1% conversion of crystalline Veraurafenib
hydrochloride to any other solid state form of Vetnurafenib
hydrochloride under the specified conditions, as measured by PXRD.
In some embodiments, the conversion is 0.5%-20%, 0.5%-10% or
0.5%-5% or 0.5%-l% or 0.1%-1%, or 0.1%-0.5%.
[0040] As used herein, and unless stated otherwise, the terms
"crystalline Vernurafenib form 2", or "form 2 of Vemurafenib"
refers to crystalline Vemurafenib um described in WO 2010/114928,
characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 8.8, 9.2, 13.5, 19.1 and 24.4
degrees 2Theta, or having characteristic peak locations of
approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7, 21.4 and
24.4 degrees 2Theta, or having characteristic peak locations of
approximately 6.7, 8.8, 9.2, 13.5, 14.1 , 14.5, 15.0, 16.2, 17.0,
17.7, 19.1, 19.7, 21.4, 22.2, 24.1 24.4, and 28.1 degrees
2Theta.
[0041] As used herein, and unless stated otherwise, the terms
"crystalline Vemurafenib hydrochloride form I", or "form I of
Veinurafetrib hydrochloride" refets to crystalline Vemurafenib
hydrochloride as described in WO 2012/161776, characterized by an
X-ray powder diffraction pattern comprising characteristic peaks at
approximately 6.6, 7.8, 11.2, 12.6, 14.1, 14.7, 16.3, 17.8, 19.3,
19.6, 20.7, 21.5, 22.7, 24.1, 25.4 and 25.8 degrees 2Theta (.+-.0.2
degrees 2Theta),
[0042] The present invention encompasses a crystalline form of
Vemurafenib hydrochloride, designated as Form II.
[0043] Form II of Vemurafenib hydrochloride can be characterized by
data selected from one or more of the following: a powder X-ray
diffraction pattern having peaks at 5.0, 9.9, 15.7, 19.8 and 22.1
degrees two theta .+-.0.2 degrees two theta; a powder X-ray
diffraction pattern substantially as depicted in FIG. 1; a
solid-state .sup.13C NMR spectrum having characteristic peaks at
51.0, 114.5, 132.3, 138.0 and 139.5 ppm, .+-.0.2 ppm; a solid state
.sup.13C NMR spectrum having chemical shift differences between
said characteristic peaks and a peak at 120.9 ppm.+-.0.2 ppm of
-69.9, -6.4 11.4, 17.1 and 18.6.+-.0.1 ppm, respectively; a solid
state .sup.13C NMR spectrum substantially as shown in FIG. 3; and
any combinations of these data.
[0044] Typically, the signal exhibiting the lowest chemical shift
in the chemical shift area of 0-200 ppm for form II of Vemurafenib
HCl is at 13.1.+-.1.ppm.
[0045] Form II, characterized by a powder X-ray diffraction pattern
having peaks at 5.0, 9.9, 15.7, 19.8 and 22.1 degrees two
theta.+-.0.2 degrees two theta, can be further characterized by an
additional one, two, three, four or five PXRD peaks selected from
18.5, 20.4, 21,0, 23.8 and 26.7 degrees two theta.+-.0.2 degrees
two theta.
[0046] Form II can be further characterized by one or more of the
following: a DSC thermogram substantially as depicted in FIG. 2; a
broad dehydrochlorination endotherm between 166.degree. C.
(.+-.5.degree. C.) and 197.degree. C. (.+-.5.degree. C.), a DSC
melting peak at about 270.8.degree. C. (.+-.1.degree. C.), and a
DSC melting onset at about 268.1.degree. C. (.+-.1.degree. C.); and
by any combinations of these data.
[0047] Form II can be characterized by any combinations of the
above data. For example, by a powder X-ray diffraction pattern
having peaks at 5.0, 9.9, 15.7, 19.8 and 22.1 degrees two theta
.+-.0.2 degrees two theta and also by a DSC thermogram
substantially as depicted in FIG. 2.
[0048] In certain embodiments, form II is an anhydrous form, as can
be determined, for example, by TGA.
[0049] The above form II of Vemurafenib HCL has advantageous
properties selected from at least one of: chemical or polymorphic
purity, flowability, solubility, dissolution rate, bioavailability,
morphology or crystal habit, stability such as such as chemical
stability as well as thermal and mechanical stability with respect
to polymorphic conversion, storage stability, stability to
dehydration, low hygroscopicity, and low content of residual
solvents and advantageous processing and handling characteristics
such as compressibility, or bulk density.
