Patent Application
20100168111
The present invention relates to polymorphic forms of rivaroxaban and methods for the preparation thereof.
Rivaroxaban (5-chloro-N-{([(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide) is a low molecular weight, orally administrable anticoagulant drug. The pharmaceutical directly inhibits the active form of serine protease Factor Xa (FXa). Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarct, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
Rivaroxaban is disclosed in WO 01/47919 and WO 2004/060887 and has the following structure:
CA 2624310 relates to polymorphic forms and the amorphous form of (5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide, methods for the production thereof, medicaments containing the same, and the use thereof for fighting diseases. Three modifications of rivaroxaban, namely modification I, II, and III are disclosed as well as an amorphous form, a hydrate, an NMP solvate and an inclusion compound with THF.
The present invention relates to a polymorphic form of the compound of formula (1), hereinafter referred to as form APO-A.
Form APO-A provides for reduced residual organic solvent in the crystalline form when compared to another polymorphic form of rivaroxaban.
Form APO-A may also exhibit increased solubility and thermal stability. Form APO-A may provide better oral bioavailability and/or a better dissolution profile for a particular formulation. Form APO-A may also provide free-flowing, easily filterable, and/or thermally stable characteristics that are suitable for use in particular formulations, for example and without limitation, liquid form formulations, solid form formulations, creams, gels, hydrogels, tablets, capsules and other known formulation forms.
In illustrative embodiments of the present invention, there is provided a polymorphic form of rivaroxaban characterized by an X-ray diffraction pattern having at least one peak in the X-ray diffraction pattern as set out in
In illustrative embodiments of the present invention, there is provided a polymorphic form of rivaroxaban characterized by an X-ray diffraction pattern as set out in
In illustrative embodiments of the present invention, there is provided a method of making form APO-A, a polymorphic form of rivaroxaban.
In illustrative embodiments of the present invention, there is provided a composition comprising form APO-A. In some embodiments, the composition is a pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients.
In illustrative embodiments of the present invention, there is provided a composition comprising a crystalline form of rivaroxaban and an organic solvent selected from the group consisting of C3 to C6 ketones, C3 to C4 amides and mixtures thereof.
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.
In drawings which illustrate embodiments of the invention,
As used herein, the term “about” generally means within ±10%, often within ±5%, and often within ±1% of a given value or range and could be any increment thereof within ±10% (e.g. 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc).
As used herein when referring to a spectrum and/or to data presented in a graph, the term “peak” refers a feature that one skilled in the art would recognize as not attributable to background noise.
As used herein, the term “polymorph” and the term “polymorphic form” refer to a crystallographically distinct form of a substance.
Different polymorphs of the same compound may have different physical, chemical, biological and/or spectroscopic properties. For example, and without limitation, different polymorphic forms may have different stability properties. A particular polymorphic form may be more sensitive to heat, relative humidity and/or light. Alternatively or additionally, a particular polymorphic form may provide more compressibility and/or density properties thereby providing more desirable characteristics for formulation and/or product manufacturing. Alternatively or additionally, a particular polymorphic form may have a different dissolution rate thereby providing more desirable bioavailability. In some cases, differences in stability result from changes in chemical reactivity, such as and without limitation, differential oxidation. Such properties may provide for more suitable product qualities such as a dosage form that is more resistant to discoloration when comprised of a particular polymorph. Mechanical characteristics of compounds may differ between polymorphs also. For example and without limitation, tablets having a higher ratio of a particular polymorph may be more resistant to crumbling on storage. Different physical properties of polymorphs may affect their processing. For example, and without limitation, a particular polymorph may be more likely to form solvates or may be more difficult to filter and/or wash.
