Note: Descriptions are shown in the official language in which they were submitted.
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SOLID FORM OF AXITINIB
TECHNICAL FIELD
The present invention is related to Axitinib and, in particular, to a solid
form thereof.
BACKGROUND
Axitinib (AXI) is a vascular endothelial growth factor (VEGF) inhibitor.
These kinds of antagonist have been recognized as an important class of
pharmaceutical agents for development due to their efficiency in controlling
growth and proliferation of cancer cells. Axitinib was reviewed by the Food
and Drug Administration (FDA), and was approved in 2012 with the trademark
INLYTATm for the treatment of patients with advanced renal cell carcinoma
(RCC).
0 NH
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Axitinib
WO 2006/123223 A1 discloses a pharmaceutical composition
comprising the compound 6-[2-(methylcarbamoyl)phenylsulfany1]-3-E-[2-
(pyridin-2-ypethenyl]indazole, or a pharmaceutically acceptable salt or
solvate
thereof, in an amorphous form.
WO 2008/122858 A2 is related to novel crystalline polymorphic and
amorphous form of 6-[2-(methylcarbamoyl)phenylsulfany1]-3-E-[2-(pyridin-2-
pethenyl]indazole and to methods for their preparation. The invention is also
directed to pharmaceutical compositions containing at least one polymorphic
form and to the therapeutic or prophylactic use of such polymorphic forms and
compositions.
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Org. Process Res. Dev. 2008, 12(4), 637-645 describes that AG13736
(Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under
investigation as an oncology drug, is currently manufactured via a three-step
process that utilizes two palladium-mediated cross-couplings. Historically,
removal of residual heavy metals from the active pharmaceutical ingredient
has been a persistent issue. The development of a much improved process
for palladium removal and a useful screening technique developed to rapidly
identify the most efficient reagents for this purpose are outlined. The
performance of the new endgame process in pilot-plant scale-up is also
discussed.
/P.com Journal (2009), 9(5A), 36 (IPC0M000182442D) discloses that
a crystal Form XLVI of Axitinib, N-methy1-2-[3-((E)-2-pyridin-2-yl-viny1)-1H-
indazol-6-ylsulfanyl]-benzamide was prepared starting from Axitinib Form VIII,
which is described in the first preparation of Example 1 of WO Application
Publication No. 2008/122858. To prepare Axitinib Form XLVI, Axitinib Form
VIII (10.0 g) was added to a reactor along with N-methyl pyrrolidone (38 ml)
and tetrahydrofuran (10 ml). The resulting slurry was heated to 65 C to allow
for complete dissolution. The resulting solution was cooled to 10 C and
ethanol (80 ml) was added to the reactor to allow for the precipitation of
solids. The resulting solids were filtered, dried under vacuum with heating to
45 C to 60 C and isolated to yield Axitinib Form XLVI.
Org. Process Res. Dev. (2009), 13(6), 1327-1337 discloses developing
a robust crystallization process for an active pharmaceutical ingredient (API)
molecule with a complex polymorphic profile can present a significant
challenge. The presented case illustrates an unusual crystallization
development problem where a polymorphically complex API has the
additional obstacles of poor solubility in standard crystallization solvents
as
well as a propensity for forming solvates. After early polymorph screening of
this candidate highlighted the potential for a complex solid form profile, a
variety of experimental approaches was utilized to determine the low-energy
polymorph and characterize the various solvates formed. Characterization of
the API crystallization process identified a critical solvent composition
range
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for the transformation from a metastable solvate form to the desired
polymorph. During subsequent crystallization process development studies, a
new lower-energy polymorph was discovered. Examination of the crystal
structures led to a rationale for the formation of solvates and the existence
of
a new lower-energy form.