[0050] Particularly, crystalline Vetnt rafenib HCl form II has high
chemical purity and excellent stability properties. Specifically,
it is stable upon storage at 25.degree. C. and 60% relative
humidity (RH); and at 30.degree. C./65% RH for up to at least 24
weeks; while crystalline Vemurafenib HCl form I converts to
Vemurafenib free base under these conditions. Furthermore,
crystalline Vernurafenib HCl form II has good solubility and it can
be used to prepare an oral formulation, i.e. a tablet or a capsule,
without the need of a solid dispersion formulation, or
co-precipitation with a polymer. Therefore, the crystalline
Vemurafenib HCl form II may be used to prepare an oral formulation
which is stable and has a relatively small tablet or capsule size
as the molar ratio of Vemurafenib to HCl is about 1:1, which is
highly advantageous for preparing pharmaceutical compositions with
high drug load.
[0051] The described solid state form II of Vemurafenib
hydrochloride can be used to prepare Vemurafenib base or other
different salts of Vemurafenib, as well as solid state forms
thereof and/or pharmaceutical formulations comprising one or more
of the salts and/or solid state forms thereof.
[0052] The present invention also encompasses a process for
preparing other Vemurafenib salts. The process comprises preparing
the solid state form II of Vemurafenib hydrochloride for example by
the processes of the present invention, and converting that form to
said other Vetnurafenib salt. The conversion can be done, for
example, by a process comprising basifying the above described
Vemurafenib hydrochloride solid state form II, and reacting the
obtained form with a suitable acid, or a base to obtain the
corresponding salt acid addition or base addition salt.
[0053] The present invention further encompasses 1) a
pharmaceutical composition comprising said solid state form
described herein; 2) a pharmaceutical formulation comprising said
solid state forms or pharmaceutical compositions described herein,
and at least one pharmaceutically acceptable excipient; 3) a
process to prepare such formulations comprising combining the
above-described solid state forms and at least one pharmaceutically
acceptable excipient; 4) the use of the above-described solid state
form in the manufacture of a pharmaceutical composition, and 5) a
method of treating cancer comprising administering a
therapeutically effective amount of the above-described solid state
forms, optionally in the form of pharmaceutical compositions or
formulations. The present invention also provides a crystalline
form of Vemurafenib HCl as described above for use as a medicament,
preferably for the treatment of cancer. The pharmaceutical
compositions can also be used for preparing said medicament.
[0054] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the preparation of the composition and methods
of use of the invention. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may
be practiced without departing from the scope of the invcntion.
Analytical Methods
[0055] .sup.1H-NMR Spectroscopy [0056] Instrument: Varian Mercury
400 Plus NMR Spectrometer, Oxford AS, 400 MHz.
HPLC/UV
[0056] [0057] Instrument: HP Series 1090 [0058] Column: Discovery
C18; 5 .mu.m; 150.times.4.6 mm [0059] Column temp.: Rt [0060] Flow
[mL/min]: 1.5 [0061] Injection volume: 5 .mu.L [0062] Solvent A:
Acetonitrile [0063] Solvent B: 0.01 M KH.sub.2PO.sub.4, pH 2.3
TABLE-US-00001 [0063] Gradient: time [min] Solvent B [%] 0 60 8 20
13 20 14 60 17 60
Differential Scanning calorimetry (DSC) [0064] Instroment: Mettler
Toledo DSC 822E coupled with a Mettler Toledo Gas-Flow-Controller
TS0800GC1 (Mettler-Toledo GmbH, Gie.beta.en, Germany) [0065]
Aluminium crucible: 40 .mu.L [0066] Lid: Perforated [0067]
Temperature range: 30.degree. C. to 350.degree. C. [0068] Heating
rate: 10.degree. C./min [0069] N itrogen flush: 50 mL/min [0070]
Software: STARe Version. 8.10 [0071] Interpretation: Endothermic
modus
X-Ray Powder Diffraction (PXRD)
[0072] The sample was analyzed on a D8 Advance X-ray powder
diffractometer (Balker-AXS, Karlsruhe, Germany). The sample holder
was rotated in a plane parallel to its surface at 20 rpm during the
measurement. Further conditions for the measurements are summarized
in the table below. The raw data Were analyzed with the program EVA
(Bruker-AXS, Germany). The samples were layered onto a silicon
specimen holder.
TABLE-US-00002 standard measurement Radiation Cu K.sub..alpha.
(.lamda. = 1.5406 .ANG.) Source 38 kV/40 mA Detector Vantec
detector slit variable divergence slit v6 antiscattering slit v6
2.theta. range/.degree. 2 .ltoreq. 2.theta. .ltoreq. 55 step
size/.degree. 0.017
Solid State .sup.3C NMR Spectroscopy Method:
[0073] .sup.13C NMR at 125 MHz using Bruker Avance II+500 [0074] SB
probe using 4 mm rotors [0075] Magic angle was set using KBr [0076]
Homogeneity of magnetic field checked using adamantane [0077]
Parameters for Cross polarization optimized using glycine [0078]
Spectral reference set according to glycine as external standard
(176.03 ppm for low field carboxyl signal, relative to the signal
of tetramethylsilane) [0079] Scanning parameters: [0080] Magic
Angle Spinning Rate: 11 kHz [0081] Delay time: 5 s [0082] Number of
Scans: 1024 [0083] Acquisition time: 30 ms
EXAMPLES
Example 1
Preparation of Vemarafenib Base
[0084] Vemurafenib was prepared in four steps according to the
procedure described in the following scheme.