Polymorphs of a molecule can be obtained by a number of methods known in the art. Such methods include, but are not limited to, recrystallization, melt recrystallization, melt cooling, solvent recrystallization (including using single or multiple solvents), precipitation, anti-solvent precipitation, evaporation, rapid evaporation, slurrying, slurry ripening, suspension equilibration, desolvation, dehydration, vapor diffusion, liquid-liquid diffusion, sublimation, grinding, milling, crystallization from the melt, heat induced transformations, desolvation of solvates, salting out, pH change, lyophilization, distillation, drying, rapid cooling, slow cooling, and combinations thereof.
Polymorphs can be detected, identified, classified and characterized using well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA), powder X-ray diffractometry (PXRD), single crystal X-ray diffractometry, vibrational spectroscopy, solution calorimetry, solid state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, quantitative analysis, solubility, and rate of dissolution.
In illustrative embodiments of the present invention, there is provided a polymorph of rivaroxaban hereinafter termed form APO-A of the compound of the formula (1):
A powder X-ray diffractogram of form APO-A was produced as described in Example 3 and the diffractogram may be found in
Depending on the nature of the methodology applied and the scale selected to display results obtained from X-ray diffraction analysis, the peak intensities of peaks obtained my vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 0.00% 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 relative orientation of the sample and its deviation from the preferred orientation of the sample, sample preparation and the methodology applied. Some illustrative and non-limiting possible observations regarding relative intensities of the peaks set out in Tables 1 and 2 above are set out below in Table 3.
In Tables 1, 2 and 3 above, the abbreviation “e.v.” stands for empirical value and represents a value obtained, in degrees 2 theta, empirically.
Information relating to the characteristics of a polymorphic or pseudopolymorphic form of a compound may be ascertained using X-ray crystallography. X-ray crystallography is also related to several other methods for determining atomic structures. Similar diffraction patterns can be produced by scattering electrons or neutrons, which are likewise interpreted as a Fourier transform.
X-ray crystallography may be used to determine the arrangement of atoms within a sample. This technique may be carried out using several different approaches. Common to all approaches is that a beam of X-rays is fired towards at least one crystal and/or crystallite (the at least one crystal and/or crystallite is a sample). Upon hitting the sample, the X-rays scatter in many different directions. The pattern of the scattering of the X-rays is recorded and from this recording the angles and intensities of the scattered X-rays may be determined. Once the angles and intensities are collected a crystallographer can determine physical properties of the sample, which in some cases is a three-dimensional picture of the electron density within the sample. Using an electron density map so produced, the positions of the atoms in the sample can then be determined, as well as their chemical bonds, their disorder and a variety of other information.
Various X-ray scattering methods can be applied to obtain physical information about the sample. Such methods include, without limitation, single crystal X-ray diffraction, fiber diffraction, powder diffraction (PXRD) and small-angle X-ray scattering (SAXS). In all these methods, the scattering is elastic and the scattered X-rays may have the same wavelength as the incoming X-ray. In some cases, these methods may provide information that is more or less detailed than another method yet can be related to each other by one or more characteristics, such as the d-spacing of a sample. Furthermore, data collected using the different types of X-ray methods can be inter-related using algorithms well know in the art, for example, obtaining a predicted powder pattern from single crystal data.
Powder X-ray diffraction, when combined with other computational techniques may be used to obtain exacting information on atomic arrangement within a particular polymorph or pseudopolymorph (structure solution from powder X-ray diffraction data). One method of analyzing such data is to evaluate the peaks obtained at particular angles in the experiment, which may be converted to d-spacings which are characteristic of the particular unit cell of the polymorph or pseudopolymorph, using Bragg's Law:
nλ=2d sin θ
where n is an integer, λ is the wavelength of light, θ relates to the angle that the beam impinges the sample and d is the d-spacing within the crystal.