J. Pharm. Sci. (2010), 99(9), 3874-3886 discloses that elucidation of
the most stable form of an active pharmaceutical ingredient (API) is a
critical
step in the development process. Polymorph screening for an API with a
complex polymorphic profile can present a significant challenge. The
presented case illustrates an extensively polymorphic compound with an
additional propensity for forming stable solvates. In all, 5 anhydrous forms
and 66 solvated forms have been discovered. After early polymorph
screening using common techniques yielded mostly solvates and failed to
uncover several key anhydrous forms, it became necessary to devise new
approaches based on an advanced understanding of crystal structure and
conformational relationships between forms. With the aid of this analysis, two
screening approaches were devised which targeted high-temperature
desolvation as a means to increase conformational populations and enhance
overall probability of anhydrous form production. Application of these
targeted
approaches, comprising over 100 experiments, produced only the known
anhydrous forms, without appearance of any new forms. The development of
these screens was a critical and alternative approach to circumvent solvation
issues associated with more conventional screening methods. The results
provided confidence that the current development form was the most stable
polymorph, with a low likelihood for the existence of a more-stable anhydrous
form.
J. Phys. Chem. A (2011), 115(45) 12809-12817 discloses that
prediction of the most stable crystal form based on the strongest
intermolecular hydrogen bonds (HBs) only, was successfully applied to ten
polymorphic drug systems, using the Quantum Theory of Atoms in Molecules
(QTA1M). The results of the predictions were demonstrated to be superior to
the thermodynamic stability ranking based on molecular mechanical
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(COMPASS forcefield), DFT and DFT-D calculations, as well as on the
QTAIM predictions based on the total intermolecular HBing interactions
strength. The obtained results support the validity of the best donor/best
acceptor hierarchical approach for polymorph stability analysis of drug-like
molecules: weak interactions are not as important for stability ranking as the
strongest HBs. In addition, the proposed QTAIM approach allowed a
reasonable ranking of the relative stability of multiple polymorphic
crystalline
forms of two test systems, axitinib and sulfathiazole.
J. Pharm. Sci. (2012), 101(10), 3687-3697 discloses that it is
demonstrated that the fluid-phase thermodynamics theory conductor-like
screening model for real solvents (COSMO-RS) as implemented in the
COSMOtherm software can be used for accurate and efficient screening of
coformers for active pharmaceutical ingredient (API) cocrystallization. The
excess enthalpy, Hex, between an API¨coformer mixture relative to the pure
components reflects the tendency of those two compounds to cocrystallize.
Thus, predictive calculations may be performed with decent effort on a large
set of molecular data in order to identify potentially new cocrystal systems.
In
addition, it is demonstrated that COSMO-RS theory allows reasonable ranking
of coformers for API solubility improvement. As a result, experiments may be
focused on those coformers, which have an increased probability of
cocrystallization, leading to the largest improvement of the API solubility.
In a
similar way as potential coformers are identified for cocrystallization,
solvents
that do not tend to form solvates may be determined based on the highest
Hexs with the API. The approach was successfully tested on tyrosine kinase
inhibitor axitinib, which has a propensity to form relatively stable solvated
structures with the majority of common solvents, as well as on thiophanate-
methyl and thiophanate-ethyl benzimidazole fungicides, which form channel
solvates.
EMA/CHMP/453325/2012 discloses that Axitinib is a white to light
yellow powder, weak base, non-hygroscopic, classified as Biopharmaceutics
Classification System (BCS) class II (low solubility, high permeability), and
exhibits polymorphism. Five crystalline anhydrous forms have been identified
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(Form I, Form IV, Form VI, Form XXV and Form XLI). A number of crystalline
solvates and hydrate forms have been observed and an amorphous form has
been prepared. The polymorphic form intended for marketing is Form XLI.
