TWI290558B - Eplerenone crystalline form exhibiting enhanced dissolution rate - Google Patents

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

1290558 A7 B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (Field of the Invention The present invention pertains to the field of active agents as aldosterone receptor antagonists, in particular to the aldosterone receptor antagonist drug ipproxone. In particular, the present invention:: novel crystallization of ipproxone Type, a method for preparing such a crystalline form, comprising a pharmaceutical composition of such a crystalline form, and the use of such a crystalline form for the treatment and/or prevention of aldosterone J conditions and/or conditions, including blood aldosterone hyperactivity associated with conditions and conditions such as Method for the treatment of hypertension, and the use of such a crystalline form for the manufacture of a medicament. BACKGROUND OF THE INVENTION The formula (I) is referred to as a compound of ipproxone methyl hydrogen 9, u_epoxy-pregnant _4_women- No. 4,559,332 to Grob et al., which discloses a class of 9,η·epoxysteroid compounds and salts thereof. Eptoprofen is an aldosterone receptor. The antagonist can be administered in a therapeutically effective amount to an indication suitable for an aldosterone receptor antagonist, such as a pathological condition for the treatment of hypercortisone in the blood such as hypertension 'heart failure including heart failure and cirrhosis.

The paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm). 1290558 A7 B7____ V. Illustrated (2) U.S. Patent No. 4,559,332, the disclosure of which is incorporated herein by reference in its entirety Preparation and preparation of a pharmaceutical composition comprising ipproxone. Other methods for the production of 9,11-epoxy steroid compounds and their salts, including edulis, are disclosed in International Patent Publication No. WO 97/21720 and WO 98/25948.

Grob et al. (1997), "Steroid aldosterone antagonists: selectivity improvement of 9α, 11-epoxy derivatives" Helvetica Chimica Acta,, 80, 566-5 85, reveals the X-ray crystal structure of aldosterone solvates Analysis of the solvate was prepared by crystallizing ippromone from a dichloromethane/ether solvent system.

De Gasparo et al. (1989), "Anti-aldosterones: the occurrence and prevention of sexual side effects", Journal of Steroid Biochemistry, 32(13), 223-227, revealed in a single dose study of ipproxone with 20 micron Unadapted ipproxone of particle size. A spironoxane-steroid having a aldosterone receptor antagonist activity is commercially available for the treatment of high blood pressure. However, spironolactone has anti-androgenic activity leading to male breast disease and male impotence. It also has weak progesterone activity and may cause irregular menstruation in women. It is therefore highly desirable to develop other active aldosterone receptor antagonists such as eplerenone that do not interact with other steroid receptor systems such as the glucose corticosteroid, progestin and androgen sterol receptor systems and/or may provide more A wide range of treatments. 67790-950421.DOC - 9 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1290558 A7 B7 V. Description of invention (3)

(Π)

Agaf〇nov et al. (1991), "Polymorphic changes in spironolactone", Medicine, 80(2), 181-185, discloses a sulphuric acid acetonitrile solvate, an ethanol solvate, an ethyl acetate solvate, Methanol solvate and two non-solvent polymorphic crystalline forms. Brittan (1999), Pharmaceutical Solids 114-116, 207, 235 and 261 (Marcel Dekker) also reveal the solid form of these spironolactones. The low solubility of ipproxone in aqueous media and the release of drugs from the oral tract in the stomach and intestines are often limiting factors in the bioavailability of the drug, particularly regarding the rate at which the therapeutic effect begins after administration. SUMMARY OF THE INVENTION A novel yptophenone crystalline form is provided today having a relatively fast dissolution rate in an aqueous medium and a unique property compared to other solid forms of ippromone. This type of crystallization is fully characterized in the following text but is conveniently referred to as "Η". In a first feature aspect, the present invention provides such a novel lycopene crystalline oxime itself. The difference between the type of Η and another type of crystal called "L type" 67790-950421.DOC - 1 0 - This paper scale applies to China National Standard (CNS) Α 4 specification (210 X 297 mm) 1290558 A7 B7 V. In the description of the invention (4), the Η type exhibits an orthorhombic system, and the diffractive powder diffraction pattern has a peak at 12 〇 ± 〇 · 2 degrees 20 and a melting point at about 247 t to about 25 Γ (: 2 range. In one aspect, the present invention provides an ipproxone drug comprising at least detectable amount of sputum-type ipproxone. In a third aspect, the present invention provides an ipproxone which is substantially pure phase, type yule Ketone. The term "pure phase" is used herein to mean the purity relative to other solid Ep4, but does not imply a chemical purity relative to other compounds. In the fourth feature, the present invention provides a solvent for ipproxone. In combination with a crystalline form, it can be obtained by removing the solvent. In the fifth special financial aspect, the present invention provides a pharmaceutical composition comprising an indole-type edetrein, optionally accompanied by one or more other solid forms. Promethone, the total unit dose of Pule _ is about gamma, And further comprising one or more pharmaceutically acceptable excipients. In the sixth aspect, the invention provides a method for preparing a composition of Η-type ipproxone by the method of Η-type apex. The present invention provides a preventive and/or therapeutic acid-solid _ from a disease or a disease (the 10,000 method comprises administering to the individual a therapeutically effective amount of two (three) _ ' wherein at least the sputum is present in the sputum type Epile-b BRIEF DESCRIPTION OF THE DRAWINGS The features of the present invention are discussed in the full text of the present specification. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a diffractive powder diffraction pattern of Η-type ipproxone. Figure 2 shows a diffractive powder diffraction pattern of type l ipproxone. -11 -

67790-950421.DOC 97 mm) The paper size is applicable to the standard (CNS) Α4 specification (210χ2_ 1290558 A7 B7 5. Inventive Note (5) Figure 3 shows the X-ray powder winding of the isobutyrone solvate of ipproxone Figure 4 shows the X-ray diffraction pattern of the n-propanol solvate of ipproxone. Figure 5 shows the X-ray diffraction pattern of the tetrahydrofuran solvate of ipproxone. Figure 6 shows the eppyrone X-ray diffraction pattern of ethyl propionate solvate. Figure 7 shows the X-ray diffraction pattern of the acetic acid solvate of ipproxone. Figure 8 shows the X-ray diffraction of the acetone solvate of ipproxone. Fig. 9 shows the X-ray diffraction pattern of the toluene solvate of ippronone. Figure 10 shows the X-ray diffraction pattern of the isopropyl alcohol solvate of ipproxone. X-ray diffraction pattern of ethanol solvate of ketone. Figure 1 2 shows the X-ray diffraction pattern of isobutyl acetate solvate of ipproleone. Figure 13 shows n-butyl acetate of ipproxone The X-ray diffraction pattern of the solvate. Figure 14 shows the X-ray diffraction pattern of the methyl acetate solvate of ipproxone. Figure 15 shows the direct diffraction from isobutyrone. Differential scanning calorimetry (DSC) thermogram of crystallized unmilled L-type ipprox. Figure 16 is prepared by solvent removal from a solvate obtained by crystallizing high purity ipproxone from isobutyl ketone. The DSC thermogram of the milled L-type ipproxone. Figure 17 shows the DSC heat of the L-type eplerenone obtained by grinding the desolvation product of the solvate obtained from the isobutyl ketone crystal high purity ipproxone. Figure 18. Figure 18 is a DSC thermogram of unmilled anthraquinone prepared by desolvation of a solvate obtained by digesting low-purity ipproxone in a suitable solvent. 67790-950421.DOC - 1 2 - Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1290558 A7 B7 V. Description of the invention (6) Figure 19 shows the DSC thermogram of the n-propanol solvate of ipproxone. 0 shows the DSC thermogram of the tetrahydrofuran solvate of ipproxone. Figure 2 1 shows the DSC thermogram of the ethyl propionate solvate of ipproxone. Figure 22 shows the acetic acid solvent of ipproxone. DSC thermogram of the material. Figure 23 shows the DSC thermogram of the chloroform solvate of ipproxone. DSC thermogram of acetone solvate. Figure 25 shows the DSC thermogram of the toluene solvate of ipproxone. Figure 26 shows the DSC thermogram of the isopropanol solvate of ipproxone. 27 shows the DSC thermogram of the ethanol solvate of ipproxone. Figure 28 shows the DSC thermogram of the third butyl acetate solvate of ipproxone. Figure 2 shows the acetic acid of ipproxone. DSC thermogram of butyl acrylate solvate. Figure 30 shows the DSC thermogram of the n-butyl acetate solvate of ipproxone. Figure 31 shows the DSC thermogram of the methyl acetate solvate of ipproxone. Figure 32 shows a DSC thermogram of propyl acetate solvate of ipproxone. Figure 33 shows a DSC thermogram of n-butanol solvate of ipproxone. Figure 34 shows the DSC thermogram of the n-octanol solvate of ipproxone. Figure 35 shows the infrared (IR) spectrum (DRIFT) of Η-type ipproxone. Figure 36 shows the IR spectrum (DRIFT) of L-type eplerenone. Figure 37 shows the IR spectrum (DRIFT) of the isobutyrone solvate of ippromone. Figure 3 shows the IR spectrum (DRIFT) of ippromone in chloroform solution. 67790-950421.DOC - 1 3 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1290558 A7 B7 V. Description of invention (7) Figure 3 9 shows n-propanol IR spectrum of the solvate. Figure 40 shows the IR spectrum of the tetrahydrofuran solvate of ipproxone. Figure 41 shows the IR spectrum of the propionate ethyl propionate solvate. Figure 4 2 shows the IR spectrum of the acetone solvate of ipproxone. Figure 43 shows the IR spectrum of the toluene solvate of ipproxone. Figure 44 shows the IR spectrum of isopropanol solvate of ipproxone. Figure 45 shows the IR spectrum of the ethanol solvate of ipproxone. Figure 46 shows the IR spectrum of isobutyl acetate solvate of ipproxone. Figure 47 shows the IR spectrum of the n-butyl acetate solvate of ipproxone. Figure 48 shows the IR spectrum of propyl acetate solvate of ipproxone. Figure 49 shows the IR spectrum of the methyl acetate solvate of ipproxone. Figure 50 shows the IR spectrum of propylene glycol solvate of ippromone. Figure 51 shows the IR spectrum of the third butyl acetate solvate of ipproxone. Figure 52 shows the 13C NMR spectrum of Η-type ipproxone. Figure 53 shows the nC NMR spectrum of L-type eplerenone. Figure 54 shows a thermogravimetric analysis of the methyl ethyl kecohe solvate of ippromone. Figure 5 5 shows the thermogravimetric analysis side of the n-propanol solvate of ipproxone. Figure 5 6 shows the thermogravimetric analysis of the tetrahydrofuran solvate of ippromone. Figure 5 7 shows the thermogravimetric analysis of the side of the propionate ethyl propionate solvate. Figure 5 8 shows the thermogravimetric analysis side of the acetonitrile acetate solvate side 67790-950421.DOC - 1 4 _ This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) A7 B7 1290558 V. Description of invention (8) Drawing. Figure 59 shows a thermogravimetric analysis of the chloroform solvate of ipproxone. Figure 60 shows the thermogravimetric analysis side of the acetone solvate of ipproxone. Figure 61 shows the thermogravimetric analysis side of the toluene solvate of ipproxone. Figure 6 2 shows a thermogravimetric analysis of the isopropanol solvate of ipproxone. Figure 63 shows a thermogravimetric analysis of the ethanol solvate of ipproxone. Figure 6 4 shows the thermogravimetric analysis of the isobutyl acetate solvate of ippromone. Figure 6 5 shows the thermogravimetric analysis side edges of the n-butyl acetate solvate of ipproxone. Figure 6 6 shows the thermogravimetric analysis of the methyl acetate solvate of ipproxone. Figure 6 7 shows the thermogravimetric analysis of the propyl acetate solvate of ipproxone. Figure 6 shows a thermogravimetric analysis of the propylene glycol solvate of ipproxone. Figure 6 shows the thermogravimetric analysis of the n-butanol solvate of ipproxone. Side view 0 Figure 7 shows the thermogravimetric analysis of the n-octanol solvate of ipproxone side 67790-950421.DOC - 1 5 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public)! 29〇558

!meeting. Figure 7 1 shows Ai Shan you, analysis side painting. * "Ethylene glycerol solvate 纟 纟 重 图 72 72 72 72 72 72 72 72 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由 经由. Figure 7 is a photomicrograph of L-type ipprox prepared by crystallization of travertine-rhoine ethyl ester. Figure 74 shows that by the difference, the taste, the wealth, the early departure of <7-methylhydrogen 4 α,5 α ; 9 α,11 α ·di-oxyloxy_17α-pregnant·7α,21-dicarboxyl A crystalline powder diffraction pattern of a crystalline form of 7-lactone (mono-oxide). ^75显七^ Isolation of 7-methylhydrogen by isopropanol 110,12 core epoxy_1' obtained _ 3 ^oxy-17α-pregnant _4-埽_7α,21_dicarboxylate, r • X-ray powder diffraction pattern of the crystalline form of lactone ("u, i2_cyclopide"). Figure 76 shows 7-methylhydrogen 17-hydroxy-3-oxo-17 heart-negative-4'9(11)-one--7-7: n-butanol-isolated, n-butanoic acid, 7 ^ X-ray powder diffraction pattern of crystallized type ("9,11-hydrocarbon"). Figure 77 illustrates the relationship between Gibbs free energy and temperature for enantiomerically related polymorphic compounds. Figure 78 shows that 7F is obtained from (a) 〇〇/〇, (b) 1%, 3% and (4) 5% diepoxide oxime isobutyl ketone crystalline isobutyl ketone solvate wet cake X-ray powder diffraction pattern . Figure 79 shows an X-ray powder diffraction pattern of dry solids obtained from (4) 0%, (b) 1%, (c) 3% and (d) 5% diepoxide oxime isobutyl ketone crystals. Figure 80 shows crystallization from isobutyrone with 3% doped diepoxide, at -16-

67790.950421.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1290558 V. INSTRUCTIONS (10) Dry (a) without drying and (b) dry solid obtained by grinding solvate X-ray powder diffraction pattern. Figure 81 shows the isobutyrone solvate wet cake from (a) 0%, (b) 1%, (c) 5% and (d) 10% 11,12-epoxide-doped isobutyl ketone crystals. X-ray powder diffraction pattern. Figure 82 shows the dry solids obtained from (a) 0%, (b) 1%, (c) 5% and (d) 10% 11,12-epoxide-doped isobutyl ketone crystals of isobutyl ketone solvate. X-ray powder diffraction pattern. Figure 83 shows a cube plot of product purity, feedstock purity, cooling rate, and endpoint temperature based on the data reported in Table 7A of Example 7. Figure 84 shows a semi-standard plot prepared using the cube diagram of Figure 83, which determines which identification has a statistically significant effect on product purity. Figure 85 is an interactive line diagram based on the reported data in Table 7A of Example 7, showing the interaction of the purity of the starting material and the effect of the cooling rate on the purity of the final material. Figure 86 shows a cube plot of the weight fraction of the Η type, the purity of the starting material, the cooling rate, and the endpoint temperature based on the data reported in Table 7A of Example 7. Figure 87 shows a semi-standard plot prepared using the cube diagram of Figure 86, which determines which identification has a statistically significant effect on the ruthenium weight fraction. Figure 88 is an interactive line diagram based on the data reported in Table 7 of Example 7, showing the interaction of the purity of the starting material and the effect of the endpoint temperature on the weight fraction of the Η type. Figure 89 shows an X-ray diffraction pattern of amorphous ippronone. Figure 90 shows a DSC thermogram of amorphous ipproxone. 67790-950421.DOC -17- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) I290i Guan 25997 Patent Application Chinese Manual Replacement Page (July 96) Λ7,96. 7. 0 3

Figure 91 shows the dissolution rate measured for the four Aishan shuanglong ketone ketone polymorphic samples. DETAILED DESCRIPTION OF THE INVENTION As with all pharmaceutical compounds and compositions, the pharmacological properties of ipproxone are of considerable importance for their commercial development. These properties include but = ^ : . , (2m mechanical properties such as melting point, vapor pressure and solubility, (7) dynamic properties such as dissolution rate and stability (including the stability of the circumferential conditions, especially for moisture and storage conditions)' ( 4) surface properties such as surface area, wettability, surface tension and shape, (5) mechanical properties such as hardness, tensile strength, compressibility, handleability, flowability and kneadability; and (6) filtration properties. For example, affecting the processing and storage of pharmaceutical compositions comprising ipproxone. It is desirable to have a solid form of ipproxone which provides an improvement over one or more of these properties compared to other solid forms of ippromone. The solid form of ipproxone, especially including a plurality of solvomorphic crystal forms, at least two non-tantalum and non-hydrated crystalline forms (labeled as Η type and L type), and amorphous ipproxone. In other solid forms disclosed in the literature, various solid forms of ipproxone as described herein have one or more of the foregoing excellent chemical and/or physical properties. Η and L are The premises are referred to as "I type" and η II type, respectively, and are occasionally referred to as "high melting point polymorphic compounds" and "low melting polymorphic compounds". Plexone. The hydrazine type has a faster dissolution rate (about 30% faster) than, for example, L-type ipproxone at temperatures below the enantiomeric transition temperature (described in detail later). Dissolved in the gastrointestinal tract is Ep-18-