The relative intensities of the peaks in a powder diffractogram are prone to larger variations than the peak positions. Each peak intensity results from diffractions from one or more d-spacing within the sample. For example, the particle size and shape properties of the sample may make it unlikely that the crystals or crystallites in the sample being analyzed are in an ideal orientation for use in a obtaining a PXRD. Some particular orientations of the crystal or crystallite in the holder may be more statistically likely and in conjunction, the d-spacings that can be viewed with such crystals or crystallites in these positions are more likely to produce more intense peaks. A person of skill in the art of crystallography understands the various different parameters and limitations regarding the comparability of different results obtained from different machines and/or using different X-ray scattering techniques and is able to interpret such differences.
There are a variety of machines available for performing X-ray crystallography in all of its variously described methods. For example, the following companies commonly manufacture many different machines for use in obtaining structural information from a variety of different samples: PANalytical, Bruker, Rigaku and Thermo as well as other companies. In many circumstances the exact result obtained may be affected by the specific machine used.
Thermal analysis methods are another set of methodologies that may be used to identify and characterize polymorphic forms. One thermal method is differential scanning calorimetry (DSC). DSC involves the measurement of the change of the difference in the heat flow to the sample and to a reference sample while the two samples are subjected to a controlled temperature program. DSC raw data shows heat flow plotted against temperature, and heat flow refers to the heat flux difference between the sample and the reference. Various DSC methodologies may be applied, for example and without limitation, temperature DSC, hyper-DSC, heat-flux DSC, modulated temperature DSC, Tzero DSC, DSC-TGA, DSC-TGA-IR and Ramen-DSC. Irrespective of the type of DSC instrument used, the type of information that may be obtained is uniform.
Other thermal methods may also be applied to obtain similar information to DSC results and they include, but are not limited to, differential thermal analysis (DTA), microthermal analysis, thermogravimetric analysis (TGA), and thermally stimulated current.
DSC of form APO-A was carried out as described in Example 4 and the thermogram may be found in
In illustrative embodiments of the present invention, there is provided a process for the preparation of form APO-A of the compound of the formula (1) comprising:
A compound of the formula (I) used in the process for the preparation of form APO-A described herein may be any form of rivaroxaban, including any polymorphic form of rivaroxaban, such as modification I.
A suitable organic solvent may be selected from the group consisting of C3 to C6 ketones such as 2-butanone, 3-pentanone, methyl isobutylketone, cyclohexanone; and C3 to C4 amides such as dimethyl formamide, dimethyl acetamide; and mixtures thereof.
The volume of the suitable organic solvent may be from about 8 to about 150 volumes. The volume of the suitable organic solvent may be from about 50 to about 130 volumes. The volume of the suitable organic solvent may be from about 80 to about 120 volumes.
The mixture may be heated to a temperature sufficient to obtain partial dissolution. The mixture may be heated to a temperature sufficient to obtain complete dissolution. The mixture may be heated to a temperature between about 20° C. to about 160° C. The mixture may be heated to a temperature between about 80° C., to about 120° C. The mixture may be heated to a temperature between about 100° C. to about 120° C.
Undissolved solid optionally may be removed by hot filtration of the mixture.
Crystal growth may be promoted by cooling the solution to a temperature between about 0° C. to about 50° C. Crystal growth may be promoted by cooling the solution to a temperature between about 0° C. to about 30° C. Crystal growth may be promoted by cooling the solution to a temperature between about 0° C. to about 15° C.
The crystals may be collected and/or purified by filtration. Drying, if desired, may also be carried out.
Form APO-A may be used in combination with other forms of rivaroxaban. Compositions comprising form APO-A and modification I are provided. Compositions comprising form APO-A and modification II are provided. Compositions comprising form APO-A and modification Ill are provided. Compositions comprising form APO-A and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification I and modification II are provided. Compositions comprising form APO-A, modification I and modification III are provided. Compositions comprising form APO-A, modification I and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification II and modification III are provided. Compositions comprising form APO-A, modification II and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification III and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification I, modification II and modification III are provided. Compositions comprising form APO-A, modification I, modification II and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification I, modification III and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification II, modification III and amorphous rivaroxaban are provided. Compositions comprising form APO-A, modification I, modification II, modification III and amorphous rivaroxaban are provided.