J. Pharm. Sci. (2011), 100(1), 186-194 discloses that there are two
major challenges in developing a solid form: (1) identifying the
thermodynamically stable form and (2) determining the method used to
crystallize that form. Often experiments performed to address these
challenges have different objectives and use separate experimental
techniques. The thermodynamically stable form is usually found on small
scale, utilizing slurries or crystallizations. Subsequently, a crystallization
process is developed to purge impurities and to increase yield and these
experiments are typically conducted on medium to large scale (greater than
10 g). Axitinib, a research compound for the treatment of cancer, forms
solvates in most solvents to which it is exposed, presenting a problem in
discovering and making a desirable anhydrous phase. A method has been
developed that will give the best chance of making a thermodynamic stable
form of the anhydrous material, necessarily not a desolvated form. This
approach relies on solvent mediated transformation (thermodynamic control),
rather than crystallization or solid-to-solid phase desolvation (generally
kinetic
control). Experimental conditions (a desolvation window) to produce an
anhydrous solid form for this compound that shows predominance for solvate
formation is detailed.
Org. Process Res. Dev., 2013, 17(3), pp. 457-471 discloses that solid
form screening is an integral part of many development plans at various
companies and includes polymorph, salt, cocrystal, amorphous, and
amorphous dispersion screens. There are a number of traditional solvent-
and nonsolvent-based methods that are employed for these screens. Over
time, specialized screens have been developed to deal with difficult molecules
and situations or to push the limits of traditional experiments. This
contribution outlines a variety of specialized screening approaches for
polymorphs, salts, cocrystals, and amorphous dispersions. Many techniques
are amenable to laboratory equipment and can be incorporated with minimal
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start-up time, while others are very specific and will need specialized
equipment and/or expertise.
SUMMARY
This invention is based, at least in part, on a solid form of Axitinib, namely
a polymorphic form of Axitinib termed herein APO-I. Processes for preparing
this
form are also provided. Form APO-I may have improved physico-chemical
properties compared to other forms of Axitinib.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib characterized by a powder X-ray diffraction (PXRD)
diffractogram comprising peaks, in terms of degrees 2-theta, at 15.8 0.2 and
18.8 0.2.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein further characterized by at least four
peaks,
in terms of degrees 2-theta, selected from the group consisting of: 15.2 0.2,
21.3 0.2, 22.2 0.2, 22.6 0.2, 24.9 0.2 and 29.2 0.2.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein characterized by a PXRD diffractogram
substantially similar to the PXRD diffractogram shown in Figure 1.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein characterized by a DSC thermogram
comprising a first endothermic peak and a second endothermic peak, the first
endothermic peak having a peak onset of approximately 108 C and the
second endothermic peak having a peak onset of approximately 218 C and
a peak maximum of approximately 219 C.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein characterized by a DSC thermogram
substantially similar to the DSC thermogram shown in Figure 2.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein having from about 4 wt % ethanol to about 6
wt % ethanol.
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Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein wherein the form is a hemi ethanol solvate
and the molar ratio of ethanol to Axitinib is approximately 0.5:1.
Illustrative embodiments of the present invention provide a polymorphic
form of Axitinib described herein wherein the form is incorporated in a
pharmaceutical formulation.
Illustrative embodiments of the present invention provide a process for
the preparation of a polymorphic form of Axitinib described herein, the
process comprising: a) preparing, at an elevated temperature, a solution
comprising Axitinib, ethanol and propylene glycol; b) cooling the solution
thereby inducing crystallization of a solid; and c) isolating the solid to
yield the
polymorphic form of Axitinib.
Illustrative embodiments of the present invention provide a process
described herein wherein an amount of ethanol is from about 42 volumes to
about 73 volumes with respect to the weight of Axitinib and an amount of
propylene glycol is from about 2.4 volumes to about 3 volumes with respect to
the weight of Axitinib.
Illustrative embodiments of the present invention provide a process
described herein wherein the elevated temperature is between about 72 C to
about 80 C.
Other aspects and features of the present invention will become apparent
to those ordinarily skilled in the art upon review of the following
description of
specific embodiments of the invention in conjunction with the accompanying
figures.
BRIEF DESCRIPTION OF THE DRAWINGS
In drawings which illustrate embodiments of the invention,
Figure 1 is a Powder X-Ray Diffraction (PXRD) diffractogram of form
APO- I of Axitinib as prepared in Example 1.
Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of form
APO-I of Axitinib as prepared in Example 1.
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DETAILED DESCRIPTION
When used in reference to a diffractogram, a spectrum and/or data
presented in a graph, the term "substantially similar" means that the subject
diffractogram, spectrum and/or data presented in a graph encompasses all
diffractograms, spectra and/or data presented in graphs that vary within
acceptable boundaries of experimentation that are known to a person of skill
in the art. Such boundaries of experimentation will vary depending on the
type of the subject diffractogram, spectrum and/or data presented in a graph,
but will nevertheless be known to a person of skill in the art.
When used in reference to a peak in a powder X-ray diffraction (PXRD)
diffractogram, the term "approximately" means that the peak may vary by 0.2
degrees 2-theta of the subject value.
When used in reference to a peak in a DSC thermogram, the term
"approximately" means that the peak may vary by 2 C of the subject value.
As used herein, when referring to a diffractogram, spectrum and/or to
data presented in a graph, the term "peak" refers to a feature that one
skilled
in the art would recognize as not attributable to background noise.
Depending on the nature of the methodology applied and the scale
selected to display results obtained from an X-ray diffraction analysis, an
intensity of a peak obtained may vary quite dramatically. For example, it is
possible to obtain a relative peak intensity of 1% when analyzing one sample
of a substance, but another sample of the same substance may show a much
different relative intensity for a peak at the same position. This may be due,
in
part, to the preferred orientation of the sample and its deviation from the
ideal
random sample orientation, sample preparation and the methodology applied.
Such variations are known and understood by a person of skill in the art.
As used herein, the term "volumes" and the abbreviated term "vol"
refers to the parts of solvent or liquids by volume (mL) with respect to the
weight of solute (g). For example, when an experiment is conducted using 1
g of starting material and 100 mL of solvent, it is said that 100 volumes of
solvent are used.
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As used herein, the term "about" means close to and that variation from
the exact value that follows the term within amounts that a person of skill in
the art would understand to be reasonable. In particular, when the term
"about" is used with respect to temperature, a variation of +/- 5 C is often
acceptable.
As used herein, when referring to a solvent content, the term "weight
percent" (wt %) refers to the ratio: weight solvent/ (weight solvent + weight
Axitinib), expressed as a percentage.
Multi-component solid forms comprising more than one type of
molecule, such as solvates may have some variability in the exact molar ratio
of their components depending on a variety of conditions understood to a
person of skill in the art. For example, a molar ratio of components within a
solvate provides a person of skill in the art information as to the general
relative quantities of the components of the solvate and, in many cases, the
molar ratio may vary by plus or minus 20% from a stated range. For example,
a molar ratio of 1:1 is understood to include the ratio 1:0.8 as well as 1:1.2
as
well as all of the individual ratios in between.
As used herein, the term pure means, unless otherwise stated,
substantially free from impurities. Often compounds of the present invention
are at least 75% pure (w/w), greater than about 90% pure (w/w), or greater
than about 95% pure (w/w).
The present invention provides a solid form of Axitinib, termed herein
APO-I.
In an embodiment, the present invention provides form APO-I of
Axitinib which may be characterized by a powder X-ray diffraction (PXRD)
diffractogram comprising peaks, expressed in degrees 2-theta, at 15.8 0.2
and 188 0.2.
In an embodiment, the present invention provides form APO-I of
Axitinib which may be characterized by a powder X-ray diffraction (PXRD)
diffractogram comprising a peak, expressed in degrees 2-theta, at 15.8 0.2
and 18.8 0.2, and further comprising at least four peaks, expressed in
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degrees 2-theta, selected from the group consisting of: 15.2 0.2, 21.3 0.2,
22.2 0.2, 22.6 0.2, 24.9 0.2 and 29.2 0.2.
An illustrative PXRD diffractogram of form APO-1 is shown in Figure 1.
