CN1891209A - Eplerenone crystalline form exhibiting enhanced dissolution rate - Google Patents
Eplerenone crystalline form exhibiting enhanced dissolution rate Download PDFInfo
- Publication number
- CN1891209A CN1891209A CN 200610101365 CN200610101365A CN1891209A CN 1891209 A CN1891209 A CN 1891209A CN 200610101365 CN200610101365 CN 200610101365 CN 200610101365 A CN200610101365 A CN 200610101365A CN 1891209 A CN1891209 A CN 1891209A
- Authority
- CN
- China
- Prior art keywords
- eplerenone
- crystal
- compound
- solvent
- particle size
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CNC*[C@](**N)O Chemical compound CNC*[C@](**N)O 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A novel crystalline form (Form H) of the aldosterone receptor antagonist drug eplerenone is provided having a relatively rapid dissolution rate in aqueous media. Also provided are novel solvated crystalline forms of eplerenone that, when desolvated, can yield Form H eplerenone. Also provided is amorphous eplerenone. Pharmaceutical compositions are provided comprising Form H eplerenone, optionally accompanied by one or more other solid state forms of eplerenone, in a total unit dosage amount of eplerenone of about 10 to about 1000 mg, and further comprising one or more pharmaceutically acceptable excipients. Processes are provided for preparing Form H eplerenone and for preparing compositions comprising Form H eplerenone. A method for prophylaxis and/or treatment of an aldosterone-mediated condition or disorder is also provided, comprising administering to a subject a therapeutically effective amount of eplerenone, wherein at least a fraction of the eplerenone present is Form H eplerenone.
Description
The application is that application number is dividing an application of 200410036808.1 applications, and application number is to be December in 2000 4 days the applyings date of 200410036808.1 applications.
Invention field
The present invention relates to pharmaceutically active agents, more precisely, the present invention relates to aldosterone receptor antagonist eplerenone (eplerenone) as aldosterone receptor antagonist.Specifically, the present invention relates to the new crystal form of eplerenone, the method for preparing this crystal form, the pharmaceutical composition that comprises this crystal form, use this crystal form to treat and/or prevent aldosterone-mediated disease and/or disease, comprise for example hypertensive method of disease relevant and disease with aldosteronism, and the application of this crystal form in the preparation medicine.
Background of invention
Have structure (I) and be called the chemical compound 9 of eplerenone, 11-epoxy-17-hydroxyl-3-oxo is pregnant-4-alkene-7, and 21-dioctyl phthalate hydrogen methyl ester, the gamma lactone reported first is in people's such as Grob US patent 4559332, one class 9 is disclosed in the document, 11-epoxide steroids and salt thereof.Eplerenone is an aldosterone receptor antagonist, and can use the indication for the treatment of aldosterone receptor antagonist with the treatment effective dose, the treatment disease relevant with aldosteronism for example comprises hypertension, comprises the heart failure and the liver cirrhosis of cardiac insufficiency.
The preparation of drug combination that above-mentioned US patent 4559332 (introducing the present invention with for referencial use) discloses the preparation of eplerenone prevailingly and contained eplerenone.No. 98/25948 international monopoly publication of WO 97/21720 and WO discloses preparation and has comprised 9 of eplerenone, other method of 11-epoxide steroids and salt thereof.
People such as Grob (1997), " steroid aldosterone antagonists: improve 9 α, the selectivity of 11-epoxides ",
Helvetica Chimica Acta, 80,566-585 discloses the X-ray structure analysis of the eplerenone solvate that makes by crystallization eplerenone from dichloromethane/ether solvent system.
People (1989) such as De Gasparo, " aldosterone antagonist: incidence rate and preventative side effect ",
Journal of Steroid Biochemistry, 32 (13), 223-227 disclose granule be 20 μ m do not prepare the application of eplerenone in the test of single dose eplerenone.
Having the alkanes of 20-spiral shell shown in the active spironolactone-structure of aldosterone receptor antagonist (II) sterin is commercially available hypertension therapeutic medicine.Yet spironolactone has the androgen antagonist activity, may cause gynecomasty and sexual impotence in the male.It also has weak pregnant preceding activity, may cause menstruation irregular in the women.Therefore, people wish to develop not that for example glucocorticoid, progestogen and androgenic steroids receptor system interact and/or other active aldosterone receptor antagonist that broad-spectrum curing scope more is provided eplerenone for example with other steroid receptor system.
People such as Agafonov (1991), " polymorph of spironolactone ",
Journal of Pharmaceutical Sciences, 80 (2), 181-185 discloses the multiform crystal form of acetonitrile compound, ethanol compound, ethyl acetate compound, methanol compound and two kinds of non-solventizations of spironolactone.Brittan (1999),
Polymorphism in Pharmaceutical Solids, pp.114-116,207,235 and 261 (Marcel Dekker) also disclose these solid-state forms of spironolactone.
Eplerenone has low-down dissolubility in aqueous medium, and the release from peroral dosage form in gastrointestinal tract of this medicine often is the limiting factor that begins to produce curative effect speed after its bioavailability, particularly oral administration.
The invention summary
The invention provides and in aqueous medium, have very fast dissolution velocity, and have the new crystal form of the eplerenone of other peculiar property with respect to other solid-state form of eplerenone.The complete characterization of crystal form of the present invention is as mentioned below, but for the purpose of convenient, this crystal form is called " form H ".
-individual aspect, the invention provides the new form H of eplerenone itself.Be different from the middle of the feature of another crystal form that is called " crystal form L " at form H, form H shows rhombic system, and at 12.0 ± 0.2 ° of 2 θ place the X-ray powder diffraction pattern at peak and fusing point being arranged is about 247 ℃-Yue 251 ℃.
Aspect second, comprise the eplerenone medicine of the eplerenone crystalline form H of detection limit at least but the invention provides.
Aspect the 3rd, the invention provides the eplerenone medicine that is essentially mutually pure eplerenone crystalline form H.Term used herein " mutually pure " is meant the purity with respect to other solid-state form of eplerenone, rather than must refer to have high chemical purity with respect to other chemical compound.
Aspect the 4th, the invention provides the eplerenone crystalline form that when dissolving, can produce the solvation of eplerenone crystalline form H.
Aspect the 5th, the invention provides pharmaceutical composition, wherein comprise eplerenone crystalline form H and one or more pharmaceutically acceptable excipient, wherein said compositions is optional other solid-state form that comprises one or more eplerenones in total eplerenone unit dose of the about 1000mg of about 10-.
Aspect the 6th, the invention provides the method and the preparation that prepare eplerenone crystalline form H and comprise eplerenone crystalline form H method for compositions.
Aspect the 7th, the invention provides and prevent and/or treat the aldosterone-mediated disease or the method for disease, comprise eplerenone to individual administering therapeutic effective dose, wherein to have a part at least be eplerenone crystalline form H to the eplerenone of being used.
Others of the present invention are discussed in the application's whole description.
Summary of drawings
What accompanying drawing 1 was represented is the X-ray powder diffraction pattern of eplerenone crystalline form H.
What accompanying drawing 2 was represented is the X-ray powder diffraction pattern of eplerenone crystalline form L.
What accompanying drawing 3 was represented is the X-ray powder diffraction pattern of the butanone compound of eplerenone.
What accompanying drawing 4 was represented is the X-ray powder diffraction pattern of eplerenone normal propyl alcohol compound.
What accompanying drawing 5 was represented is the X-ray powder diffraction pattern of eplerenone oxolane compound.
What accompanying drawing 6 was represented is the X-ray powder diffraction pattern of eplerenone ethyl propionate compound.
What accompanying drawing 7 was represented is the X-ray powder diffraction pattern of eplerenone acetic acid compound.
What accompanying drawing 8 was represented is the X-ray powder diffraction pattern of eplerenone acetone compound.
What accompanying drawing 9 was represented is the X-ray powder diffraction pattern of eplerenone toluene compound.
What accompanying drawing 10 was represented is the X-ray powder diffraction pattern of eplerenone isopropyl alcohol compound.
What accompanying drawing 11 was represented is the X-ray powder diffraction pattern of eplerenone ethanol compound.
What accompanying drawing 12 was represented is the X-ray powder diffraction pattern of eplerenone isobutyl acetate compound.
What accompanying drawing 13 was represented is the X-ray powder diffraction pattern of eplerenone n-butyl acetate compound.
What accompanying drawing 14 was represented is the X-ray powder diffraction pattern of eplerenone methyl acetate compound.
What accompanying drawing 15 was represented is differential scanning calorimetry (DSC) differential thermogram of the non-grinding eplerenone crystalline form L of direct crystallization from butanone.
Accompanying drawing 16 expression be the DSC differential thermogram of the non-grinding eplerenone crystalline form L that the solvate desolvation by will crystallization high-purity eplerenone obtains from butanone makes.
Accompanying drawing 17 expression be to grind the DSC differential thermogram of the eplerenone crystalline form L that makes by desolvation product that will the solvate that crystallization high-purity eplerenone obtains from butanone.
What accompanying drawing 18 was represented is the DSC differential thermogram of the non-grinding eplerenone crystalline form L that will make by the solvate desolvation that steaming and decocting from appropriate solvent (digestion) low-purity eplerenone obtains.
What accompanying drawing 19 was represented is the DSC differential thermogram of eplerenone normal propyl alcohol compound.
What accompanying drawing 20 was represented is the DSC differential thermogram of eplerenone oxolane compound.
What accompanying drawing 21 was represented is the DSC differential thermogram of eplerenone ethyl propionate compound.
What accompanying drawing 22 was represented is the DSC differential thermogram of eplerenone acetic acid compound.
What accompanying drawing 23 was represented is the DSC differential thermogram of eplerenone chloroform compound.
What accompanying drawing 24 was represented is the DSC differential thermogram of eplerenone acetone compound.
What accompanying drawing 25 was represented is the DSC differential thermogram of eplerenone toluene compound.
What accompanying drawing 26 was represented is the DSC differential thermogram of eplerenone isopropyl alcohol compound.
What accompanying drawing 27 was represented is the DSC differential thermogram of eplerenone ethanol compound.
What accompanying drawing 28 was represented is the DSC differential thermogram of eplerenone tert-butyl acetate compound.
What accompanying drawing 29 was represented is the DSC differential thermogram of eplerenone isobutyl acetate compound.
What accompanying drawing 30 was represented is the DSC differential thermogram of eplerenone n-butyl acetate compound.
What accompanying drawing 31 was represented is the DSC differential thermogram of eplerenone methyl acetate compound.
What accompanying drawing 32 was represented is the DSC differential thermogram of eplerenone propyl acetate compound.
What accompanying drawing 33 was represented is the DSC differential thermogram of eplerenone n-butyl alcohol compound.
What accompanying drawing 34 was represented is the DSC differential thermogram of eplerenone n-octyl alcohol compound.
What accompanying drawing 35 was represented is infrared (IR) spectrum (DRIFT) of eplerenone crystalline form H.
What accompanying drawing 36 was represented is the IR spectrum (DRIFT) of eplerenone crystalline form L.
What accompanying drawing 37 was represented is the IR spectrum (DRIFT) of the butanone compound of eplerenone.
What accompanying drawing 38 was represented is the IR spectrum (DRIFT) that is present in the eplerenone in the chloroformic solution.
What accompanying drawing 39 was represented is the IR spectrum of eplerenone normal propyl alcohol compound.
What accompanying drawing 40 was represented is the IR spectrum of eplerenone oxolane compound.
What accompanying drawing 41 was represented is the IR spectrum of eplerenone ethyl propionate compound.
What accompanying drawing 42 was represented is the IR spectrum of eplerenone acetone compound.
What accompanying drawing 43 was represented is the IR spectrum of eplerenone toluene compound.
What accompanying drawing 44 was represented is the IR spectrum of eplerenone isopropyl alcohol compound.
What accompanying drawing 45 was represented is the IR spectrum of eplerenone ethanol compound.
What accompanying drawing 46 was represented is the IR spectrum of eplerenone isobutyl acetate compound.
What accompanying drawing 47 was represented is the IR spectrum of eplerenone n-butyl acetate compound.
What accompanying drawing 48 was represented is the IR spectrum of eplerenone propyl acetate compound.
What accompanying drawing 49 was represented is the IR spectrum of eplerenone methyl acetate compound.
What accompanying drawing 50 was represented is the IR spectrum of eplerenone propylene glycol compound.
What accompanying drawing 51 was represented is the IR spectrum of eplerenone tert-butyl acetate compound.
That accompanying drawing 52 is represented is eplerenone crystalline form H
13C NMR spectrum.
That accompanying drawing 53 is represented is eplerenone crystalline form L
13C NMR spectrum.
What accompanying drawing 54 was represented is the thermogravimetry analysis chart of eplerenone butanone compound.
What accompanying drawing 55 was represented is the thermogravimetry analysis chart of eplerenone normal propyl alcohol compound.
What accompanying drawing 56 was represented is the thermogravimetry analysis chart of eplerenone oxolane compound.
What accompanying drawing 57 was represented is the thermogravimetry analysis chart of eplerenone ethyl propionate compound.
What accompanying drawing 58 was represented is the thermogravimetry analysis chart of eplerenone acetic acid compound.
What accompanying drawing 59 was represented is the thermogravimetry analysis chart of eplerenone chloroform compound.
What accompanying drawing 60 was represented is the thermogravimetry analysis chart of eplerenone acetone compound.
What accompanying drawing 61 was represented is the thermogravimetry analysis chart of eplerenone toluene compound.
What accompanying drawing 62 was represented is the thermogravimetry analysis chart of eplerenone isopropyl alcohol compound.
What accompanying drawing 63 was represented is the thermogravimetry analysis chart of eplerenone ethanol compound.
What accompanying drawing 64 was represented is the thermogravimetry analysis chart of eplerenone isobutyl acetate compound.
What accompanying drawing 65 was represented is the thermogravimetry analysis chart of eplerenone n-butyl acetate compound.
What accompanying drawing 66 was represented is the thermogravimetry analysis chart of eplerenone methyl acetate compound.
What accompanying drawing 67 was represented is the thermogravimetry analysis chart of eplerenone n-propyl acetate compound.
What accompanying drawing 68 was represented is the thermogravimetry analysis chart of eplerenone propylene glycol compound.
What accompanying drawing 69 was represented is the thermogravimetry analysis chart of eplerenone n-butyl alcohol compound.
What accompanying drawing 70 was represented is the thermogravimetry analysis chart of eplerenone n-octyl alcohol compound.
What accompanying drawing 71 was represented is the thermogravimetry analysis chart of eplerenone tert-butyl acetate compound.
Accompanying drawing 72 expression be the scanning electron microscopy of the eplerenone crystalline form L that makes by butanone compound desolvation with eplerenone.
Accompanying drawing 73 expression be the scanning electron microscopy of the eplerenone crystalline form L that makes by direct crystallization from ethyl acetate.
That accompanying drawing 74 is represented is isolating 4 α from butanone, 5 α; 9 α, 11 α-diepoxy-17-hydroxyl-3-oxo-17 alpha-pregnane-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, the X-ray powder diffraction pattern of gamma lactone (" diepoxide ") crystal form.
That accompanying drawing 75 is represented is isolating 11 α from isopropyl alcohol, 12 alpha-epoxy-17s-hydroxyl-3-oxo-17 α-pregnant-4-alkene-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, the X-ray powder diffraction pattern of gamma lactone (" 11, the 12-epoxide ") crystal form.
That accompanying drawing 76 is represented is isolating 17-hydroxyl-3-oxo-17 α from n-butyl alcohol-pregnant-4,9 (11)-diene-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, the X-ray powder diffraction pattern of gamma lactone (" 9,11-alkene ") crystal form.
What accompanying drawing 77 was represented is for the relevant polymorph of enantiotropy, the relation between Gibbs free energy and the temperature.
Accompanying drawing 78 expression be to derive to have mixed (a) 0%, (b) 1%, (c) 3% and (d) the X-ray powder diffraction pattern of the wet cake of the crystalline butanone compound of butanone of 5% diepoxide.
Accompanying drawing 79 expression be to derive to have mixed (a) 0%, (b) 1%, (c) 3% and (d) the X-ray powder diffraction pattern of the crystalline drying solid of butanone of 5% diepoxide.
Accompanying drawing 80 expression be the X-ray powder diffraction pattern of the drying solid that obtains from the butanone crystallization of mixing 3% diepoxide, wherein (a) do not grind this solvate before the drying, is to have ground this solvate before the drying (b).
Accompanying drawing 81 expression be derive from mixed (a) 0%, (b) 1%, (c) 5% and (d) 10% 11, the X-ray powder diffraction pattern of the wet cake of the crystalline butanone compound of the butanone of 12-epoxide.
Accompanying drawing 82 expression be to derive to have mixed (a) 0%, (b) 1%, (c) 5% and (d) 10%11, the X-ray powder diffraction pattern of the crystalline drying solid of butanone of 12-epoxide.
This paper embodiment 7 that is based on of accompanying drawing 83 expressions shows the data that 7A reported, the isometric chart of product purity, material purity, rate of cooling and outlet temperature.
What accompanying drawing 84 was represented is in order to determine product purity is had the variable of remarkable statistics influence, to use half standard drawing of the isometric chart drafting of accompanying drawing 83.
Accompanying drawing 85 is based on the interaction diagram of this paper embodiment 7 table data that 7A reported, its expression be the influence of the interaction partners product purity between material purity and the rate of cooling.
This paper embodiment 7 that is based on of accompanying drawing 86 expressions shows the data that 7A reported, the isometric chart of form H weight fraction, material purity, rate of cooling and outlet temperature.
What accompanying drawing 87 was represented is in order to determine the form H weight fraction is had the variable of remarkable statistics influence, to use half standard drawing of the isometric chart drafting of accompanying drawing 86.
Accompanying drawing 88 is based on the interaction diagram of this paper embodiment 7 table data that 7A reported, its expression be the influence of the interaction partners form H weight fraction between material purity and the outlet temperature.
What accompanying drawing 89 was represented is the x-ray diffraction pattern of amorphous eplerenone.
What accompanying drawing 90 was represented is the DSC differential thermogram of amorphous eplerenone.
What accompanying drawing 91 was represented is the dissolution velocity of 4 eplerenone polymorphic samples.
Detailed Description Of The Invention
The same with composition as all medical compounds, extremely important aspect its business development according to chemistry and the physical property of a happy ketone. These character include but not limited to: (1) packing character is mole volume, density and hygroscopicity for example, (2) thermodynamics character for example melts temperature, vapour pressure and solubility, (3) for example dissolution velocity and stability (are included in the stability under the environmental condition to kinetic property, especially to the stability of moisture, with the stability under the storage condition), (4) for example surface area, wettable, interface tension force and shape of surface nature, (5) engineering properties is hardness, stretching intensity, compressibility, operability, flowability and Combination for example; (6) filtering property. These character can affect processing and the storage that for example comprises according to the pharmaceutical composition of a happy ketone. The solid-state form according to a happy ketone that can improve one or more these character with respect to other solid-state form is desirable.
The invention provides the new solid-state form according to a happy ketone. Specifically, these solid-state forms comprise the crystalline form (being called " form H " and " crystalline form L ") of the crystalline form of various solvations, at least two kinds of non-solvents and non-hydrated and amorphous according to a happy ketone. With respect to describe herein and disclosed other solid-state form in the literature, the various solid-state forms according to a happy ketone of describing in this application have one or more above-mentioned favourable chemistry and/or physical propertys. In the desired priority file of this paper, form H and crystalline form L are called " crystalline form I " and " Form II ", and sometimes respectively as " high-melting-point polymorph " and " low melting point polymorph ".
The present invention relates to eplerenone crystalline form H. Compare with for example eplerenone crystalline form L, be lower than under the change transition temperature temperature of (as discussed below), form H shows faster dissolution velocity (fast about 30%) in the water medium. When according to the dissolving of happy ketone in intestines and stomach being when the speed that is discharged into target cell or tissue according to a happy ketone is controlled step, dissolves the biological utilisation degree that improvement generally can be provided faster. Therefore, form H can provide and compare the biological utilisation degree feature that is improved with crystalline form L. In addition, with respect to the solid-state form with low dissolution velocity, selection have very fast dissolution velocity can be same according to happy ketone solid-state form so that larger elasticity is arranged when the excipient of selecting pharmaceutical composition and the compounding pharmaceutical composition, particularly all the more so when planning to discharge rapidly when complying with happy ketone.