67790-960703.DOC This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 1290558 A7 p.----- B7 ____ V. Description of invention (12) Rate of delivery of ketone to target cells or tissues Deciding on the steps, faster dissolution usually results in improved bioavailability. Therefore, comparing L-forms provides an improved bioavailability profile. In addition, the selection of a solid form of eptrozone with a faster dissolution rate can also provide greater flexibility in surfactant selection for formulation and formulation in pharmaceutical compositions, particularly with respect to other forms having a slower dissolution rate. The form of ipprox release rate. L-type ipproxone also has advantages over other solid-state forms. In particular, having a higher physical stability at temperatures lower than the enantiomeric transition temperature (described in detail later) of the oxime type requires a solid form of eptrozone such as type l which requires no special handling or storage conditions and Avoid the need for frequent equipment investment replacement. For example, when selected for use in the manufacturing process (for example, in the process of grinding ipproxone to obtain a material having a smaller particle size and a larger surface area), selecting a solid-state form of ippronone which is stable in physical properties can avoid special processing conditions and The cost is increased due to special processing conditions. For the same reason, the solid-state form of ipproxone, which is selected for use in a wide range of storage conditions (especially considering the different storage conditions that may occur during the life of the product), helps to avoid the use of ipproxone. Polymorphism or other decomposition changes can result in poor product consumption or product efficiency. Therefore, the selection of a solid form of ippronone having a higher physical stability such as an L form can provide a more meaningful effect than the more unstable form of ippronone. The invention is also directed to a solvent crystalline form of ipproxone. These solvated forms can be used as intermediates in the preparation of quinone and L-type ipproxone; in the month of this month, the most interesting ones are those obtained when the solvent is removed, Η type 67790-950421. DOC -19- 1290558 A7 ------------B7 V. INSTRUCTIONS (13) ~--- The ketone ketone ketone ketone solvent crystal form. The special use of the solvent-based crystal form as an intermediate is to discuss the "essential micro-powder" of the crystal* when the solvent is removed. This "essential micronization" reduces or eliminates the need for grinding. Further, when additional grinding is still required, it is easier to grind some of the solvate before the solvent removal step than to grind the Η or L type after the solvo- crystallization type is removed. The pharmaceutically acceptable crystalline form of Pharmacopoeia can also be used directly in medical touch products. In a specific embodiment, the crystal form of the mixture can be used to directly prepare such a composition without dichloromethane, isopropanol or diethyl ether; in another embodiment, 'free of dichloromethane, isopropanol, Ether, isobutyl ketone or ethanol; or in another embodiment, free of dichloromethane, isopropanol, diethyl ether, isobutyl ketone, ethanol, ethyl acetate or acetone. Optimally used for this purpose, the dextro- y-yield crystalline form of opiarin substantially excludes solvents that are not pharmaceutically acceptable solvents. The solvent crystalline form for use in a pharmaceutical composition typically and preferably comprises a higher pharmaceutically acceptable melting point and/or a hydrogen bonding solvent such as, but not limited to, butanol. It is believed that the solvated crystalline form can be combined to provide a range of different dissolution rates, and if the rate of dissolution of ipproxone in the gastrointestinal tract is the rate controlling step of the target cell or tissue that delivers ipproxone, then relative to the sputum type And £ offers different bioavailability ranges. The present invention is also directed to an amorphous form of ippronone, which can be used as an intermediate in the preparation of quinone and L-type ipproxone. In addition, it is believed that amorphous ipproxone has different dissolution rates, if amorphous eppoxone is present in the pharmaceutical composition and if the dissolution of ipproxone in the gastrointestinal tract is to deliver Epson

67790-950421.DOC

1290558 V. INSTRUCTIONS (14) The rate at which the ketone reaches the target cell is controlled by half, and the amorphous epipone can be used for the different bioavailability of the sputum type and the L type. Also of interest are a combination of solid forms selected from the group consisting of type 11 ipproxone, L-type ipproxone, lycopene solvate crystalline form, and amorphous type Epson copper. Such combinations can be used, for example, in the preparation of a variety of dissolution remedies, including controlled release compositions. In the specific embodiment of the present invention, the combination of providing a solid form includes at least a detectable amount of sputum-type ipproxone, and the difference is one or more solid forms selected from the group consisting of L-type Epson _, Ai ketone solvent A group consisting of a combined crystal form and an amorphous type of ipproxone. Fields Depending on the intended use of the solid form of ipproxone, process considerations may assist in the selection of a particular solid form or a combination of specific solid forms. For example, the pure phase L form is usually easier to prepare than the pure phase Η type. However, mixtures of bismuth and L-forms are generally easier to prepare than pure phase L-types, allowing the use of relatively low chemical purity epipone starting materials. The use of a solvent-based crystalline form in place of the H-form or L-form in the composition allows the solvent to be removed without the need for a processing step, otherwise the process is carried out by removing the solvent from the solvent crystalline form. Further, if the L-form is directly crystallized by a suitable solvent without intervening in the intermediate preparation and the intermediate solvent-crystallization type desolvation, the solvent removal step can be eliminated. Details of this method are detailed later. DEFINITIONS The term "amorphous" is used in the case of ipproxone, which means a solid state in which the ezetone molecules are present in a disordered arrangement and do not form a distinguishable lattice or unit cell. Amorphous ipproxone does not produce any characteristic crystallization peaks when subjected to X-ray powder diffraction analysis. The boiling point of a substance or solution is mentioned here. The term "boiling point" means a substance or -21-

67790-950421.DOC This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1290558 A7 ------ B7 V. Invention description (15 ) ^~^ Falling liquid under proper process conditions The boiling point. The term "crystalline" is used in the form of a solid form in which edetone is arranged to form a distinguishable lattice (1) comprising distinguishable unit cells and (ii) obtained when subjected to X-ray radiation. The diffraction peaks. The term "gamma crystallization" is used herein to mean crystallization and/or recrystallization depending on the applicable conditions for the preparation of the eplerenone starting material. The term "cooking" means a process in which a slurry of a solid ipproxone in a solvent or solvent mixture is heated at the boiling point of a solvent or solvent mixture under suitable process conditions. The term "direct crystallization" is used herein to mean a solvent-solid crystalline solid form in which the intermediate solvent is directly crystallized from a suitable solvent without forming an eppocone and the form is removed. The term "prolone ketone drug" is used herein to mean that if the noun uses the genus of the term "iplotone itself", it may mean that the unadapted ippronone or the component of the composition of the king's medicinal composition is present. Promethone. The term "particle size" is used herein to mean the measurement of K particle size by the industry's conventional particle size measurement techniques such as laser diffraction, deposition field flow fractionation, photonic fork spectroscopy or disk centrifugation. The "D(10) particle size" is 9% by weight by weight of the particles smaller than the particle size of the particle size measured by the conventional particle size measuring technique. "DSC" means differential scanning calorimetry. The term "HPLC" means high pressure liquid chromatography. The term "IR" means infrared light. The term "purity" is used herein unless otherwise stated.

67790-950421.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X297 Gongdong) A7 B7 1290558 V. Description of invention (16) HPLC purity analysis of ipproxone chemical purity. As used herein, "low purity ipproxone" generally means ipproxone containing an effective amount of a quinoid crystal growth promoter and/or an L-type crystal growth inhibitor. As used herein, "high purity ipproxone" generally means ippromone which does not contain or contains less than an effective amount of a quinoid type crystal growth promoter and/or an L-type crystal growth inhibitor. The term "phase purity" is used herein to mean the solid purity of ipproxone as measured by infrared spectroscopy as described herein for a particular crystalline or amorphous form of ipproxone. "XRPD" means X-ray powder diffraction. "rpm" means the speed per minute. "TGA" means thermogravimetric analysis. "Tm" means a melting point. Characterization of Crystalline Type 1. Molecular Configuration Single crystal X-ray analysis indicates that the molecular configuration of ipproxone is different from the oxime type and L type, especially in terms of the ester orientation of the 7-position of the steroid ring. The directionality of the ester group can be defined by the twist angle of C8-C7-C23-01. In the Η-type lattice, the ipproxone molecule adopts a configuration in which the methoxy group of the ester is approximately aligned with the C-H bond at the 7-position, and the carboxyl group is located approximately at the center of the oxime-steroid ring. The twist angle of the C8-C7-C23-01 is typically about -73.0 degrees in this configuration. In this directionality, the carbonyl oxygen atom (01) of the ester group is in intimate contact with the oxygen atom (04) of the 9,11-epoxide ring. The 01-04 distance is about 2.97 angstroms, just below the 3.0 angstrom van der Waals contact distance (assuming the oxygen atom has a radius of 1.5 angstroms). 67790-950421.DOC - 2 3 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) A7 B7 1290558 V. Description of invention (17) In the L-type lattice, the ipproxone molecule has a structure Type wherein the ester group is rotated about 150 degrees with respect to the oxime and has a C8-C7-C23-01 twist angle of about +76.9 degrees. In this directionality, the methoxy direction of the ester is toward the 4,5-membered segment of the winter steroid ring. In this directionality, the pitch of the ester group oxygen atom, 〇2) and the 9,11-epoxide epoxide atom (〇4) is increased relative to the η-type determining distance. The distance from 02-04 is about 3_04 angstroms, just above the Van der Waals contact distance. 01-04 distance is about 3.45 angstroms. Up to now, in the solvo- crystallization type by the early crystal X-ray diffraction analysis, the ipproxone molecule apparently has an L-type configuration. 2. Twilight powder diffraction A variety of Epson crystallization types were analyzed using a Siemens D5000 powder diffraction meter or an Inel multipurpose diffractometer. For the Siemens d5® powder diffractometer, measure the raw data for a 20-value measurement of 2 to 50, with 阶2〇 per step and two seconds per step. As for the Ino multi-purpose diffractometer, the sample was placed on an aluminum sample holder while the original data was collected at full 20 values for 3 minutes. Tables, 1B and 1C are the following significant parameters such as the main peak and the intensity in terms of 20 values: Η type (prepared by solvent removal of ethanol solvate obtained by cooking low-purity ipproxone), L type (via high Preparation of isobutyrone solvate obtained by recrystallization of purity ipproxone, and isobutyrone solvate (converted by high-purity ipproxone to isobutyl ketone at room temperature), = crystal form (X-ray light shot wavelength 1.54056 angstroms). As a result of the crystal diffraction plane associated with imperfect enthalpy and L-type manufacturing pathways (i.e., solvate desolvation), the diffraction pattern of the Η type and the type may have a slight displacement at the position of the smear. In addition, the Η type is steamed -24-

67790-950421.DOC This paper scale applies to the towel® S standard (CNS) Α4 specification (210&gt;&lt; 297 mm factory-----------——A7 B7 1290558 V. Description of invention (18 The crude ipproxone is cooked and separated from the solvate. This method results in a low total chemical purity (about 90%) of the quinone type. The solvent form of the solvent is also expected to be due to solvent molecules in the lattice. The increase in activity inside the channel is expected to show several displacements of the position of the diffraction peak. 67790-950421.DOC - 2 5 - This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1290558 A7 B7 V. Description of the invention (19) Table 1A: X-ray diffraction data, Η angle 2 Θ d-space strength Cps strength % 6.994 11628 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 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 。 。 。 。 。 。 。 。 。

Binding

Line 67790-950421.DOC - 2 6 _ This paper scale applies to China National Standard (CNS) Α4 size (210 X 297 mm) A7 B7 1290558 V. Invention description (20) Table IB: X-ray diffraction data, L-shaped Angle 2Θ d-inter-pitch strength Cps 珐%% 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 24279 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 26251 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 。 。 。 。 。 。 。 。 。 。 。 。 。 2 7 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1290558 V. Description of invention (21) Table 1C: X-ray diffraction data, isobutyrone solvate angle 2Θ d-spacer Strength Cps Strength | % 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 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. s 6.4 27.357 3.257 1944 11.3 27.605 3.229 2116 12.3 27.900 3.195 858 5.0 28378 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

67790-950421.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1290558 V. Description of invention (22) Η type, L type and isobutyl ketone solvate crystalline ipproxone The legends of the X-ray diffraction pattern are shown in Figures 1, 2 and 3, respectively. Figure Η shows the peaks at 7.0 ± 0.2, 8·3 ± 0·2 and 12·0 ± 0·2 degrees. The L type is shown in 8.0 〇.2, 12.4 〇.2, 12.8±〇.2 and 13.3 〇. 2 degrees 20 甄 崎 峰 peak. The isobutyrone solvate crystalline form is shown at 7.6 ± 〇.2, 7.8 ± 0.2 and 13.6 ± 0.2 degrees 20 甄 崎 峰 peak. The X-ray diffraction pattern is shown, for example, in the following solvate crystal forms of ippronone, respectively, in Figures 4 to 14 · n-propanol solvate, tetrahydrofuran solvate, propionic acid solvate, acetic acid solvent Compound, acetone solvate, toluene solvate, isopropanol solvate, ethanol solvate, isobutyl acetate solvate 'n-butyl acetate solvate and methyl acetate solvate. 3. Melting point/decomposition point The melting point and/or decomposition point of the non-solvent eppocone crystalline form was determined using a Texas Instruments 2920 differential scanning calorimeter. The amount of each sample is υmg placed in a sealed or unsealed aluminum pan and heated to provide a temperature increase rate of approximately 10 ° C per minute. The melting point/decomposition point is defined by the dissolution/decomposition endotherm from the starting point to the highest temperature. The melting of the Η-type and L-type ipprox is related to the chemical decomposition and the trapped solvent is lost by the crystal lattice. The melting point/decomposition point was also affected by solids treatment prior to analysis. For example, an unmilled L-form having a Dm particle size of about 180-450 microns is prepared by direct crystallization from a suitable falling agent or by solvating the solvate obtained by crystallization of high-purity ippronone in a suitable solvent or solvent mixture, without The milled L-form typically has a melting point/decomposition point in the range of from about 237 °C to about 242 °C. A milled L-type having a Dm particle size of from about 80 to about 1 micron is obtained by crystallization from 67790-950421.DOC-29-

A7 B7 1290558 V. INSTRUCTIONS (23) The solvate of a solution of high-purity ippronone in a suitable solvent or solvent mixture is prepared by removing the solvate from the solvent and grinding the resulting L-form, usually having a lower and comparative The broad melting point/decomposition point ranges from about 223 ° C to about 234 ° C. An unmilled n-type having a Dm particle size of about 180-450 microns is prepared by desolvating a solvate obtained by cooking low-purity ipproxone, usually having a higher melting point at 247 ° C to about 251 ° C / Decomposition point range. (a) an unmilled L form directly crystallized from isobutyl ketone, (b) an unground L form prepared by desolving a solvate obtained by crystallizing high purity ippromone from isobutyl ketone, (c) an L-form prepared by solvating a solvent-free solvate of a solvate obtained by crystallizing high-purity ippromone from isobutyl ketone, and (d) by using a low-purity prolone The DSC thermogram of the unmilled quinone prepared by solvent extraction of the solvate obtained by ketone digestion is shown, for example, in Figures 5, i6, i7 and 18. The DSC thermogram of the solvate form of ipproxone was determined using a Perkin Elmer Pyris 丨 differential scanning calorimeter. Each sample was 1-2 milligrams in volume to an unsealed aluminum pan and heated to provide a rate of temperature increase of about 1 °C per minute. One or more endothermic events occurring at lower temperatures are related to enthalpy changes that occur when the solvent is lost from the solvate lattice. The highest p endothermic system relates to the melting/decomposition of L· or Η type ipproxone. DSC thermograms are shown in the following epoxidone solvate crystal forms in Figures 9 to 34: n-diol solvate, tetrahydrofuran solvate, ethyl propionate solvate, acetic acid solvate 'chloroform solvent Compound, acetone solvate, toluene solvate, isopropanol solvate, ethanol solvate, acetic acid tert-butyl acetate solvate, isobutyl acetate solvate, butyl acetate solvate, acetic acid A

1290558 A7 B7 V. INSTRUCTION DESCRIPTION (24) Ester solvates, propyl acetate solvates, n-butanol solvates and n-octanol solvates. 4. Infrared light absorption spectroscopy Non-solvent edproxone Η type and L type infrared absorption spectrum system using Nicolet DRIFT (diffuse reflectance infrared light Fourier transform) Magna system 550 Spectrophotometer obtained. Use a spectral technology collector system and a micro sample cup. The sample (5%) was analyzed by potassium bromide and was scanned from 400 to 4000 cm. Epsonone in chloroform solution (3%) or in solvated crystalline form of infrared absorption spectrum using Baiou cuisine ( Biorad) FTS-45 spectrophotometer was obtained. The chloroform solution sample was analyzed using a solution tube with a diameter of 0.2 mm and a sodium chloride plate. The solvate FTIR spectrum was measured using IBM micro MIR (multiple internal reflectance). Attachment collection. Samples are scanned from 400 to 4000 cm -1 (a) Type H, (b) Form L, (c) Isobutyl ketone solvate and (d) Infrared absorption of ipproxone in chloroform solution Spectral examples are shown in Figures 35, 36, 37 and 38. Table 2 shows exemplary absorption bands of crystalline, eppyrone and isobutyl ketone solvate crystalline ipprox. Example absorption of ipproxone in chloroform solution The bands are also disclosed for comparison. For example, the difference between the Η type and the L form or the isobutyrone solvate is observed in the carbonyl region of the spectrum. The oxime type has an ester carbonyl group stretching of about 1739 cm 4 and the L form and isobutyl ketone solvent combination. The corresponding extensions are respectively at about 1724 and 1722 cm -1 . The ester carbonyl group extends from ipproxone to chlorine. Solution appears at about 1727 cm. " The change in the ester carbonyl stretching frequency between the Η type and the L type reflects the change in the directionality of the two crystallization type ester groups. In addition, the ester of the conjugated ketone of the oxime-steroid ring is stretched from about 1664-1667 cm -1 of the oxime or isobutyl ketone solvate to about 67790-950421 of the L type. DOC -31&quot; National Standard (CNS) Α4 Specification (210X 297 mm) 1290558 A7 B7 V. Description of Invention (25) 1655 cm "The carbonyl stretching corresponding to the chloroform solution appears to be approximately 1665 cm _1. The difference between the Η type and the L type appears in CH Bending zone. The Η type has an absorption of about 1399 cm", which is not found in L-form, isobutyrone solvate or ipproxone in chloroform solution. 1399 cm "stretched in the CH2 scissor region adjacent to the C2 of the carbonyl group and the C21 methylene group. Table 2: IR absorption bands of various forms of ipproxone (cm... absorption zone Η type L-type isobutyl ketone solvate chloroform solution vC=0(lactone) 1773 1775 1767 1768 vC=0(ester) 1739 1724 1722 1727 vC=0(3-keto) 1664 1655 1667 1665 vC=0(3,4-olefin) 1619 1619 1622 1623 5asCH3, 5CH2, 5CH2 (α position of carbonyl) 1460, 1444, 1426 1467, 1438, 1422, 1399 1467, 1438, 1422 1464, 1438, 1422 δ sCU3 1380 1381 ~ 1380 1378