Form APO-1 may have a reflection ("peak") at any one or more of the
values expressed in degrees 2-theta given in Table 1. Although values are
given in the tables below, APO-1 may be defined by the claimed peaks and a
particular claim may be limited to one peak only, or several peaks. The form
APO-1 does not have to include all or even many of the peaks listed in Table
1. Some illustrative and non-limiting possible observations regarding relative
intensities of the peaks are set out in Table 1.
Table 1: Relative peak intensities of form APO-1
Angle 2-theta Relative intensity %
7.56 1.81
9.06 5.26
9.97 100
13.04 2.56
15.20 27.16
15.84 7.03
16.76 6.93
17.54 5.08
18.36 6.93
18.75 8.83
19.54 8.48
19.96 6.91
20.95 8.93
21.33 38.39
22.15 5.88
22.63 4.11
23.26 8.03
24.85 16.60
25.78 7.42
26.27 19.78
26.78 4.80
27.24 8.48
29.18 10.78
29.51 5.53
30.68 3.68
31.20 3.55
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An illustrative DSC thermogram of form APO-I is shown in Figure 2.
The DSC thermogram shown in Figure 2 may be illustrative of the type of
results obtained when analysing form APO-I by DSC.
The DSC thermogram may be characterized by first and second
endothermic peaks, the first endothermic peak having a peak onset of
approximately 108 C and the second endothermic peak having a peak onset
of approximately 218 C and a peak maximum of approximately 219 C.
In an embodiment, form APO-I contains between 4 wt (3/0 ethanol and 6
wt % ethanol.
In an embodiment, form APO-I is a hemi ethanol solvate wherein the
molar ratio of ethanol to Axitinib is approximately 0.5:1, respectively.
Form APO-I Axitinib may be prepared by a process comprising: a)
preparing a solution of Axitinib, ethanol and propylene glycol at an elevated
temperature; b) cooling the solution to induce crystallization of solid; and
c)
isolating the solid to yield form APO-I Axitinib.
Often about 42 volumes to about 73 volumes of ethanol with respect to
the weight of Axitinib and often about 2.4 volumes to about 3 volumes of
propylene glycol with respect to the weight of Axitinib may be used to prepare
the solution. Often, dissolution is achieved at elevated temperatures between
about 72 C to about 80 C. The solution may be stirred for a suitable amount
of time to allow total dissolution. After that, the solution may be cooled
down
to 20-25 C, often crystallization occurs at about 45 C. The mixture may be
stirred for a suitable amount of time to allow the formation of APO-I. Often,
the mixture is stirred for about 1.5 hours at about 20 C to about 25 C
before
isolating form APO-I.
Once isolated, the form APO-I may be washed with a suitable volatile
organic solvent such as ethanol. Following isolation, form APO-I may be
dried in vacuo at a temperature of from about 20 C to about 50 C. The
drying time may vary depending on the conditions, with a minimum of about
16 hours often employed.
Amorphous form of Axitinib is used to prepare form APO-I in the
following examples. Other polymorphic forms of Axitinib are suitable as
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starting material, for example anhydrous forms such as Form IV disclosed in
W02006/048751 A1.
EXAMPLES
The following examples are illustrative of some of the embodiments of
the invention described herein. These examples do not limit the spirit or
scope
of the invention in any way.
Powder X-Ray Diffraction Analysis:
Data were acquired on a PANanalytical X-Pert Powder diffractometer
with fixed divergence slits and a Pixcel detector. The diffractometer was
configured in Bragg-Brentano geometry; data was collected over a 2-theta
range of 4.5 to 40 degrees using CuKa radiation at a power of 40 mA and 45
kV. CuK8 radiation was removed using a divergent beam nickel filter. A step
size of 0.013 degrees was used. Samples were rotated to reduce preferred
orientation effects. Samples were lightly ground prior to analysis.