With respect to other solid-state form, crystalline form L also has advantage. Particularly, compare with for example eplerenone crystalline form H, be lower than under the change transition temperature temperature of (as discussed below), crystalline form L has stronger physically stable. Do not need special processing or storage condition and avoided frequently carrying out the stock changes according to a happy ketone solid-state form for example crystalline form L be desirable. For example, during being chosen in processing (for example during grinding according to the material of a happy ketone with the surface area that obtains to have the particle diameter that reduces and increase) have physically stable according to a happy ketone solid-state form, needing can to avoid special processing conditions and usually by the special processing conditions of this kind bring expensive. Similarly, be chosen in and (especially will consider and to store condition according to the difference that may occur during the useful life of a happy ketone product) the happy ketone solid-state form of complying with physically stable under the wide scope storage condition, can avoid changing according to polymorphic or other degradability that generation in the happy ketone can cause product loss or destruction product to be renderd a service. Therefore, select to have stronger physically stable according to a happy ketone solid-state form for example crystalline form L the meaningful benefit according to a happy ketone form that is better than less stable can be provided.
The invention still further relates to the eplerenone crystalline form of solvation. The crystalline form of these solvations can be used as preparation form H and crystalline form L according to the intermediate of a happy ketone; In the context of the invention, what make special concern is the eplerenone crystalline form that can produce the solvation of eplerenone crystalline form H when dissolving. The crystalline form of using solvation is can cause crystal " inner little efflorescence " when the desolventizing as the special advantage of intermediate, hereinafter will discuss it in the application. " inner little efflorescence " like this can reduce the necessity of grinding, perhaps there is no need fully to grind. In addition, when needs grind in addition, grinding some solvent compounds before the desolventizing step than after the crystalline form desolventizingization with solvation, grinding form H or L is easy.
The eplerenone crystalline form of acceptable solvent also can directly be used in the pharmaceutical composition. In one embodiment, being used for directly, the solvation crystalline form of this kind of preparation pharmaceutical composition does not comprise carrene, isopropyl alcohol or ether; In another embodiment, do not comprise carrene, isopropyl alcohol, ether, butanone or ethanol; In an embodiment again, do not comprise carrene, isopropyl alcohol, ether, butanone, ethanol, ethyl acetate or acetone. For this application most preferably be that the eplerenone crystalline form of solvation is substantially devoid of non-acceptable solvent.
The solvation crystalline form of using in pharmaceutical composition comprises usually and preferably can medicinal higher and/or hydrogen bond bonding solvent, such as but not limited to butanols. It is believed that the set of solvation crystalline form can provide different dissolution velocities, and when being when being discharged into the speed control step of target cell or tissue according to a happy ketone according to the dissolving of happy ketone in intestines and stomach, with respect to form H and crystalline form L, the solvation crystalline form can provide different biological utilisation degree.
The invention still further relates to the amorphous thing according to a happy ketone. The amorphous intermediate that can be used as preparation form H and crystalline form L according to a happy ketone. In addition, it is believed that an amorphous happy ketone of complying with can provide different dissolution velocities, and be present in the pharmaceutical composition and when being when the speed that is discharged into target cell or tissue according to a happy ketone is controlled step according to the dissolving of happy ketone in intestines and stomach according to a happy ketone when amorphous, with respect to form H and crystalline form L, so amorphous happy ketone of complying with can provide different biological utilisation degree.
What also merit attention is eplerenone crystalline form and the amorphous combination of complying with the solid-state form of a happy ketone that is selected from eplerenone crystalline form H, eplerenone crystalline form L, solvation. Such combination can be used for for example preparing the pharmaceutical composition with various dissolving characteristics, comprises controlling releasing composition. In one embodiment of the invention, the combination of solid-state form is provided, but wherein comprise at least eplerenone crystalline form H of detection limit, all the other parts are eplerenone crystalline form and amorphous one or more solid-state forms according to a happy ketone that are selected from eplerenone crystalline form L, solvation.
Purpose according to the eplerenone solid-state form is used, and can be of value to processing by the combination of selecting specific solid state form or specific solid state form.For example, mutually pure crystal form L is easier to preparation than mutually pure form H usually.And form H is easier to preparation than mutually pure crystal form L usually with the mixture of crystal form L, and makes it possible to use the eplerenone raw material with low chemical purity.With compare by the course of processing that solvation crystal form intermediate desolvation is carried out, in compositions, use the solvation crystal form to replace form H or crystal form L can save a step, i.e. desolvation step.Perhaps, direct crystallization goes out crystal form L in solvation crystal form intermediate preparation and the desolvated appropriate solvent if for example never relate to, and also can save the desolvation step.The method of sampling has hereinafter been described in more detail.
Definition
In this article, term " amorphous " refers to solid-state when being used for eplerenone, and wherein this eplerenone molecule exists with the lack of alignment form, and does not form tangible lattice or structure cell.When carrying out the X-ray powder diffraction, amorphous eplerenone does not produce any characteristic crystal peak.
When mentioning the boiling point of material or solution in this article, term " boiling point " refers to this material or the boiling point of solution under applicable treatment conditions.
In this article, term " crystal form " is used for eplerenone and refers to solid-state form, and wherein the eplerenone molecules align forms the lattice (i) that significantly contains structure cell and (ii) produce diffraction maximum when carrying out x-ray radiation.
But according to the applied environment relevant with the eplerenone feedstock production, term " crystallization " can refer to crystallization and/or recrystallization when being used for the application.
In this article, term " steaming and decocting " refers to a kind of method, wherein under applicable treatment conditions, the serosity of solid eplerenone in solvent or solvent mixture is heated under the boiling point of solvent or solvent mixture.
Term used herein " direct crystallization " is meant directly crystallization eplerenone from The suitable solvent, and does not form the intermediate flux crystalline solid forms of eplerenone, and desolvation not.
Term used herein " eplerenone medicine " is meant the eplerenone that context limited self as using this term, and can refer to the eplerenone do not prepared or as the eplerenone of pharmaceutical composition component.
Term used herein " particle diameter " is meant that for example the particle diameter of centrifugal mensuration is coiled in laser light scattering, the mobile segmentation in decanting zone, the related spectroscopy of photon or garden by conventional particle diameter detection technique well known in the art." D
90Particle diameter " refers to such particle diameter, promptly measures by so conventional particle diameter detection technique 90% particle grain size is arranged less than this D
90Particle diameter.
Term " DSC " is meant differential scanning calorimetry.
Term " HPLC " is meant high pressure lipuid chromatography (HPLC).
Term " IR " is meant infrared spectrometry.
In this article, unless other limit, term " purity " is meant the chemical purity of the eplerenone of measuring according to conventional H PLC detection method.In this article, " low-purity eplerenone " refers generally to contain the form H crystal growth promoters of effective dose and/or the eplerenone of crystal form L crystal growth inhibitor.In this article, " high-purity eplerenone " refers generally to not contain or contain less than the form H crystal growth promoters of effective dose and/or the eplerenone of crystal form L crystal growth inhibitor.
Term " phase purity " is meant about specific crystalline or unbodied eplerenone, as the solid solid purity of measuring by the infrared spectrum analysis of describing herein of eplerenone.
Term " XPRD " is meant the X-ray powder diffraction.
Term " rpm " is meant revolutions per minute.
Term " TGA " is meant the TGA analysis.
Term " T
m" be meant fusing point.
The feature of crystal form
1, molecular conformation
The monocrystalline x-ray analysis shows the orientation difference of the molecular conformation difference of eplerenone between form H and crystal form L, the particularly ester group of cyclopentanoperhydro-phenanthrene 7-position.The orientation of this ester group can be by C8-C7-C23-O1 torsion angle definition.
In the lattice of form H, in the conformation that the eplerenone molecule adopts on the 7-position methoxyl group and the c h bond of ester approximately be in line, and carbonyl approximately is positioned at the center of B-cyclopentanoperhydro-phenanthrene.The C8-C7-C23-O1 torsion angle approximately is-73.0 ° in this conformation.In this orientation, the carbonylic oxygen atom of ester group (O1) and 9, the oxygen atom of 11-epoxide ring (O4) is contact closely.The distance of O1-O4 is about 2.97 dusts, and it just is lower than Van der Waals contact distance-3.0 dusts (van der Waals radius of supposing oxygen atom is 1.5 dusts).
In the lattice of crystal form L, in the conformation that the eplerenone molecule adopts with respect to form H this ester group approximately rotated 150 °, and the C8-C7-C23-O1 torsion angle is+76.9 ° approximately.In this orientation, the methoxyl group of this ester directly with 4 of A-cyclopentanoperhydro-phenanthrene, 5-alkene part is relative.In this orientation, to compare with the distance that form H is determined, (O1, O2) with 9, the distance between the oxygen atom of 11-epoxide ring (O4) has all strengthened each oxygen atom of this ester group.The O2-O4 distance is about 3.04 dusts, just is higher than Van der Waals contact distance.The O1-O4 distance is about 3.45 dusts.
As if in the solvation crystal form of analyzing by the monocrystalline X-ray diffraction, the eplerenone molecule adopts the conformation of crystal form L feature.
2.X-ray powder diffraction
Analyze the various crystal forms of eplerenone with Siemens D5000 powder diffraction meter or Inel Multipurpose diffractometer.For Siemens D5000 powder diffraction meter, for 2 θ values, measure initial data from 2-50, its spacing is 0.020 and pitch period is 2 seconds.For the InelMultipurpose diffractometer, sample is placed the aluminum sample holder, and collect 30 minutes initial data simultaneously in all 2 θ values.
Table 1A, 1B and 1C have provided the important parameter (x-ray radiation, wavelength are 1.54056 dusts) of main peaks of the butanone compound (making by the conversion of room temperature serosity in butanone high-purity eplerenone) of form H (making by the ethanol compound desolvation that steaming and decocting low-purity eplerenone is obtained), crystal form L (making by the butanone compound desolvation that recrystallization high-purity eplerenone is obtained) and eplerenone crystalline form respectively according to 2 θ values and intensity.
The less displacement of peak position may appear in the diffraction pattern of form H and crystal form L, this be the imperfect institute of the spacing of crystal diffraction face extremely, and this (being the desolvation of solvent compound) that to be the preparation approach of form H and crystal form L cause.In addition, form H is isolating from the solvate by the preparation of steaming and decocting crude product eplerenone.This method causes the overall chemical purity of form H lower (about 90%).At last, estimate that some displacements have appearred in the diffraction maximum position of eplerenone solvation form owing to increase in the flowability of the solvent channel internal solvent molecule of lattice.
Table 1A:X-ray diffraction data, form H
| Angle |
| 2 θ | D-spacing | Intensity Cps | Intensity % |
| 6.994 | 12.628 | 1188 | 7.2 |
| 8.291 | 10.655 | 2137 | 13.0 |
| 10.012 | 8.827 | 577 | 3.5 |
| 11.264 | 7.849 | 1854 | 11.3 |
| 12.040 | 7.344 | 7707 | 46.8 |
| 14.115 | 6.269 | 3121 | 19.0 |
| 14.438 | 6.130 | 15935 | 96.8 |
| 15.524 | 5.703 | 637 | 3.9 |
| 16.169 | 5.477 | 1349 | 8.2 |
| 16.699 | 5.305 | 1663 | 10.1 |
| 16.940 | 5.230 | 1692 | 10.3 |
| 17.147 | 5.167 | 2139 | 13.0 |
| 17.660 | 5.018 | 6883 | 41.8 |
| 17.910 | 4.949 | 16455 | 100.0 |
| 18.379 | 4.823 | 3106 | 18.9 |
| 18.658 | 4.752 | 1216 | 7.4 |
| 19.799 | 4.480 | 1499 | 9.1 |
| 20.235 | 4.385 | 383 | 2.3 |
| 21.707 | 4.091 | 1267 | 7.7 |
| 21.800 | 4.073 | 1260 | 7.7 |
| 21.959 | 4.044 | 1279 | 7.8 |
| 22.461 | 3.955 | 4264 | 25.9 |
| 23.191 | 3.832 | 1026 | 6.2 |
| 23.879 | 3.723 | 1000 | 6.1 |
| | D-spacing | Intensity Cps | Intensity % |
| 24.599 | 3.616 | 1688 | 10.3 |
| 25.837 | 3.445 | 931 | 5.7 |
| 26.034 | 3.420 | 686 | 4.2 |
| 26.868 | 3.316 | 912 | 5.5 |
| 27.093 | 3.288 | 1322 | 8.0 |
| 27.782 | 3.209 | 1236 | 7.5 |
| 28.340 | 3.147 | 1845 | 11.2 |
| 28.861 | 3.091 | 957 | 5.8 |
| 29.866 | 2.9892 | 745 | 4.5 |
| 30.627 | 2.9166 | 992 | 6.0 |
| 31.108 | 2.8726 | 1205 | 7.3 |
| 33.215 | 2.6951 | 1287 | 7.8 |
| 33.718 | 2.6560 | 802 | 4.9 |
| 34.434 | 2.6024 | 914 | 5.6 |
Table 1B:X-ray diffraction data, crystal form L
| Angle |
| 2 θ | D-spacing | Intensity Cps | Intensity % |
| 7.992 | 11.054 | 11596 | 26.6 |
| 10.044 | 8.799 | 12048 | 27.6 |
| 11.206 | 7.889 | 4929 | 11.3 |
| 12.441 | 7.109 | 1747 | 4.0 |
| 12.752 | 6.936 | 4340 | 9.9 |
| 13.257 | 6.673 | 2444 | 5.6 |
| 14.705 | 6.019 | 43646 | 100 |
| 15.460 | 5.727 | 2670 | 6.1 |
| 15.727 | 5.630 | 7982 | 18.3 |
| 16.016 | 5.529 | 3519 | 8.1 |
| 17.671 | 5.015 | 8897 | 20.4 |
| 17.900 | 4.951 | 2873 | 6.6 |
| 18.352 | 4.830 | 612 | 1.4 |
| 18.703 | 4.740 | 689 | 1.6 |
| 19.524 | 4.543 | 1126 | 2.6 |
| 20.103 | 4.413 | 3753 | 8.6 |
| 20.630 | 4.302 | 1451 | 3.3 |
| 21.067 | 4.214 | 876 | 2.0 |
| 21.675 | 4.097 | 2760 | 6.3 |
| 22.232 | 3.995 | 1951 | 4.5 |
| 22.652 | 3.922 | 1657 | 3.8 |
| 23.624 | 3.763 | 827 | 1.9 |
| 24.279 | 3.663 | 1242 | 2.8 |
| 25.021 | 3.556 | 5144 | ?11.8 |
| 25.485 | 3.492 | 1702 | 3.9 |
| 25.707 | 3.463 | 2493 | 5.7 |
| | D-spacing | Intensity Cps | Intensity % |
| 26.251 | 3.392 | 1371 | 3.1 |
| 26.850 | 3.318 | 1970 | 4.5 |
| 27.319 | 3.262 | 1029 | 2.4 |
| 27.931 | 3.192 | 440 | 1.0 |
| 27.969 | 3.187 | 440 | 1.0 |
| 28.937 | 3.083 | 1128 | 2.6 |
| 29.703 | 3.005 | 1211 | 2.8 |
| 30.173 | 2.9594 | 1506 | 3.5 |
| 30.584 | 2.9206 | 1602 | 3.7 |
| 30.885 | 2.8928 | 1550 | 3.6 |
| 31.217 | 2.8628 | 1068 | 2.4 |
| 31.605 | 2.8285 | 1038 | 2.4 |
| 32.059 | 2.7895 | 1211 | 2.8 |
| 32.640 | 2.7412 | 684 | 1.6 |
| 32.747 | 2.7324 | 758 | 1.7 |
| 33.460 | 2.6759 | 506 | 1.2 |
| 34.194 | 2.6201 | 1085 | 2.5 |
| 34.545 | 2.5943 | 915 | 2.1 |
Table 1C:X-ray diffraction data, the butanone compound
| Angle |
| 2 θ | D-spacing | Intensity Cps | Intensity % |
| 7.584 | 11.648 | 5629 | 32.6 |
| 7.753 | 11.393 | 15929 | 92.3 |
| 10.151 | 8.707 | 2877 | 16.7 |
| 11.310 | 7.817 | 701 | 4.1 |
| 12.646 | 6.994 | 1027 | 5.9 |
| 13.193 | 6.705 | 15188 | 88.0 |
| 13.556 | 6.526 | 14225 | 82.4 |
| 14.074 | 6.287 | 1966 | 11.4 |
| 14.746 | 6.002 | 2759 | 16.0 |
| 15.165 | 5.837 | 801 | 4.6 |
| 15.548 | 5.694 | 1896 | 11.0 |
| 17.031 | 5.202 | 7980 | 46.2 |
| 17.280 | 5.127 | 17267 | 100.0 |
| 17.706 | 5.005 | 6873 | 39.8 |
| 18.555 | 4.778 | 545 | 3.2 |
| 18.871 | 4.699 | 1112 | 6.4 |
| 19.766 | 4.488 | 1704 | 9.9 |
| 20.158 | 4.401 | 1396 | 8.1 |
| 20.725 | 4.282 | 2644 | 15.3 |
| 21.787 | 4.076 | 1127 | 6.5 |
| 22.060 | 4.026 | 451 | 2.6 |
| 22.864 | 3.886 | 1542 | 8.9 |
| | D-spacing | Intensity Cps | Intensity % |
| 23.412 | 3.796 | 14185 | 82.2 |
| 23.750 | 3.743 | 1154 | 6.7 |
| 24.288 | 3.662 | 3063 | 17.7 |
| 25.253 | 3.524 | 1318 | 7.6 |
| 25.503 | 3.490 | 1736 | 10.1 |
| 25.761 | 3.455 | 1225 | 7.1 |
| 26.176 | 3.402 | 1346 | 7.8 |
| 26.548 | 3.355 | 1098 | 6.4 |
| 27.357 | 3.257 | 1944 | 11.3 |
| 27.605 | 3.229 | 2116 | 12.3 |
| 27.900 | 3.195 | 858 | 5.0 |
| 28.378 | 3.142 | 583 | 3.4 |
| 28.749 | 3.103 | 763 | 4.4 |
| 29.300 | 3.046 | 1182 | 6.8 |
| 29.679 | 3.008 | 2606 | 15.1 |
| 30.402 | 2.9377 | 2184 | 12.6 |
| 30.739 | 2.9063 | 648 | 3.8 |
The instance graph of the x-ray diffraction pattern of the butanone compound crystal form of form H, crystal form L and eplerenone is seen Fig. 1 respectively, 2 and 3.Form H has demonstrated the difference peak at 7.0 ± 0.2,8.3 ± 0.2 and 12.0 ± 0.2 ° of 2 θ.Crystal form L has demonstrated the difference peak at 8.0 ± 0.2,12.8 ± 0.2 and 13.3 ± 0.2 ° of 2 θ.The crystal form of butanone solventization has demonstrated the difference peak at 7.6 ± 0.2,7.8 ± 0.2 and 13.6 ± 0.2 ° of 2 θ.
Accompanying drawing 4-14 has shown the instance graph of the x-ray diffraction pattern of following eplerenone solvate crystal form respectively: normal propyl alcohol compound, oxolane compound, ethyl propionate compound, acetic acid compound, acetone compound, toluene compound, isopropyl alcohol compound, ethanol compound, isobutyl acetate compound, n-butyl acetate compound and methyl acetate compound.
3. fusing/decomposition temperature
Measure the fusing and/or the decomposition temperature of the eplerenone crystalline form of non-solventization with TA Instruments 2920 differential scanning calorimetry (DSC)s.Each sample (1-2mg) placed sealing or unsealed aluminum pot and with the heating of about 10 ℃/minute programming rate.Fusing/decomposition range from fusing/decomposition endotherm extrapolation begin define to maximum.
The fusing of eplerenone crystalline form H and crystal form L is with the loss of the solvent of catching in chemolysis and the lattice.The influence of solids treatment before fusing/decomposition temperature is also analyzed.For example, by direct crystallization from appropriate solvent or will be in the mixture of appropriate solvent or solvent the non-grinding crystal form L (D that makes of the solvate desolvation that obtains of crystallization high-purity eplerenone
90Particle diameter is about 180-450 μ m) general fusing/decomposition range be about 237 ℃-Yue 242 ℃.Crystal form L (the D that grinds
90Particle diameter is about the about 100 μ m of 80-) (by recrystallisation solvent compound from the solution of high-purity eplerenone appropriate solvent or solvent mixture, with this solvate desolvation, and grinding resulting crystalline forms L makes) generally have the fusing/decomposition temperature scope of low and broad, be about 223 ℃-Yue 234 ℃.Form H (the D of the non-grinding that makes by the solvate desolvation that steaming and decocting low-purity eplerenone is obtained
90Particle diameter is about 180-450 μ m) generally have higher fusing/decomposition range, be about 247 ℃-Yue 251 ℃.(a) the crystal form L of the non-grinding that directly crystallization prepares from butanone, (b) by will be from butanone the crystal form L of the non-grinding for preparing of the solvate desolvation that obtains of crystallization high-purity eplerenone, (c) the crystal form L for preparing by the desolvated solvate that grinds crystallization high-purity eplerenone acquisition from butanone, (d) by will be from butanone the example of DSC differential thermogram of form H of non-grinding of the solvate desolvation preparation that obtains of steaming and decocting low-purity eplerenone, respectively as accompanying drawing 15, shown in 16,17 and 18.