The infrared absorption spectrum of the following epoxidone solvated crystalline form is shown, for example, in Figures 39 to 51: n-propanol solvate, tetrahydrofuran solvate, ethyl propionate solvate, acetone solvent , toluene solvate, isopropanol solvate, ethanol solvate, isobutyl acetate solvate, butyl acetate solvate, propyl acetate solvate, methyl acetate solvate, propylene glycol solvent And a butyl acetate solvate. 5. Nuclear Magnetic Resonance (NMR) Spectroscopy The 13 C NMR spectroscopy was obtained at the 31.94 megahertz field. The 13C NMR spectra of the Η-type and L-type ipproxone are shown in Figures 52 and 53, respectively. Analysis of the type of Epson 67990-950421.DOC _32_ This paper scale applies to the Chinese National Standard (CNS) Α 4 specifications (210X297 gong) 1290558 V. Description of the invention (26) The information obtained by the ketone in Figure 52 is not pure phase but includes small L-type eplerenone. The Η type is the clearest difference between carbon resonances of approximately 64.8 ppm, 24.7 ppm and 19.2 ppm. The L-type is the most obvious difference by carbon resonance of about 67.1 ppm and 16.0 ppm. 6. Thermogravimetric Thermogravimetric analysis was performed using a Texas Instruments TGA 2950 Thermogravimetric Analyzer. The sample was placed in an unsealed aluminum pan under nitrogen purge. The starting temperature was 25 ° C and the temperature was increased at a rate of about 10 ° C per minute. The thermogravimetric analysis of the following epoxidone solvated crystalline forms is shown in Figure 5 to 71, respectively: isobutyrone solvate, n-propanol solvate, tetramethylene solvate, propionic acid B Ester solvate, acetic acid solvate, chloroform solvate, acetone solvate, toluene solvate, isopropanol solvate, ethanol solvate, isobutyl acetate solvate, n-butyl acetate solvent Compound, methyl acetate solvate, propyl acetate solvate, propylene glycol solvate, n-butanol solvate, n-octanol solvate and tert-butyl acetate solvate. 7. Microscopy Thermal platform microscopy of single crystals of ipproxone isobutyrone solvate was performed using a Linkam THMS 600 thermal platform with a Zeiss universal polarizing microscope. The solvate crystals are birefringent and translucent at room temperature under polarized light, indicating that the crystal lattice is highly ordered. As the temperature increased to about 6 (rc, significant defects began to appear along the length of the carcass. Scanning electron micrographs of L-type eplerenone obtained by dissolving the isobutyl solvate $ solvent are shown in the figure. μ, showing surface flaws, pore cracks, and lattice breaks in the crystal lattice. From ethyl acetate 67790-950421.DOC -33-12590558 A7 B7 V. Description of invention (27) Direct crystallization of L-type ipproxone Scanning electron micrographs are shown in Figure 73, without similar surface flaws, voids, cracks, and breaks in the crystal lattice. 8. Clamping cell parameters Tables 3A, 3B, and 3C below summarize the Η type, L type, and several Unit cell parameters determined by solvent crystallization of ippronone. Table 3 Α: unit cell parameters of eppoconone crystal form H-type L-type isobutyl ketone solvate crystal system oblique single oblique square space group 2ϊ2ι2ι Ρ2ι a 21.22 埃 8.78 埃 23.53 埃 b 15.40 埃 11.14 埃 8.16 埃 埃 6.34 埃 11.06 埃 13.08 埃 a 90 degrees 90 degrees 90 degrees β 90 degrees 93.52 degrees 90 degrees r 90 degrees 90 degrees 90 degrees z 4 2 4 volume (A) 2071.3 1081.8 2511.4 P 1.329 g/cm3 1.275 g / cm3 1.287 g / cm 3 R 0.0667 0.062 0.088 67790-950421.DOC - 3 4 This paper scale applies to China National Standard (CNS) Α 4 specifications (210 X 297 mm) 1290558 A7 B7 V. Description of invention (28 Table 3B: unit cell parameter parameters of ippromone crystal form acetone solvate toluene solvate butyl acetate solvate 1 crystal system orthorhombic orthorhombic space group νΐχΐχΐχ 2λ2χ2χ ?212121 a 23.31 ang: 23.64 ang 23.07 ang b 13.13 ang 13.46 ang 13.10 ang c 8.28 angstrom! S.16 angstrom 8.24 angstrom a 90 degree ' 〇 degree 90 degrees β 90 degrees! 〇 degree 90 degrees r 90 degrees ί 》 degrees 90 degrees z 4 ^ \ 4 Volume (Angstrom) 2533.7 : 1596.6 2490.0 P 1.239 g/cm 3 : 1.296 g / cm 3 1.334 g / cm 3 R 0.058 ( ).089 0.093 1 butyl acetate solvate molecule due to solvent molecules in the channel Table 3C: unit cell parameters of ippromone crystal form parameters Space group νΐ Χΐχΐχ P212121 ?212121 a 23.19 angstroms 23.15 angstroms 23.51 angstroms b 12.95 angstroms 12.73 angstroms 13.11 angstroms c 8.25 angstroms 8.25 angstroms 8.27 angstroms a 90 degrees 90 degrees 90 degrees β 90 degrees 90 degrees 90 degrees r 90 degrees 90 degrees 90 degrees z 4 4 4 Volume (Angstrom) 2476.4 2433.2 2548.6 P 1.337 g/cm 2 1.296 g/cm 2 1.234 g/cm 3 R 0.098 0.152 0.067 1 Solvate molecules cannot be completely refined due to the dissociation of solvent molecules in the channels. 67790-950421.DOC - 3 5 - This paper scale applies to China National Standard (CNS) A4 specification (210x 297 dongdong) A7 B7 1290558 V. Description of invention (29) Additional for selected eppoconne solvate crystal form The information is reported in Table 4 below. The unit cell data reported for the isobutyrone solvate in Table 3A above also represents the unit cell parameters for various additional ippromone crystalline solvates. Most of the experimental eppocone crystalline solvates are substantially identical in structure to each other. Although there may be a small amount of displacement of the X-ray powder diffraction peak from one solvated crystalline form to the next solvated crystalline form due to the size of the combined solvent molecules, the overall diffraction pattern is approximately the same, as well as unit cell parameters and molecules. The position is essentially the same for all solvates tested. Table 4: Additional information on eppoconone solvates Solvents Solenometry Solvents: Is ipproxone identical to isobutyrone solvate? Desolvation temperature Yc) Isobutyl ketone 1 1 89 Acetic acid 1 2 is 203 Acetone 1 1 is 117 Methyl acetate 1 1 is 103 Propyl acetate 1 1 is 130 Butyl acetate 1 2 is 108 Isobutyl acetate 1 2 Yes 112 tert-butyl acetate - is 109 chloroform - is 125 ethanol 1 1 is 166 n-propanol 1 1 is 129 isopropanol 1 1 is 121 n-butanol 1 1 is 103 n-octanol - is 116 propionic acid acetic acid 1: 1 is 122 propylene glycol - is 188 tetrahydronethane 1:1 is 136 toluene 1:1 is 83 67790-950421.DOC - 3 6 This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1290558 V. INSTRUCTION DESCRIPTION (30) 1 is defined as the removal of the solvent temperature from the final solvent weight loss step as determined by thermogravimetric analysis at a heating rate of 10 ° C per minute under nitrogen purge. However, the solvent removal temperature is affected by the solvent synthesis method. Different methods can produce different numbers of nucleation sites that can be desolvated at a lower temperature than the solvate. The unit cell line of the solvate consists of four ipproxone molecules. The stoichiometry of the ipproxone molecule and solvent molecule of the unit cell is also reported in Table 4 above for various solvates. The unit cell type of the Η type consists of four ipproxone molecules. The L-type unit cell line is composed of two ipproxone molecules. When the ipproxone molecule is translated and rotated to fill the space left by the solvent molecule, the solvate unit cell is converted to hydrazine and/or L-form during solvent removal. Table 4 also reports the solvent removal temperatures for a variety of different solvates. 9. Crystal Properties of Hydrazine The selected impurities of ipproxone may form during the desolvation of the solvate. Special evaluation of the effects of the following two impurity molecules: 7-methylhydrogen 4α, 5α; 9α, 11α-diepoxy-17-hydroxy-3-oxy-17α-pregnane·7 α,2·1-dicarboxyl Acid ester r-lactone (III) ("diepoxide") and 7-methylhydrogen 11 α,12 α -epoxy-17-hydroxy-3.oxy-17 α _pregna-4-ene 7 α , 21-dicarboxylate, Τ-lactone (IV) (“11,12·epoxide”). 67790-950421.DOC - 3 7 _ ΐ Paper scale applicable to China National Standard (CNS) Α 4 specification (210X297 public) 1290558 A7 B7

1290558 A7 B7 V. Description of invention (32)

The single crystal type is isolated from each impurity compound. Representative X-ray powder diffraction patterns of diepoxide, 11,12-epoxide and 9,11-olefin crystals are shown in Figures 74, 75 and 76, respectively. The X-ray powder diffraction pattern of each impurity molecule is similar to the X-ray powder diffraction pattern of the Η type, suggesting that the Η type and the three impurity compounds have a similar single crystal structure. Each impurity compound single crystal was also confirmed to have a quinoid-like single crystal structure by single ionization and X-ray structure measurement. The single crystal of the diepoxide is isolated from isobutyl ketone. The single crystal of 11,12-epoxide is isolated from isopropanol. The single crystal of 9,11-galactin is isolated from n-butanol. The crystal structure data of the crystal form of each impurity compound are shown in Table 5. The resulting crystal system and unit cell parameters are substantially the same for the quinoid, diepoxide, 11,12-epoxide and 9,11-nonane hydrocarbon crystal forms. Table 5: Comparison of high-order lattice parameters of impurity crystals with Η type Aipu Lejian parameters Η-type diepoxide 11,12-epoxide 9,11-anthracene hydrocarbon system orthorhombic oblique slant Square space group Ρ2ι2ι2ι Ρ2ι2ι2ι Ρ2ι2ι2ι Ρ2ι2ι2ι a 21.22 ang 21.328 angstrom 20.90 angstrom 20.90 angstroms 67790-950421.DOC 3 9 _ This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) A7 B7 1290558 V. Description of invention (33) b 15.40 ang 16.16 ang 15.55 angstrom 15.74 angstrom C 6·34 angstrom 6.15 angstrom 6.38 angstrom 6.29 angstrom a 90 degree 90 degree 90 degree 90 degree β 90 degree 90 degree 90 degree 90 degree r 90 degree 90 degree 90 degree 90 degree 90 degree z 4 4 4 4 Volume (Angstrom) 2071.3 2119.0 2073.2 2069.3 P 1.329 g/cm 3 1.349 g/cm 3 1.328 g/cm 3 1.279 g/cm 3 R 0.0667 0.0762 0.0865 0.0764 The four compounds reported in Table 5 crystallize into the same space Groups have similar unit cell parameters (ie, equal structures). It is assumed that the diepoxide, 11,12-epoxide and 9,11-cation have a quinoid configuration. Each impurity compound is relatively easy to separate from the Η-type package (directly from the solution), indicating that the Η type is a stable package mode for a series of similar compounds. It is expected that any compound having substantially the same crystal structure as the quinone type can be used as a dopant when crystallization of hydrazine-type ipproxone from a solution. Thus, in a particular embodiment, a method for promoting crystallization of quinoid eplerenone by a solution of ipproxone in a solvent or solvent mixture is provided, the method comprising using an effective amount of crystallography substantially prior to crystallization A doped solution of a compound of the 艾 type ipproxone equivalent structure. It should be understood that the term "noisy" here may be an active or deliberate addition of a doping compound to a solution, or passive, that is, due to the presence of a dopant compound in the solution as an impurity. Preferred doped compounds according to this embodiment are dicycloepoxide, 11,12-epoxide and 9,11-olefin, i.e., compounds (III), (IV) and (V). Preparation of ipproxone 67790-950421.DOC - 4 0 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1290558 A7 B7 V. Description of Invention (34) For the preparation of the present invention The novel crystalline form of the ipproxone starting material can be prepared by known methods, including the methods described in the aforementioned International Patent Publication No. WO 97/21720 and WO 98/25948, in particular the reaction chart of these publications. Preparation of crystalline form 1 - Preparation of solvated crystalline oxime The solvate crystalline form of ipproxone can be prepared by crystallizing ipproxone in a suitable solvent or a suitable solvent mixture. A suitable solvent or mixture of suitable solvents will usually contain an organic solvent or mixture of organic solvents which will dissolve the ipproxone with any of the impurities at elevated temperatures, but will preferably crystallize the solvate upon cooling. The solubility of the iptone in such solvents or solvent mixtures is usually from about 2 to about 200 g/3⁄4 liters at room temperature. Preferably, the solvent or solvent mixture is selected from the solvents previously used in the preparation of the procumone feedstock, particularly if it is included in the inclusion of Epson.

Ketone's stomach contains unacceptable.

a group consisting of esters. Further preferably, the hydrazine, toluene, methanol and acetic acid tert-butyl solvent are selected from the group consisting of isobutyl ketone and ethanol.

1290558 A7 __________ V. Description of invention (35) Group. In another embodiment of such a method, the solvent or solvent mixture is selected from the group consisting of 1-propanol, 2-pentanone, acetic acid, acetone, butyl acetate, chloroform, isobutanol, isobutyl acetate, methyl acetate A group consisting of ethyl propionate, n-butanol, n-octanol, propyl acetate, propylene glycol, tert-butanol, tetrahydrofuran, toluene, methanol, and tert-butyl acetate. In another embodiment of such a method, the solvent or solvent mixture is selected from the group consisting of 1-propanol, 2-pentanone, acetic acid, acetone, butyl acetate, chloroform, isobutanol, isobutyl acetate, methyl acetate A group consisting of ethyl propionate, n-butanol, n-octanol, n-propanol, propyl acetate, propylene glycol, tert-butanol, tetrahydrofuran, toluene, methanol, and tert-butyl acetate. In order to prepare a solvent-solved crystal form of ipproxone, the quantitative ipproxone starting material is dissolved in a constant volume solvent and cooled until crystal formation. The solvent temperature at which edetone is added to the solvent is usually selected based on the solubility curve of the solvent or solvent mixture. For example, for most of the solvents herein, such solvents typically have a temperature of at least about 25 ° C, preferably from about 3 (TC to the boiling point of the solvent, and more preferably from about 25 ° C to the boiling point of the solvent. In addition, the 'hot solvent can be added to the ipproxone and the mixture is cooled until the crystal is formed. The solvent temperature added to the ipproxone is usually selected based on the solubility curve of the solvent or solvent mixture. For most of the solvents described herein For example, the solvent temperature is typically at least about 25 ° C, preferably from about 50 ° C to about the temperature of the solvent stagnation point and more preferably from about 15 ° C below the solvent point to the temperature of the solvent stagnation point. The amount of the ketone raw material mixed in the specified volume of solvent is based on the solvent or 67790-950421.DOC - 4 2 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1290558

The solubility curve of the solvent mixture is determined. Typical ipproxone is added to the solvent without dissolving it in the solvent at room temperature. For example, for most of the solvents described herein, the amount of the ipprox starting material to be mixed with the specified volume of solvent is generally at least at least about 1.5 to about 4.0 times the amount of eptrodone dissolved in the volume of solvent at room temperature, preferably. It is about 2_〇 to about 3.5 times and more preferably about 2. 5 times. After the eplerenone starting material is completely dissolved in the solvent, the solution is typically slowly cooled to crystallize the eplotone solvate crystalline form. For most of the dissolutions described herein, for example, the solution is cooled at a slower rate than 20 ° C / minute, preferably about 10 ° C / minute or less, more preferably about 5. [; / minute or slower and more preferably at a rate of about 1 C / minute or slower. The endpoint temperature for the solvo- crystallization type is determined by the solubility curve of the solvent or solvent mixture. For example, for most of the solvents described herein, the endpoint temperature is typically less than about 25 ° C, preferably less than about 5 X: and more preferably less than about _ 5 ° C. Lowering the endpoint temperature is generally advantageous for the formation of a solvent crystalline form. Additionally, other techniques can be employed to prepare the solvates. Such techniques include, for example but are not limited to: (1) dissolution of the ipprox starting material in a solvent and addition of a co-solvent to aid in crystallization of the solvo-crystalline form, (ii) vapor-phase diffusion growth of the solvate, (iii) evaporation by evaporation For example, rotary solvate separates the solvate, and (iv) the slurry conversion reaction. The crystal of the solvent-crystalline type prepared as described above can be separated from the solvent by any appropriate conventional means such as filtration or centrifugation. An increase in the agitation of the solvent system during crystallization typically results in a smaller crystal particle size. U solvate preparation L-type ipproxone can be directly prepared from solvent-based crystal form by solvent removal -43-

67790-950421.DOC This paper scale applies to the towel aa standard (CNS) A4 listens ^ (21G X297 mm) &quot;'~ --——- 1290558 A7 -----------B7_ V. Description of the invention (37) &quot; ------ Preparation. Removal of the solvent can be accomplished by any solvent removal means such as, but not limited to, heating the falling composition, reducing the pressure around the solvate, or a combination thereof. If the solvate is heated, for example, in an oven to remove the solvent, then the temperature of the solution &lt;temperature typically does not exceed the enantiomeric transition temperatures of the H and L forms. This temperature does not exceed about 150 °C. 2, solvent pressure and time are not narrow _ special restrictions. The solvent removal pressure is usually about 1 atmosphere or less. As the solvent pressure is reduced, the temperature at which the solvent can be removed and/or the solvent removal time is also reduced and reduced. Especially for solvates with higher desolvation temperature, the lower dehydration temperature is used for dehydration. The solvent removal time only needs to be sufficient to allow the solvent to be removed, so that the L-form can be formed. To ensure that the product produced contains substantially all of the L form, the procproxil material is typically high purity ippromone, preferably substantially pure ipproxone. The propranone starting material used to prepare the L-type ipproxone is usually at least 9% by mass 'preferably at least 95% pure and more preferably at least 99% pure. As discussed in detail in this case, certain impurities in the ipprox starting material may adversely affect the process yield and the L-form content of the product obtained from the process. The crystalline ipproxone product prepared from the high purity ipprox starting material in this manner typically comprises at least 10% L form, preferably at least 50% L form, more preferably at least 75% L form, and even more preferably at least 90%. The type is preferably at least 95% l type, and more preferably substantially pure phase L type. The solvate can be prepared in substantially the same manner as described above for the preparation of Form 1. The process is based on (1) using low purity ipprox starting material instead of high purity 67790-950421.DOC-44- The paper scale applies to the Chinese National Standard (CNS) Α4 specification (21〇Χ297 mm) 1290558 A7 B7 V. Description of invention (38) Degree of ipprox starting material, (ii) using pure phase 晶体 type crystal seeding solvent system or (iii ) A combination of (1) and (ii). 3.1 The use of impurities for the growth of the enamel growth promoter and the inhibitor selected impurities and the amount of the starting material of the ipproxone (not all impurities in the total amount of ipproxone) affect the solvate desolvation solvent The possibility of forming a germanium crystal during the period. The impurities selected are usually sputum growth promoters or L-type growth inhibitors. These impurities may be included in the ipprox starting material, in a solvent or solvent mixture prior to the addition of the ipproxone, and/or to the solvent or solvent mixture after the addition of the euploid to the starting material. Bonafede et al. (1995) 'Selective nucleation and growth of organic polymorphic compounds that direct the growth of insect crystals on a molecular crystal substrate, US, 117 (30), and for this References, discussed in growth promoters and growth inhibitors of polymorphic compound systems. For the purposes of the present invention, suitable impurities typically comprise a compound of substantially single crystal structure of a single crystal structure of the oxime type. The impurity is preferably a compound having an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern of the Η-type ipproxone, and more preferably selected from the group consisting of 'di-epoxide, 11,12-epoxy A group consisting of a compound, a 9,11-olefin, and combinations thereof. The typical amount of impurities required to prepare the ruthenium crystals is determined by the solvent or solvent mixture and the solubility of the impurities relative to ipproxone. For example, when the yttrium type is crystallized from a butyl ketone, the weight ratio of the diepoxide to the low purity ipprox starting material is typically at least about 1:1 Torr, preferably at least about 3:1 Torr, more preferably Approximately 3:100 to about 1:5, and more preferably about 3:1 to about 1:1. The u, i2_epoxide has a higher solubility in isobutyrone than the diepoxide, usually = _45-