Compositions comprising form APO-A may comprise form APO-A in any quantity. Compositions may comprise from 1% or more form APO-A. Compositions may comprise 1% to 100% of form APO-A. Compositions may comprise 5% to 95% form APO-A. Compositions may comprise 10% to 95% form APO-A. Compositions may comprise 15% to 95% form APO-A. Compositions may comprise 20% to 95% form APO-A. Compositions may comprise 25% to 95% form APO-A. Compositions may comprise 30% to 95% form APO-A. Compositions may comprise 35% to 95% form APO-A. Compositions may comprise 40% to 95% form APO-A. Compositions may comprise 45% to 95% form APO-A. Compositions may comprise 50% to 95% form APO-A. Compositions may comprise 55% to 95% form APO-A. Compositions may comprise 60% to 95% form APO-A. Compositions may comprise 65% to 95% form APO-A. Compositions may comprise 70% to 95% form APO-A. Compositions may comprise 75% to 95% form APO-A. Compositions may comprise 80% to 95% form APO-A. Compositions may comprise 85% to 95% form APO-A. Compositions may comprise 90% to 95% form APO-A. Compositions may comprise 1% to 90% form APO-A. Compositions may comprise 1% to 85% form APO-A. Compositions may comprise 1% to 80% form APO-A. Compositions may comprise 1% to 75% form APO-A. Compositions may comprise 1% to 70% form APO-A. Compositions may comprise 1% to 65% form APO-A. Compositions may comprise 1% to 60% form APO-A. Compositions may comprise 1% to 55% form APO-A. Compositions may comprise 1% to 50% form APO-A. Compositions may comprise 1% to 45% form APO-A. Compositions may comprise 1% to 40% form APO-A. Compositions may comprise 1% to 35% form APO-A. Compositions may comprise 1% to 30% form APO-A. Compositions may comprise 1% to 25% form APO-A. Compositions may comprise 1% to 20% form APO-A. Compositions may comprise 1% to 15% form APO-A. Compositions may comprise 1% to 10% form APO-A. Compositions may comprise 1% to 5% form APO-A.
5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide in the modification I was suspended in 40 mL of methyl-isobutylketone (MIBK), and 0.5 mL dimethylacetamide and heated to a temperature of 100° C. to 115° C. The resulting suspension was stirred at that temperature for 1 hour and filtered hot. The filtrate was cooled to room temperature and the solid was collected by filtration and dried at a temperature of 50° C.
5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide in the modification I was suspended in 50 mL of methyl-isobutylketone (MIBK) and heated to a temperature of 100° C. to 115° C. The resulting suspension was stirred at that temperature for 1 hour and filtered hot. The filtrate was cooled to room temperature and the solid was collected by filtration and dried at a temperature of 50° C.
The X-ray powder diffraction patterns of the individual crystalline polymorphs prepared as described in Examples 1 and 2 were recorded with a PANalytical X'Pert Pro MPD diffractometer with fixed divergence slits and an X'Celerator RTMS detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2 theta range of 4-40 using CuK.alpha radiation at a power of 40 mA and 45 kV. CuK.beta radiation was removed using a divergent beam nickel filter. A step size of 0.017 degrees and a step time of 30 seconds were used. Samples were rotated to reduce preferred orientation effects. Results are shown in
DSC thermograms were collected on a Mettler-Toledo 821e instrument. Samples were weighed into a 40 uL aluminum pan and were crimped closed with an aluminum lid containing a 50 um pinhole. The samples were analyzed under a flow of nitrogen at a scan rate of 10° C./minute. Results are shown in
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. Furthermore, numeric ranges are provided so that the range of values is recited in addition to the individual values within the recited range being specifically recited in the absence of 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 references 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. Any priority document(s) are incorporated herein by reference as if each individual priority document were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.