Measure the DSC differential thermogram of the solvation form of eplerenone with Perkin Elmer Pyris 1 differential scanning calorimetry (DSC).Each sample (1-2mg) placed unsealed aluminum pot and with the heating of 10 ℃/minute programming rate.When from the solvate lattice solvent loss being arranged, one or more endothermic processes at a lower temperature are with the variation of enthalpy.Maximum temperature endotherm (one or more) is relevant with the fusing/decomposition of eplerenone crystalline form L or form H.Accompanying drawing 19-34 has shown the example of DSC differential thermogram of the solvation crystal form of following eplerenone: be respectively normal propyl alcohol compound, oxolane compound, ethyl propionate compound, acetic acid compound, chloroform compound, acetone compound, toluene compound, isopropyl alcohol compound, ethanol compound, tert-butyl acetate compound, isobutyl acetate compound, butyl acetate compound, methyl acetate compound, propyl acetate compound, n-butyl alcohol compound and n-octyl alcohol compound.
4. infrared absorption spectroscopy
With Nicolet DRIFT (soaking the reflective infrared Fourier transformation) Magna is the infrared absorption spectroscopy that 550 spectrogrphs obtain non-solvent eplerenone crystalline form H and crystal form L.Use Spectra-Tech collector system and little specimen cup.Analytic sample in potassium bromide (5%) and from 400 to 4000cm
-1Scanning.With the infrared absorption spectroscopy of Bio-rad FTS-45 spectrogrph acquisition at rare chloroformic solution (3%) or the eplerenone in the solvation crystal form.Solution pool with 0.2mm path band sodium chloride salt crystal is analyzed the chloroformic solution sample.With IBM little-MIR (multi-functional internal reflection degree) auxiliary facilities collects solvate FTIR spectrum.From 400 to 4000cm
-1Scanning samples.(a) form H, (b) crystal form L, (c) butanone compound and (d) example of the infrared absorption spectroscopy of the eplerenone in chloroformic solution respectively as accompanying drawing 35,36, shown in 37 and 38.
Table 2 discloses the exemplary absorbent band of the eplerenone of form H, crystal form L and butanone compound crystal form.The exemplary absorbent band that also discloses the eplerenone in the chloroformic solution is with as a comparison.Observed the difference between form H and crystal form L or the butanone compound, for example, the district has observed difference at spectrographic carbonyl.The ester carbonyl group drawing zone of form H is at about 1739cm
-1, and crystal form L and butanone compound are respectively about 1724 and 1722cm
-1Has corresponding stretching.Eplerenone in chloroformic solution is at about 1727cm
-1Produce the stretching of ester carbonyl group.The variation of the stretching frequency of ester carbonyl group has reflected the variation of the ester group orientation between these two kinds of crystal forms between form H and the crystal form L.In addition, in the A cyclopentanoperhydro-phenanthrene stretching of the ester of conjugation ketone from about 1664-1667cm of form H or butanone compound
-1Be moved to about 1665cm of crystal form L
-1Corresponding carbonyl stretches and occurs in about 1665cm in chloroformic solution
-1
Another difference between form H and the crystal form L sees the C-H buckled zone.Form H is at about 1399cm
-1Absorption is arranged, and this does not observe in crystal form L, butanone compound or the eplerenone in chloroformic solution.This 1399cm
-1Stretching occurs in the C2 of contiguous carbonyl and the CH of C21 methylene
2The shear zone.
Table 2: the IR absorption band (cm of eplerenone form
-1)
| The absorption region | Form H | Crystal form L | The butanone compound | Chloroformic solution |
| ν C=O (lactone) | 1773 | 1775 | 1767 | 1768 |
| ν C=O (ester) | 1739 | 1724 | 1722 | 1727 |
| ν C=O (3-ketone group) | 1664 | 1655 | 1667 | 1665 |
| ν C=C (3,4-alkene) | 1619 | 1619 | 1622 | 1623 |
| δ HCH 3δCH 2， δCH 3(the α position of carbonyl) | 1460，1444， 1426 | 1467，1438， 1422，1399 | 1467，1438， 1422 | 1464，1438， 1422 |
| δCH 3 | 1380 | 1381 | ～1380 | 1378 |
Accompanying drawing 39-51 has shown the example of infrared absorption spectroscopy of the solvation crystal form of following eplerenone respectively: normal propyl alcohol compound, oxolane compound, ethyl propionate compound, acetone compound, toluene compound, isopropyl alcohol compound, ethanol compound, isobutyl acetate compound, butyl acetate compound, propyl acetate compound, methyl acetate compound, propylene glycol compound and tert-butyl acetate compound.
5. nuclear magnetic resonance, NMR (NMR) spectrum
Obtain in 31.94 districts
13C NMR spectrum.Eplerenone crystalline form H and crystal form L's
13The spectrographic example of C NMR is respectively shown in accompanying drawing 52 and 53.By analyzing the data of eplerenone crystalline form H, found that eplerenone crystalline form H is not mutually pure and contains eplerenone crystalline form L in a small amount to obtain in Figure 52, to reflect.Form H makes it the most clearly be different from other form by the carbon resonance around 64.8ppm, 24.7ppm and 19.2ppm.Crystal form L makes it the most clearly be different from other form by the carbon resonance around 67.1ppm and 16.0ppm.
6. hot weight fraction folding method
Carry out thermogravimetry with TA Instruments TGA 2950 thermogravimeters.Under the nitrogen flushing, sample is placed the aluminum pot that seals.Initial temperature is 25 ℃, and temperature heats up with about 10 ℃/minute speed.Accompanying drawing 54-71 has shown the example of thermogravimetry analysis chart of the solvation crystal form of following eplerenone respectively: be respectively the butanone compound, the normal propyl alcohol compound, the oxolane compound, the ethyl propionate compound, the acetic acid compound, the chloroform compound, the acetone compound, the toluene compound, the isopropyl alcohol compound, the ethanol compound, the isobutyl acetate compound, the n-butyl acetate compound, the methyl acetate compound, the propyl acetate compound, the propylene glycol compound, the n-butyl alcohol compound, n-octyl alcohol compound and tert-butyl acetate compound.
7. microscopy
The Linkam THMS 600Hot-Stage that use has a Zeiss Universal Polarized Light Microscope carries out the Hot-Stage microscopy to the monocrystalline of eplerenone butanone compound.Under room temperature, polarized light, solvate crystals has birefringence effect, and is translucent, and this shows the lattice high-sequential, and when temperature rose to about 60 ℃, beginning occurred damaged significantly along long crystalline size.Scanning electron microscopy sheet by eplerenone crystalline form L that butanone compound desolvation is obtained is shown in accompanying drawing 72, and this displaing micro picture has shown intracell surface damage, hole, crack and fracture.Scanning electron microscopy sheet by the eplerenone crystalline form L that directly obtains from crystallization the ethyl acetate is shown in accompanying drawing 73, and this displaing micro picture does not demonstrate intracell surface damage, hole, crack and fracture.
8. cell parameter
Following table 3A, 3B and 3C have summed up the cell parameter of form H, crystal form L and several eplerenone solvation crystal forms measured.
Table 3A: the cell parameter of eplerenone crystalline form
| Parameter | Form H | Crystal form L | The butanone compound |
| Crystallographic system | Quadrature | Monocline | Quadrature |
| Space group | P2，2，2， | P2， | P2，2，2， |
| a | 21.22 | 8.78 | 23.53 |
| b | 15.40 | 11.14 | 8.16 |
| c | 6.34 | 11.06 | 13.08 |
| | 90° | 90° | 90° |
| | 90° | 93.52° | 90° |
| | 90° | 90° | 90° |
| | 4 | 2 | 4 |
| Volume () | 2071.3 | 1081.8 | 2511.4 |
| Parameter | Form H | Crystal form L | The butanone compound |
| ρ (value of calculation) | 1.329g/cm 3 | 1.275g/cm 3 | 1.287g/cm 3 |
| R | 0.0667 | 0.062 | 0.088 |
Table 3B: the cell parameter of eplerenone crystalline form
| Parameter | The acetone compound | The toluene compound | The butyl acetate compound 1 |
| Crystallographic system | Quadrature | Quadrature | Quadrature |
| Space group | P2，2，2， | P2，2，2， | P2，2，2， |
| a | 23.31 | 23.64 | 23.07 |
| b | 13.13 | 13.46 | 13.10 |
| c | 8.28 | 8.16 | 8.24 |
| | 90° | 90° | 90° |
| | 90° | 90° | 90° |
| | 90° | 90° | 90° |
| | 4 | 4 | 4 |
| Volume () | 2533.7 | 2596.6 | 2490.0 |
| ρ (value of calculation) | 1.239g/cm 3 | 1.296g/cm 3 | 1.334g/cm 3 |
| R | 0.058 | 0.089 | 0.093 |
1Because the disorder of solvent molecule in the passage, butyl acetate adduct molecule are thoroughly not refining.
Table 3C: the cell parameter of eplerenone crystalline form
| Parameter | The isobutyl acetate compound 1 | The isopropyl alcohol compound 1 | The ethanol compound 1 |
| Crystallographic system | Quadrature | Quadrature | Quadrature |
| Space group | P2，2，2， | P2，2，2， | P2，2，2， |
| a | 23.19 | 23.15 | 23.51 |
| b | 12.95 | 12.73 | 13.11 |
| c | 8.25 | 8.25 | 8.27 |
| | 90° | 90° | 90° |
| | 90° | 90° | 90° |
| | 90° | 90° | 90° |
| | 4 | 4 | 4 |
| Volume () | 2476.4 | 2433.2 | 2548.6 |
| ρ (value of calculation) | 1.337g/cm 3 | 1.296g/cm 3 | 1.234g/cm 3 |
| R | 0.098 | 0.152 | 0.067 |
1Because the disorder of solvent molecule in the passage, solvate molecule are thoroughly not refining.
Out of Memory to selected eplerenone solvation crystal form is reported in following table 4.The structure cell data of the butanone compound of reporting among the last table 3A have also been represented the cell parameter of a lot of other eplerenone recrystallisation solvent compounds.Tested most of eplerenone recrystallisation solvent compounds are isomorphism each other basically.Though owing to mix varying in size of solvent molecule, a kind of solvation crystal form and another kind of some very little displacements of existence in X-ray powder diffraction peak, but whole diffraction pattern is substantially the same, and cell parameter is consistent basically for most of solvates of testing with the molecule position.
Table 4: about the out of Memory of eplerenone solvate
| Solvent | Stoichiometry solvent: eplerenone | With butanone compound isomorphism whether? | The desolvation temperature 1(℃) |
| | 1∶1 | 89 | |
| | 1∶2 | Be | 203 |
| | 1∶1 | Be | 117 |
| | 1∶1 | Be | 103 |
| | 1∶1 | Be | 130 |
| | 1∶2 | Be | 108 |
| | 1∶2 | Be | 112 |
| Tert-butyl acetate | --- | Be | 109 |
| Chloroform | --- | Be | 125 |
| | 1∶1 | Be | 166 |
| | 1∶2 | Be | 129 |
| | 1∶1 | Be | 121 |
| N- | 1∶1 | Be | 103 |
| N-octyl alcohol | --- | Be | 116 |
| | 1∶1 | Be | 122 |
| Propylene glycol | --- | Be | 188 |
| | 1∶1 | Be | 136 |
| | 1∶1 | Be | 83 |
1Be defined as from the desolvation temperature of final weight of solvent loss step extrapolation, this is to measure under nitrogen wash with 10 ℃/minute firing rate by thermogravimetry.But the desolvation temperature may be subjected to the influence of solvate preparation method.Diverse ways may produce the nucleation site of varying number, and this site can cause the desolvation of solvate at lower temperature.
The structure cell of solvate is divided in forming by 4 eplerenones.For multiple solvate, eplerenone molecule and the solvent molecule stoichiometry in this structure cell also is reported in table 4.The form H structure cell is by 4 eplerenone molecular compositions.Crystal form L structure cell is by two eplerenone molecular compositions.When eplerenone molecule crystal form migration and rotation during with the space filling up solvent molecule and stay, the solvate structure cell changes form H and/or crystal form L structure cell in the desolvation process.Table 4 has also been reported the desolvation temperature of a lot of different solvents things.
9. the crystallographic property of impurity
In the desolvation process of solvate, selected impurity can be induced the formation of form H in eplerenone.Particularly estimate the effect of following two kinds of impurity molecules: 4 α, 5 α; 9 α, 11 α-diepoxy-17-hydroxyl-3-oxo-17 alpha-pregnane-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, gamma lactone (III) (" diepoxide "); With 11 α, 12 alpha-epoxy-17s-hydroxyl-3-oxo-17 α-pregnant-4-alkene-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, gamma lactone (IV) (" 11, the 12-epoxide ").
These impurity molecules are described in more detail to acting among this paper embodiment of desolvation gained eplerenone crystalline form.
Because 17-hydroxyl-3-oxo-17 α-pregnant-4,9 (11)-diene-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, the mono-crystalline structures and the form H eplerenone of gamma lactone (V) (" 9; 11-alkene ") are similar, therefore our supposition is during the desolvation of solvate 9, and 11-alkene also can be induced the formation of form H.
The monocrystalline that separates every kind of impurity compound.Isolating diepoxide, 11,12-epoxide and 9, the representative X-ray powder diffraction pattern of 11-alkene crystal form is respectively shown in accompanying drawing 74,75 and 76.The X-ray powder diffraction pattern of every kind of impurity molecule is similar to the X-ray powder diffraction pattern of form H, and this shows that three kinds of impurity compounds of form H and this have similar mono-crystalline structures.
The monocrystalline that has also separated every kind of impurity compound, and carry out the X-ray structure and measure to confirm that the mono-crystalline structures that these three kinds of chemical compounds adopt is similar to form H.The monocrystalline that from butanone, separates this diepoxide.From isopropyl alcohol, separate 11, the monocrystalline of 12-epoxide.From n-butyl alcohol, separate 9, the monocrystalline of 11-alkene.The crystal structure gained data of measuring every kind of impurity compound crystal form are as shown in table 5.To form H, diepoxide, 11,12-epoxide and 9, the gained crystallographic system of 11-alkene crystal form is identical with cell parameter basically.
Table 5: compare eplerenone crystalline form H and the crystalline cell parameter of impurity
| Parameter | Form H | Diepoxide | 11, the 12- | 9,11-alkene |
| Crystallographic system | Quadrature | Quadrature | Quadrature | Quadrature |
| Space group | P2，2，2， | P2，2，2， | P2，2，2， | P2，2，2， |
| a | 21.22 | 21.328 | 20.90 | 20.90 |
| b | 15.40 | 16.16 | 15.55 | 15.74 |
| c | 6.34 | 6.15 | 6.38 | 6.29 |
| | 90° | 90° | 90° | 90° |
| | 90° | 90° | 90° | 90° |
| | 90° | 90° | 90° | 90° |
| Parameter | Form H | Diepoxide | 11, the 12- | 9,11- |
| Z | ||||
| 4 | 4 | 4 | 4 | |
| Volume () | 2071.3 | 2119.0 | 2073.2 | 2069.3 |
| ρ (value of calculation) | 1.329g/cm 3 | 1.349g/cm 3 | 1.328g/cm 3 | 1.279g/cm 3 |
| R | 0.0667 | 0.0762 | 0.0865 | 0.0764 |
4 kinds of compound crystals of report become identical space group in the table 5, and have similar cell parameter (being that they are isomorphisms).Suppose this diepoxide, 11,12-epoxide and 9,11-alkene adopts the form H conformation.For every kind of impurity compound, relatively easily separate form H filler (directly from solution), this shows that the form H lattice is stable filling mode in the similar chemical compound of this series structure.Therefore, the adulterant that all can be used as crystallization eplerenone crystalline form H from solution with any chemical compound of eplerenone crystalline form H crystallography isomorphism.
Therefore, in a particular, the invention provides the method for crystallization eplerenone crystalline form H from the solution of eplerenone in solvent or solvent mixture, described method is included in before the crystallization with effective dose and compound doped this solution eplerenone crystalline form H crystallography isomorphism.Should be appreciated that " doping " in this article can be initiatively, add doped compound in the solution that promptly has a mind, or passive, promptly this doping is owing to exist in the solution as due to the doped compound of impurity.
According to this embodiment, preferred doped compound is a diepoxide, 11,12-epoxide and 9, and 11-alkene promptly is respectively top chemical compound (III), (IV) and (V).
The preparation eplerenone
The eplerenone raw material that is used to prepare the new crystal form of the present invention can pass through known method own, is included in the method that provides among above-mentioned international monopoly publication WO 97/21720 and the WO 98/25948, and the scheme 1 that particularly provides in the two makes.
The preparation crystal form
1. prepare the solvation crystal form
The solvation crystal form of eplerenone can prepare by crystallization eplerenone from the mixture of The suitable solvent or suitable solvent.The mixture of The suitable solvent or suitable solvent generally comprises the such organic solvent or the mixture of organic solvent, and it dissolves eplerenone and any impurity at elevated temperatures, preferential crystallization solvate when still cooling off.Under the room temperature in the mixture of these solvents or solvent the dissolubility of eplerenone be generally these solvents of the about 200mg/mL. of about 5-or solvent mixture and be preferably selected from used solvent in the process of preparation eplerenone raw material, if be pharmaceutically useful solvent when particularly being included in the final pharmaceutical composition that contains eplerenone crystalline form.For example, the solvent system that contains dichloromethane that obtains containing the solvate of dichloromethane generally is worthless.
Used each solvent is acceptable solvent preferably, particularly at " impurity: residual solvent guide ", 2 classes or 3 kind solvents of definition in the international conference (InternationalConference On Harmonisation Of Technical Requirements ForRegistration Of Pharmaceuticals For Human Use) (step 4 that ICH steering committee was recommended in the ICH program on July 17th, 1997 adopts) are coordinated in human drug legislation specification requirement.More preferably, these solvents or solvent mixture are selected from butanone, 1-propanol, 2 pentanone, acetic acid, acetone, butyl acetate, chloroform, ethanol, isobutanol, isobutyl acetate, methyl acetate, ethyl propionate, n-butyl alcohol, n-octyl alcohol, isopropyl alcohol, propyl acetate, propylene glycol, the tert-butyl alcohol, oxolane, toluene, methanol and tert-butyl acetate.More preferably, described solvent is selected from butanone and ethanol.
In another embodiment of this method, described solvent or solvent mixture are selected from 1-propanol, 2 pentanone, acetic acid, acetone, butyl acetate, chloroform, isobutanol, isobutyl acetate, methyl acetate, ethyl propionate, n-butyl alcohol, n-octyl alcohol, propyl acetate, propylene glycol, the tert-butyl alcohol, oxolane, toluene, methanol and tert-butyl acetate.
In another embodiment of this method, described solvent or solvent mixture are selected from 1-propanol, 2 pentanone, acetic acid, acetone, butyl acetate, chloroform, isobutanol, isobutyl acetate, methyl acetate, ethyl propionate, n-butyl alcohol, n-octyl alcohol, propyl acetate, propylene glycol, the tert-butyl alcohol, oxolane, toluene, methanol and tert-butyl acetate.
In order to prepare the solvation crystal form of eplerenone, in the solvent of certain volume, and cooling is until forming crystal with a certain amount of eplerenone material dissolution.Solvent temperature when adding eplerenone in solvent generally is to select according to the solubility curve of this solvent or solvent mixture.For most of solvents described herein, for example this solvent temperature is generally at least about 25 ℃, and the boiling temperature of preferred about 30 ℃-this solvent more preferably is lower than the boiling temperature of the about 25 ℃ temperature of this solvent boiling point-this solvent.
Perhaps, hot solvent can be added in the eplerenone, and can be with this mixture cooling until forming crystal.Solvent temperature when adding solvent in eplerenone generally is to select according to the solubility curve of this solvent or solvent mixture.For most of solvents described herein, for example this solvent temperature is generally at least about 25 ℃, and the boiling temperature of preferred about 50 ℃-this solvent more preferably is lower than the boiling temperature of the about 15 ℃ temperature of this solvent boiling point-this solvent.