67790-950421.DOC^The paper scale applies to the Chinese National Standard (CNS) A4j^^_297 public)

-46- 1290558 A7 ______B7____ V. INSTRUCTIONS (39) A larger amount of 11,12-epoxide is used to prepare a sputum-type Epson crystal. If the impurity comprises 11,12-epoxide, the weight ratio of the diepoxide to the low purity ipprox starting material is typically at least about 丨: 5, more preferably at least about 3:25, and still more preferably 3:25 to about 1:5. If both the diepoxide and the ruthenium epoxide impurity are used to prepare the quinoid crystal, the weight ratio of the individual impurity to the eptrozol raw material may be lower than that of the case where only one impurity is used to prepare the quinoid crystal. 0 A mixture of a type and an L type is usually obtained when a solvate containing a selected impurity is removed from the solvent. The weight component of the product obtained by preliminarily removing the solvent from the nt form to the solvate is typically less than about 50%. As discussed later, further processing of the product by crystallization after crystallization can increase the weight component of the L form to the product. 3.2 Seeding Seeds The Η-type crystals can also be prepared by seeding the solvent system with pure phase η-type crystals (or Η-type growth promoters and growth inhibitors, as discussed above) prior to crystallization of ippromone. The eplerenone starting material can be low purity ippromone or high purity ippromone. t Preparation of 6 scoops of the solvate from the starting material # When the solvent is removed, the weight fraction of the quinoid form in the product is typically at least about 7% and can be as high as about 100%. The quinone seed pair added to the volume system is added to The weight ratio of the volume of the eplerenone starting material is at least about 0.75:100, preferably from about 075:100 to about i:20 and more preferably from about 1:100 to about 1:50. The ruthenium seed crystal can be prepared by the method of preparing a crystal of the present invention, in particular, by any of the methods of cooking and preparing a ruthenium crystal as discussed later. Η type seed crystals can be all once, divided into multiple times or substantially experienced for a period of time

67790-950421.DOC This paper scale applies to China National Standard (CNS) Α4 specification (210X297)

1290558 A7 B7 V. Description of invention (4〇) Continuously added =. However, the addition of the quinoid seed crystal is usually accomplished prior to the start of crystallization of the procyanone from the solution, i.e., the seeding is completed prior to reaching the cloud point (the bottom end of the metastable zone). The seeding crystal is typically at a solution temperature of from about 0_5 ° C above the cloud point to about 1 ° C above the cloud point and preferably above the cloud point. 〇 to about 3 °C. As the seed crystal is added above the cloud point temperature, the number of seed crystals required for crystallization of the quinoid crystal generally increases. The seeding crystal not only appears above the cloud point, but also appears in the metastable zone. The cloud point and the metastable zone are determined by the degree of resolution and concentration of ippromone in a solvent or solvent mixture. For example, for a 12-fold dilution of isobutyl ketone, the high end of the metastable zone is typically from about 70 ° C to about 73 〇 c, while the lower end of the metastable zone (ie, the cloud point) is about 57 ° C. Up to about 63 ° C. For a concentration of 8 times the volume of isobutyl ketone, the metastable zone is narrower because the solution is supersaturated. At this concentration, the cloud point of the solution occurs from about 75 ° C to about 76 ° C. Since isobutyrone is boiled at an ambient temperature of about 80 ° C, such solution seeding is typically carried out at a temperature of from about 76.51 to the boiling point. A description of the use of a sputum seeding crystal is shown in Example 7 without limitation. The crystallized ipproxone product obtained using a sputum growth promoter or an L-type growth inhibitor and/or a n-type seed crystal typically comprises at least 2% hydrazine type, preferably at least 5% hydrazine type, more preferably at least 7% quinoid type. And better at least about 10% Η type. The remaining crystallized ipproxone product is typically L-form. U. Preparation of n-type by research on waste ipprox In another embodiment, it was found that a small amount of quinone can be prepared by appropriately grinding ipproxone. It was observed that the concentration of the sputum of the pulsin was as high as about 3%. Preparation of L-47- from solvates prepared from low-purity Zhan Aisin

67790-950421.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm). V. INSTRUCTIONS (41) As discussed earlier, low purity ippromone crystallizes to form a solvate followed by a solvent. The solvent is removed, and a product comprising a quinone type and an L type is usually obtained. The product having a higher L-form content can be prepared from low-purity ipproxone in substantially the same manner as described above for the preparation of the η-type by seeding the solvent system using pure phase L-type crystals, or By using an L-type growth promoter and a sputum growth inhibitor. The seeding scheme and the weight ratio of the L-type seed crystals added to the volume system to the amount of the ipproxone material added to the solvent system are generally similar to the preparation of the η-type ipproxone using seed crystals of the pure phase Η type crystal. The ratios discussed. The crystallized ipproxone product prepared in this manner typically comprises at least 1% L form, preferably at least 50% L form, more preferably at least 75% l form, more preferably at least 90% L form, and even more preferably at least about 95% L type and more preferably substantially pure phase B. The preparation of the seeding species described above with respect to the sputum type ipproxone also allows for improved control of the particle size of the crystallized ipproxone. 5 · Crystallization directly from solution L-L-type eplerenone is also prepared by direct crystallization of eptrozolone from a suitable solvent or solvent mixture without the formation of an intermediate solvate and without the need for solvent removal. Typically, (1) the molecular size of the solvent is incompatible with the channel space available for the solvate lattice, (ii) ipproxone and any impurities present in the solvent at room temperature, and (iii) cooling Crystallization of B-type Epson without solvent. The solubility of eplerenone in a solvent or solvent mixture is usually from about 5 to about 2 mg/ml at room temperature. The solvent or solvent mixture preferably comprises one or more selected from the group consisting of methanol, ethyl acetate, isopropyl acetate, 67790-950421.DOC^g. This paper scale applies the towel g national standard (CNS) Μ specification ((10)X tear public love) 1290558 A7 B7 V. INSTRUCTIONS (42) A group consisting of acetonitrile, nitrobenzene, water and ethylbenzene. In order to crystallize L-type eplerenone directly from the solution, the quantitative ipproxone material is dissolved in a constant volume solvent and cooled to crystal formation. The solvent temperature at which edetone is added to the solvent is usually selected based on the solubility curve of the solvent or solvent mixture. For most of the solvents described herein, such solvents typically have a temperature of at least about 25 ° C, preferably from about 30 ° C to the boiling point of the solvent, and more preferably from 25 ° C below the boiling point of the solvent to the boiling point of the solvent. temperature. Alternatively, a hot solvent may be added to the ipproxone and the mixture cooled until the crystals are formed. The solvent temperature when added to ipproxone is usually selected based on the solubility curve of the solvent or solvent mixture. For most of the solvents described herein, such solvent temperatures are typically at least 25 ° C, preferably from about 50 ° C to about the boiling point of the solvent, and more preferably from about 15 ° C below the boiling point of the solvent to the solvent. The temperature of the boiling point. The amount of the ample solvent mixed with the volume of the solvent is also determined by the solubility curve of the solvent or solvent mixture. The amount of typical ipproxone added to the solvent does not completely dissolve in the volume of solvent at room temperature. For the majority of the solvents described herein, the amount of the eplerenone starting material to be mixed with the constant volume solvent is usually from about 1.5 to about 4.0 times the amount of ippromone which is soluble in the volume of solvent at room temperature, preferably about From 2.0 to about 3.5 times, for example about 2.5 times. To ensure the preparation of a product comprising a substantially pure phase L form, the eplerenone feedstock is typically high purity ipproxone. The edetone starting material is preferably at least about 65% pure, more preferably at least about 90% pure, more preferably at least about 98% pure, and most preferably at least about 99% pure. After the solvent of Eppone is completely dissolved in the solvent, the solution is typically slow 67790-950421.DOC -49&quot; This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1290558 A7 B7 V. Invention Description (43) Crystallization of L·type eplerenone by cooling. For example, for the large half-solvent described herein, the Lu's solution is cooled at a slower rate than about 1 ° C / minute, preferably at a rate of about 2 ° C / minute or slower and more preferably about 〇 . 冷却 5 ° C / min to about 〇. pc / min rate of cooling. The endpoint temperature at which the L-shaped crystal is harvested will depend on the solubility curve of the solvent or solvent mixture. For the majority of the solvents described herein, the endpoint temperature is typically less than about 25 ° C, preferably less than about 5 ° C and more preferably less than about -5 ° C. In addition, other techniques can be used to prepare L-type procanone crystals. Such techniques include, for example, but are not limited to, (i) dissolving the ipproxone starting material in a solvent and adding a co-solvent to aid in the crystallization of the oxime type ipproxone, (ii) vapor phase diffusion growth of the L-type prolone '(丨丨丨) by evaporation such as rotary evaporation of l-type ipproxone, and (iv) slurry conversion reaction. The L-type procanone crystals prepared as described above may be separated from the solvent by any conventional means such as filtration or centrifugation. Further, 'L-type ipproxone can be prepared by cooking (described in detail later) high-purity ippronone in a slurry of isobutyl ketone and ipproxone after filtration at the boiling point of the slurry. i. Direct preparation of the Η shape from the solution If the crystallization is carried out above the enantiomeric transition temperature (Tt) of the Η type and the L type, especially if the Η type growth promoter or the L type growth inhibitor is present, or When the solvent is seeded with a pure phase Η type crystal, the type 11 will be directly crystallized from the solution because the Η type has a higher temperature stability and higher. The solvent system used preferably comprises a high boiling solvent such as nitrobenzene. Suitable growth promoters include, but are not limited to, the above-defined diepoxides and 丨U2_ 67790-950421.DOC - 5 0 _ I paper scale applicable towel country g standard (CMS) A4 specifications (2igx 297 mm) &quot ; - Binding

A7 B7

1290558 V. INSTRUCTIONS (44) Compound compounds. 7·Using a spirulina steamed sapphire half-yield and a sulphuric acid mixture crystal form, H-type and type II can also be prepared from a cold solvent mixture via cooking eppoxone starting material. In the middle of the 'apple ketone slurry is heated at the boiling point of the solvent or solvent mixture, such as quantitative edetone raw material combination volumetric solvent or solvent mixture, Z heat to reflux, and the distillate is removed while adding an additional amount of solvent . In addition, the product can be condensed and recycled without adding additional solvent during the cooking process. Typically, the solvent of the original volume has been removed or condensed and recycled, and the slurry is cooled and the solvated crystals are formed. The solvate crystals can be separated from the solvent by any suitable means such as filtration or concentration. The solvent for removing the aforementioned solvate can be obtained by selecting whether or not a selected impurity is present in the solvated crystal. Suitable solvents or solvent mixtures typically include one or more of the solvents previously disclosed. The solvent may, for example, be selected from the group consisting of isobutyl ketone and ethanol. The amount of the eplerenone starting material added to the solvent used in the cooking process is usually sufficient to maintain the slurry at the boiling point of the solvent or solvent mixture (i.e., the ipproxone is not completely dissolved in the solvent or solvent mixture). For example, an Epson concentration of about 0.25 g/ml in isobutyrone or about 25 ml of ethanol can be used. Once the solvent is completely turned on, the slurry is typically slowly cooled to crystallize the solvate form of the solvent. For the test solvent, the slurry is cooled at a slower rate than about 20 ° C / minute, preferably about 10 ° C / minute or slower, more preferably about 5 ° C / minute or slower, and even better. About fC/min or slower.

67790-950421.DOC This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Order

Line -51- A7 B7 1290558 V. INSTRUCTIONS (45) The endpoint of the solvated crystalline form is determined by the solubility curve of the solvent or solvent mixture. For most of the solvents described herein, the endpoint temperature is typically less than about 25 tons, preferably less than about and more preferably less than about -5 °C. High purity eplotone starting materials are typically cooked if it is desired to predominantly or exclusively comprise the L-form product. The high purity ipprox starting material is preferably at least about 98% pure, more preferably at least about 99% pure, and still more preferably at least about 99.5% pure. The post-cooked ipproxone product prepared in this manner typically comprises at least about 10%, preferably at least about 50%, more preferably at least about 75%, still more preferably at least about 90%, and even more preferably at least about 95% L-form. And the best is essentially pure phase L type. A low purity ipprox starting material is typically cooked if it is desired to predominantly or exclusively comprise a quinoid product. The low-purity ipprox starting material usually contains only the quintic growth promoter and/or the L-form growth inhibitor which are required to obtain the quinoid type. Preferably, the low purity ippromone starting material is at least about 65% pure, more preferably at least about 75% pure, and still more preferably at least about 80% pure. The cooked ipproxone product prepared in this manner typically comprises at least about 10%, preferably at least about 50%, more preferably at least about 75%, still more preferably at least about 90%, and even more preferably at least about 95%. The type and the best are substantially pure phase type. 8. Preparation of amorphous ipprodone Amorphous ipproxone can be prepared in small amounts by means of a suitable solid lypodex, for example by crushing, grinding and/or pulverizing. The pure phase amorphous ipproleone, i.e., the amorphous ipproxone substantially free of crystalline ipproleone, can be prepared, for example, by lyophilizing an aqueous solution of ipproxone, particularly an aqueous solution of ippromone. These methods are described in Examples 13 and 14 of this case. Additional treatment considerations 67990-950421.DOC - 5 2 - This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) A7 B7 1290558 V. Description of invention (46) 1. Thermodynamic stability consideration L-type The ambient temperature is more stable than the thermodynamics of the Η type. As described in Example 5 of the present example, when an organic slurry containing an equal amount of hydrazine type and L type was allowed to stand at room temperature overnight, then the residual solids were collected and analyzed by diffraction of X-ray powder, and the analysis indicated that ippromone had completely converted into L. type. The differential scanning calorimetry (DSC) data discussed above indicates the thermodynamic stability of the higher temperature enthalpy than the L type because of its higher melting point/decomposition point. In summary, the slurry conversion and DSC data indicate that the Η type and L type are enantiomeric, that is, the stability between the two polymorphic compounds is related to the change of the transition temperature (Tt). The low temperature is relatively stable. Figure 77 shows the relationship between the Gieber's free energy and the temperature observed for a general enantiomerically related polymorphic compound such as anthraquinone and L-type eplerenone, where Tt represents the transition temperature & Tm represents the indole type and the L-type melting point. . Thus, during the preparation of the composition comprising the L-form, the treatment temperature is preferably maintained below the transition temperature. For example, the drying temperature for solvent removal is typically less than about 150 ° C, preferably less than about 125 ° C, more preferably less than about 115 ° C, more preferably less than about 110 ° C, and more preferably from about 80 ° C to about 110 ° C. In addition, cooling (e.g., using liquid nitrogen cooling) may require cooling during the particle size reduction process to maintain the L-type crystal temperature below the transition temperature. 2. Intrinsic micronization considerations The preparation of crystalline ipproxone may affect the resulting crystalline form. For example, the L-form prepared by solvent removal from the solvent has a higher incidence of lattice internal surface flaws, pores, cracks and fractures than the L-form which is directly crystallized by the solution. The "essential micronization" of such desolvent crystals results in an increase in crystal available surface area and crystal dissolution rate. Therefore, the dissolution time can be 67790-950421.DOC -53&quot; This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 public) 1290558 A7 ---------- B7 V. Invention description (47) L-type crystals prepared by solvent removal, by L-type crystals prepared by direct crystallization, or by appropriate combination of B-crystals prepared by solvent removal and L-type crystals prepared by direct crystallization The dissolution time was adjusted by combination. Intrinsic micronization can also be effective in reducing or eliminating the need to reduce the crystal size during the processing step. Here, L-type crystals prepared by solvent removal are used to prepare medical compositions. However, the disadvantage of using such an L-type crystal is that it requires a solvent removal step. This is not required for the preparation of an L-type crystal by direct crystallization. Products of the 1-State Form Method The specific embodiments of the present invention also include the special solid-increase forms and combinations thereof prepared according to the methods disclosed herein. In particular, the sputum-type ipproxone, either alone or in combination with one or more other solid forms (including solvent-based, L-form and amorphous ipproxone prepared as described herein) are specific embodiments of the invention. . Further, it can be used as a solvent solvate type for preparing an intermediate of quinone type ipproxol by solvent, and a specific embodiment of the invention is disclosed by the preparer as described in the present specification. The solid-state composition is in a combination comprising a first solid-type ippronone and a second solid-type apex, wherein the first and second solid-type ipproxone are selected from the group consisting of Η type, type l, and solvent combination Both ipproxone and amorphous ipproxone can be used in any suitable weight ratio of the first type to the second solid type. Generally, in such a combination, the weight of the first to second solid forms is preferably from about 1:99 to about 99:1, and 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 and optimally at least about 9:1. -54-

67790-950421.DOC This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 mm) 1290558 A7 _______Β7___ V. Inventive Note (48) According to an embodiment of the present invention, the first solid type is a Η type and The second solid type is an L type. A third solid state is also present in another embodiment. Particle size of ippronone Although the various solid-type ipproxone combinations and combinations thereof cover a wide range of ipproxone particle sizes, it has been found that the particle size of solid eppocone is reduced to a particle size of less than about 400 microns. The bioavailability of the unadapted ipproxone and the pharmaceutical composition comprising the solid type Epson can be improved. The unadapted ipproxone or the D9 oxime particle size of ipproxone used as a starting material for the preparation of a pharmaceutical composition is generally less than about 4 Å, preferably less than about 200 μm. About 15 microns, more preferably less than about 1 inch and more preferably less than about 90 microns. In a specific embodiment, the Dm particle size is no less than about 25 microns. D9 〇 particle size in the range of from about 25 to about 400 microns is typically used for most applications with acceptable bioavailability, in order to prevent cost increases and to increase the need for grinding to control the environmentally-friendly exclusion of smaller size. An acceptable bioavailability of this particle size range is particularly obtainable when there is a substantial proportion of Epson® in the presence of indole-type ipproxone, at least in part due to an increase in the dissolution rate of the crystalline form. The reason. Suitable d9 〇 particles in accordance with this embodiment range from about 40 to about 1 Å. Another suitable range is from about 3 Torr to about 5 Å microns. Yet another suitable range is from about 5 Å to about 15 Å microns. Yet another suitable range is from about 75 to about 125 microns. Any grinding, milling, micronizing or other particle size reduction known in the industry can be used to smear the sorrower to any of the aforementioned predetermined particle sizes.