Differential Scanning Calorimetry Analysis:
The DSC thermograms were collected on a TA Instruments Q200
instrument. Samples (1 ¨ 5 mg) were weighed into a 40 pL aluminum pan
and were crimped closed with an aluminum lid. The samples were analyzed
under a flow of nitrogen (ca. 50 mL/min) at a scan rate of 10 C/minute
Example 1: Preparation of APO-1 polymorphic form of Axitinib
A round bottom flask was charged with Axitinib amorphous form (5.0
g), ethanol (365 mL, 73 vol) and propylene glycol (racemic mixture, 15 mL, 3
vol). The mixture was heated up to reflux temperature and maintained for 1
hour at which point a clear solution was observed. The solution was then
cooled to about 25 C over 3 hours and maintained for 1.5 hours.
Crystallization was observed at 45 C without the use of seed. The
suspension was collected by paper filtration and dried at about 45 C under
vacuum for 16 hours. Form APO-1 was obtained as a pale yellow to off-white
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solid (4.43 g, 88.6 % yield). The solid contained 5.4 wt % ethanol by 1H NMR.
Chromatographic Purity: 98.91%. 1H NMR (DMSO-d6; 300 MHz) 6 (ppm)
13.340 (s), 8.600 (d), 8.394 (d), 8.207 (d), 7.956 (d), 7.823-7.777 (m), 7.658
(d), 7.609 (s), 7.55 (s), 7.491 (dd), 7.476-7.245 (m), 7.188 (dd), 7.036 (dd),
3,426 (m) 2.772 (d), 1.049 (t). Figure 1 depicts a PXRD diffractogram and
Figure 2 depicts a DSC thermogram that were obtained using sample
prepared by this method.
Example 2: Preparation of APO-I polymorphic form of Axitinib
A round bottom flask was charged with Axitinib amorphous form (10.0
g), ethanol (730 mL, 73 vol) and propylene glycol (racemic mixture, 30 mL, 3
vol). The mixture was heated up to reflux temperature and maintained for 1
hour at which point a clear solution was observed. The solution was then
cooled to about 25 C over 3 hours and maintained for 1.5 hours.
Crystallization was observed at 45 C without the use of seed. The
suspension was filtered through paper and dried at about 45 C under
vacuum for 16 hours. Form APO-I was obtained as a pale yellow to off-white
solid (8.79 g, 87.9 % yield). Chromatographic Purity: 99.12%. Analysis of the
samples by DSC and PXRD showed results consistent with the data obtained
in Figures 1 and 2.
Example 3: Comparative filtration rate of Axitinib forms
As described in Example 1, a round bottom flask was charged with
Axitinib amorphous form (10.0 g), ethanol (730 mL, 73 vol) and propylene
glycol (racemic mixture, 30 mL, 3 vol). The mixture was heated up to reflux
temperature and maintained for 1 hour at which point a clear solution was
observed. The solution was then cooled to about 25 C over 3 hours and
maintained for 1.5 hours. Crystallization was observed at 45 C without the
use of seed. The suspension was then filtered through paper. The time
required to separate the solid form APO-I from the solvent by filtration was 3
minutes from transfer of the suspension until solvent ceased dripping from the
filter. On the other hand, when Form IV prepared according to known
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procedures such as, for instance, Org. Process Res. Dev. 2014, 18, 266-274,
the comparative filtration time measured in the same manner was 5.5
minutes.
Although various embodiments of the invention are disclosed herein, many
adaptations and modifications may be made within the scope of the invention
in accordance with the common general knowledge of those skilled in this art.
Such modifications include the substitution of known equivalents for any
aspect of the invention in order to achieve the same result in substantially
the
same way. Numeric ranges are inclusive of the numbers defining the range.
The word "comprising" is used herein as an open-ended term, substantially
equivalent to the phrase "including, but not limited to", and the word
"comprises" has a corresponding meaning. As used herein, the singular forms
"a", "an" and "the" include plural referents unless the context clearly
dictates
otherwise. Thus, for example, reference to "a thing" includes more than one
such thing. Citation of references herein is not an admission that such
references are prior art to the present invention. The invention includes all
embodiments and variations substantially as hereinbefore described and with
reference to the examples and drawings.