Depend on the solubility curve of this solvent or solvent mixture equally with the amount of the eplerenone raw material of the solvent of given volume.Generally speaking, the amount that is added to the eplerenone in the solvent at room temperature can not be dissolved in the solvent of this volume fully.For most of solvents described herein, for example with the amount of the eplerenone raw material of the solvent of given volume be generally when the room temperature can solvent at this volume in dissolved eplerenone amount at least about about 4.0 times of 1.5-, be preferably about 3.5 times of about 2.0-, more preferably about 2.5 times.
When the eplerenone raw material has been dissolved in the solvent fully, usually this solution is cooled off lentamente the solvation crystal form that goes out eplerenone with crystallization.For most of solvents described herein, for example be lower than about 20 ℃/minute speed, preferably with about 10 ℃/minute or lower speed, more preferably with about 5 ℃/minute or lower speed, also more preferably cool off this solution with about 1 ℃/minute or lower speed.
The outlet temperature of results solvation crystal form depends on the solubility curve of solvent or solvent mixture.For most of solvents described herein, for example this outlet temperature be generally be lower than about 25 ℃, preferably be lower than about 5 ℃, more preferably less than-5 ℃ approximately.Reduce the formation that this outlet temperature helps the solvation crystal form usually.
Perhaps, can use other technology to prepare solvate.The example of such technology include but not limited to (i) with the eplerenone material dissolution in a kind of solvent, and the adding cosolvent promotes the crystallization of solvation crystal form, the (ii) vapor diffusion of solvate growth, (iii) rotary evaporation separates solvate and (iv) serosity conversion by for example evaporating.
Can for example filter by the conventional means of any appropriate or the crystal of the centrifugal solvation crystal form that will make is as mentioned above separated from solvent.The stirring that improves solvent system during crystallization causes generating the littler crystal of particle diameter usually.
2. prepare crystal form L from solvate
Eplerenone crystalline form L can directly be made by the solvation crystal form by desolvation.Can be by the desolvation means of any appropriate, such as but not limited to ambient pressure around solvate heating, the reduction solvate or the combination of the two are realized desolvation.If the solvate heating is for example heated to remove in baking oven to desolvate, generally is no more than the change conversion temperature of form H and crystal form L in the temperature of this operating period.This temperature preferably is no more than about 150 ℃.
Desolvation pressure and desolvation time are also not really important.Desolvation pressure is preferably about 1 atmospheric pressure or lower.Yet, when reducing desolvation pressure, to reduce equally and can carry out desolvated temperature and/or desolvation time.Particularly for the solvate with higher desolvation temperature, vacuum drying makes can adopt lower baking temperature.Only need to be enough to desolvation to form the desolvation time of crystal form L.
In order to guarantee to make the product of all being made up of crystal form L basically, the eplerenone raw material generally is the high-purity eplerenone, is pure eplerenone basically preferably.The eplerenone raw material that is used to prepare eplerenone crystalline form L generally has at least 90% purity, preferred at least 95 purity, more preferably at least 99% purity.As discussing in the application other places, some impurity in the eplerenone raw material may cause adverse effect to productive rate and the crystal form L content by this method products therefrom.
The eplerenone crystallized product that makes by high-purity eplerenone raw material by this method generally comprise at least 10% crystal form L, preferred at least 50% crystal form L, more preferably at least 75% crystal form L also more preferably at least 90% crystal form L, more more preferably at least about 95% crystal form L, further more preferably be mutually pure crystal form L basically.
3. prepare form H by solvate
The product that can comprise form H according to identical with above-mentioned crystal form L preparation method basically method preparation, and (i) use low-purity eplerenone raw material to replace high-purity eplerenone raw material, (ii) in solvent system, add the crystalline crystal seed of mutually pure form H, perhaps unite use (i) and (ii).
3.1 use impurity as crystal growth promoters and inhibitor
In the eplerenone raw material, have selected impurity and its content, rather than the total amount of all impurity influences the crystalline formation potentiality of form H in the eplerenone during the desolvation of solvate.Selected impurity generally is form H growth promoter or crystal form L growth inhibitor.Selected impurity can be included in the eplerenone raw material, is included in (before adding the eplerenone raw material) in solvent or the solvent mixture, and/or is added to (after adding the eplerenone raw material) in solvent or the solvent mixture.People such as Bonafede (1995), " by the selectivity nucleation and the growth of organic polymorph of the extension of outstanding guiding on the molecular crystal substrate ", J.Amer.Chem.Soc., 117 (30) (introducing the present invention with for referencial use) have been discussed and used growth promoter and growth inhibitor in the polymorph systems.For the present invention, suitable impurity generally comprises the chemical compound with mono-crystalline structures substantially the same with the mono-crystalline structures of eplerenone crystalline form H.Impurity is preferably its X-ray powder diffraction pattern chemical compound substantially the same with the X-ray powder diffraction pattern of eplerenone crystalline form H, more preferably is selected from diepoxide, 11,12-epoxide, 9,11-alkene and their combination.
The amount of the impurity that preparation form H crystal is required generally depends in part on solvent or solvent mixture and the impurity dissolubility with respect to eplerenone.When crystalline form H from butanone solvent, for example the weight ratio of diepoxide and low-purity eplerenone raw material be generally at least about 1: 100, be preferably at least about 3: 100, more preferably about 3: about 1: 5 of 100-, also more preferably about 3: about 1: 10 of 100-.11, the dissolubility of 12-epoxide in butanone be than diepoxide height, and in order to prepare eplerenone crystalline form H crystal, need usually more substantial 11, the 12-epoxide.When impurity comprises 11, during the 12-epoxide, the weight ratio of this diepoxide and low-purity eplerenone raw material is generally at least about 1: 5, more preferably about 3: 25, also more preferably about 3: about 1: 5 of 25-.When not only using diepoxide but also use 11 in preparation form H crystalline process, during 12-epoxide impurity, the weight ratio of every kind of impurity and eplerenone raw material can be lower than the corresponding ratio when only using a kind of impurity in the crystalline process of preparation form H.
When handle comprises the solvate desolvation of selected impurity, can obtain the mixture of eplerenone crystalline form H and crystal form L usually.By solvate being begun in the product that desolvation obtains, the weight fraction of form H is generally and is lower than about 50%.As described below by crystallization or steaming and decocting this product is further handled after, the weight fraction of crystal form L generally can increase in the product.
3.2 adding crystal seed
The form H crystal can make by the crystal seed (or aforesaid form H growth promoter and/or crystal form L growth inhibitor) that added mutually pure form H before the crystallization eplerenone in solvent system.The eplerenone raw material can be low-purity eplerenone or high-purity eplerenone.When the solvate desolvation that made by any raw material, the weight fraction of form H in product is generally at least about 70% and can be greatly to about 100%.
Be added to form H crystal seed and the weight ratio that is added to the eplerenone raw material in the solvent system in the solvent system be generally at least about 0.75: 100, be preferably about 0.75; About 1: 20 of 100-, more preferably about 1: about 1: 50 of 100-.The form H crystal seed can by describe among the application about preparation form H crystalline any means, particularly as described belowly prepare the crystalline method of form H by steaming and decocting and make.
The form H crystal seed can disposablely add, adds several times or adds substantially continuously through a period of time.Yet, begin from solution, to finish before the crystallization adding of form H crystal seed usually at eplerenone, promptly reaching the preceding crystal seed that adds fully of cloud point (metastable zone hangs down terminal point).General when solution temperature be more than the cloud point about 0.5 ℃-about 10 ℃, adding crystal seed when being preferably more than the cloud point about 2 ℃-Yue 3 ℃ more than the cloud point.When the temperature more than the cloud point when adding crystal seed increased, the required crystal seed addition of crystalline form H crystal was generally increase.
Add crystal seed and preferably not only can more than cloud point, carry out, and can in metastable zone, carry out.Cloud point and metastable zone all depend on dissolubility and the concentration of eplerenone in solvent or solvent mixture.For example, for 12 volume dilution of butanone, the high terminal point of metastable zone is generally about 70 ℃-Yue 73 ℃, and metastable zone hangs down terminal point (being cloud point) and is about 57 ℃-Yue 63 ℃.For the concentration of 8 volume butanone, metastable zone is much narrow, and this is because due to the solution supersaturation.Under this concentration, the cloud point of this solution is about 75 ℃-Yue 76 ℃.Because the boiling point of butanone is about 80 ℃ under environmental condition, so generally in this solution, add crystal seed about 76.5 ℃-this boiling temperature.
This paper embodiment 7 has provided the limiting examples that adds the form H crystal seed.
With form H growth promoter or crystal form L growth inhibitor and/or add eplerenone crystallized product that the form H crystal seed obtained generally comprise at least 2% form H, preferably at least 5% form H, more preferably at least 7% form H, also more preferably at least about 10% form H.Remaining eplerenone crystallized product is generally to be crystal form L.
3. prepare form H by grinding eplerenone
In another embodiment, have been found that a spot of form H can make by suitably grinding eplerenone.Observe, in the eplerenone that grinds, the concentration of form H is up to about 3%.
4. prepare crystal form L from the solvate that makes by the low-purity eplerenone
As mentioned above, crystallization low-purity eplerenone generally can make the product that comprises form H and crystal form L with this solvate desolvation then to form solvate.According to the method substantially the same with the mode of above-mentioned preparation form H, by in solvent system, adding mutually pure crystal form L crystal seed, or, can make product by the low-purity eplerenone with big crystal form L content by using crystal form L growth promoter and/or form H growth inhibitor.The amount that adds the scheme of crystal seed and be added to the crystal form L crystal seed in the solvent system be added to solvent system in the weight ratio of amount of eplerenone raw material with above similar about preparing the described weight ratio of eplerenone crystalline form H by the mutually pure form H crystal seed of adding.
The eplerenone crystallized product that makes with this method generally comprise at least 10% crystal form L, preferred at least 50% crystal form L, more preferably at least 75% crystal form L, more preferably at least 90% crystal form L, also more preferably at least about 95% crystal form L, further more preferably be mutually pure crystal form L basically.
Adding crystal seed scheme about preparation eplerenone crystalline form H described herein also can be used for improving the control of crystalline eplerenone particle diameter.
5. direct crystallization crystal form L from solution
Eplerenone crystalline form L also can make by direct crystallization eplerenone from suitable solvent or solvent mixture, and need not form the solvate intermediate and the desolvation that needs of following.Generally speaking, (i) solvent have with the solvate lattice in the inconsistent molecular size in available channel space, (ii) existing any impurity of eplerenone can be dissolved in this solvent at elevated temperatures, and (iii) cooling causes crystallization to go out the eplerenone crystalline form L of non-solventization.At room temperature, the dissolubility of eplerenone in solvent or solvent mixture is generally the about 200mg/ml of about 5-.Described solvent or solvent mixture preferably comprise one or more solvents that is selected from methanol, ethyl acetate, isopropyl acetate, acetonitrile, Nitrobenzol, water and ethylo benzene.
For directly from solution crystallization go out eplerenone crystalline form L, in the solvent of certain volume, and cooling is until forming crystal with a certain amount of eplerenone material dissolution.Solvent temperature when adding eplerenone in solvent generally is to select according to the solubility curve of this solvent or solvent mixture.For most of solvents described herein, this solvent temperature is generally at least about 25 ℃, and the boiling temperature of preferred about 30 ℃-this solvent more preferably is lower than the boiling temperature of the about 25 ℃ temperature of this solvent boiling point-this solvent.
Perhaps, hot solvent can be added in the eplerenone, and can be with this mixture cooling until forming crystal.Solvent temperature when adding solvent in eplerenone generally is to select according to the solubility curve of this solvent or solvent mixture.For most of solvents described herein, this solvent temperature is generally at least about 25 ℃, and the boiling temperature of preferred about 50 ℃-this solvent more preferably is lower than the boiling temperature of the about 15 ℃ temperature of this solvent boiling point-this solvent.
Depend on the solubility curve of this solvent or solvent mixture equally with the amount of the eplerenone raw material of the solvent of given volume.Generally speaking, the amount that is added to the eplerenone in the solvent at room temperature can not be dissolved in the solvent of this volume fully.For most of solvents described herein, with the amount of the eplerenone raw material of the solvent of given volume be generally when the room temperature can solvent at this volume in dissolved eplerenone amount at least about about 4.0 times of 1.5-, be preferably about 3.5 times of about 2.0-, for example be about 2.5 times.
In order to guarantee to make the product that comprises mutually pure basically crystal form L, the eplerenone raw material generally is a high-purity raw.The eplerenone raw material preferably has at least about 65% purity, more preferably has at least about 90% purity, also more preferably has at least about 98% purity, most preferably has at least about 99% purity.
When the eplerenone raw material has been dissolved in the solvent fully, usually this solution is cooled off lentamente with crystallization and go out eplerenone crystalline form L.For most of solvents described herein, for example be lower than about 1 ℃/minute speed, preferably with about 0.2 ℃/minute or lower speed, more preferably cool off this solution with about 0.05 ℃/minute-Yue 0.1 ℃/minute speed.
The outlet temperature of results crystal form L depends on the solubility curve of solvent or solvent mixture.For most of solvents described herein, this outlet temperature be generally be lower than about 25 ℃, preferably be lower than about 5 ℃, more preferably less than-5 ℃ approximately.
Perhaps, can use other technology to prepare solvate.The example of such technology include but not limited to (i) with the eplerenone material dissolution in a kind of solvent, and the adding cosolvent promotes the crystallization of eplerenone crystalline form L, the (ii) vapor diffusion of eplerenone crystalline form L growth, (iii) by for example evaporate rotary evaporation isolate eplerenone crystalline form L and (iv) serosity transform.
Can for example filter by the conventional means of any appropriate or the crystal of the centrifugal eplerenone crystalline form L that will make is as mentioned above separated from solvent.
In addition, eplerenone crystalline form L can pass through the serosity steaming and decocting (as described below) of high-purity eplerenone in butanone, and the eplerenone of filtration steaming and decocting under the boiling temperature of this serosity makes.
6. from solution, directly prepare form H
According to supposition, if at the change transition temperature (T of form H and crystal form L
t) more than carry out crystallization, if particularly have form H growth promoter or crystal form L growth inhibitor or add mutually pure form H crystal seed, form H will directly crystallize out from solution, this is because form H more stable cause under these higher temperature conditions.The preferred solvent system that uses comprises for example Nitrobenzol of high boiling solvent.Suitable form H growth promoter includes but not limited to aforesaid diepoxide and 11,12-alkene.
7. with solvent steaming and decocting eplerenone
The solvation crystal form of eplerenone, form H and crystal form L also can be by making the steaming and decocting in suitable solvent or solvent mixture of eplerenone raw material.In this boiling method, the eplerenone serosity heats under solvent or solvent mixture boiling point.For example, solvent or solvent mixture merging with a certain amount of eplerenone raw material and certain volume are heated to backflow, remove distillate, add certain amount of solvent simultaneously again and remove distillate.Perhaps, can and recycle, just need not add solvent more in addition in steaming and decocting operating period like this distillate condensation.Generally speaking, in case the solvent of initial volume has been removed or condensation and circulation, is about to the serosity cooling, and has formed the solvation crystal form.Can for example filter or centrifugal crystal with solvation is separated from solvent by any conventional means.Still there is not selected impurity according to existing in the crystal of this solvation, as mentioned above the solvate desolvation can be generated eplerenone crystalline form H or crystal form L.
Suitable solvent or solvent mixture generally comprise one or more above-mentioned solvents.Solvent can be selected from for example butanone and ethanol.
In the steaming and decocting operation, the amount that is added to the eplerenone raw material in the solvent for use generally is the amount that is enough to keep serosity (being that eplerenone can not dissolve fully) under the boiling temperature of this solvent or solvent mixture in solvent or solvent mixture.For example, in about 0.25g/ml butanone or the eplerenone concentration in about 0.125g/ml ethanol be operable.
In case after the solvent turnover (turnover) fully, promptly serosity is cooled off the solvation crystal form that goes out eplerenone with crystallization lentamente usually.For test solvent, be lower than about 20 ℃/minute, preferred about 10 ℃/minute or lower, more preferably from about 5 ℃/minute or lower, also more preferably from about 1 ℃/minute or lower speed are cooled off this serosity.
The outlet temperature of results solvation crystal form depends on the solubility curve of solvent or solvent mixture.For most of solvents described herein, this outlet temperature be generally be lower than about 25 ℃, preferably be lower than about 5 ℃, more preferably less than-5 ℃ approximately.
Mainly comprise or only comprise the product of crystal form L if desired, usually with high-purity eplerenone material cooking.Described high-purity eplerenone raw material preferably have at least about 98% purity, more preferably at least about 99% purity, also more preferably at least about 99.5% purity.The eplerenone steaming and decocting product that makes in this mode generally comprise at least about 10% crystal form L, preferably at least about 50% crystal form L, more preferably at least about 75% crystal form L, also more preferably at least about 90% crystal form L, more more preferably at least about 95% crystal form L, most preferably be mutually pure crystal form L basically.
Mainly comprise or only comprise the product of form H if desired, usually with low-purity eplerenone material cooking.Low-purity eplerenone raw material comprises usually in order to generate the form H growth promoter and/or the crystal form L growth inhibitor of the minimum necessary amounts of form H.This low-purity eplerenone raw material preferably have at least about 65% purity, more preferably at least about 75% purity, also more preferably at least about 80% purity.The eplerenone steaming and decocting product that makes in this mode generally comprise at least about 10% form H, preferably at least about 50% form H, be preferably at least about 75% form H, also more preferably at least about 90% form H, more more preferably at least about 95% form H, most preferably be mutually pure form H basically.
8. prepare amorphous eplerenone
Amorphous eplerenone can pass through the suitable pulverizing of eplerenone solid, for example by crushing, grinding and/or micronization the eplerenone solid is pulverized on a small quantity to make.Mutually pure amorphous eplerenone, promptly being substantially free of the crystalline amorphous eplerenone of eplerenone can be by for example making eplerenone solution, the particularly lyophilization of eplerenone aqueous solution.This paper embodiment 13 and 14 for example understands these methods.
Other processor considers
1. thermodynamic stability is considered
In room temperature, crystal form L is more stable on thermodynamics than form H.As described in this paper embodiment 5, when being placed in room temperature, the organic slurry that contains equivalent form H and crystal form L spends the night, and to collect residual solid then and pass through the X-ray powder diffraction when analyzing, analysis result shows that eplerenone has changed into crystal form L fully.Above the differential scanning calorimetry of Miao Shuing (DSC) data show that form H is more stable on thermodynamics than crystal form L under higher temperature, and this is because form H has due to higher fusing/decomposition temperature.Serosity transforms and the DSC data show that together form H is that change is relevant with crystal form L, promptly at transition temperature (T
t) near, can change in the stability contact between these two kinds of polymorphs, crystal form L is more stable at a lower temperature.Accompanying drawing 77 expression be for the relevant polymorph of change for example eplerenone crystalline form H and crystal form L, the relation between Gibbs free energy and the temperature, wherein T
tBe meant transition temperature and T
mBe meant the fusing point of form H and crystal form L.
Therefore, comprise in preparation during the compositions of crystal form L, processing temperature preferably remains on below the transition temperature.For example, the baking temperature that desolvation adopted generally be lower than about 150 ℃, preferably be lower than about 125 ℃, more preferably less than about 115 ℃, more preferably less than about 110 ℃, also more preferably about 80 ℃-Yue 110 ℃.In addition, during particle diameter reduces procedure of processing,, may must cool off (for example using liquid nitrogen to cool off) for the crystalline temperature of crystal form L is remained on below the transition temperature.
2. inner micronization is considered
Be used to prepare the character that the crystalline method of eplerenone may influence resulting crystalline forms.For example, and compare, in lattice, show higher surface damage, hole, crack and fracture incidence rate by the crystal form L that the solvate desolvation is made by the crystal form L that directly crystallization makes from solution.Desolvated crystalline this " inner micronization " causes crystalline active surface and crystalline dissolution velocity all to increase.Therefore, dissolution time can shorten by the crystal form L crystal of selection via the desolvation preparation, prolong by the crystal form L crystal of selection, perhaps by selecting to regulate dissolution time with the crystalline appropriate combination of crystal form L for preparing via direct crystallization via the crystal form L crystal of desolvation preparation via the direct crystallization preparation.