##STR00002##
[0085] Step a: Pre aration of intermediate 4
(propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl]-2,4-difluoro-phenyl}-amide)
[0086] Under a stream of nitrogen, 300 g (0.48 mol) intermediate 3
(propane-1-sulfonic acid
{3-[5-bromo-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl-
]-2,4-difluoro-phenyl}-amide) and 81.74 g (0.52 mol, 1.1 eq.)
4-chlorophenylboronic acid were suspended in 1.3 L toluene, instead
of anisole as shown in the scheme above. Sodium carbonate (202 g,
1.90 mol, 4 eq.) and water (1.1 L) were added at 2..degree. C. and
the mixture was heated to 70.degree. C. Afterwards,
bis(triphenylphosphine)palladium(II) chloride (3.33 g, 4.8 mmol,
0.01 eq.) was added and the reaction mixture was heated to
80-80.degree. C. (external temperature did not exceed 110.degree.
C.) for 2 hours. Then the reaction was cooled to 70.degree. C., the
two phases were separated and the organic phase was washed at
70.degree. C. with 0.1N H.sub.2SO.sub.4 (1.3 L) and water (1.3 L).
The organic layer was evaporated to dryness. Propane-1-sulfonic
acid
{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-H-pyrrolo[2,3-b]pyridine-
-3-carbonyl]-2,4-difluoro-phenyl}-amide (359.73 g, 114.2%) was
isolated as a reddish, glassy solid (yield higher than 100% due to
residual toluene).
[0087] Step b: Preparation of Vemurafenib.
[0088] Intermediate 41788 g 1.19 mol, propane-1-sulfonic acid
{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-
e-3-carbonyl]-2,4-difluoro-phenyl}-amide) was suspended at
25.degree. C. in 1200 mL DMF and 900 mL methanol. To this
suspension, 700 mL 15% ammonia in methanol (4.77 mol, 4.01 eq.)
were added and the mixture was heated to 50-55.degree. C. for 18
hours. The resulting clear solution was concentrated (330
mbar/55.degree. C.), until no ammonia was smelled. Afterwards
methanol (4 L) was added slowly over 30 minutes, whereby the
temperature was kept between 45-55.degree. C. The resulting
suspension was cooled to 25.degree. C. and stored at 4.degree. C.
overnight. The solid was filtered, washed with methanol (1 L) and
dried under vacuum (50.degree. C.-40 mbar). Vemurafenib (374.85 g,
64.4%) was isolated as an off-white solid.
Example 2
Preparation of Vemurafenib-HCl, Form II.
[0089] Vemurafenib (Form 2, 0.5 g, 1.02 mmol) was suspended in 5 mL
acetone and the mixture was warmed to 35.degree. C. While
maintaining this temperature, 0.8 ml of 1.25 M HCl in ethanol
(approximately 1 equivalent) were added dropwise. A clear solution
was obtained. Thereafter, the solution was allowed to cool to RT
and stirred overnight. The obtained precipitate was filtered,
washed with acetone and dried under ambient conditions (RT,
atmospheric pressure) for approximately 20 h. Yield: 0.49 g
(91%).
Example 3
Preparation of Vemurafenib-HCl, Form II.
[0090] The procedure was identical to that described in Example 2
with the following modification: 1.0 ml of 1M HCl in diethylether
instead of 0.8 ml of 1.25 M HCl in ethanol, corresponding to 1
equivalent of HCl, was added to the suspension of 0.5 g
Vennirafenib in 5 ml acetone. Yield: 0.50 g (93%)
Example 4
Preparation of Vemorafenib-HCl, Form II.
[0091] Vemurafenib (97.8 g, 199.6 mmol) was suspended in 900 mL
acetone and the mixture was warmed to 35.degree. C. While
maintaining this temperature, 200 ml of 1.25 M HCl in ethanol (250
mmol HCl, 1.25 equivalents) were added dropwise. A clear solution
was obtained. Thereafter, the solution was stirred for another 5
min at 35.degree. C. and then allowed to cool to RT and stirred
overnight. The obtained precipitate was filtered, washed with
acetone and dried at 40.degree. C. under reduced pressure (30 mbar)
for approximately 16 h. Yield: 95.8 g (91%)
* * * * *