67790-950421.DOC This paper scale applies to China National Standard (CNS) A4 specification (21〇X297 公董) 1290558 A7 Factory _ B7 V. Invention Description (49) Wai. For example, air jet or segmented grinding can be effectively used for this project. When the right ratio needs to consider the cost and the highest possible bioavailability is required, it is found that reducing the particle size of the solid epulsone to a particle size of Dm of less than about 15 μm can further improve the unadapted ipproxone and include the solid type. The bioavailability of the 4 drug composition of ipproxone is even higher than the bioavailability of the d9G particle size range as defined above. Thus, in one embodiment, the d9() particle size is from about 0 to about 10 microns (10 nanometers) to about 15 microns. Preferably, in the specific embodiment, the D9G particle size is less than about 1 Å, more preferably less than about 1 μm, still more preferably less than about 800 nm, still more preferably less than about 600 nm, and most preferably less than about 400 nm. ^Depending on the application, a suitable D9G particle size is in the range of from about 100 to about 800 nanometers. Another suitable range is from about 200 Å to about 600 nm. Yet another suitable range is from about 400 nanometers to about 800 nanometers. Yet another suitable range is from about 500 nanometers to about 1 micrometer. Solid-type ipproxone having a D9G particle size of less than about 15 microns can be prepared according to suitable particle size reduction techniques known in the art. Such techniques include, but are not limited to, the techniques described in the following patents and announcements, each of which is incorporated herein by reference.

U.S. Patent No. 4,826,689 to Violanto and Fischer °

U.S. Patent No. 5,145,684 to Liversidge et al.

U.S. Patent No. 5,298,262 to Na and Rajagopalan.

U.S. Patent No. 5,302,4,1 to Liversidge et al.

U.S. Patent 5,336,507 to Na and Rajagopalan.

U.S. Patent No. 5,340,564 to Illig and Sarpotdar.

U.S. Patent No. 5,346,702 to Na and Rajagopalan.

67790-950421.DOC This paper size is suitable for the country of wealth (10) A4 size 297 mm)

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1290558 A7 B7 V. Description of invention (50)

U.S. Patent No. 5,352,459 to Hollister et al. U.S. Patent No. 5,354,560 to Lovrecich. U.S. Patent No. 5,384,124 to Courteille et al. U.S. Patent No. 5,429,824 to June.

U.S. Patent No. 5,503,723 to Ruddy et al.

U.S. Patent No. 5,5,10,118 to Bosch et al.

U.S. Patent No. 5,518,187 to Bruno et al. U.S. Patent No. 5,518,738 to Eickhoff et al.

U.S. Patent No. 5,534,270 to De Castro.

U.S. Patent No. 5,536,508 to Canal et al. U.S. Patent No. 5,552,160 to Liversidge et al. U.S. Patent No. 5,560,931 to Eickhoff et al. U.S. Patent No. 5,560,932 to Bagchi et al.

U.S. Patent No. 5,565,188 to Wong et al.

U.S. Patent No. 5,569,448 to Wong et al. U.S. Patent No. 5,571,536 to Eickhoff et al. U.S. Patent No. 5,573,783 to Desieno and Stetsko. U.S. Patent No. 5,580,579 to Ruddy et al.

U.S. Patent No. 5,585,108 to Ruddy et al.

U.S. Patent No. 5,587,143 to Wong.

U.S. Patent No. 5,591,456 to Franson et al. U.S. Patent No. 5,622,938 to Wong.

U.S. Patent No. 5,662,883 to Bagchi et al. U.S. Patent No. 5,665,331 to Bagchi et al. 67790-950421.DOC - 5 7 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1290558 A7 B7 V. Description of invention (51)

U.S. Patent No. 5,718,919 to Ruddy et al.

U.S. Patent No. 5,747,001 to Wiedmann et al. International Patent Publication No. WO 93/25 190. International Patent Publication No. WO 96/24336. International Patent Publication No. WO 98/35666. In the illustrated method, the crude solid ipproxone is added to a liquid medium which is substantially insoluble in the liquid medium to form a premix suspension. The concentration of eplerenone in the liquid medium can vary from about 0.1% to about 60% and preferably from about 5% to about 30% by weight. The premix suspension preferably has a nominal viscosity of less than about 1000 centipoise (cP). The premix can be directly subjected to mechanical means such as using a ball mill to reduce the particle size of the D9® of the ipproxone to a predetermined range. Further, the premix may first be agitated, for example, using a roll mill or a Cowles type mixer until a uniform dispersion is observed, in which there are no large aggregates visible to the naked eye, and then the grinding is performed without using a circulating media mill. . The particles can be ground in the presence of a surface modifying agent such as a polymer or humectant. In addition, the particles may contact the surface modifier after grinding. Surface modifiers reduce particle agglomeration and have other effects. The particles must be reduced in particle size at temperatures that do not significantly decompose the ipproxone. Processing temperatures below about 30-40 ° C are generally preferred. If desired, the processing equipment can be cooled using conventional cooling equipment. The method is conveniently carried out at ambient temperature and at a safe and effective processing pressure during the grinding process. For example, the surrounding pressure point type uses a ball mill, a grinding mill, and a vibration mill. Temperature control can be achieved by adding a jacket or immersing the grinding chamber in ice water. Pre 67790-950421.DOC - 5 8 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Line 1290558 A7 ___ _B7 V. Inventive Note (52) A treatment pressure of from about 0.07 to about 3.5 kg/cm 2 is used, with a typical pressure of about 0.7 to 4 kg/cm 2 . After the completion of the milling, the grinding media is separated from the ground product in the form of a dry or liquid dispersion using conventional separation techniques such as filtration, sieving through a mesh screen, and the like. The pharmaceutical combination t is also included in the scope of the present invention as a class of pharmaceutical compositions comprising (1) Η type Epler _ 'selectively connected with one or more additional solid forms of eppoconone selected from the group consisting of L-form, solvo-crystal, and amorphous a group consisting of ipproxone and (ii) one or more pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "excipients") and selectivity (Hi) One or more active ingredients other than ippromone. In a preferred embodiment, the total amount of ipproxone substantially contained in the composition is in the form of a pure phase; however, if a combination of solid forms is present, the preferred weight ratio of the solid form is as previously stated. Further, substantially all of the ippronone contained in the composition may be present as a pure phase-combining crystalline ippronone or amorphous ipproxone. In another embodiment of the invention, the composition comprises a Η type and an L type. The weight ratio of the L-form to the oxime in the composition is usually from about ι:2 〇 to about 20:1. In another embodiment, the child to hand ratio is from about 10:1 to about 1:10; from about 5:1 to about 1:5; from about 2:1 to about 1:2; for illustrative weight ratios It is about ι:1. The compositions of the present invention may be adapted for any suitable route of administration including, but not limited to, oral, buccal, sublingual, parenteral, such as intravascular endothelium or muscle, local and rectal (e.g., a test). These compositions comprise the required amount of ipproxone combination of one or more suitable pharmaceutical routes for the intended route of administration. 67790-950421.DOC - 5 9 - This paper scale applies to the Chinese National Standard (CNS) Α 4 specification (210 X 297 PCT) ' — 1290558 A7 B7 V. INSTRUCTIONS (53) Receptive excipients. 1. Oral compositions and oral dosage forms thereof which are formulated into such compositions preferably comprise one or more groups selected from the group consisting of diluents, disintegrating agents, binders and adhesives, wetting agents, lubricants, and anti-adhesive agents. Group of excipients. More preferably, these oral dosage forms are administered by tableting or encapsulating. As a result, the resulting (iv) or capsule may contain a formulation which provides an immediate release formulation and/or a controlled release formulation such as a dispersion of ipproxone in hydroxypropylmethylcellulose (HPMC). By appropriate choice of excipients and excipients, the composition is effective, bioavailability, clearance time, stability, compatibility of ipproxone with excipients, safety, dissolution profile, disintegration Improved properties in terms of side draw and/or other pharmacodynamic, chemical and/or physical properties. The excipient is preferably water-repellent or water-dispersible, and has a wettability to compensate for ipproxone &lt;low solubility in water. If the composition is formulated as a lozenge, the combination of excipients selected to provide the lozenge provides properties such as improved solubility and disintegration, hardness, milk strength and/or brittleness. 1.1 Diluent The compositions of the present invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents include, for example, individual or combination, lactose, including anhydrous lactose and lactose monohydrate; starches include direct compressed starches and hydrolyzed starches (e.g., Celutab and Emdex); mannitol ; sorbitol; xylitol; glucose (eg, Cerelose 2000) and glucose monohydrate; phosphate dicalcium phosphate dihydrate, recommended diluent for sugar; sugar for pastry; Qiji Ma Yishui

67790-950421.DOC -60- This paper size is applicable to τ _ ^: Standard (CNS) specification (plus χ公公爱) 1290558 A7 —----—— —_B7___ V. Description of invention (54) I—&quot;- -- : substance, sulfuric acid dance dihydrate; granular lactic acid #5 trihydrate; polydextrose, esters, inositol; hydrolyzed cereal solids; pentose; cellulose including micro-glycocellulose, food grade α • and amorphous cellulose sources (such as Rexcel) and powdered cellulose; calcium carbonate; glycerin; bentonite; polyglycols &quot; Biha bite. If present, such diluents comprise from about 5% to about &quot;%, preferably from about 10% to about 85%, and more preferably from about 20% to about 8%, based on the total weight of the composition. The dilution W selected preferably has suitable flow properties and is suitably compressible when intended to be formulated into a tablet. Lactose and microcrystalline cellulose are preferred diluents when used alone or in combination. Both diluents are chemically compatible with ipprodone. The use of extragranular microcrystalline cellulose (i.e., the drying step or microcrystalline cellulose added to the wet granulation composition) can be used to improve hardness (tablet hardness) and/or break time. Lactose is particularly preferred as lactose monohydrate. Lactose is typically available at relatively low diluent cost to provide a composition having a suitable rate of release, stability, pre-compression flow and/or drying properties. A high density matrix can be provided which facilitates densification during granulation (if wet granulation is employed), thereby improving the flow properties of the mash. 1.2 Disintegrating Agents The compositions of the present invention optionally comprise one or more pharmaceutically acceptable disintegrating agents as excipients, particularly for lozenge formulations. Suitable disintegrating agents, whether used individually or in combination, include starches, including sodium starch glycolate (eg, Epithettab from PenWest) and pregelatinized corn starch (eg, Nesino) National 1551, Nesino 1550 and Colocorn), clay (eg Veeguin), cellulose such as pure 67790-950421.DOC -61- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇X 297 DON) A7 B7 1290558 V. Description of invention (55) Cellulose, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, and dimethyl cellulose nano gram Croscarmellose steel (such as Ac-Di-Sol from FMC), alginate, cr〇sp〇vid〇ne, and gums such as agar, guar, locust bean gum, Caraya (karaya), pectin and western gum. The disintegrating agent can be added at any suitable step in the preparation of the composition, particularly prior to granulation or during the lubrication step prior to tableting. Such disintegrating agents, when present, comprise from about 0.2% to about 30%, preferably from about 0.2% to about 10%, and more preferably from about 0.2% to about 5%. Kecamerol sodium is a preferred disintegrating agent for the disintegration of tablets or capsules, if present, from 0.2% to about 10%, more preferably from about 0.2% to about 7%, and more preferably from about 3% to about 7% of the total weight of the composition. 0.2% to about 5%. Kecamerol sodium provides excellent intragranular disintegration properties to the granulation compositions of the present invention. 1.3 Adhesives The compositions of the present invention optionally comprise one or more pharmaceutically acceptable binders or adhesives as excipients, particularly for lozenge formulations. These binders and adhesives preferably provide sufficient cohesion to the tablet powder to allow for normal processing operations such as sieving, lubrication, compression, and packaging, but still allow the bond to collapse upon ingestion and the composition to be absorbed. Suitable binders and adhesives, including acacia gum; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (eg, Nesino 15 11 and Nesino 1 500). Cellulose such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (such as Tylose); alginic acid and alginate; magnesium aluminosilicate; polyethylene glycol (PEG); Glue; polysaccharide acid; soap

67790-950421.DOC This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

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Line-62- 1290558 A7 B7 V. Description of invention (56) Soil, polyethylidene pyrrolidone (povidone or PVP), such as Pvillon K-15, K-30 and K-29/ 32; polymethyl propyl benzoate; HPMC; hydroxypropyl cellulose (e.g., Klucel); and ethyl cellulose (e.g., Ethocel). Such binders and/or adhesives, if present, comprise from about 0.5% to about 25%, preferably from about 0.75% to about 15%, and more preferably from about 1% to about 10%, by total weight of the composition. HPMC is a preferred adhesive for providing cohesive properties to powder mashes of ipprodone formulations. The HPMC, if present, comprises from about 0.5% to about 10%, preferably from about 1% to about 8%, and more preferably from about 2% to about 4%, by total weight of the composition. Low molecular weight HPMC having a viscosity of from about 2 to about 8 centipoise may be used, preferably from about 2 centipoise to about 6 centipoise, and preferably from about 2 centipoise to about 4 centipoise. The HPMC viscosity was measured as a 2% aqueous solution at 20 °C. The methyl oxygen content of HPMC is typically from about 15% to about 35%, while the hydroxypropyl content is typically up to about 15%, preferably from about 2% to about 12%. 1.4 Wetting agent Apexone is mostly insoluble in aqueous solution. Thus, the compositions of the present invention are selective but also contain one or more pharmaceutically acceptable wetting agents as excipients. Preferably, such humectants are selected to maintain the close binding of ippromone to water, which conditions are believed to improve the relative bioavailability of the composition. Non-limiting examples of surfactants useful as humectants in the compositions of the present invention include tetraammonium compounds such as decane chloride, phenethyl chloride, and cetylpyridinium chloride, sodium sulfosuccinate Octyl ester, polyoxyethylene ethyl phenyl ethers such as nonoxynol 9, Nanosour 10 and octoxynol 9, poloxamers (polyoxo extension) Ethyl to 67790-950421.DOC - 6 3 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1290558 A7 _____ Β7 V. Invention description (57) and polyoxypropylene block copolymerization , polyoxylated ethyl glycerides and oils such as polyoxyethyl (8) octanoic acid / citric acid mono- and di-glycerides (such as La Basso of Gattefoss6) (Labrasol)), polyoxyethylene ethyl (35) castor oil and polyoxyethylene (4〇) hydrogenated castor oil; polyoxyalkylene alkyl ethers such as polyoxyethyl (2) cetyl Base stearyl ether, polyoxyethylidene esters such as polyoxyethylidene (4〇) stearate, polyoxyethylene ethyl sorbitol ester Such as P〇lys〇rbate 20 and Polisso 80 (such as Tween 80 from ICI), propylene glycol fatty acid esters such as propylene glycol laurate (such as Laroche from Jatford) (Lauroglycol), sodium lauryl sulfate, fatty acids and salts thereof such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters such as monostearyl glyceride, polysorbate such as Polysorbate laurate-polysorbate monooleate, a palmitic acid polysorbate and a stearin fel polysorbate, tyl〇xap〇l and mixture. Such humectants, if present, comprise from about 0.25% to about 15% by weight of the total composition, preferably from about 0.4% to about 10%, and more preferably from about 5% to about 5%. The humectant is preferably an anionic surfactant. Sodium lauryl sulfate is a preferred wetting agent. Sodium lauryl sulfate, if present, comprises from about 0.25% to about 7% by weight of the total composition of the composition, more preferably from about 4% to about 4%, and still more preferably from about 5% to about 2%. 1.5 Lubricants, Sliding Agents and Anti-Adherents The compositions of the present invention optionally comprise one or more pharmaceutically acceptable lubricants and/or slip agents as excipients. Suitable lubricants and/or slip agents, individually or in combination, include glyceryl behenate (for example, C〇mprit〇l 888); hard-64-

67790-950421.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 dongdong) 1290558 A7 B7 V. Description of invention (58) Fatty acid and its salts include magnesium, calcium and sodium stearate; hydrogenation Vegetable oil (eg, Sterotex); colloidal cerium oxide; talc; wax; boric acid; sodium benzoate, sodium acetate; sodium fumarate; sodium chloride, · DL-leucine; (eg Carb〇wax 4〇〇〇 and Carbowa 6〇〇〇); sodium oleate; sodium lauryl sulfate and magnesium lauryl sulfate. Such lubricants and/or slip agents, if present, comprise from about 1% to about 10%, preferably from about 2% to about 8%, and more preferably from about 25% to about 5% by weight of the total composition. 〇/〇. Magnesium stearate is a preferred lubricant, for example, to reduce friction between the tablet formulation during compression and the granulation mixture. Suitable anti-adhesive agents include talc, corn starch, DL_leucine, sodium lauryl sulfate and metal stearates. Talc is a preferred anti-adherent or slip agent for, for example, reducing the adhesion of the formulation to the surface of the device and/or reducing the static communication of the composition. The talc, if present, comprises from about % to about, more preferably from about 0.25% to about 5%, and more preferably about 5%, of the total weight of the composition. /❶ to about 2%. U Other Fuling Pain | Other excipients such as coloring agents, colorants and sweeteners are known in the pharmaceutical industry and can be used in the compositions of the present invention. Tablets may, for example, be enteric coated or uncoated. The compositions of the present invention further comprise, for example, a buffer. 1__7 Preferred Oral Usa In one embodiment, the compositions of the present invention comprise a predetermined amount of ipproxone and one or more cellulosic excipients. The term "cellulose excipient" encompasses excipients containing fibrin or its derivatives, including but not limited to purified cellulose. "Cellulose and burnt cellulosics and their derivatives and salts." (eg methyl cellulose 'ethyl cellulose, hydroxypropyl cellulose, HPMC, carboxymethyl