When using the crystal form L crystal pharmaceutical compositions that makes by desolvation, inner micronization can also reduce or eliminate the needs that reduce crystal particle diameter during procedure of processing effectively.Yet using the crystalline shortcoming of such crystal form L is to need the desolvation step, and this is unwanted for the crystal form L crystal that makes by direct crystallization.
The solid-state form of the product that makes by the inventive method
Embodiment of the present invention also comprises special solid-state eplerenone form and the combination thereof that makes according to the disclosed method of the application.Particularly, the eplerenone crystalline form H that makes according to the described method of the application separately or the combination of itself and one or more other solid-state form (comprising solvation crystal form, crystal form L and amorphous eplerenone) be embodiment of the present invention.In addition, be embodiment of the present invention as the solvation crystal form for preparing the intermediate of eplerenone crystalline form H by desolvation and make according to the described method of the application.
The combination of solid-state shape
In the combination that comprises first kind of solid-state form eplerenone and second kind of solid-state form eplerenone, wherein said first kind and second kind of solid-state form eplerenone are selected from the eplerenone and the amorphous eplerenone of form H, crystal form L, solvation, and first kind of any appropriate weight ratio with second kind of solid-state form all is spendable.In such combination, first kind of weight ratio with second kind of solid-state form is preferably about 1 usually: about 99: 1 of 99-, more preferably at least about 1: 9, more preferably at least about 1: 1, more preferably at least about 2: 1, more preferably at least about 5: 1, most preferably be at least about 9: 1.
According to embodiment of the present invention, first kind of solid-state form is form H, and second kind of solid-state form is crystal form L.
In another embodiment, also there is the third solid-state form.
The eplerenone particle diameter
Though the eplerenone of every kind of above-mentioned solid-state form and combination thereof can comprise the eplerenone particle diameter of wide region, have been found that the D that the particle diameter of solid-state form eplerenone is brought down below about 400 μ m
90Particle diameter can improve the eplerenone of not preparation and comprise the bioavailability of the pharmaceutical composition of this solid-state form eplerenone.Therefore, do not prepare eplerenone or in preparation of pharmaceutical compositions, be used as the D of the eplerenone of raw material
90Particle diameter generally be lower than about 400 μ m, preferably be lower than about 200 μ m, more preferably less than about 150 μ m, also more preferably less than about 100 μ m, further more preferably less than about 90 μ m.
In one embodiment, D
90Particle diameter is not less than about 25 μ m.It is found that, for most of intended purposes, between the D of the about 400 μ m of about 25-
90Particle diameter generally has acceptable bioavailability, and avoided aspect the environmental pollution control relevant when grinding to form than granule expense and to the demand of its increase.When the major part of eplerenone is eplerenone crystalline form H, in this particle size range, can especially obtain acceptable bioavailability, this is that part has due to the higher dissolution velocity owing to this crystal form at least.According to the present embodiment, suitable D
90Particle size range is the about 100 μ m of about 40-.Another suitable scope is the about 50 μ m of about 30-.Also having another suitable scope is the about 150 μ m of about 50-.Another suitable scope is the about 125 μ m of about 75-.
Can use any grinding, mill, micronization or the particle diameter method that reduces known in the art be processed into above-mentioned required particle size range arbitrarily with solid-state eplerenone.For example, aerojet or crushing grinding are realized this purpose effectively.
When under the precursor of not too considering cost, needing the highest possible bioavailability, have been found that the particle diameter of solid-state form eplerenone is reduced to D
90Particle diameter is lower than the bioavailability that about 15 μ m can further strengthen not the eplerenone of preparation and comprise the pharmaceutical composition of this solid-state form eplerenone, though with above-mentioned D
90It also is like this that particle size range is compared.Therefore, in one embodiment, D
90Particle diameter is about 0.01 μ m (10nm)-Yue 15 μ m.In this embodiment, D
90Particle diameter preferably be lower than about 10 μ m, more preferably less than about 1 μ m, also more preferably less than about 800nm, still more preferably less than about 600nm, most preferably be lower than about 400nm.Use suitable D according to this
90Particle size range is the about 800nm of about 100-.Another suitable scope is the about 600nm of about 200nm-.Another suitable scope is the about 800nm of about 400nm-.Another suitable scope is the about 1 μ m of about 500nm-.
D
90The eplerenone that particle diameter is lower than the solid-state form of about 15 μ m can reduce technology according to suitable particle diameter known in the art and make.Such technology includes but not limited to the technology described in following patent and publication, each described patent and publication are all introduced the present invention with for referencial use:
Violanto﹠amp; The US patent 4826689 of Fischer;
People's such as Liversidge US patent 5145684;
Na﹠amp; The US patent 5298262 of Rajagopalan;
People's such as Liversidge US patent 5302401;
Na﹠amp; The US patent 5336507 of Rajagopalan;
Illig﹠amp; The US patent 5340564 of Sarpotdar;
Na﹠amp; The US patent 5346702 of Rajagopalan;
People's such as Hollister US patent 5352459;
The US patent 5354560 of Lovrecich;
People's such as Courteille US patent 5384124;
The US patent 5429824 of June;
People's such as Ruddy US patent 5503723;
People's such as Bosch US patent 5510118;
People's such as Bruno US patent 5518187;
People's such as Eickhoff US patent 5518738;
People's such as De Castro US patent 5534270;
People's such as Canal US patent 5536508;
People's such as Liversidge US patent 5552160;
People's such as Eickhoff US patent 5560931;
People's such as Bagchi US patent 5560932;
People's such as Wong US patent 5565188;
People's such as Wong US patent 5569448;
People's such as Eickhoff US patent 5571536;
Desieno﹠amp; The US patent 5573783 of Stetsko;
People's such as Ruddy US patent 5580579;
People's such as Ruddy US patent 5585108;
The US patent 5587143 of Wong;
People's such as Franson US patent 5591456;
The US patent 5622938 of Wong;
People's such as Bagchi US patent 5662883;
People's such as Bagchi US patent 5665331;
People's such as Ruddy US patent 5718919;
People's such as Wiedmann US patent 5747001;
International monopoly publication WO 93/25190;
International monopoly publication WO 96/24336;
International monopoly publication WO 98/35666.
In an exemplary method, be that coarse solid-state eplerenone is added to wherein in the undissolved basically therein liquid medium of eplerenone to form the premixing suspension.The concentration of eplerenone in this liquid medium can be about 60% for about 0.1%-, be preferably about 30% weight of about 5%-.The apparent viscosity of this premixing suspension is preferably and is lower than about 1000cP.
This premix directly can be carried out machining, for example use ball mill processing, with D with eplerenone
90Particle diameter is reduced to required scope.Perhaps, can be at first this premix be stirred, for example stirs with roller press or Cowles type blender, until observe formed wherein homodisperse liquid without any macroscopic big agglomerated thing till, grind then, for example grind with recirculation media mill machine.
Can be at surface modifier abrasive grains in the presence of polymer or the wetting agent for example.Perhaps, after grinding, granule can be contacted with surface modifier.Surface modifier can reduce particulate coalescent, and has other advantage.
Should under the temperature of the eplerenone of significantly not degrading, reduce particle grain size.The processing temperature that is lower than about 30-40 ℃ generally is preferred.If necessary, available conventional chiller cools off processing unit (plant).For the purpose of convenient, this method is carried out under the room temperature and the tonnage that can grind safely and effectively.For example, the environment tonnage is the typical pressure that ball mill, attritor mill and vibration mill adopt.The control temperature can by with the grinding chamber chuck or be immersed in the frozen water and realize.Can adopt the about 3.5kg/cm of about 0.07-
2Tonnage, the general about 1.4kg/cm of about 0.7-that adopts
2Pressure.
After grinding is finished, for example filter, sieve etc. via screen cloth abrasive media is separated with drying or liquid dispersion form and grinding product with conventional isolation technics.
Pharmaceutical composition
Also comprise in the present invention be a class pharmaceutical composition, wherein comprise (i) eplerenone crystalline form H, choose wantonly and comprise the eplerenone that one or more are selected from other solid-state form of crystal form L, solvation crystal form and amorphous eplerenone together, (ii) one or more pharmaceutically suitable carrier and/or diluent and/or adjuvant (being referred to as " excipient " in this article) and randomly (iii) comprise one or more active components except that eplerenone.In preferred embodiments, all eplerenones that are included in the compositions all are mutually pure form H basically; Yet if there is the combination of solid-state form, the weight ratio of preferred solid-state form as mentioned above.
Perhaps, all eplerenones that are included in the compositions all are mutually pure solvation eplerenone crystal or amorphous eplerenone basically.
In another embodiment of the present invention, compositions comprises form H and crystal form L.In compositions, the weight ratio of crystal form L and form H is generally about 1: about 20: 1 of 20-.In another embodiment, this weight ratio is about 10: about 1: 5 of about 1: 10 of 1-, about 5: 1-, about 2: about 1: 2 of 1-; For example, this weight ratio is about 1: 1.
Can make the route of administration of the present composition and any appropriate adapt, that these route of administration include but not limited to is oral, cheek, Sublingual, parenteral route for example in the blood vessel, intraperitoneal, subcutaneous or intramuscular, part and rectum (for example by the suppository administration) approach.The eplerenone that these compositionss comprise aequum is suitable for the pharmaceutically acceptable excipient of required route of administration with one or more.
1. Orally administered composition and excipient thereof
The peroral dosage form of compositions preferably comprises one or more excipient that is selected from diluent, disintegrating agent, binding agent and sticker, wetting agent, lubricant and antiplastering aid.More preferably, for the ease of administration, such peroral dosage form is made compacting in flakes or incapsulate.Gained tablet or capsule can contain immediate release formulations and/or controlled release preparation, and wherein controlled release preparation can for example provide in the dispersion of eplerenone in hydroxypropyl emthylcellulose (HPMC).
By suitable selection and combination excipient, can be provided at effectiveness, bioavailability, checkout time, stability, eplerenone and excipient compatibility, safety, dissolution characteristics, disintegration properties and/or other pharmacokinetics, chemistry and/or physical property aspect etc. and show the compositions of improving performance.Excipient is preferably water solublity or water-dispersible material, and has wetting characteristics to remedy the low water solubility of eplerenone.When compositions was mixed with tablet, selected excipient composition provided the dissolving that shows improvement and the tablet of disintegration properties, hardness, crushing strength and/or fragility etc.
1.1 diluent
The present composition is optional to comprise one or more pharmaceutically acceptable diluents as excipient.For example suitable excipient comprises separately or unites the lactose of use, comprises Lactis Anhydrous or lactose monohydrate; Starch comprises the starch that can directly compress and hydrolyzed starch (Celutab for example
TMAnd Emdex
TM); Mannitol; Sorbitol; Xylitol; Glucose (Cerelose for example
TM2000) and Dextrose monohydrate; Dicalcium phosphate dihydrate; Diluent based on sucrose; The sugar that confection manufacturer produces; The calcium bisulfate monohydrate; Calcium sulfate dihydrate; Calcium lactate three water contain composition granule; Glucosan (dextrates); Inositol; The frumentum solid of hydrolysis; Amylose; Cellulose comprises the α of microcrystalline Cellulose, food stage and amorphous cellulose (Rexcel for example
TM) and the cellulose of powdered; Calcium carbonate; Glycine; Bentonite; Polyvinylpyrrolidone etc.If present, such diluent accounts for about 99%, preferred about 85%, the 20%-about 80% more preferably from about of about 10%-of about 5%-of composition total weight altogether.Selected diluent (one or more) preferably shows suitable flowability and compressibility (when needs prepare tablet).
Separately or the lactose and the microcrystalline Cellulose of uniting use be preferable absorbent.These two kinds of diluent are chemically all compatible with eplerenone.Use granule outer fiber element (being the microcrystalline Cellulose that is added to behind the drying steps in the wet granulation compositions) to can be used for improving hardness (for tablet) and/or disintegration time.Lactose, especially lactose monohydrate are particularly preferred.Lactose generally provides the compositions with mobile and/or dry property before suitable eplerenone rate of release, stability, the compression with lower diluent cost.It provides the high-density matter that helps densification during granulate (wherein adopting wet granulation), and has therefore improved mixed flow.
1.2 disintegrating agent
The present composition is optional to comprise one or more pharmaceutically acceptable disintegrating agents as excipient, particularly all the more so for tablet.Suitable disintegrants comprises separately or unites the starch of use, comprises the sodium starch glycolate (Explotab of Pen West for example
TM) and pregel corn starch (National for example
TM1551, National
TM1550 and Colocorn
TM1500), clay (Veegum for example
TMHV), cellulose cellulose, microcrystalline Cellulose, methylcellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, the cross-linking sodium carboxymethyl cellulose of the purification (Ac-Di-Sol of FMC for example for example
TM), alginate, polyvinylpolypyrrolidone, natural gum be arabic gum, guar gum, tracasol, karaya, pectin and tragacanth gum for example.
During the preparation compositions, disintegrating agent can add in the step of any appropriate, particularly adds during the lubricated step before granulation or before tabletting.If present, such disintegrating agent accounts for about 30%, preferred about 10%, the 0.2%-about 5% more preferably from about of about 0.2%-of about 0.2%-of composition total weight altogether.
For tablet or capsule disintegrate, cross-linking sodium carboxymethyl cellulose is preferred disintegrating agent, and if present, and it preferably accounts for about 10%, about 7%, the 0.2%-about 5% more preferably from about also of 0.2%-more preferably from about of about 0.2%-of composition total weight.Cross-linking sodium carboxymethyl cellulose has brought disintegrate ability in the good granule to the compositions that the present invention granulates.
1.3. binding agent
The present composition is optional to comprise one or more pharmaceutically acceptable binding agents or sticker as excipient, particularly all the more so for tablet.Such binding agent and sticker provide enough viscosity preferably for the powder of desiring tabletting, for example finalize the design (sizing), lubricate, compress and pack so that can carry out normal process operation, but make that tablet still can disintegrate and make compositions can be absorbed when taking in.Suitable bonding and sticker comprise separately or unite the arabic gum of use; The tragakanta; Sucrose; Gelatin; Glucose; Starch is such as but not limited to starch,pregelatinized (National for example
TM1551 and National
TM1550); Cellulose is such as but not limited to methylcellulose and sodium carboxymethyl cellulose (Tylose for example
TM); Alginic acid and alginate; Aluminium-magnesium silicate; Polyethylene Glycol (PEG); Guar gum; Polysaccharide acid; Bentonite; Polyvinylpyrrolidone (polyvidone or PVP), for example 30 POVIDONE K 30 BP/USP-15, K-30 and K-29/32; The polyisobutylene acid esters; HPMC; Hydroxypropyl cellulose (Klucel for example
TM); And ethyl cellulose (Ethocel for example
TM).If present, about 25%, preferred about 15%, the 1%-about 10% more preferably from about of about 0.75%-of such binding agent and/or sticker about 0.5%-of accounting for composition total weight altogether.
HPMC is used for providing fusible preferred adhesive to the mixture of powders of eplerenone preparation.If present, HPMC accounts for about 10%, preferred about 8%, the 2%-about 4% more preferably from about of about 1%-of about 0.5%-of composition total weight altogether.Generally can use the low molecular weight HPMC of viscosity, and the viscosity of the about 6cP of about 2cP-is preferred, the viscosity of the about 4cP of particularly about 2cP-for the about 8cP of about 2-.Described HPMC viscosity as 2% aqueous solution 20 ℃ of mensuration.It is about 35% that the methoxyl content of HPMC is generally about 15%-, and that hydroxypropyl content generally is up to is about 15%, preferred about 2%-about 12%.
1.4. wetting agent
Eplerenone solution very not soluble in water.Therefore, the present composition is optional still preferably comprises one or more pharmaceutically acceptable wetting agent as excipient.The such wetting agent of preferred selection can improve the condition of compositions bioavailability to keep eplerenone and water closely to associate-it is believed that.
The limiting examples that can be used as the surfactant of wetting agent in the present composition comprises quaternary ammonium compound, for example benzalkonium chloride, benzethonium chloride and cetyl pyridinium hydrochlorate, dioctyl sodium sulfosuccinate, polyoxyethylene alkyl phenyl ether is nonoxinol 9, nonoxinol 10 and octoxinol 9 for example, poloxamer (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glyceride and oil be polyoxyethylene (8) caprylic/capric monoglyceride and the diglyceride (Labrasol of Gattefoss é for example for example
TM), polyoxyethylene (35) Oleum Ricini and polyoxyethylene (40) castor oil hydrogenated; Polyxyethylated ester is polyoxyethylene (20) cetearyl ether for example, and polyoxyethylene fatty acid ester is polyoxyethylene (40) stearate for example, and Sorbitan ethoxylate is polysorbas20 and the Tween 80 (Tween of ICI for example for example
TM80), the methyl glycol fatty acid ester propylene glycol laurate (Lauroglycol of Gattefoss é for example for example
TM), sodium lauryl sulphate, fatty acid and salt thereof is oleic acid, enuatrol and triethanolamine oleate for example, fatty acid glyceride is monostearin for example, Isosorbide Dinitrate for example anhydro sorbitol one lauric acid ester, anhydro sorbitol monooleate, anhydro sorbitol one palm fibre is put acid esters and anhydro sorbitol monostearate, tyloxapol and their mixture.If present, such wetting agent account for altogether about 0.25%-of composition total weight about 15%, preferably about 0.4%-about 10%, more preferably from about 0,5%-about 5%.
Wetting agent as anion surfactant is preferred.Sodium lauryl sulphate is particularly preferred wetting agent.If present, sodium lauryl sulphate accounts for about 7%, about 4%, the 0.5%-about 2% more preferably from about also of 0.4%-more preferably from about of about 0.25%-of composition total weight.
1.5. lubricant, fluidizer and antiplastering aid
The present composition is optional to comprise one or more pharmaceutically acceptable lubricants and/or fluidizer as excipient.Examples of suitable lubricants and/or fluidizer comprise separately or unite the glycerol behapate (Compritol for example of use
TM888); Stearic acid and salt thereof comprise magnesium stearate, calcium stearate and sodium stearate; Hydrogenated vegetable oil (Sterotex for example
TM); Colloidal silica; Pulvis Talci; Wax; Boric acid; Sodium benzoate; Sodium acetate; Fumaric acid sodium; Sodium chloride; The DL-leucine; Polyethylene Glycol (Carbowax for example
TM4000 and Carbowax
TM4000); Enuatrol; Sodium lauryl sulphate; And Stepanol MG.If present, about 10%, preferred about 8%, the 0.25%-about 5% more preferably from about of about 0.2%-of such lubricant and/or fluidizer about 0.1%-of accounting for composition total weight altogether.
Magnesium stearate is preferred lubricant, and it is used for for example in the friction that reduces during the tabletting between device and the granulation mixture.
Suitable antiplastering aid comprises Pulvis Talci, corn starch, DL-leucine, sodium lauryl sulphate and Metallic stearates.Pulvis Talci is preferred antiplastering aid or fluidizer, and it is used for for example reducing the adhesion of preparation and apparatus surface and the static (static) in the reduction mixture.If present, Pulvis Talci accounts for about 10%, about 5%, the 0.5%-about 2% more preferably from about also of 0.25%-more preferably from about of about 0.1%-of composition total weight.
1.6 other excipient
Other excipient for example coloring agent, correctives and sweeting agent is that drug world is known, and can be used in the present composition.Can be with tablet coating, for example with enteric coating with tablet coating, perhaps coating not.The present composition can also comprise for example buffer agent.
1.7 preferred Orally administered composition
In one embodiment, the present composition comprises eplerenone and one or more cellulose family excipient of aequum.Term " cellulose family excipient " is meant the excipient that comprises the cellulose or derivatives thereof, includes but not limited to cellulose, microcrystalline Cellulose and the alkylcellulose of purification and their derivant and salt (for example methylcellulose, ethyl cellulose, hydroxypropyl cellulose, HPMC, carboxymethyl cellulose, comprise the sodium carboxymethyl cellulose of cross-linking sodium carboxymethyl cellulose etc.).Preferably, at least a such cellulose family excipient is selected from (C
1-6Alkyl) cellulose and their derivant and salt.More preferably, described cellulose family excipient is selected from hydroxyl (C
2-4Alkyl)-(C
1-4Alkyl) cellulose and their derivant and salt.
The compositions of this embodiment preferably also comprises the excipient that one or more are selected from diluent, disintegrating agent, binding agent, wetting agent, lubricant and antiplastering aid.These compositionss more preferably comprise one or more and are selected from lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, HPMC, sodium lauryl sulphate, magnesium stearate and talcous excipient.These compositionss also more preferably comprise lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and HPMC, most preferably also comprise one or more and are selected from sodium lauryl sulphate, magnesium stearate and talcous other excipient.
In this embodiment, if necessary, listed single excipient can be chosen wantonly with other suitable excipient and replace.Acceptable alternative excipient and eplerenone are all chemical compatible with other excipient.Though can use other diluent, disintegrating agent, binding agent and sticker, wetting agent, lubricant and/or antiplastering aid or fluidizer, comprise eplerenone nano-particle, lactose, microcrystalline Cellulose, sodium carboxymethyl cellulose and HPMC and optional sodium lauryl sulphate, magnesium stearate and/or the talcous compositions that comprises is better than other compositions in pharmacokinetics, chemistry and/or physical features combined aspects usually.
In another embodiment, the present composition comprises:
About 95% eplerenone of about 1%-;
About 99% pharmaceutically acceptable diluent of about 5%-;
About 0.5%-about 30% pharmaceutically acceptable disintegrating agent; With
About 0.5%-about 25% pharmaceutically acceptable binding agent;
Wherein said percentage ratio all is by weight.Such compositions can be chosen wantonly and also comprise about 0.25%-about 15% pharmaceutically acceptable wetting agent; About 0.1%-about 10% pharmaceutically acceptable lubricant; And/or about 0.1%-about 15% pharmaceutically acceptable antiplastering aid.
In another embodiment, the present composition is and contains eplerenone and the form of the oral unit dosage form of cellulose family excipient, preferred tablet or capsule as defined above.Said composition preferably comprises one or more and is selected from lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, sodium lauryl sulphate, magnesium stearate and talcous excipient.
2. parenteral administration compositions
But the solid-state eplerenone form of the present invention parenteral administration, for example by the solid-state eplerenone of intravenous, intramuscular or subcutaneous injection liquid-carrier for example the suspension in saline, glucose solution or the water come administration.Suspension composition can comprise the suitable vehicle component of the excipient that is selected from Orally administered composition disclosed above.
3. percutaneous administration compositions
Other compositions can be the form of part or percutaneous administration unguentum or cream, described unguentum or cream comprise the solid-state eplerenone that is scattered in wherein, wherein the content of eplerenone, preferably about 0.2%-about 20% weight, more preferably from about 0.4%-about 15% weight about 30% for for example about 0.075%-.For the purpose of favourable, such part or percutaneous administration compositions can comprise can promote the chemical compound of eplerenone via skin absorbs or transdermal.This skin penetration promotes that examples for compounds comprises dimethyl sulfoxine and related compound.
The new solid-state form of eplerenone can also use drug storehouse storage and porous membranous type or solid matrix type patch to come transdermal administration.For any situation, eplerenone all via film from drug storehouse storage or microcapsule, be delivered to continuously with individual's skin or the contiguous eplerenone permeable adhesive of mucosa in.If eplerenone is via skin absorbs, the eplerenone of controlled and predetermined amount of flow can be administered to the receiver.For microcapsule, but the also effect of skinning of encapsulation agent.
Treatment or prevention method
The present invention also comprises the aldosterone-mediated disease or the method for disease for the treatment of and/or preventing, described method comprises the individuality of suffering from or easily suffer from described disease or disease with the solid-state eplerenone of treatment effective dose or the medicine composite for curing that comprises solid-state eplerenone, it is eplerenone crystalline form H that but wherein said solid-state eplerenone has a test section at least, and remaining part comprises the eplerenone crystal and the amorphous eplerenone of one or more eplerenone crystalline forms L, solvation.Such method can be used for treating and/or preventing disease or the disease that needs to use aldosterone antagonists in the individuality, include but not limited to treat aldosteronism sexually transmitted disease (STD) disease, for example hypertension, heart failure comprise that cardiac insufficiency, liver cirrhosis, collagen are excessive, fibre modification, benign prostatauxe and depression.
Except can be used for treating the people, the eplerenone of these solid-state forms and pharmaceutical composition thereof also can be used for for example veterinary treatment of horse, Canis familiaris L. and cat of house pet, external and farm-animals.
The eplerenone of solid-state form and compositions thereof can (i) partially or completely replace other aldosterone receptor antagonist in therapeutic alliance, and/or (ii) carry out therapeutic alliance with other medicines.Term " therapeutic alliance " is meant uses every kind of medicine in a sequential manner in the scheme that the drug regimen beneficial effect is provided, with with simultaneously mode drug administration together basically, for example in the single capsule or single injection of these activating agents, perhaps in a plurality of independent dosage forms that have a kind of activating agent respectively or injection, use with fixed proportion.The limiting examples of such therapeutic alliance comprises as using aldosterone receptor antagonist and angiotensin I I receptor antagonist to treat cardiovascular disease in uniting described in the international monopoly publication WO 96/24373, as using aldosterone receptor antagonist and Angiotensin II antagonist to treat congestive heart failure in uniting described in the international monopoly publication WO 96/40257, as uniting the use aldosterone receptor antagonist described in the international monopoly publication WO 96/24372, ACE inhibitor and diuretic are treated heart failure, and all these publications are all introduced the present invention with for referencial use.
Embodiment
Following embodiment describes the method for preparation various solid-state form eplerenones as herein described in detail.These are described in detail within the scope of the present invention, and are to illustrate of the present invention, rather than limit the scope of the invention by any way.Unless otherwise noted, otherwise all percentage ratios all be by weight.The eplerenone raw material that uses in each following embodiment all is according to scheme 1 preparation of the international monopoly publication WO 98/25948 that above quotes.
Embodiment 1: prepare eplerenone crystalline form L by high-purity eplerenone feedstock production butanone compound with by this solvate
A. prepare the butanone compound
Under the magnetic of 900rpm stirs, 437mg high-purity eplerenone (purity＞99%, and diepoxide and 11, the total content of 12-epoxide＜0.2%) is dissolved in the 10ml butanone by on electric hot plate, being heated to boil.Under the magnetic that continues stirs, gained solution is cooled to room temperature, in case reach room temperature, just this solution is transferred in 1 ℃ of bath, and continued to stir 1 hour.From this cold soln, collect butanone compound solid by vacuum filtration.
B. prepare eplerenone crystalline form L
With the butanone compound solid that makes as mentioned above in baking oven under 100 ℃, normal pressure dry 4 hours.Confirmed that by DSC and XRPD analysis this exsiccant solid is pure crystal form L.
Embodiment 2: prepare other solvate by high-purity raw
According to identical with embodiment 1 basically method, replace butanone to prepare other solvate with following solvents respectively: normal propyl alcohol, 2 pentanone, acetic acid, acetone, butyl acetate, chloroform, ethanol, isobutanol, isobutyl acetate, isopropyl alcohol, methyl acetate, ethyl propionate, n-butyl alcohol, n-octyl alcohol, propyl acetate, propylene glycol, the tert-butyl alcohol, oxolane and toluene.
Embodiment 3: by vapor diffusion growing and preparing butanone compound
By warm on electric hot plate 400mg eplerenone (purity＞99.9%) is dissolved in the 20ml butanone, to form stock solution.With butanone this stock solution of 8ml is diluted to 10ml, gained solution is called 80% diluted sample.With butanone this stock solution of 4ml is diluted to 10ml (40% diluted sample), this stock solution of 2ml is diluted to 10ml (20% diluted sample) with butanone.Will each diluted sample in the 20ml scintillation vial transfer to and contain in the dry cylinder of a small amount of hexane as anti-solvent (anti-solvent).Should seal by the drying cylinder, and make hexane vapor be diffused in the butanone solution.In 24 hours, in 80% diluted sample, grown the crystal of eplerenone butanone compound.
Embodiment 4: prepare the eplerenone solvate crystals by Rotary Evaporators
The about 400mg eplerenone (purity＞99.9%) of weighing places the 250ml round-bottomed flask.The solvent that 150ml is selected from butanone and embodiment 2 listed solvents is added in this flask, if necessary the solution mild heat is dissolved until eplerenone.The gained settled solution is placed Buchi Rotary Evaporators with about 85 ℃ of bath temperature.When stopping except that desolvating during the about 10ml solvent of residue in the flask.Analyze the gained solid to determine crystal form by proper method (for example XPRD, DSC, TGA, microscopic method etc.).
Embodiment 5: serosity transforms
About 150mg eplerenone crystalline form L and 150mg eplerenone crystalline form H are added in the 5ml ethyl acetate.The gained serosity is spent the night with the stirring of 300rpm magnetic.Second day by filtering collection gained solid sample.By the XRPD analyzing samples, the result shows that this sample is made up of eplerenone crystalline form L fully.
Embodiment 6:(a) by low-purity eplerenone feedstock production solvate and (b) prepare eplerenone crystalline form H by the gained solvate
By being added to prepare in the 7ml scintillation vial with a certain amount of eplerenone that is enough to provide this quality of 100mg gross sample, the impurity of aequum contains not commensurability aforesaid diepoxide or 11, the sample of 12-epoxide impurity.The content of impurity is shown in table 6A and 6B in each sample, and wherein impurity is respectively diepoxide or 11, the 12-epoxide.In each scintillation vial, add miniature magnetic stirrer and 1ml butanone.With the capping of scintillation vial pine loose ground, solid is dissolved by on electric hot plate, being heated to backflow under stirring at magnetic.When dissolving is finished, continuing under the stirring gained solution to be cooled to room temperature.Collect the gained solid by vacuum filtration then, and analyze by XRPD immediately.Then solid is placed 100 ℃ of baking ovens, and under normal pressure dry 1 hour.Analyze exsiccant solid by XRPD, determine form H content at the area of the form H diffraction maximum of about 12.1 ° of 2 θ by monitoring.All XRPD diffraction patterns all write down on the InelMultipurpose diffractometer.
The composition of eplerenone raw material among table 6A: the embodiment 6
| The % diepoxide | Eplerenone (mg) | Diepoxide (mg) |
| 0 | 100.44 | 0 |
| 1 | 99.08 | 1.24 |
| 2 | 98.09 | 2.24 |
| 3 | 97.08 | 3.04 |
| 5 | 95.09 | 5.04 |
The composition of eplerenone raw material among table 6B: the embodiment 6
| %11, the 12-epoxide | Eplerenone (mg) | 11,12-epoxide (mg) |
| 0 | 101.38 | 0 |
| 1 | 99.23 | 1.10 |
| 5 | 94.97 | 5.36 |
| 10 | 90.13 | 10.86 |
A. diepoxide result
Accompanying drawing 78 has shown to derive from and has mixed (a) 0%, (b) 1%, (c) 3% and (d) the XRPD figure of the wet cake of butanone crystalline butanone compound of 5% diepoxide.For the ease of relatively, peak intensity has been carried out standardization (normalized).In diffraction pattern without any the characteristic peak of form H or diepoxide.This figure is the feature of eplerenone butanone compound.
Accompanying drawing 79 has shown to derive from and has mixed (a) 0%, (b) 1%, (c) 3% and (d) the solid XRPD figure of 5% diepoxide butanone crystallizing and drying.For the ease of relatively, peak intensity has been carried out standardization.Be not detect any form H in 0% or 1% the corresponding dry sample of butanone crystallization with the doped level of diepoxide wherein.Be to have detected form H in 3% or 5% the corresponding dry sample of butanone crystallization with the doped level of diepoxide wherein.For each sample, at the area of the form H diffraction maximum of about 12.1 ° of 2 θ and the form H content estimated shown in table 6C.
Butanone crystallization gained data among table 6C: the embodiment 6
| % diepoxide in the raw material | % diepoxide (HPLC) in the crystal | Form H peak area at 12.1 ° of 2 θ | The form H % content of |
| 0 | 0 | Do not detect | ?0 |
| 1 | 0.29 | Do not detect | ?0 |
| 3 | 0.58 | ?1168 | ?10 |
| 5 | 1.05 | ?4157 | ?30 |
The result who reports among the table 6C has confirmed to exist during desolvation diepoxide to influence the formation of eplerenone crystalline form H.In the time of on diepoxide being incorporated into and/or being adsorbed onto butanone compound crystal, the formation of form H has been led in slander.
Carry out second 3% diepoxide mix experiment with the analyte preparation approach to desolvation during the influence of formed form H amount.In this real leading to, will be by the butanone compound separated into two parts of doping crystallization acquisition.First does not handle, and second portion grinds lightly with pestle in mortar, to induce the len coloboma of higher level.With these two parts all under normal pressure in 100 ℃ of dryings 1 hour.Analyze exsiccant solid by XRPD.Accompanying drawing 80 has shown that wherein (a) do not grind this solvate before the drying, is to have ground this solvate before the drying (b) from the XRPD figure of the drying solid of the butanone crystallization acquisition of mixing 3% diepoxide.XRPD figure shows, compares with the sample that does not grind, and contains more form H in the sample of grinding.These results show that the condition of separation and processing butanone compound can influence the formed crystal form of desolvation.
B.11,12 epoxide results
Accompanying drawing 81 shown derive from mixed (a) 0%, (b) 1%, (c) 5% and (d) 10% 11, the XRPD figure of the wet cake of 12-epoxide butanone crystallization butanone compound.For the ease of relatively, peak intensity has been carried out standardization.In diffraction pattern without any the characteristic peak of form H or 11.12-epoxide.This figure is the feature of eplerenone butanone compound.
Accompanying drawing 82 has shown to derive from and has mixed (a) 0%, (b) 1%, (c) 5% and (d) 10%11, the solid XRPD figure of 12-epoxide butanone crystallizing and drying.For the ease of relatively, peak intensity has been carried out standardization.With wherein 11, the doped level of 12-epoxide is not detect any form H in 0%, 1% or 5% the corresponding dry sample of butanone crystallization, with wherein 11, the doped level of 12-epoxide is to have detected form H in 10% the corresponding dry sample of butanone crystallization.For each sample, at the area of the form H diffraction maximum of about 12.1 ° of 2 θ and the form H content estimated shown in table 6D.
Butanone crystallization gained data among table 6D: the embodiment 6
| %11 in the raw material, the 12-epoxide | Form H peak area at about 12.1 ° of 2 θ | The form H % content of |
| 0 | Do not detect | ?0 |
| 1 | Do not detect | ?0 |
| 5 | Do not detect | ?0 |
| 10 | 1541 | ?10-15 |
The result who reports among the table 6D has confirmed to have 11 during desolvation, and the 12-epoxide influences the formation of eplerenone crystalline form H.For the impurity level of inducing in the required butanone crystallization of formation eplerenone crystalline form H, 11, as if the 12-epoxide be greater than diepoxide.
Embodiment 7. crystallizations and dry influence to final crystal form
Carry out following 4 experiments with minute precipitation and crystallization and dry influence: (i) the butanone crystallization (2 of eplerenone to final crystal form
3+ 3 experimental statisticses designs), the (ii) crystallization of low quality mother solution residue, (iii) add the form H crystal seed the high-purity eplerenone crystallization and (iv) add the crystallization of the low-purity eplerenone of crystal form L crystal seed.Variable in these experiments comprises rate of cooling, material purity level and crystalline outlet temperature.In this embodiment, the high-purity eplerenone is defined as the eplerenone that ultrapure (HPLC) ground, and it is 89% eplerenone that the low-purity eplerenone is defined as purity.In order to prepare the low-purity eplerenone, the mother solution stripping that will in the process of preparation eplerenone, be obtained, and mix to obtain to contain 61.1% eplerenone, 12.8% diepoxide and 7.6%11, the material of 12-epoxide.Then this material being mixed to obtain purity with capacity high-purity eplerenone is 89% eplerenone.
A. butanone crystallization
In this butanone crystallization experiment, all batches all carry out with 60g high-purity eplerenone.High terminal point is defined as 45 ℃, and low terminal point is defined as 5 ℃.High rate of cooling is defined as 3 ℃/minute, and low rate of cooling is defined as 0.1 ℃/minute.Mid point is that 1.5 ℃ of/minute rate of cooling, purity are eplerenone and 25 ℃ of terminal points of 94.5%.
After carrying out background reading with FTIR, the 250ml butanone is placed 1 liter of Mettler RC-1, in the MP10 reactor, and stir with 100rpm.After the scanning several times, in this reactor, add eplerenone, and then add the 470ml butanone.Mixing speed is increased to 500rpm with suspended solid, and this mixture temperature is increased to 80 ℃.The temperature of this mixture is remained on 80 ℃ to guarantee the eplerenone dissolving.In the gained clear solution, generally can see black or white dot.With required speed this mixture temperature is reduced to required terminal point by the slope cooling then, kept 1 hour, be poured into then and move in the liquid bottle and filtration, obtained wet cake in this outlet temperature.Wash this reactor, move liquid bottle and wet cake with the 120ml butanone then.For every increment this, will the wet cake of about 10g in vacuum drying oven under 75 ℃, the slight blended standard conditions of nitrogen vacuum drying.Under high and low condition, pass through fluid-bed drying dry wet cake.For fluid bed drying, high conditional definition is 100 ℃, 4 blower fans is installed that low condition is defined as 40 ℃, 1 blower fan is installed.
B. crystallization low quality mother solution residue
In the experiment of crystallization low quality mother solution residue, the eplerenone and the 720ml butanone of 60g 61.1% purity directly is added to 1 liter of Mettler RC-1, in the MP10 reactor.Before in being added to reactor, impure eplerenone does not mix with the high-purity eplerenone.With gained mixture heated to 80 ℃, it is opaque serosity in room temperature.Continue crystallization, filtering this mixture in 45 ℃ under the cooling condition rapidly.
C. add the form H crystal seed
In the experiment that adds the form H crystal seed, 60g high-purity eplerenone and 720ml butanone are added to 1 liter of Mettler RC-1, in the MP10 reactor.With this mixture heated to 80 ℃, be cooled to 25 ℃ with 1.5 ℃/minute speed then.When solution is cooled to 62 ℃, to wherein adding the mutually pure form H crystal of 3g with induced crystallization.Described form H crystal seed is to make by the cooking process in following embodiment 9.
D. add crystal form L crystal seed
In the experiment that adds crystal form L crystal seed, the eplerenone of 66.6g 89.3% (making by 48.3g high-purity eplerenone is mixed with 18.3g 61.1% eplerenone) and 720ml butanone are added to 1 liter of Mettler RC-1, in the MP10 reactor.With this mixture heated to 80 ℃, be cooled to 25 ℃ with 1.5 ℃/minute speed then.When solution is cooled to 63 ℃, to wherein adding the mutually pure crystal form L crystal of 3g with induced crystallization.Described crystal form L crystal seed is by making in crystallization described in the embodiment 1 and desolvation method.
E. result
These experiment gained are the result be reported among the table 7A.
In the butanone crystallization experiment, have only when using the low-purity eplerenone that contains diepoxide, just to detect form H.The level of also observing diepoxide in the end-product under higher rate of cooling increases.
The experiment of crystallization low quality mother solution residue has generated downhill, detect to find its mixture of diepoxide and eplerenone crystalline form H seemingly by XRPD.
In the product that the experiment that adds the form H crystal seed (use the high-purity eplerenone, add the form H crystal seed) generates, analyze it according to XRPD and contain 77% form H, but it all is a form H according to DSC.Yet for the linearity that surpasses about 15% form H, the XRPD model was never tested.In the middle of these 4 experiments, this experiment is a unique experiment that does not exist diepoxide promptly to generate form H.
It all is the product of crystal form L that the experiment of adding crystal form L crystal seed (use the low-purity eplerenone, add crystal form L crystal seed) has generated.
As if for the high condition fluid bed drying of eplerenone, the gained data are consistent with the dry gained data of vacuum drying oven.The result who is obtained from the low condition fluid bed drying is different with the dry gained result of vacuum drying oven.