67790-950421.DOC -65- 1290558 A7 ___ B7 V. INSTRUCTION DESCRIPTION (59) The base cellulose 'carboxymethylcellulose sodium includes cladamerol sodium, etc.). Preferably, at least one of the cellulose excipients is selected from the group consisting of (Ci 6 alkyl) cellulose esters and derivatives thereof and salts. More preferably, the cellulose excipient is selected from the group consisting of hydroxy (Cwfe-based HCw alkyl)-cellulose and derivatives thereof and salts. The compositions of this embodiment preferably further comprise one or more excipients selected from the group consisting of diluents, disintegrating agents, binders, wetting agents, lubricants, and anti-adhesive agents. More preferably, such combinations comprise one or more excipients selected from the group consisting of lactose, microcrystalline cellulose, cicamelol sodium, HPMC, sodium lauryl sulfate, magnesium stearate and talc. Still more preferably such compositions comprise lactose monohydrate, microcrystalline cellulose, cicamelol sodium and HPMC; preferably further comprising one or more other groups selected from the group consisting of sodium lauryl sulfate, magnesium stearate and talc Group of excipients. The individual excipients listed above in this particular embodiment may be replaced by other suitable excipients if desired. Acceptable alternative excipients are compatible with the chemical nature of ipproxone and other excipients. Although other diluents, disintegrating agents, binders and adhesives, wetting agents, lubricants, and anti-adhesives or slip agents can be used, but include nanoparticulate eptrodone, lactose, microcrystalline cellulose, gram Combinations of sodium melamine and HPMC, as well as selective sodium lauryl sulfate, magnesium stearate and/or talc, generally have a combination of superior pharmacokinetic, chemical and/or physical properties over these other compositions. In another embodiment, the composition of the present invention comprises: from about 1% to about 95% ipproxone; from about 5 to about 99% to about 99% of a pharmaceutically acceptable diluent; -66-

67790-950421.DOC This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1290558

From about 0.5% to about 30% of a pharmaceutically acceptable disintegrating agent; and from about 0.5% to about 25% of a pharmaceutically acceptable binding agent; all 4% by weight. These compositions optionally comprise from about 25% to about 15% of a pharmaceutically acceptable humectant; from about 1% to about 1% by weight of a receptive lubricant, and/or from about 1% to about 1% to About 15% pharmaceutically acceptable anti-adherent. In still another embodiment, the compositions of the present invention are in oral unit dosage form, preferably a troche or capsule, comprising ipproxone and a cellulosic excipient as defined above. Preferably, the composition comprises one or more excipients selected from the group consisting of lactose monohydrate, microcrystalline cellulose, cicamelol sodium, hydroxypropyl methylcellulose, sulfuric acid lauric S steel, stearic acid money and talc. Group of people. 2. Parenteral composition The solid eppocone crystalline form of the present invention can be administered parenterally, for example, by intravenous, intramuscular or subcutaneous injection of a solid ippronone in a carrier liquid such as a saline solution, a glucose solution or a suspension of water. The suspension composition comprises a suitable excipient ingredient selected from the foregoing for oral compositions. 3. The transdermal composition The other composition may be in the form of a sirloin or a transdermal ointment or a cream, wherein the amount of the dispersed solid ipodone is, for example, from about 0.075% to about 30%, preferably from about 0.2% to about 20%. % by weight, and more preferably from about 4% to about 5% by weight. Such topical or transdermal compositions desirably include a composition which promotes transdermal absorption or passage through the skin of ippromone. Such percutaneous penetration enhancers include, for example, dimethyl sulfoxide and related compounds. The novel solid-type eplerenone can also be administered by patch transdermal administration. The patch is 67790-950421.DOC - 6 7 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1290558 A7 - -------------B7_ V. Invention ^^( 61 a) A ------- in the reservoir type and porous membrane type or solid matrix type. In either case, Epson is continuously delivered to the ipproxone permeable agent by a filter or by a microcapsule through a membrane which contacts the skin or mucous membrane of the individual. If ipproxone is collected, ipproxone is administered to the recipient at a controlled and predetermined flow rate. = Microcapsules, for example, encapsulation can also be used as an outer membrane. The present invention also encompasses a method of treating and/or preventing a aldosterone vector condition or disorder comprising the use of a therapeutically effective amount of solid ipproxone or a pharmaceutical composition having solid ipproxone To treat individuals who have or are sensitive to these conditions, at least a portion of the solid ipproxone can be detected as sputum-type ipproxone, and the difference includes one or more L-type ipproxone, solvent Combined with crystallization of ipproxone and amorphous ipprodone. This method is suitable for use in individuals with aldosterone antagonists for the prevention and/or treatment of conditions or conditions, including but not limited to the treatment of conditions such as high levels of aldosterone in the blood such as hypertension, heart failure including heart failure, cirrhosis, collagen Excessive, fibrotic, benign prostatic hypertrophy and depression. In addition to being useful in the treatment of humans, such solid epproxone and its pharmaceutical compositions are also useful in the treatment of companion animals, exotic animals and farm animals such as horses, dogs and cats for use in animals. Solid-type eplerenone and its compositions can also be used in combination with (1) partial or partial replacement of other aldosterone receptor antagonists and/or (ii) in combination with other drugs. The term "combination therapy" includes the sequential administration of various drugs in a treatment plan that provides the beneficial effects of a combination of drugs and the simultaneous administration of drugs in a substantially simultaneous manner, such as in a single capsule or injection-68 -

67790-950421.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇χ297 mm) A7 B7 1290558 V. Invention description (62) Contains a fixed proportion of active agent or multiple separate dosage forms or injections There is one active agent for the dosage form or for each injection. Non-limiting examples of such combination therapies include the use of an acid: ketone receptor antagonist in combination with an angiotensin II receptor antagonist to treat cardiovascular disease, as described in International Patent Publication No. 96/24373, Treating congestive heart failure using a combination of an acid ketone receptor antagonist and an angiotensin II antagonist, as described in International Patent Publication No. WO 96/40257; and using an acid ketone receptor antagonist, A combination of an ace inhibitor and a diuretic for the treatment of heart failure, as described in International Patent Publication No. WO 96/24372, the entire disclosure of which is incorporated herein by reference. EXAMPLES The following examples contain detailed descriptions of the various solid-type eplerenone processes described herein. The detailed description is intended to be illustrative, and not restrictive. All percentages are by weight unless otherwise indicated. The aldosterone starting materials used in the following examples were prepared in accordance with the reaction scheme described in the aforementioned International Patent Publication No. WO 98/25948. __Example 1: Preparation of isobutyl ketone solvate from high-purity aldosterone raw material and preparation of L-type aldosterone △ • isobutyl ketone thick sulphate from solvate with a high purity aldosterone of 437 mg (purity greater than 99%, the total amount of the diepoxide and the 11,12-epoxide was less than 0.2%) was dissolved in 1 ml of isobutyl ketone by heating to boiling on a hot plate at a magnetic stirring of 900 rpm. The resulting solution was allowed to cool to room temperature with continuous magnetic stirring. Once at room temperature, the solution was transferred to 1 bath with continuous stirring for 1 hour and continuously agitated for 1 hour. Solid isobutyl ketone solvate was collected from cold solution by vacuum filtration ^ -69-

67790-950421.DOC Paper Quality Standards® National Standard (CNS) ΜSpecifications (21G 297 297 gong) 1290558 A7 ___B7 V. Description of Invention (63) This type 1 _ ipproxone is prepared as above The solid isobutyl ketone solvate was dried in an oven at ambient pressure for 4 hours at ambient pressure. The dry solid was determined to be pure 1^ by DSC &amp; XRpD*. g. Preparation of a high hydrazone eploc solvate. The additional solvate crystalline form was prepared essentially as in Example i by replacing the isobutyl ketone with n-propanol, 2-pentanone, acetic acid, using the following solvents: Acetone, butyl acetate, chloroform, ethanol, isobutanol, isobutyl acetate, isopropanol, methyl acetate, ethyl propionate, n-butanol, n-octanol, propyl acetate, propylene glycol, third butanol , tetrahydrofuran and toluene. Reproducible Example 3: Preparation of isobutyrone phthalate in an amount of 400 mg of ipproxone (greater than 99.9% purity) by means of gas diffusion. Phase diffusion was carried out by hot plate heat; 4 solution was 203⁄4 liters of isobutyl ketone. A backup solution is formed. 8 ml of the preparation was diluted with isobutyl ketone to i0 ml, and the resulting solution was weighed as an 80% dilution sample. 4 liters of the standby solution was diluted to 丨〇ml (4〇% ml diluted sample) using isobutyl ketone. A 2 ml amount of the stock solution was diluted to 1 mL (20% diluted sample) using isobutyl ketone. Each diluted sample was transferred to a desiccant bottle in a 2 ml scintillation vial containing a small amount of hexane as the anti-volume. The desiccant bottle is sealed and any hexane vapor is diffused into the isobutyrone solution. The ipproxone isobutyrone solvate crystals were grown into 8 〇〇/0 diluted samples within 24 hours. The evaporator was prepared by crystallizing hydrazine solvate crystallization. About 4003⁄4 grams of ipproxone (greater than 99.9% purity) was weighed into a 25 liter round bottom bottle. A solvent selected from the group consisting of isobutyl ketone and a solvent content of 15 liters as exemplified in Example 2 were added to the flask, and if necessary, the solution was gently heated until the ipproxone was dissolved. -70-

67790-950421.DOC This paper scale coffee Chinese National Standard (CNS) A4 specification (210X 297 dongdong) 1290558

The resulting clear solution was placed on a Buehi rotary evaporator at a bath temperature of about 85 c^ and the solvent was removed under vacuum. The removal of the solvent was stopped when about 1 ml of solvent was left in the flask. The resulting solid is analyzed by a suitable method (e.g., xrpd, DSC, TGA, microscopy, etc.) to determine the crystalline form. Exemption Example 5 ····································································· The resulting slurry was magnetically stirred overnight at 3 rpm. The solid sample obtained the next day was collected by filtration. The XRPD analysis sample indicated that the sample consisted entirely of L-type levulone. Preparation of tanning agent for ketone raw materials! Preparation of solvate to prepare cobalt crystal eppyrone, containing unequal amount of diepoxide or bismuth U2-epoxide impurity sample here by adding a predetermined amount of impurities to 7 The so-called scintillation vial together with the quantitative ipproxone is sufficient to provide a total sample mass of 100 mg. The impurity content of each sample is π in Tables 6A and 6B, where the impurities are respectively a diepoxide or a ruthenium, an epoxide. A micro magnetic stirrer was added to each scintillation vial along with 1 liter of isobutyl ketone. The bottle was capped and the solid was heated to reflux at a hot plate using magnetic stirring. Upon completion of the dissolution, the resulting solution was allowed to cool to room temperature and stirring was continued. The resulting solid was then collected by vacuum filtration and immediately analyzed by XRpD. The solid is placed in an oven at 100 ° C and dried at atmospheric pressure in Zhouyuan! hour. The dry solids were analyzed for H content by monitoring the area of the diffraction peak of about 2.112. All XRPD diffraction patterns were recorded using an Ino multi-purpose diffractometer. Table 6 A: Example 6 Apoleone raw material composition 丨 Eppone (mg) | bicyclic fly-form (mg) - 67790-950421.DOC -71 1290558 A7 B7 V, invention description (65) 0 100.44 0 1 99.08 1.24 2 98.09 2.24 3 97.08 3.04 5 95.09 5.04 Table 6B: Example 6 Apoleone Raw Material Composition %11,12-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. Binary gasification results Figure 78 shows from (a) 0%, (b) 1%, (c) 3% and (d) 5% diepoxide The XRPD pattern of the isobutyl ketone solvate wet cake obtained by the doping of isobutyl ketone. The peak intensity is routinely compared for comparison. No peaks having the characteristics of Η-type or di-epoxide are present in the diffraction pattern. The pattern is characterized by the edetrone isobutyrone solvate. Figure 79 shows the XRPD pattern of the dry solid obtained by crystallizing (a) 0%, (b) 1%, (c) 3% and (d) 5% of the diepoxide oxa isobutyl ketone. Peak intensity is routinely compared for comparison. The dry sample corresponding to the crystallization of isobutyl ketone did not detect any ruthenium type, where the epoxide impurity was 0% or 1%. The ruthenium type was detected on a dry sample corresponding to the crystallization of isobutanone, where the degree of abundance was 3% or 5%. Η Type The diffraction peak area of the diffraction peak area of about 12·1 degree 20 and the Η type content of each sample are shown in Table 6C. 67790-950421.DOC - 7 2 The paper size is applicable to China National Standard (CNS) Α4 specification (210X297 dongdong) 1290558 A7 B7 V. Description of invention (66) Table 6C: Data obtained from crystallization of isobutyrone of Example 6% Diepoxide in starting material % diepoxide in crystal (by HPLC) Η type peak area 12.1 degree 20 Η type estimated % 0 0 not detected 0 1 0.29 not detected 0 3 0.58 1168 10 5 1.05 4175 30 The results reported in Table 6C confirm the presence of dicyclopentoxides affecting the formation of quinoid eplerenone when the solvent is removed. The formation of the quinoid form is induced when the diepoxide is mixed and/or adsorbed to the isobutyrone solvate crystal. A second 3% diepoxide doping experiment was performed to analyze the effect of the number of quinones in the preparation pathway during solvent removal. In this experiment, the isobutyl ketone solvate obtained by doping crystallization was divided into two portions. The first one remained untreated, while the second one was slightly ground in a mortar and pestle to cause high crystal defects. The two parts were dried at 100 ° C for 1 hour at ambient pressure. Dry solids were analyzed by XRPD. The XRPD pattern for a dry solid obtained from the crystallization of isobutanone containing 3% doped diepoxide before drying (a) and (b) the ground solvate was shown in Fig. 80. The XRPD pattern indicates that the ground sample contains a higher amount of ruthenium than the unground sample. The results suggest that the isobutyrone solvate may affect the crystal form obtained by removing the solvent by isolation and treatment conditions. 11,. 11,12-epoxylate results Figure 81 shows crystallization from (a) 0%, (b) 1%, (c) 5% and (d) 10% 11,12-epoxide-doped isobutyl ketone The XRPD pattern of the resulting isobutyl ketone solvate wet cake. The peak intensity is easily compared by comparison. The diffraction pattern does not have the characteristic peak of the Η type or the 11,12-epoxide. This pattern is characteristic of the edetone isobutyl ketone solvate. 67790-950421.DOC - 7 3 _ This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 dongdong) 1290558

-74- Figure 82 shows from 0〇/λ,, K, t λ U U) 0/. (b) 1%, (c) 5% and (4) 1〇% n, i2 oxide doped isobutyl ketone granules 4, XRPD pattern of dry solid obtained by yang. The intensity of the Qifeng is easily compared by comparison. If the degree of doping of u, 12_epoxide is 〇%, 1% or 5%, the Η type should not be measured for the dry sample corresponding to the crystallization of isobutyl ketone. When the doping concentration of 11,12-alkaline oxide was 1%, the dry sample corresponding to the isobutyl crystallization was detected to be in the form of a ruthenium. The area of the 绕-type diffraction front at about ι2 度 ^ ^ and the estimated content of each sample is shown in Table 6 Ε ^ % 11, 12 · epoxide starting material N Η ag g Ming % West π Η type peak area 12.1 degrees 20 估计 type estimate. /〇 0 Not detected 〇 1 Not detected [0 5 Not detected 0 10 1541 10-15 ^ -rv, -a- ^ ^ m ^ Formation of type H ipproxone. The degree of impurity formation of the H-type ipprone to form the desired crystallization of the butyl ketone is apparently greater for the 丨U2_epoxide than for the bisoxide. t Example 7: Effect of crystallization and drying on the final crystallizing scraping The following four experiments were conducted to analyze the effect of crystallization and drying on the final crystal form: (i) Isoprofen crystallization of ipproxone (23+3 experimental statistic) Design), ((1) crystallization of poor quality mother liquor residue, (iii) crystallization of high-purity ipproxone using sputum seeding, and (iv) use of low-purity ipproxone [crystallization of type seeding. The experimental variables include cooling rate, feedstock purity, and crystallization endpoint temperature. For the purposes of this example, high purity ipproxone is defined as ultrapure (defined by HPLC) milled ipproxone, which is defined as low purity ipproxone.

67790-950421.DOC This paper scale is suitable for household goods (CNS) A4 specifications (210X297 mm) -----

A7 B7 1290558 V. INSTRUCTIONS (68) 89% purity ipprodone. In order to prepare low-purity ipproxone, the mother liquor obtained by the ipproxone method was analyzed and mashed to obtain a material comprising 61.1% ipproxone, 12.8% diepoxide and 7.6% 11,12-epoxide. . This material was then mixed with a sufficient amount of high purity ipproxone to obtain 89% ipproxone. A. Isobutyl Hydrazine and Crystalline 4 匕 In the crystallization experiment of isobutyl ketone, all treatments were carried out using 60 g of high-purity ipprodone. The high endpoint is defined as 45 ° C and the low endpoint is defined as 5 ° C. The high cooling rate is defined as 3 ° C / min and the low cooling rate is defined as 0.1 ° C / min. The midpoint was 1.5 ° C / min cooling rate, 94.5% purity ippronone and 25 ° C endpoint. After obtaining the background reading using FTIR, 250 ml of isobutyl ketone was fed to 1 liter of Mettler RC-1, MP10 reactor and stirred at 100 rpm. After several scans, ipproxone was fed to the reactor followed by a further feed of 470 ml of isobutyl ketone. The agitation was accelerated to 500 rpm to suspend the solids and the batch temperature was increased to 80 °C. The batch temperature was maintained at 80 ° C to ensure dissolution of ipprodone. The resulting clear solution typically shows black or white spots. The batch temperature was then gradually cooled down to a predetermined end point at a predetermined rate, where it was maintained for 1 hour, then extracted into a transfer bottle and filtered to obtain a wet cake. The reactor, transfer bottle and wet cake were washed with 120 ml of isobutyl ketone. Approximately 10 grams of the wet cake was dried in a vacuum oven at 75 ° C under conventional conditions with nitrogen breeze. The wet cake is dried by a fluidized bed under high and low conditions. The high condition for fluidized bed drying is defined as 100 ° C and the blower is set to 4; while the low condition for fluidized bed drying is defined as 40 ° C and the blower is set to 1. B. Poor quality crystallization of mother liquor residue involves crystallization of poor quality mother liquor residue, 60 g 61.1% 67790-950421.DOC -7 5~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 hectares)

Order

Line A7 B7 1290558 V. INSTRUCTIONS (69) Pure ipproxone and 720 ml of isobutyl ketone were fed directly into a 1 liter Mettler RC-1, MP10 reactor. Impure ipproxone was not highly homogenous ipproxone before feeding the reactor. The resulting mixture was heated to 80 ° C at which temperature was an opaque slurry. Crystallization was continued and the mixture was filtered at 45 ° C under rapid cooling. C. Sputum seeding crystal In the sputum seeding crystal experiment, 60 g of high-purity ippronone and 720 ml of isobutanone were fed to 1 liter of Mettler RC-1, ΜΡ10 reactor. The mixture was heated to 80 ° C and then cooled to 25 ° C at a rate of 1 - 5 ° C per minute. When the solution was cooled to 62 ° C, crystallization was started using 3 g of pure phase Η type crystals. The indole type seed crystals were prepared by the cooking method described in Example 9 below. D. L-type seeding crystal In the sputum seeding crystal experiment, 66.6 g 89.3 ° /. Eplotone (prepared by mixing 48.3 g of high purity ipproxone with 18.3 g of 61.1% ipproxone) and 720 ml of isobutyl ketone were fed to a 1 liter Metele RC-1, ΜΡ10 reactor. The mixture was heated to 80 ° C and then cooled to 25 t at a rate of 1 - 5 ° C per minute. When the solution was cooled to 63 ° C, crystallization was started using 3 g of pure phase L-type crystals. Η-type seed crystals were prepared by the crystallization and desolvation methods described in Example 1 above. Ε. Results The experimental results are reported in Table 7. In the isobutyl ketone crystallization experiment, only the quinone type was detected, and a low-purity ipproxone containing a bisepoxide was used here. The increase in the concentration of the diepoxide of the final product was also observed at a higher cooling rate. The experiment involves the crystallization of the poor quality mother liquor residue, and the poor quality is obtained 67790-950421.DOC - 7 6 - The paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1290558 A7 B7 V. Invention description ( 70) The material, when analyzed by XRPD, is clearly a mixture of diepoxide and quinone ipproxone. The sputum seeding crystal experiment (here, the high-purity ipproxone type using the sputum seeding type) obtained the product based on XRPD analysis of 77% Η type, but based on DSC is the full Η type. However, the XRPD mode has not tested its linearity above about 5% Η. This experiment is the only case in which the four types of experiments in this example were formed in the absence of a bicyclic oxide. The L-type seeding crystal experiment (where high-purity ipproxone uses L-type seeding crystal) gives a product which is completely L-form. The data obtained for high-condition fluidized bed drying of ipproxil clearly correspond to the data obtained for vacuum oven drying. The results obtained by low-condition fluidized bed drying were different in vacuum oven drying. 67790-950421.DOC -77- This paper size applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) A7 B7 1290558 V. Description of invention (71) Table 7A.