The result of table 7A: embodiment 7
| Rate of cooling (℃/min.) | The cooling terminal point (℃) | Raw material % purity | Nucleation temperature (℃) | %11, the 12-epoxide 1 | The % diepoxide | The crystalline analysis of desolvation | The % productive rate | % form H (XRPD) |
| 3 | 45 | 94.5 | 57.0 | ND | ND | 100.3 | 66.1 | |
| 3 | 5 | 94.5 | 54.9 | ND | ND | 100.3 | 98.1 | ND |
| 0.1 | 45 | 94.5 | 60.9 | ND | ND | 100.3 | ND | |
| 0.1 | 5 | 94.5 | 63.4 | ND | ND | 100.5 | 79.3 | |
| 3 | 45 | 61.1 | 4.8 | 36.6 | 43.3 | 27 | 100 2 | |
| 3 | 45 | 89.3 | 52.2 | 0.49 | 0.88 | 98.3 | 62 | 29 |
| 3 | 5 | 89.3 | 53.3 | 0.56 | 1.0 | 98.1 | 87 | 9 |
| 1.5 | 25 | 100 | 59.0 | 0.18 | 0.36 | 99.4 | 75 | 5 |
| 0.1 | 45 | 89.3 | 63.3 | 0.20 | 0.44 | 99.4 | 36 | 31 |
| 0.1 | 5 | 89.3 | 61.4 | 0.18 | 0.40 | 99.5 | 87 | ND |
| 1.5 | 25 | 100 | 60.6 | 0.18 | 0.36 | 99.5 | 79.2 | ND |
| 1.5 | 25 | 100 | 55.9 | 0.38 | 0.80 | 98.6 | 80.5 | ＜3％ |
| 1.5 | 25 | 100 add the form H crystal seed | 0.03 | ND | 100.4 | 82.2 | 77/100 3 | |
| 1.5 | 25 | 89.3 add crystal form L crystal seed | 0.33 | 0.50 | 97.5 | 80.2 | ND |
1With solvate in vacuum drying oven in 75 ℃ of dried weight %
2Analyze by XRPD and to find the mixture of form H and diepoxide seemingly
3Analyze seemingly 77% form H and by dsc analysis 100% form H seemingly by XRPD
ND=does not detect
F. material purity
Accompanying drawing 83 has shown based on showing the data that 7A reported, the isometric chart of product purity, material purity, rate of cooling and outlet temperature.This isometric chart shows, uses the higher degree eplerenone can generate the higher degree product when the beginning crystallization.As if crystalline outlet temperature little to the influence of product purity.Yet it is influential that rate of cooling seems, caused generating the low slightly product of purity than the piece rate of cooling.In fact, under the rate of cooling than piece, the level of diepoxide is generally higher.
Accompanying drawing 84 expression be, in order to determine the purity of end-product is had the variable (if any) of remarkable statistics influence, with half standard drawing of this isometric chart result drafting.Material purity has maximum remarkable statistics influence to product purity, and the interaction between the influence of rate of cooling and rate of cooling and the material purity also has significance,statistical.
Accompanying drawing 85 is based on these results' interaction diagram, its expression be the influence of the interaction partners product purity between material purity and the rate of cooling.When using the high-purity eplerenone, rate of cooling looks very little or without any influence to the influence of final purity.Yet, when using low-purity eplerenone (89.3% eplerenone raw material), along with the increase product purity of rate of cooling has descended.This result shows, when when higher rate of cooling is carried out crystallization, can crystallization go out more impurity.
G. form H content
The data that 7A reported, the isometric chart of form H weight fraction, material purity, rate of cooling and outlet temperature are shown in being based on of accompanying drawing 86 expressions.This isometric chart shows, uses the eplerenone of higher degree can obtain more a spot of form H when the beginning crystallization.As if crystalline outlet temperature also influential to the form of end-product.Rate of cooling looks little to the formation of form H influence, though in the presence of impurity, in low outlet temperature with can some form Hs of generation than the cooling of piece speed.
Accompanying drawing 87 expression be, in order to determine variable (if any), with half standard drawing of this isometric chart result drafting with remarkable statistics influence to the content of form H in the end-product.Look that the interaction between material purity, crystalline outlet temperature and this two variablees has remarkable statistics influence.
Accompanying drawing 88 be based on the table data that 7A reported interaction diagram, its expression be the influence of the interaction partners end-product purity between material purity and the outlet temperature.When using the high-purity eplerenone, look that outlet temperature is very little to the form H content influence.In two experiments using pure eplerenone, all do not generate any form H.Yet, when using low-purity eplerenone (the eplerenone raw material of 89.3% purity), in two experiments, all generated form H, and generated more form H significantly in higher outlet temperature.
Table 7B has reported and has used fluid bed (Lab-Line/P.R.L.Hi-Speed fluidized bed dryer, Lab-Line Instruments, Inc) or the weight fraction of the form H of measuring in the exsiccant material of vacuum drying oven (BaxterScientific Products vacuum drying oven, Model DP-32).For exsiccant comparable material in high fluid bed or vacuum drying oven, observed similar form H content.Yet for exsiccant comparable material in low fluid bed, the result who is observed is different with vacuum drying oven.
Table 7B: performance variable is to the influence of form H content
| Rate of cooling | Terminal point | Impurity level | Drying condition | The % form H |
| High | High | High | Vacuum drying oven | 29 |
| High | High | High | | 25 |
| High | High | High | Low fluid bed | 4.7 |
| Low | Low | Low | Vacuum drying oven | ND |
| Low | Low | Low | High fluid bed | ND |
| Low | Low | Low | Low fluid bed | 5.5 |
ND=does not detect
Embodiment 8: adopt desolvation crystalline form L from butanone
10g eplerenone crystalline form H and 80ml butanone are merged.With this mixture heated to refluxing (79 ℃), and under this temperature stir about 30 minutes.Then by with this serosity 65 ℃, 50 ℃, 35 ℃ and 25 ℃ keep respectively 90 minutes with the gained serosity with progressively, stop (holdpoint) point mode cool off.Filter this serosity, and wash with about 20ml butanone.The isolated solid of institute is at first dry on filter, then in vacuum drying oven in 40-50 ℃ of drying.In vacuum drying oven, finish drying in 90-100 ℃.Yield with 82% has obtained desolvated solid.XRPD, MIR and DSC have confirmed that this solid has crystal form L crystal structure.
Embodiment 9: prepare form H with solvent steaming and decocting low-purity eplerenone raw material
A. use the alcohol solvent steaming and decocting
24.6g low-purity eplerenone (purity that HPLC measures is 64%) is merged with 126ml ethanol 3A.This serosity is heated to backflow, and removes distillate.When the 126ml solvent is removed by air-distillation, add 126ml ethanol 3A simultaneously.After solvent turnover is finished, this mixture is cooled to 25 ℃ and stirred 1 hour.With the gained solid filtering, and with ethanol 3A washing, air-dry then, obtained the ethanol compound.With this solvate in vacuum drying oven in 90-100 ℃ further dry 6 hours, obtained 14.9g eplerenone crystalline form H.
B. use the butanone solvent steaming and decocting
In another boiling method,, then this mixture is cooled to room temperature with 1g low-purity eplerenone (purity of mensuration is 65%) steaming and decocting 2 hours in the 4ml butanone.In case cooling is promptly collected the gained solid by vacuum filtration, confirmed that by the XRPD analysis it is the butanone compound.With this solid at 100 ℃ of dry 30-60 minutes.XPRD confirms that this exsiccant solid is pure form H.
Embodiment 10: prepare crystal form L with solvent steaming and decocting high-purity eplerenone raw material
A. use the alcohol solvent steaming and decocting
With about 2 hours of 1g high-purity eplerenone steaming and decocting in 8ml ethanol.Then this solution is cooled to room temperature, and collects solid by vacuum filtration.Analyze this solid by XRPD immediately after the filtration, the result shows that this solid is solvate (supposition is the ethanol compound).Then with this solid 100 ℃ under normal pressure dry 30 minutes.Analyze this exsiccant solid by XRPD, the result has confirmed that it mainly is crystal form L (not detecting any form H).
B. use the butanone solvent steaming and decocting
With about 2 hours of 1g high-purity eplerenone steaming and decocting in the 4ml butanone.Then this solution is cooled to room temperature, and collects solid by vacuum filtration.Analyze this solid by XRPD immediately, the result shows that this solid is solvate (supposition is the butanone compound).Then with this solid 100 ℃ under normal pressure dry 30-60 minute.Analyze this exsiccant solid by XRPD, the result has confirmed that it mainly is crystal form L, does not exist any form H diffraction maximum.
Embodiment 11: direct crystallization crystal form L from solution
Method A
By being heated to 75 ℃ the 2.5g eplerenone is dissolved in the ethyl acetate.This solution is kept 30 minutes to guarantee dissolving fully at 75 ℃, be cooled to 13 ℃ with 1 ℃/minute rate of cooling then.The gained serosity was stirred 2 hours with 750rpm with the overhead type agitator.Collect solid by vacuum filtration, and in vacuum drying oven in 40 ℃ of dryings 1 hour.This solid XRPD figure and DSC differential thermogram are the features of eplerenone crystalline form L.This solid TGA shows, do not have the loss in weight being up to 200 ℃ of these solids.
Method B
In other method, the 2g eplerenone is dissolved in the mixture of 350ml 15% acetonitrile and 85% water by on electric hot plate, heating under stirring at magnetic.In case eplerenone dissolves, under magnetic stirs with this solution in the room temperature cool overnight.Collect the gained solid by vacuum filtration.Crystal has birefringence effect, and has triangle lamellar crystal habit.This solid has XRPD and the dsc analysis feature of eplerenone crystalline form L.TGA shows and is being up to 200 ℃ also without any the loss in weight.
Method C
In other method, the 640mg eplerenone is placed 50ml flask with 20ml ethylo benzene.The gained serosity is heated to 116 ℃, and this mixture has become settled solution, with 30 minutes it is cooled to 25 ℃ then.During cooling 84 ℃ of beginning nucleation.The gained solid is filtered out from this solution, air-dry, obtained 530mg solid (yield 83%).Hot-stage microscopy and XRPD have confirmed that this solid is eplerenone crystalline form L.
Method D
In other method, be added to the 1.55g eplerenone in the 2.0ml Nitrobenzol and be heated to 200 ℃.The gained serosity is spent the night 200 ℃ of stirrings, and this mixture has become settled solution, by the natural air convection current it is cooled to room temperature to isolate solid then.Confirmed that by XRPD and micropolariscope this solid is eplerenone crystalline form L.
Method E
In other method, 5.0g eplerenone (purity＞99%) is added in 82g (104ml) methanol.Under stirring, this solution is heated to 60 ℃, and under this temperature, keeps dissolving fully guaranteeing in 20 minutes with 210rpm.Under agitation this solution is cooled to-5 ℃ then with 0.16 ℃/minute speed.By filter collecting the gained solid, and in vacuum drying oven in 40 ℃ of vacuum dryings 20 hours.DSC and XRPD analyze and have confirmed that this exsiccant solid is pure eplerenone crystalline form L.
Method F
In other method, 6.0g eplerenone (contain 9% alcoholic acid ethanol compound, its corrected purity is 95.2%) is added in 82g (104ml) methanol.Under stirring, this solution is heated to 60 ℃, and under this temperature, keeps dissolving fully guaranteeing in 20 minutes with 210rpm.With 0.14 ℃/minute speed this solution is cooled to 50 ℃ then, and under this temperature, kept 2.5 hours.Under agitation this solution is cooled to-5 ℃ then with 0.13 ℃/minute speed.By filter collecting crystal, and in vacuum drying oven in 40 ℃ of vacuum dryings 16 hours.DSC and XRPD analyze and have confirmed that this exsiccant solid is pure eplerenone crystalline form L.
Embodiment 12: direct crystallization form H from solution
150.5mg diepoxide and 2.85g eplerenone are added in the 1.5ml Nitrobenzol.This mixture was stirred several hours at 200 ℃ of magnetic.By the natural air convection current gained serosity is cooled to room temperature then.With the sample drying and by micropolariscope and XRPD analyzing samples.XRPD the analysis showed that this sample is the mixture of form H and crystal form L.This crystal is translucent at microscopically, and this shows desolvation and (changing into form H or crystal form L) are not taken place.
Embodiment 13: by pulverizing the amorphous eplerenone of preparation
With about 60g eplerenone (purity＞99.9%) on about 1 half steel system Wig-L-Bug vessel filling.Steel ball and lid are placed on this sample container, and stirred 30 seconds by this Wig-L-Bug device.The surface of eplerenone from this Wig-L-Bug container scraped off, and with this container restir 30 seconds.By XRPD and dsc analysis gained solid, found that this solid is the mixture of amorphous eplerenone and eplerenone crystalline form L.
Embodiment 14: prepare amorphous eplerenone by lyophilization
About 100mg eplerenone crude product of weighing places the beaker that contains 400ml water.With gained mixture mild heat 5 minutes, ultrasonic then, and restir 5 minutes is to obtain dispersion liquid.About 350ml eplerenone dispersion liquid is filled in the 1000ml round-bottomed flask that contains 50mlHPLC water.With this dispersion liquid in dry ice/acetone batch rapid freezing 1-2 minute, flask is connected on Labconco Freezone 4.5 freeze dryers, and content dried overnight that will be wherein.With the solid transfer in the flask in brown vial.Under micropolariscope in 10 *, 1.25 * optivar amplification observes the little aliquot in cargille oil (1.404), and observe and have 95% amorphous eplerenone at least.Accompanying drawing 89 and 90 has shown the XRPD figure and the DSC differential thermogram of amorphous eplerenone.In accompanying drawing 89, be because due to the aluminum sample container at 39 ° of 2 observed peak of θ.
Embodiment 15: the dissolubility of eplerenone crystalline form L
At pH 7 (100mM phosphate buffer) in 5,25 and 40 ℃ of water solubilities that detect eplerenone.At 5 and 25 ℃ about 30mg eplerenone crystalline form L is mixed to form the eplerenone serosity with about 10ml buffer.At 40 ℃ about 40mg eplerenone crystalline form II is mixed to form the eplerenone serosity with about 10ml buffer.For each condition, with duplicate preparation sample.Serosity is carried out balance in the water electromagnetic shaker is bathed, and measure the content of eplerenone in the solution with the 1st, 5,12,19,27 and 36 day interval by UV-VIS spectrophotometry (245nm) under proper temperature.To carry out fair average determining the eplerenone dissolubility under each temperature in the data under each temperature, and be reported in the table 8.When balance finished in the 36th day, analyze the residual solid of each time point by DSC and TGA, found that it is eplerenone crystalline form L.
Table 8: the dissolubility of eplerenone crystalline form L
| Temperature (℃) | Crystal form L dissolubility (mg/ml) |
| 5 | 0.24 |
| 25 | 0.29 |
| 40 | 0.39 |
Embodiment 16: measure intrinsic dissolution velocity
Measure the intrinsic dissolution velocity of following 4 kinds of eplerenone polymorph samples: (i) make water as anti-solvent, according to embodiment 11, the method that method B is identical is by the eplerenone crystalline form L that directly crystallization makes from acetonitrile; (ii) according to the identical mode of embodiment 9 method A, the eplerenone crystalline form H that makes by steaming and decocting in ethanol; The (iii) mixture of 5% form H and 95% crystal form L; (iv) carry out micronization with granule that the eplerenone crystalline form L:10% weight with following particle size distribution is provided below 9 μ m, the granule of 50% weight below the 22 μ m and the granule of 90% weight below 41 μ m.
Weigh 150mg eplerenone and place the intrinsic lysing chamber of VanKel.Use the Carver tablet machine in the 8280kPa compacting in flakes with powder.Then sample is fixed on the intrinsic dissolver.Used dissolve medium is the solution of 1% sodium lauryl sulphate (SDS) in HPLC water.All tests all are to carry out 2 hours 37 ℃ of tests.Before beginning experiment, with the 500ml dissolve medium in the dissolving bathroom in 37 ℃ of balances 30 minutes.From each dissolution vessel, take out initial sample, with at initial time (T
0) test.Then the eplerenone tablet is reduced in the dissolve medium.Extract sample at the fixed time at interval to measure dissolution velocity.Careful operation is to prevent forming bubble in tablet surface.By UV absorption measurement method at the 243nm analyzing samples.(proofreaied and correct volume and according to concentration-time curve with the surface area normalized (0.5cm of solution tablet
2)) the slope of straight line portion calculate intrinsic dissolution velocity.
Accompanying drawing 91 has been reported the intrinsic dissolution velocity of these 4 kinds of samples of being measured.These experiments show that the intrinsic dissolution velocity of eplerenone crystalline form H is faster than eplerenone crystalline form L.Relatively compression is measured with the XRPD that does not compress eplerenone and has been confirmed that polymorph does not transform mutually under contractive condition or during dissolution experiment.
Embodiment 17: eplerenone polymorph compositions
Preparation has the tablet of forming shown in the table 9 that contains 25mg, 50mg, 100mg and 200mg dosage eplerenone crystalline form L.
The composition of table 9: embodiment 17 tablets
| Component | % weight |
| Eplerenone crystalline form L | 29.41 |
| Eplerenone crystalline form H | Do not detect |
| Lactose monohydrate, NF (#310) | 42.00 |
| Microcrystalline Cellulose, NF (Avicel TMPH-101) | 18.09 |
| Cross-linking sodium carboxymethyl cellulose, NF (Ac-Di-Sol TM) | 5.00 |
| HPMC，USP(#2910，Pharmacoat TM 603) | 3.00 |
| Sodium lauryl sulphate, NF | 1.00 |
| Pulvis Talci, USP | 1.00 |
| Magnesium stearate, NF | 0.5 |
| Altogether | 100.00 |
Embodiment 18: eplerenone polymorph compositions
Preparation contain 100mg dosage eplerenone and have shown in the table 10 capsule formed (hard gelatin capsule, #0)
The capsular composition of the 100mg of table 10: embodiment 18
| Component | Content (mg) |
| Eplerenone crystalline form L | 90.0 |
| Eplerenone crystalline form H | 10.0 |
| Lactose hydrous, NF | 231.4 |
| Microcrystalline Cellulose, NF | 45.4 |
| Pulvis Talci, USP | 10.0 |
| Cross-linking sodium carboxymethyl cellulose, NF | 8.0 |
| Sodium lauryl sulphate, NF | 2.0 |
| Colloidal silica, NF | 2.0 |
| Magnesium stearate, NF | 1.2 |
| The total filling weight of capsule | 400.0 |
Embodiment 19: eplerenone polymorph compositions
Preparation contains 200mg dosage eplerenone and has the capsule of forming shown in the table 11 (hard gelatin capsule, big or small #0).
The capsular composition of the 200mg of table 11: embodiment 19
| Composition | Content (mg) |
| Eplerenone crystalline form L | 190.0 |
| Eplerenone crystalline form H | 10.0 |
| Lactose hydrous, NF | 147.8 |
| Microcrystalline Cellulose, NF | 29.0 |
| Pulvis Talci, USP | 10.0 |
| Cross-linking sodium carboxymethyl cellulose, NF | 8.0 |
| Sodium lauryl sulphate, NF | 2.0 |
| Colloidal silica, NF | 2.0 |
| Magnesium stearate, NF | 1.2 |
| The total filling weight of capsule | 400.0 |
Embodiment 20: the preparation of eplerenone fine powder
At first, exsiccant eplerenone butanone compound is sieved so that it deblocks via 20 eye mesh screens on the Fitz mill.Then, under cooled with liquid nitrogen, use Alpine Hosakawa post bolt disk pin type to grind (stud disk pin mill) crushing operation with about 250kg/ hour charging rate the solid that deblocks is carried out the pin type grinding.The D of the eplerenone after pin type is ground
90Particle diameter is about 65-100 μ m.
Embodiment 21: the eplerenone particle diameter is to the influence of pharmacokinetic parameter in the Canis familiaris L. experiment
In dog model, studied of the influence of the particle diameter of eplerenone crystalline form L to eplerenone plasma concentration and relative bioavailability.One of female Sexual health screech owl short-leg beagle (beagle dogs) intragastric administration of four body weight 8-12kg is contained the quick-release capsules (#0, White-opalescent) of following table 12 described prescriptions, about then 10ml water.
The capsular composition of table 12: embodiment 21 used eplerenones
| Composition | Percentage by weight | Content (Mg) |
| Eplerenone crystalline form L | 50.00 | 200.00 |
| Lactose hydrous (Fast-Flo) | 36.95 | 147.80 |
| Microcrystalline Cellulose (Avicel TMPH-102) | 7.25 | 29.00 |
| Sodium lauryl sulphate | 0.50 | 2.00 |
| Cross-linking sodium carboxymethyl cellulose | 2.00 | 8.00 |
| Pulvis Talci | 2.50 | 10.00 |
| Colloidal silica | 0.50 | 2.00 |
| Magnesium stearate | 0.30 | 1.20 |
| Total amount | 100.00 | 400.00 |
Before giving Drug Capsule, allow Canis familiaris L. fasting 15-20 hour, allow the Canis familiaris L. feed at least after 4 hours again in administration then.In administration 0,0.5,1,2,3, collect blood sample (about 3 milliliters) by venipuncture respectively after 4,6,8 and 24 hours and place the cryovial that contains heparin.Immediately blood sample is placed on ice.After centrifugal about 15 minutes, finish separated plasma from blood sample.The plasma sample that obtains is freezing and store until analysis under-20 ℃ of temperature approximately.Using the LC/MS/MS method analyzes.
Use three kinds of preparations of this four Canis familiaris L. tests, every kind of preparation has shown in the table 12 to be formed, but has different eplerenone particle diameters.The D of eplerenone raw material
90Particle diameter is respectively about 212 μ m, about 86 μ m and about 36 μ m.Be that 5 days minimum is cleaned the phase blanking time of twice successive administration.Its average result is shown in following table 13 and 14.Calculate relative bioavailability from AUC result, select D
90The preparation that is 86 μ m is as standard.
Table 13: serum eplerenone concentration (μ g/ml), embodiment 21
| Time (hour) | D 90212μm | D 9086μm | ?D 9036μm |
| 0 | 0 | 0 | ?0 |
| 0.5 | 1.83 | 3.65 | ?1.99 |
| 1 | 2.40 | 6.18 | ?5.86 |
| 2 | 3.77 | 6.89 | ?6.77 |
| 3 | 2.85 | 5.70 | ?6.60 |
| 4 | 2.61 | 4.39 | ?5.56 |
| 6 | 1.63 | 3.11 | ?3.31 |
| 8 | 1.10 | 1.90 | ?2.09 |
| 24 | 0.0252 | 0.032 | ?0.0706 |
Table 14: pharmacokinetics (PK) parameter that from embodiment 21 data, calculates
| The PK parameter | D 90212μm | D 9086μm | ?D 9036μm |
| C max(μg/ml) | 3.98 | 7.02 | 7.39 |
| T max(hour) | 1.50 | 1.75 | 2.25 |
| AUC((μg/ml)hr) | 26.6 | 49.2 | 53.1 |
| Relative bioavailability (%) | 53.25 | 100 | 107.9 |
Embodiment 22: the eplerenone particle diameter is to the influence of pharmacokinetic parameters in human experimentation
In human model, studied of the influence of the particle diameter of eplerenone crystalline form L to eplerenone plasma concentration and relative bioavailability.Three kinds of used pharmaceutical compositions are as shown in table 15 below.Allowed the eplerenone crystalline form L compositions of the medicament forms that the experimenter takes single 100 milligrams of dosage at the 1st, 8,15,22 and 29 day according to random fashion.Take medicine at every turn and all took 180 ml waters at 0800 hour.-0.5 (before the administration) after administration, 0.5,1,2,3,4,6,8,10,12,16,24,36 and 48 hour blood sample collection are used for the eplerenone pharmacokinetic analysis.
Use effective HPLC method, adopt MS/MS to detect the plasma concentration of determining eplerenone.Its pharmacokinetic data available is shown in table 16.Use to swash and be scattered in the particle size distribution that dry powder is determined at the eplerenone crystalline form L that uses in the preparation of compositions earlier.
Table 15: embodiment 22 used eplerenone compositionss (weight %)
| Component | Capsules A | Tablet A | Capsule B |
| Eplerenone crystalline form L (D 9040μm) (D 9082μm) (D 9096μm) | ? 25 -- -- | ? -- 30 -- | ? -- -- 25 |
| Lactose monohydrate | -- | 42 | 57.86 |
| Lactose hydrous | 57.8 | -- | -- |
| Microcrystalline Cellulose (Avicel TMPH-101) (Avicel TMPH-102) | ? 11.4 -- | ? 17.5 1 -- | ? -- 11.34 |
| Cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol TM) | 2 | 5 | 2 |
| HPMC(Pharmacoat TM 603) | -- | 3 | -- |
| Sodium lauryl sulphate | 0.5 | 1 | 0.5 |
| Pulvis Talci | 2.5 | 1 | 2.5 |
| Magnesium stearate | 0.3 | 0.5 | 0.3 |
| Colloidal silica | 0.5 | -- | 0.5 |
| | 100 | 100 | 100 |
1In 7.5% granule, outside 10% granule
Table 16: pharmacokinetics (PK) parameter that goes out from embodiment 22 data computation
| The PK parameter | 100mg capsules A (D 9040μm) | 100mg tablet A (D 9082μm) | 100mg capsule B (D 9096μm) |
| C max(ng/ml) | 1747 | 1704 | 1669 |
| T max(hour) | 1.8 | 1.8 | 1.3 |
| AUC((ng/ml)hr) | 11349 | 11945 | 11981 |
Although the present invention is described by specific embodiments, the details of these schemes can not be interpreted as limitation of the present invention.
Claims (85)
1. the eplerenone that comprises form H crystal eplerenone, wherein, described eplerenone has the phase purity of 90%-100% form H crystal eplerenone, wherein, described form H crystal eplerenone has the peak that rhombic system and its X-ray powder diffraction pattern are included in 7.0 ± 0.2 ° and 12.0 ± 0.2 ° 2 θ.
2. the eplerenone of claim 1, wherein, the X-ray powder diffraction pattern of described form H crystal eplerenone also is included in the peak of 8.3 ± 0.2 ° of 2 θ.
3. the eplerenone of claim 1, wherein, the X-ray powder diffraction pattern of described form H crystal eplerenone basically as shown in fig. 1.
4. the eplerenone of claim 1, wherein, the melting range of described form H crystal eplerenone is 247-251 ℃.
5. the eplerenone of claim 1, wherein, the IR of described form H crystal eplerenone spectrum is included in 1739cm
-1The peak.
6. the eplerenone of claim 1, wherein, the IR of described form H crystal eplerenone spectrum is included in 1399cm
-1The peak.
7. the eplerenone of claim 1, wherein, the IR of described form H crystal eplerenone spectrum is included in 1724cm
-1The peak.
8. the eplerenone of claim 1, wherein, the IR of described form H crystal eplerenone composes basically as shown in Figure 35.
9. the eplerenone of claim 1, wherein, described form H crystal eplerenone
13C NMR spectrum is included in the carbon resonance of 24.7ppm.
10. the eplerenone of claim 1, wherein, described form H crystal eplerenone
13The CNMR spectrum is included in the carbon resonance of 24.7ppm and 64.8ppm.
11. being 247-251 ℃ and IR spectrum, the eplerenone of claim 1, the melting range of described form H crystal eplerenone be included in 1739cm
-1The peak.
12. being 247-251 ℃ and IR spectrum, the eplerenone of claim 1, the melting range of described form H crystal eplerenone be included in 1399cm
-1And 1739cm
-1The peak.
13. being 247-251 ℃ and IR spectrum, the eplerenone of claim 1, the melting range of described form H crystal eplerenone be included in 1399cm
-1And 1739cm
-1The peak, and comprise the carbon resonance that is included in 24.7ppm
13C NMR spectrum.
14. the eplerenone of claim 1, described form H crystal eplerenone has P2
12
12
1Space group.
15. the eplerenone of claim 1, a of the unit structure cell of described form H crystal eplerenone, the value of b and c is respectively 21.22 , 14.50 and 6.33 .
16. the eplerenone of claim 1, the α of the unit structure cell of described form H crystal eplerenone, the value of β and γ respectively is 90 °.
17. the eplerenone of claim 1, wherein said eplerenone are the described form H crystal eplerenones of mutually pure form basically.
18. the eplerenone of claim 1, the phase purity of wherein said eplerenone are at least 95% form H crystal eplerenone.
19. any one eplerenone of claim 1-18 also comprises crystal form L crystal eplerenone, wherein, described crystal form L crystal eplerenone has monoclinic system.
20. any one eplerenone of claim 1-19 also comprises the crystal form eplerenone of solvation.
21. the eplerenone of claim 20, the crystal form eplerenone of wherein said solvation are selected from the crystal butanone compound of eplerenone, crystal 2-pentanone compound, crystal acetic acid compound, crystal acetone compound, crystal butyl acetate compound, crystal chloroform compound, crystal ethanol compound, crystal isobutanol compound, crystal isobutyl acetate compound, crystal methyl acetate compound, crystal ethyl propionate compound, crystal n-butyl alcohol compound, crystal n-octyl alcohol compound, crystal normal propyl alcohol compound, crystal isopropyl alcohol compound, crystal propyl acetate compound, crystal propylene glycol compound, crystal tert-butyl alcohol compound, crystal oxolane compound, crystal toluene compound and crystal tert-butyl acetate compound.
22. the eplerenone of claim 21, the crystal form eplerenone of wherein said solvation are the crystal butanone compounds of eplerenone.
23. any one eplerenone of claim 1-22 also comprises unformed eplerenone.
24. any one eplerenone of claim 1-23, its form is a granule, this particulate D
90Particle size is less than 400 μ m.
25. the eplerenone of claim 24, its form are granule, this particulate D
90Particle size is less than 200 μ m.
26. the eplerenone of claim 24, its form are granule, this particulate D
90Particle size is less than 150 μ m.
27. the eplerenone of claim 24, its form are granule, this particulate D
90Particle size is less than 100 μ m.
28. any one eplerenone of claim 1-23, its form is a granule, this particulate D
90Particle size is 25-400 μ m.
29. the eplerenone of claim 28, its form are granule, this particulate D
90Particle size is 25-200 μ m.
30. the eplerenone of claim 28, its form are granule, this particulate D
90Particle size is 25-150 μ m.
31. the eplerenone of claim 28, its form are granule, this particulate D
90Particle size is 25-100 μ m.
32. the eplerenone of claim 28, its form are granule, this particulate D
90Particle size is 30-50 μ m.
33. any one eplerenone of claim 1-23, its form is a granule, this particulate D
90Particle size is 50-150 μ m.
34. the eplerenone of claim 33, its form are granule, this particulate D
90Particle size is 75-125 μ m.
35. the eplerenone of claim 34, its form are granule, this particulate D
90Particle size is 40-100 μ m.
36. any one eplerenone of claim 1-23, its form is a granule, and this particulate Dx particle size is less than 15 μ m.
37. the eplerenone of claim 36, its form are granule, this particulate D
90Particle size is less than 10 μ m.
38. the eplerenone of claim 36, its form are granule, this particulate D
90Particle size is less than 1 μ m.
39. any one eplerenone of claim 1-38 also contains one or more form H crystal growth promoters.
40. any one eplerenone of claim 1-38 also contains on one or more crystallography basically the chemical compound with described eplerenone crystalline form H isomorphism.
41. any one eplerenone of claim 1-38 also contains one or more and is selected from (a) 4 α, 5 α; 9 α, 11 α-diepoxy-17-hydroxyl-3-oxo-17 alpha-pregnane-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, gamma lactone; (b) 11 α, 12 alpha-epoxy-17s-hydroxyl-3-oxo-17 α-pregnant-4-alkene-7 (α, 21-dioctyl phthalate hydrogen 7-methyl ester, gamma lactone; (c) 17-hydroxyl-3-oxo-17 α-pregnant-4,9 (11)-diene-7 α, 21-dioctyl phthalate hydrogen 7-methyl ester, the chemical compound of gamma lactone.
42. the eplerenone of claim 41, wherein said eplerenone comprise one or more described chemical compounds of at least 0.5 weight %.
43. the eplerenone of claim 42, wherein said eplerenone comprise one or more described chemical compounds of at least 1 weight %.
44. the eplerenone of claim 42, wherein said eplerenone comprise one or more described chemical compounds of at least 2 weight %.
45. pharmaceutical composition comprises any one crystal form and at least a pharmaceutically acceptable carrier, auxiliary agent or the diluent of claim 1-44 for the treatment of effective dose.
46. the pharmaceutical composition of claim 45 comprises the eplerenone that 10-1000mg measures.
47. the pharmaceutical composition of claim 46, wherein said amount are 25-200mg.
48. the compositions of claim 46 or 47, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 400 μ m.
49. the compositions of claim 48, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 200 μ m.
50. the compositions of claim 48, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 150 μ m.
51. the compositions of claim 48, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 100 μ m.
52. the compositions of claim 46 or 47, wherein said eplerenone form is a granule, this particulate D
90Particle size is 25-400 μ m.
53. the compositions of claim 52, wherein said eplerenone form is a granule, this particulate D
90Particle size is 25-200 μ m.
54. the compositions of claim 52, wherein said eplerenone form is a granule, this particulate D
90Particle size is 25-150 μ m.
55. the compositions of claim 52, wherein said eplerenone form is a granule, this particulate D
90Particle size is 25-100 μ m.
56. the compositions of claim 52, wherein said eplerenone form is a granule, this particulate D
90Particle size is 30-50 μ m.
57. the compositions of claim 52, wherein said eplerenone form is a granule, this particulate D
90Particle size is 50-150 μ m.
58. the compositions of claim 52, wherein said eplerenone form is a granule, this particulate D
90Particle size is 75-125 μ m.
59. the compositions of claim 46 or 47, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 15 μ m.
60. the compositions of claim 59, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 10 μ m.
61. the compositions of claim 59, wherein said eplerenone form is a granule, this particulate D
90Particle size is less than 1 μ m.
62. the compositions of claim 46 or 47 preparation be used for the treatment of or the medicine of the disease of prophylaxis of aldosterone-mediated or disease in purposes.
63. the purposes of claim 62, wherein said disease or disease are selected from, and hypertension, heart failure, liver cirrhosis, collagen are excessive, fibre modification, benign prostatauxe and depression.
64. the purposes of claim 62, wherein said disease or disease are hypertension.
65. the purposes of claim 62, wherein said disease or disease are heart failure.
66. according to any one eplerenone crystalline form of claim 1-44, it substantially as described herein.
67. according to any one eplerenone or eplerenone crystalline form of claim 1-44, its with reference to embodiment 1-14 and/or Fig. 1-91 any one substantially as described herein.
68. eplerenone or eplerenone crystalline form, its with reference to embodiment 1-14 and/or Fig. 1-91 any one substantially as described herein.
69. according to any one pharmaceutical composition of claim 45-61, it substantially as described herein.
70. according to any one pharmaceutical composition of claim 45-61, its with reference to embodiment 1-20 and/or Fig. 1-91 any one substantially as described herein.
71. pharmaceutical composition, its with reference to embodiment 1-20 and/or Fig. 1-91 any one substantially as described herein.
72. according to any one purposes of claim 62-65, it substantially as described herein.
73. according to any one purposes of claim 62-65, its with reference to embodiment 1-22 and/or Fig. 1-91 any one substantially as described herein.
74. prepare the method for crystal eplerenone, this method is included in high boiling solvent or contains the solution that the eplerenone initiation material is provided in the solvent mixture of high boiling solvent; With the direct crystal form of crystallization eplerenone from described solution, this crystal form has rhombic system and its X-ray powder diffraction pattern has the peak at 7.0 ± 0.2 ° of 2 θ and 12.0 ± 0.2 ° of 2 θ, and wherein said crystallisation step is to carry out under the temperature of the change transition temperature that is higher than described crystal form.
75. the method for claim 74, wherein before the crystallisation step or during in solvent or solvent mixture, add the crystal seed of eplerenone crystal form.
76. the method for claim 74 or 75 also is included in the D that crystallizes into less than about 400 μ m
90Grind the step of eplerenone after the particle size.
77. prepare the method for crystal eplerenone, this method comprises that (a) is at the solvent that can form eplerenone solvation crystal form or contain the eplerenone initiation material of the molten low-purity that disappears in the mixture of this kind solvent; (b) from this solvent or mixture the crystallization eplerenone to form the step of solvate; (c) this solvate desolvation had rhombic system and its X-ray powder diffraction pattern have the peak at 8.3 ± 0.2 ° of 2 θ and 12.0 ± 0.2 ° of 2 θ eplerenone crystal form to provide.
78. the method for claim 77, wherein said solvent are selected from butanone, 1-propanol, 2 pentanone, acetic acid, acetone, butyl acetate, chloroform, ethanol, isobutanol, isobutyl acetate, methyl acetate, ethyl propionate, n-butyl alcohol, n-octyl alcohol, isopropyl alcohol, propyl acetate, propylene glycol, the tert-butyl alcohol, oxolane, toluene, methanol and tert-butyl acetate.
79. the method for claim 78, wherein said solvent is selected from butanone and ethanol.
80. any one method of claim 77-79, also being included in desolvates changes into D less than about 400 μ m
90Grind the step of eplerenone before or after the particle size.
81. prepare the method for crystal eplerenone, this method comprises that (a) is at the solvent that can form eplerenone solvation crystal form or contain the molten eplerenone initiation material that disappears in the mixture of this kind solvent; (b) from this solvent or mixture the crystallization eplerenone to form the step of solvate; (c) this solvate desolvation is had rhombic system and its X-ray powder diffraction pattern and at 7.0 ± 0.2 ° of 2 θ and 12.0 ± 0.2 ° of 2 θ the eplerenone crystal form at peak is arranged to provide, wherein before the crystallisation step or during in solvent or solvent mixture, add the crystal seed of the described crystal form of eplerenone.
82. according to any one method of claim 74-81, it substantially as described herein.
83. according to any one method of claim 74-81, its with reference to embodiment 1-14 and/or Fig. 1-91 any one substantially as described herein.
84. prepare the method for eplerenone crystalline form, its with reference to embodiment 1-14 and/or Fig. 1-91 any one substantially as described herein.
85. according to any one the eplerenone crystalline form of method preparation of claim 74-84.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16968299P | 1999-12-08 | 1999-12-08 | |
| US60/169807 | 1999-12-08 | ||
| US60/169556 | 1999-12-08 | ||
| US60/169608 | 1999-12-08 | ||
| US60/169690 | 1999-12-08 | ||
| US60/169639 | 1999-12-08 | ||
| US60/169682 | 1999-12-08 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004100368081A Division CN1557833A (en) | 1999-12-08 | 2000-12-04 | Eplerenone crystalline form exhibiting enhanced dissolution rate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1891209A true CN1891209A (en) | 2007-01-10 |
Family
ID=37596574
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610101365 Pending CN1891209A (en) | 1999-12-08 | 2000-12-04 | Eplerenone crystalline form exhibiting enhanced dissolution rate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1891209A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844681A (en) * | 2014-02-13 | 2015-08-19 | 合肥久诺医药科技有限公司 | L-crystal form eplerenone refining method |
-
2000
- 2000-12-04 CN CN 200610101365 patent/CN1891209A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104844681A (en) * | 2014-02-13 | 2015-08-19 | 合肥久诺医药科技有限公司 | L-crystal form eplerenone refining method |
| CN104844681B (en) * | 2014-02-13 | 2016-06-01 | 合肥久诺医药科技有限公司 | The process for purification of the brilliant type eplerenone of a kind of L |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1275962C (en) | Novel anticholinergic agents that can be used as medicaments and method for the production thereof | |
| CN1022184C (en) | Process for preparing (1 H-imidzol-1-ylmethyl) substituted benzotriazole derivatives | |
| CN1146567C (en) | Olanzapine dihydrate D | |
| CN101035759A (en) | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms | |
| CN1291986C (en) | Anticholinergics, processes for the preparation thereof, and pharmaceutical compositions | |
| CN1152886C (en) | Eplerenone crystalline form exhibiting enhanced dissolution rate | |
| CN1076124A (en) | A kind of method that is used to prepare the enteric coating oral medicine that contains sour unstable compound | |
| CN1890220A (en) | A crystalline of the salt form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same | |
| CN1463191A (en) | Low hygroscopic aripiprazole drug substance and process for the preparation thereof | |
| CN1675177A (en) | Modafinil polymorphic forms | |
| CN101066264A (en) | Solid olmesartan medoxmil dispersion and its prepn and medicinal application | |
| CN1085223A (en) | The 17-beta substitution-4-azepine-5 α-androstane-3-one derivative | |
| CN1080639A (en) | The inhibitor of 5-α-testosterone reductase | |
| CN1039228C (en) | Novel substituted tert-amino compund | |
| CN1045583A (en) | Tetrahydrobenzimidazderivative derivative | |
| CN1221738A (en) | Chinolinelone derivative, its prepn. method and antiabnormal reaction agent | |
| CN1745065A (en) | 4-oxo-3-(1-oxo-1h-isoquinolin-2-ylacetylamino)-pentanoic acid ester and amide derivatives and their use as aspartic specifity cysteine proteinase inhibitors | |
| CN101052631A (en) | Crystalline mycophenolate sodium | |
| CN1433427A (en) | Eplerenone crystalline form | |
| CN1162153C (en) | Benzothiophenes, formulations containing same, and methods | |
| CN101068916A (en) | Use of atazanavir for improving the pharmacokinetics of drugs metabolized by UGT1A1 | |
| CN1272842A (en) | 2-acylaminopropanamines as tachykinin receptor antagonists | |
| CN1145617A (en) | Indole derivative and medicine containing the same | |
| CN1665504A (en) | Novel crystalline forms of gatifloxacin | |
| CN1891209A (en) | Eplerenone crystalline form exhibiting enhanced dissolution rate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20070110 |