Cooling rate (°c/min) Cooling end point CC) Raw material % purity condensate temperature ΓΟ % 11,12-epoxide 1 % diepoxide 1 Desolvation of solvent crystals Analysis % yield % ( type (by XRPD Measurement) 3 45 94.5 57.0 ND ND 100.3 66.1 ND 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 ND 3 45 61.1 4.8 36.6 43.3 27 1002 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 &lt; 3% 1.5 25 100 seeding crystal type 0.03 ND 100.4 82.2 77/1003 1.5 25 89.3 seeding crystal L type 0.33 0.50 97.5 80.2 ND 1 after drying the solvate in a vacuum oven at 75 ° C Weight percentage. 2 By XRPD analysis, it is apparently a mixture of quinone and diepoxide. 3 by XRPD analysis is 77% Η type and DSC is 100% Η type. ND=Not detected. F. Material Purity A cubic diagram of product purity, feedstock purity, cooling rate, and endpoint temperature based on the data reported in Table 7A is shown in Figure 83. The cube plot suggests that higher purity materials can be used to obtain higher dullness products at the crystallization starting point. The crystallization end temperature obviously does not greatly affect the purity of the product. However, the cooling rate obviously has an effect, which is faster than the cold. 67790-950421.DOC - 7 8 _ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7

Ϊ 290558 V. Description of the invention (72) However, the purity of the product obtained at a rate is slightly lower. In fact, the diepoxide concentration is higher at a faster cooling rate. Figure 84 shows a semi-standard plot prepared using the results of the cube plot, which determines which variables, if any, have a statistically significant effect on product purity. Feed purity has the most statistically significant effect on product purity, but the interaction between cooling rate and cooling rate and feedstock purity is also statistically significant. Figure 85 is an interactive line diagram based on these results showing the interaction of feedstock purity and cooling rate on product purity. With high purity ipproxone, the cooling rate clearly has little or no effect on the final purity. However, using low purity ipproxone (89.3% ipprox starting material), the purity of the product decreases as the cooling rate increases. This result suggests that more impurities crystallize when the crystallization is carried out at a higher cooling rate. G. Η嘭 音 sound Based on the data reported in Table 7Α, the cubes of the weight fraction of the Η type, the purity of the raw material product, the cooling rate and the endpoint temperature are shown in Fig. 86. The cube plot suggests that using a higher purity ipprox at the beginning of the crystallization will result in a lower amount of hydrazine. The endpoint temperature of crystallization also apparently has an effect on the form of the final product. The cooling rate obviously does not greatly affect the formation of the ruthenium type, but some ruthenium types may be caused by rapid cooling at low end temperatures due to the presence of impurities. Figure 87 shows a semi-standard plot prepared using the results of the cube plot to determine which variables, if any, have a statistically significant effect on the number of casts in the final material. The initial material purity, crystallization endpoint, and interaction between the two variables can be seen to have statistically significant effects. Figure 88 is an interaction line diagram based on these results, showing the purity of raw materials and 67790-950421.DOC 7 9 - The paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1290558 A7 B7 V. Invention Description (73) The interaction of the endpoint temperature on the final sputum content. With high-purity ipproxone, the endpoint temperature clearly has little effect on the sputum content. In either case, pure ipproxone was not formed into a sputum type. However, the use of low-purity ipproxone (89.3% procumone raw material), in both cases, has a sputum type, and the sputum type with a higher end temperature is significantly larger. Table 7 Β reports using a fluidized bed (experimental line / PRL high-speed fluidized bed dryer, experimental pipeline instrument company) or vacuum oven (Baxter scientific product vacuum drying oven model DP-32) dry material measured Η type Weight component. Similar bismuth content is observed for comparative materials in high fluidized bed or vacuum oven drying. However, there are differences between the comparative materials in which the low fluidized bed is dried relative to the vacuum oven. Table 7Β: Effect of process variables on the content of Η type Cooling rate End point Impurity content Drying condition % ugly high and high vacuum oven 29 High and high fluidized bed 25 High and low fluidized bed 4.7 Low low and low vacuum oven ND Low low and low Fluidized bed ND low low low low fluidized bed 5.5 ND=not tested Example 8: crystallized from isobutyrone L form with solvent removal

10 g of 艾 type ipproxone combined with 80 ml of isobutyl ketone. The mixture was heated to reflux (79 ° C) and stirred at this temperature for about 30 minutes. The resulting slurry was then cooled using a step-wise maintenance scheme maintained at each temperature for about 90 minutes by maintaining the slurry at 65 ° C, 50 ° C, 35 ° C and 25 ° C. The slurry was filtered and washed with about 20 ml of isobutyl ketone. The obtained separated solid is preliminary to the filter and then applied at 40-50 ° C 67790-950421.DOC - 80 - This paper wave scale applies Chinese National Standard (CNS) A4 specification (210X297 Gongdong) A7 B7 1290558 V. Invention description (74) Dry in a vacuum oven. Drying was done in a vacuum oven at 90·100 °C. The solvent-free solid was obtained at a recovery of 82%. XRPD, MIR and DSC confirmed that the solid has an L-type crystal structure. Example 9: Preparation of a low purity ipprox starting material using solvent cooking A. Cooking with ethanol solution 24.6 grams of low purity ipproxone (64% by HPLC assay) combined with 126 ml of ethanol 3 A. The slurry is heated to reflux and the museum is removed. At the same time, 126 ml of ethanol 3A was added to the 126 ml of solvent by atmospheric distillation. When the solvent turnover was completed, the mixture was cooled to 251 and stirred for 1 hour. The obtained solid was filtered and washed with ethanol 3A, and then air-dried to obtain an ethanol solvate. The solvate was further dehydrated in a vacuum oven at 90-100 ° C for 6 hours to obtain 14.9 g of hydrazine-type ipproxone.使用. Isobutyl ketone solvent cooking In the alternative cooking method, 1 gram of low-purity ipproxone (approximately 65% purity of the assay) was cooked in 4 ml of isobutyl ketone for 2 hours, and then the mixture was allowed to cool to room temperature. Upon cooling, the solid obtained was collected by vacuum filtration and analyzed by XRPD to be an isobutyl ketone solvate. The solid was dried at 10 ° C for 30 to 60 minutes. The dry solids were determined to be pure Η by XRPD. Example 10: Preparation of L-form using a solvent to cook high-purity ipprolone A. Using an ethanol solvent to steam 1 g of high-purity ippronone was cooked in 8 ml of ethanol for about 2 hours. The solution was then cooled to room temperature and the solid was collected by vacuum filtration. Immediately after filtration, the solid indicating solid was analyzed by XRPD as a solvate (presumed to be an ethanol solvent). The solid was then dried at ambient temperature for 30 minutes at ambient temperature. Dry solids 67790-950421.DOC -81- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1290558 A7 B7 V. Invention description (75) By XRPD analysis, the main measurement is L type (not detected Measured type). Β. Using isobutyl ketone solvent to cook 1 gram of high purity ippronone was cooked in 4 milliisobutyl ketone for 2 hours, then the solution was cooled to room temperature and the solid was collected by vacuum filtration. The solid was immediately determined by XRPD analysis to be an eppoconone solvate (presumed to be isobutyl ketone solvate). The solvate is then dried at ambient temperature for 30 to 60 minutes at ambient temperature. The dry solids were mainly L-formed by XRPD analysis, and there was no diffraction peak of the ruthenium type. ,

Example 11: L-form crystallization directly from solution Procedure A 2.5 g of ipproxone was dissolved in ethyl acetate by heating to 75 °C. The solution was maintained at 75 °C for 30 minutes to ensure complete dissolution and then cooled to 13 °C at a cooling rate of 1 °C per minute. The resulting slurry was stirred at 750 rpm with an overhead stirrer for 2 hours. The solid was collected by vacuum filtration and dehydrated in a vacuum oven at 40 ° C for 1 hour. Both the XRPD pattern of the solid and the thermal spectrum of the DSC are characteristic of the L-type ipproxone. The solid TGA index is as high as 200 ° C without any heavy loss from solids.

In the procedure B alternative procedure, 2 grams of ipproxone was dissolved in 350 ml of a mixture of 15% acetonitrile and 85% water by heating with magnetic stirring on a hot plate. Once the ipproxone was dissolved, the solution was cooled to room temperature overnight with magnetic stirring. The resulting solid was collected by vacuum filtration. The crystal is birefringent and has a triangular plate crystal representation. Solid XRPD and DSC analysis showed L-type ipproxone characteristics. The TGA indicates no weight loss up to 200 °C. 67790-950421.DOC - 8 2 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1290558 A7 B7 V. Invention description (76)

Procedure C In another alternative procedure, 640 mg of ipproxone was placed in a 50 ml flask containing 20 ml of ethylbenzene. The resulting slurry was heated to 116 ° C to become a clear solution and then cooled to 25 ° C over a period of 30 minutes. The condensation nucleus begins at 84 °C during the cooling period. The solid obtained was filtered from the solution and air dried to give 530 mg (yield: 83%). Hot plate microscopy and XRPD confirmed that the solid was L-type eppocone crystal.

Procedure D In another alternative procedure, 1.55 grams of ipproxone was added to 2.0 milliliters of nitrobenzene and heated to 200 °C. The resulting slurry was turned into a clear solution at 20 (TC stirring overnight) and then allowed to cool to room temperature by natural air convection to separate the solid. The solid was measured by XRPD and polarized light microscopy as L-type ipproxone.

Procedure E In another alternative procedure, 5.0 grams of ipproxone (purity greater than 99%) was added to 82 grams (104 milliliters) of methanol. The solution was heated to 60 ° C with stirring at 210 rpm and maintained at this temperature for 20 minutes to ensure complete dissolution. The solution was cooled to a rate of 0.16 ° C per minute under agitation. The crystals obtained were collected by filtration and dried in a vacuum oven at 40 ° C for 20 hours. The dry solids were determined to be pure L-type ipproxone by DSC and XRPD analysis.

In the procedure F replacement procedure, 6.0 grams of ipproxone (ethanol solvate containing 9% ethanol and having a corrected purity of 95.2%) was added to 82 grams (104 milliliters) of methanol. The solution was heated to 60 ° C with stirring at 210 rpm and maintained at this temperature for 20 minutes to ensure complete dissolution. The solution is then cooled at a rate of 0.14 ° C per minute to 50 67790-950421.DOC - 8 3 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1290558 A7 B7 V. Description of invention (77) ° C, then maintained at this temperature for about 2.5 hours. The solution was then cooled to -5 °C at a rate of 0.13 ° C per minute with stirring. The crystals were collected by filtration and dried in a 4 (TC vacuum oven for 16 hours. The dry solids were determined to be pure L-type ipproxone by DSC and XRPD analysis. Example 12: Crystallization of solution 150.5 mg of diepoxide directly from solution 2.85 g of ipproxone was added to 1.5 ml of nitrobenzene. The mixture was stirred by magnetic force for several hours at 200 ° C. The resulting slurry was then convected by natural air to room temperature. The sample was dried and analyzed by polarized light microscopy and XRPD. The XRPD analysis indicated that the sample was a mixture of Η and L. The crystal was translucent as measured by microscopy, indicating that no solvent was removed (and converted to Η or L). Example 13: Preparation by non-development The Wig-L-Bug container of the crystal type Epkoone steel is filled with about 60 g of ipproxone (greater than 99.9% purity) in half volume. The steel ball and steel cover are placed on the sample container and the The apparatus was agitated for 30 seconds. The surface of the wafer was scraped off from the surface of the Wilbur container, and the container was stirred for another 30 seconds. The obtained solid was analyzed by XRPD and DSC to determine amorphous eplotone and L-form crystallinity. Mixture of ipproxone. Example 14: Preparation of amorphous ipproxone by stalking about 100 The crude edpregone was weighed into a beaker containing 400 ml of water, and the mixture was slightly heated for 5 minutes, then sonicated and heated with stirring for 5 minutes to obtain a dispersion. About 350 ml of ipprox dispersion was filtered. Into a 1000 ml round bottom flask containing 50 ml of HPLC water. The dispersion was rapidly cooled in a dry ice/acetone bath for 1-2 minutes. The flask was attached to a Labconco Freezone 4.5 freeze dryer and the contents were dried overnight. Solid in the flask 67790-950421.DOC - 8 4 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1290558 A7 B7 V. Invention description (78) Move to small brown bottle. The microscope was observed for 1 aliquot with a 10x magnification 1.25X optivar in cargille oil (1.404) and observed to be at least 95% amorphous edetone. Figures 89 and 90 show the amorphous Epp. XRPD pattern and DSC thermogram obtained from ketone. The peak observed at 39 degrees 20 in Fig. 89 is attributed to the aluminum sample container. Example 15: L-type ipproxone dissolved in 庶L-type ipproxone water Solubility at pH 7 (100 mM phosphate buffer) at 5 ° C, 25 ° C and 40 Measured at ° C. Approximately 30 mg of L-type eplerenone was prepared by mixing about 10 ml of buffer at 5 ° C and 25 ° C. About 40 mg of type II eppoconone was mixed with about 10 ml of buffer. An ippronone slurry formed at 40 ° C. The sample was prepared repeatedly for each condition. The slurry was equilibrated in a bath of water shaker at an appropriate temperature, and the solution was applied at 1, 5, 12, 19, 27 and 36 days. The ipproxone content was analyzed by ultraviolet light analysis (245 nm) at intervals. The data for each temperature is appropriately averaged to determine the solubility of ipproxone at each temperature and is reported in Table A. The residual solids obtained at each time point were determined to be L-type levulone by DSC and TGA analysis at the end of equilibrium at day 36. Table 8: Solubility temperature of L-type ipproxone (°c) L-type solubility (mg/ml) 5 0.24 25 0.29 40 0.39 Example 16: Measurement of characteristic dissolution rate for the following four eptrozol polymorphic compounds Specimen measurement characteristics Dissolution rate: (i) L-type ipproxone, prepared by direct crystallization from acetonitrile in the same manner as in Example 11 Procedure B using water as an anti-solvent; (ii) Η-type ippronone, 67790-950421 .DOC - 8 5 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1290558 A7 B7 V. Description of invention (79) Prepared in ethanol in the same manner as in Example 9 Procedure A; (iii) 5% Η type and 95% L type mixture and (iv) L type eppoone, micronized to obtain the following particle size distribution: 10% by weight of particles less than 9 microns, 50% by weight of particles less than 22 microns and 90 The % by weight particles are less than 41 microns. 150 mg of ipprodone was weighed and placed in a VanKel characteristic dissolution chamber. The powder was compressed into a tablet using a Carver* press at 8280 km. The sample is then mounted to a characteristic dissolution device. The dissolution medium used was 1% sodium dodecyl sulfate (SDS) in HPLC water. All experiments were carried out at 37 ° C for 2 hours. Before the start of the experiment, 500 ml of the dissolution medium was equilibrated in the dissolution bath chamber at 37 t for 30 minutes. The sample was taken out from each dissolution vessel as the initial time (T〇) of the test. The ipproxone is then lowered into the interior of the dissolution medium. The sample was taken at predetermined intervals to determine the dissolution rate. Care should be taken to avoid the formation of air bubbles on the surface of the tablet. The samples were analyzed by a 243 nm UV light absorbing pen. The characteristic dissolution rate is calculated from the correction of the volume of the straight line portion relative to the time side plot and the slope of the dissolved ingot surface area (0.5 cm 2 ). Figure 91 reports the characteristic dissolution rates measured for the four samples. Studies have shown that Η-type ipproxone has a faster rate of dissolution than L-type ipproxone. The XRPD measurement compares the compressed and uncompressed ipproxone, confirming that no interconversion occurs between the polymorphs during compression or during the dissolution study. Example 17: Apoleone polymorph composition A tablet containing 25 mg, 50 mg, 100 mg and 200 mg doses of L-type ipproxone was prepared to have the composition shown in Table 9. 67790-950421.DOC -86 This paper scale is applicable to China National Standard (CNS) Α4 specification (210X297 mm) A7 B7 1290558 V. Invention description (80) Table 9: Example 17 tablet composition weight % L-type Epp Leke ketone 29.41 Η type ipproxone did not detect lactose monohydrate, NF (#310) 42.00 microcrystalline cellulose, NF (Avicel PH-101) 18.09 carbamol sodium, NF (Asian Ac-Di-Sol) 5.00 HPMC, USP (#2910, Pharmacoat 603) 3.00 Lauryl sulfate, NF 1.00 talc, USP 1.00 Magnesium stearate, NF 0.5 Total 100.00 Example 18: A polymorphic composition of ipproxone prepared capsules (hard gelatin capsules, nickname) containing 100 mg of ipproxone and having the composition shown in Table 10. Table 10: Example 100 of 100 mg capsules Ingredient Quantity (mg) L. type Eproleone 90.0 Η type ipproxone 10.0 Lactose, hydrate, NF 231.4 microcrystalline cellulose, NF 45.4 talc, USP 10.0 g Carmeline Sodium, NF 8.0 Sulfate Sulfate Steel, NF 2.0 Colloidal Ceria, NF 2.0 Magnesium Stearate, NF 1.2 Total Capsule Filling Weight 400.0 Example 19: Polypene Composition of Apoxone Preparation Capsules The agent (hard gelatin capsule, nickname) contained 200 mg of ipproxone and had the composition shown in Table 11. 67790-950421.DOC -87&quot; This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1290558 A7 B7 V. Description of invention (81) Table 11: Example 19 200 mg capsule composition (mg L-type ipproxone 190.0 艾-type ipproxone 10.0 lactose, hydrate, NF 147.8 microcrystalline cellulose, NF 29.0 talc, USP 10.0 carmelos sodium, NF 8.0 sulfated laurel steel, NF 2.0 colloid Cerium Oxide, NF 2.0 Magnesium Stearate, NF 1.2 Total Capsule Filling Weight 400.0 Example 20: Preparation of Grinded Aproxone Anhydrous Ipoetone Isobutyrone Solvate First the solvate in Philippine (Fitz) The mill was passed through a No. 20 sieve to remove the agglomerates. The solids after removal of the agglomerates were then needle milled using an Alpine Hosakawa column needle mill operating at a feed rate of about 250 kg/hr under liquid nitrogen cooling. The needle mill produces a post-milling ipproxone having a D9G particle size of about 65-100 microns. Example 21: Effect of the particle size of ipproxone on the pharmacokinetic parameters in dogs The effect of L-type ipprole size on the plasma concentration and relative bioavailability of ipproxone was studied in the canine study model. Four healthy female beagle weighing 8 to 12 kilograms were administered intragastrically with one immediate release capsule (white opaque No. 0) containing the formulation described in Table 12 below followed by administration of 10 ml of water. 67790-950421.DOC -88- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Order

Line 1290558 A7 B7 V. Description of invention (82)

The dog is fasted for 15 to 20 hours before being administered to the capsule and then fed again until at least 4 hours after administration. Blood samples (approximately 3 ml) were collected from heparin-containing cryotubes by venipuncture at 〇·5,j, 2,3,4,6,8 and 24 hours after administration. The blood sample was immediately placed on ice and the plasma was separated from the blood sample by centrifugation for about 15 minutes. The resulting plasma samples were frozen and stored at about 2 〇 〇 c until analysis. The analysis was performed using the LC/MS/MS program. The same four dogs were used to test three formulations, each with the composition shown in Table 12 but with different ipproxone particle sizes. The ipprox starting material has a Dm particle size of about 212 microns, about 86 microns and about 36 microns, respectively. Continuous administration: The preparation period is at least 5 days clear. The average results are reported in the following table ^ and 14. The relative bioavailability was calculated from the AUC results, and a formulation having d of % micron was selected as the standard. ' 90... 67790-950421.DOC -89- A7 B7 1290558 V. INSTRUCTIONS (83) TABLE 13 · · Serum Apole Concentration (μg/ml), Example 21 Time (hours) D90 212 μm D9〇86 μm D90 36 μm 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: Calculation of the pharmacodynamics calculated from the data in Example 21 (PK) parameters PK parameters D9 〇 212 micron D90 86 micron 36 micron cmax (micrograms / ml) 3.98 7.02 7.39 Tmax (hours) 1.50 1.75 2.25 AUC ((microgram / halo) hours 26.6 49.2 53.1 relative bioavailability 53.25 100 107.9 Really inverted 22: In human studies, the effect of ipproxone particle size on the pharmacodynamics of the L-type ipproleone particle size on the plasma concentration and relative bioavailability of ipprox is in the human test mode. The three pharmaceutical compositions were studied. Individuals received a single dose of 100 mg L-type ipproxone as a drug on a random schedule on days 1, 8, 15, 22 and 29. All drugs were administered at 8 am in the morning using 18 ml of water. 〇-〇·5 (before administration), 0.5,1,2' 3.4,6,8,10,12,16,24 after administration, "and collecting blood samples for epoch ketone pharmacokinetics The plasma concentration of ipproxone was determined by MS/MS detection using an effective HPLC method. The pharmacokinetic data are reported in Table 16. The L-type Ep 67590-950421.DOC-90- used to prepare the composition.

A7 B7 1290558 V. INSTRUCTIONS (84) The particle size distribution of ketone is measured by laser light diffraction in the dry powder state. Capsules Group A sputum, Pharmacy A 〖(% by weight) 腺台淼1 RL type Apex Ketone (D9G 40 micron) 25 (D9G 82 micron) - 30 (D9Q 96 micron) - 25 lactose monohydrate - w U 57 86 lactose, hydrated #_ 57.8 microcrystalline cellulose (Yavisuo PH-101 11.4 17.51 -1:_ (Yavisuo PH-102) -- _ _ 11.34 Carmelol sodium (Yadiso) - 2 ._ 5 HPMC (Famark 603) ---- __3_ --- Sulfuric acid Sodium lauryl sulfate 0.5 0 5 talc 2.5 ___1 2.5 Magnesium stearate 0.3 Colloidal cerium oxide 0.5 0.5 Total 100 100 5% granules, 10% extragranular W by f Example 22 Data One parameter Pharmacokinetic parameters 100 mg Capsule A (D90 40 micron) --- 々 子 UT 100 亳 锭 锭 A (D〇n 82 μm) 欢 〇〇亳 1 〇〇亳 capsule B (D90 96 micron) Bosak / ml) 1747 1704 1669 1.8 1.8 1.3 AUC ((ng/ml) hours) __ 11349 11945 11981 Although the invention has been described in terms of specific embodiments, the contents of such embodiments It can be regarded as limiting.

67790-950421.DOC -91- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)

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Claims (1)

[佩?. 〇 12 9^5) δ &amp; 5997 Patent Application g Chinese Patent Renewal (June 96) VI. Application for Patent Fan Park - 1 - A disease or condition for treatment or pre- (4) stagnation media Oral dosage form pharmaceutical compositions comprising from about 10 to about 1 mg of eplerenone (epi_〇ne), and at least one pharmaceutically acceptable excipient, wherein: (a) the presence The ipproxone in the composition has a phase purity of from about 9% to about 100% H-type crystalline ipproxone, and (b) the quinone-type crystalline ipproxone is characterized in that it has a diffractive powder diffraction pattern at a wavelength of 1.54056 angstroms, the re-light powder diffraction pattern comprising 7·〇±〇·2 degrees, 83±〇2 degrees and 12·0±0·2 degrees 20 . 2. The oral dosage form pharmaceutical composition according to claim 1, wherein the phase purity is from about 95% to about 1 〇 〇 〇/〇 η type crystalline ipproxone. 3. The oral dosage form pharmaceutical composition according to claim 2, wherein the Epson® is a substantially pure phase quinone crystalline ipproxone. 4. The oral dosage form pharmaceutical composition according to claim i, wherein the composition is substantially free of one or more L-type crystalline ipproxone, solvo-crystalline apperone and amorphous AI Plexone^5. The oral dosage form pharmaceutical composition according to claim 1, wherein the remaining ipproxone is (1) L-type crystalline ipproxone (ii) with monoclinic system One or more of a solvent crystallization type of pluronicone and (iii) an amorphous ipprodone. 6. The oral dosage form pharmaceutical composition according to claim 1, wherein the η-type crystalline ipproxone is characterized by having the following unit cell parameters: (a) orthorhombic system, 67790-960703.DOC The paper scale applies to the Chinese National Standard (CMS) A4 specification (210X297 mm) 1290558 as Jd〇C8 _______ D8 VI. Application for patent garden (b) P 2丨2 ! 2〗 Space group, (c) Unit cell a, b The values of c and c are about 21.22 angstroms, about 15 4 〇 Egypt is about 6.34 angstroms, (d) unit cell α, and the cold and τ values are each about 9 〇. (e) a volume of 2071.3 angstroms, and (f) a Z value of 4 〇 7. The oral dosage form pharmaceutical composition of claim i, wherein the luminescent powder diffraction pattern comprises 12 〇 ± 〇 2 degrees, 8·3 soil 〇 2 degrees 20 and 7 〇 soil 0.2 degrees 2 0 peak. 8. The oral dosage form pharmaceutical composition according to claim 1, wherein the n-type crystalline eplerenone is characterized by having a Fourier transform infrared absorption spectrum, the spectrum comprising about 1399 cm-i, about 1 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; A Fourier transform infrared light absorption spectrum of the absorption band (signifieant abs〇rpti〇n band). 10. The oral dosage form pharmaceutical composition according to claim i, wherein the Η-type crystalline Apula is characterized by having From about 247. (: to a melting point temperature of about 25 1 ° C 〇 11 · as claimed in the scope of the patent, paragraph 0 of the oral dosage form of the medical composition, wherein the Η type crystalline Epson _ the point is different The scanning calorimeter is measured at a heating rate of 10 ° C per minute. 12. The oral dosage form pharmaceutical composition of claim i, wherein the quinoid crystalline crystalline apexamine is characterized by having a differential scanning thermogram 67 790-960703.DOC 1290558 as B8 C8 _____ D8 VI. Applying for a patent, 'There is a single endotherm that occurs in a temperature range from about 2 4 7 to about 25 ° C. 13 · If you apply for a patent The oral sputum type pharmaceutical composition of the present invention, wherein the η-type crystalline ippronone is characterized by the following: a) an X-ray powder diffraction pattern at a wavelength of 1.54056 angstroms, the X-ray powder diffraction pattern system Contains 12 〇 ± 〇 2 degrees 2 0, 8 · 3 ± 〇 · 2 degrees 2 0 and 7 · 0 ± 0 · 2 degrees 20 peak; b) - Fourier transform infrared absorption spectrum, the spectrum contains about 1739 An absorption band of cm-1 and about 1399 cm-1; and c) a differential scanning thermograviogram having a single endotherm occurring in a temperature range from about 2 4 7 π to about 2 5 1 C. The oral dosage form pharmaceutical composition of the invention of claim i, further comprising L-type crystalline ipproxone, wherein the fluorene-type crystalline ipproleone has an early slant crystal system. Oral dosage form pharmaceutical composition further comprising a solvent crystallization type of ipproxone. Oral dosage form pharmaceutical composition according to claim 15, wherein the solvate crystal form of the eplerenone is a crystalline solvate of methyl ethy 1 ket ο ne. 17 · The oral dosage form pharmaceutical composition of item i, which further comprises amorphous ipproxone. 18. The oral dosage form pharmaceutical composition of claim 2, further comprising one or more quinoid type crystal growth promoters. 19. For example, if the oral dosage form pharmaceutical composition of the scope of patent application is item i, enter a 67790-960703.DOC. This paper size is applicable to the Hg standard (CNS) A4 specification (21GX297 public)^ ---— - A8 B8 C8 1290558 Shen Qing Patent Fan Yuan Step contains one or more compounds of the group consisting of: (a) 7• methyl hydrogen 4〇;, 5〇:, 9〇:, 11〇!_二epoxide_ 17_Hydroxy_3-oxy-176^_pregnane _7 〇:,21-dioxalate, 7-lactone, (^)7-methylhydrogen 11邙, 12-core epoxy-17- Each _3-oxy-πα-pregnant _4_ene·7α,21_dicarboxylate, r-lactone, and (c) 7-fluorenylhydrogen 17_ hydroxy-3_oxy-17^-pregnant- 4,9(11)-diene α,21-dicarboxylate, τ_lactone, and mixtures thereof. 20. The oral dosage form pharmaceutical composition according to the scope of the invention, wherein the oral dosage form is a solid oral dosage form selected from the group consisting of a tablet, a capsule and a powder. 21. The oral dosage form pharmaceutical composition of claim 1, wherein the n-type crystalline ipproxone has a d9 〇 particle size range from about 25 microns to about 4 microns. 22. The oral dosage form pharmaceutical composition according to claim 1, which comprises any one of the following combinations: (a) Η-type crystalline ippronone and [type crystalline ipproxone; (b) Η Type crystalline ippronone and solvohydrate type ipproxone; (Ο 结晶 type crystalline ippronone and amorphous ipproxone; (e) Η-type crystalline ippronone and solvent combination Crystalline ipproxone and L-type crystalline ipproxone; (f) Η-type crystalline ipproxone and amorphous ippronone and type 1 crystalline ipproxone; (i) Η type Crystalline ipproxone and amorphous ippronone, type l crystalline ippronone and solvohydrate crystallized ipproxone. 23) a method for preparing η-type crystalline ipproxone, contain: 67790-960703.DOC This paper scale is applicable to China National Standard (CNS) Α4 specification (210X297 mm) A8 B8 C8 D8 1290558 夂, application for patent garden a) Provide a ipprox starting material at a boiling point higher than 1 5 a solvent of hydrazine or a solution of a solvent mixture comprising a solvent having a boiling point higher than 150 ° C, and b) crystallizing n-type crystalline ipprox directly from the solution, the η-type crystalline ipproxone having An orthorhombic system, and an X-ray powder diffraction pattern at a wavelength of κ1β54056 angstroms, the X-ray powder diffraction pattern comprising 12.〇±〇.2 degrees 2 0, 8.3±〇.2 degrees 2 0 and 7 .〇+ 0.2 degrees 20 saki, wherein the crystallization step is carried out at a temperature of at least 1 Torr. Wherein the solvent or solvent mixture is seeded with cerium-type crystalline ippromone crystal before or during the crystallization step. 24. The method of claim 23, wherein the solvent is nitrobenzene. 25. The method of claim 23, wherein the solvent is other than methylene chloride, di-methane/diethyl ether, diethyl ether, di-methane/isopropanol and ethyl acetate. 26. The method of claim 23, wherein the solvent is other than dichloromethane, dichloromethane/diethyl ether, diethyl ether, dichloromethane/isopropanol, ethyl acetate, isobutyl ketone, ethanol and acetone. . 27. The method of claim 23, further comprising the step of grinding the quinoid crystalline eppoconazole to a cerium particle size of less than about 4 Å after crystallization. For example, the method of claim 27, further comprising the step of grinding the fluorene-type crystalline ipprone to a particle size ranging from about 4 Å to about 100 μm after crystallization. 67790- The method of claim 23, wherein the solution further comprises one or more quinoid type crystal growth promoters. 3. The method of claim 29, wherein (4) The crystal growth promoter is selected from the group consisting of: (a) 7-methylhydrogen 4a, 5a, 9m α·diepoxy-17_hydroxy-3-oxy_ι7α_pregnane- 7α, 21_dicarboxylic acid vinegar, vinegar in the factory; (b) 7-methyl hydrogen ι 1α, 12α_epoxy-17 gin 3 oxy heart ~ gest-4-ene _7α, 21-dicarboxylic vinegar , r _ internal vinegar, and (c) 7-methyl hydrogen", hydroxy-3-oxy] 7α-pregnancy-4,9(11)-two-seven-seven, 21/diacids, caprolactone, And a mixture of them. 31. A method of preparing a quinoid crystalline ipproxone, the method comprising: (a) digesting a low purity ipproxone starting material in a solvate form which forms an eptrozolone a solvent or a mixture comprising the solvent, wherein the solvent is selected from the group consisting of: isobutyl S and '2-pentanol, acetic acid, acetone, butyl acetate, chloroform, ethanol, isobutanol , isobutyl acetate, methyl acetate, ethyl propionate n-butanol, n-octanol, n-propanol, isopropanol, propyl acetate, propylene glycol, tert-butanol, tetrahydrofuran, toluene and acetic acid third An ester, and a mixture thereof; and (b) crystallizing ipproxone from the solvent or mixture to form a solvate of ipproxone; and (c) removing the solvate from the solvent to provide an n-type a crystalline ipproxone having an orthorhombic system and having an X-ray powder diffraction pattern at a wavelength of 1.54056 angstroms, the X-ray powder diffraction pattern comprising selected from the group consisting of 12 ·〇±〇·2 degrees 2 0,8·3±0·2 degrees 2 0 _ 6 · 67790-960703.DOC The paper size is suitable Chinese National Standard (CNS) Α4 size (210X297 public purple) 1290558, patent Fan Park and 7 · 0 ± 0 · 2 degrees Kawasaki peak of 20. 32. The method of claim 3, wherein the solvent or solvent mixture is from the group consisting of isobutyl ketone, ethanol, and mixtures thereof. 33. The method of claim 3, wherein the solvent is other than methylene chloride, di-methane/diethyl ether, diethyl ether, dichloromethane/isopropanol and ethyl acetate. The solvent is in addition to dichloro-chloromethane/isopropanol, B. 34. For example, the method of claim 3, the method of A, B, 2, A, B, B, B, B, B, </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> . 36. The method of claim 31, further comprising the step of grinding the ipproxil to a Dm particle size of from about 4 Å to about 1 Å after crystallization. The method of claim 31, wherein the consuming step comprises/containing heating the low purity ipprox starting material in the solvent or solvent mixture until the boiling point of the solvent or solvent mixture is reached. The method of claim 31, wherein the ipproxone starting material further comprises one or more H-type crystal growth promoters. 39. The method of claim 38, wherein the 晶体-type crystal growth promoting agent is selected from the group consisting of τ columns: (4) 7_methyl gas ", 5α «, 11 heart epoxide-17 - hydroxy-3_oxy_17. _ pregnane seven, 21_ dicarboxylic acid vinegar, r-endo vinegar; (b) 7-methyl gas 11α, 12α_ epoxidation is a small oxygen _ I pregnant. 4 services 7«, 21_2_6, 67790-960703.DOC I paper scale applies to China National Standard (CNS) Α 4 specifications (210 X 297^53&quot; 1290558, patent application park A8 B8 C8 D8 17-jing- 3-oxy-17α-pregnant _4,9(11)_di-conclusion_7^21_ diwellic acid vinegar, lactone, and a mixture thereof. 4〇_ - Preparation of Η-type crystalline Epson _ a method comprising the steps of: (4) crystallizing eplerenone from a solvent in the form of a solvate or a mixture comprising the solvent, wherein the eplerenone/troche combination crystal form It is selected from the group consisting of: isobutyl _ 1 · propanol ' 2- pentyl g, acetic acid, propylene _, butyl acetate, gas imitation 'ethanol' isobutanol, isobutyl acetate, methyl acetate, Propane I, 6 曰 n-butanol, n-octanol, isopropanol, B Acid propyl ester, propylene glycol, tert-butanol, tetrahydrofuran, toluene, methanol and tributyl acrylate acetate solvate, and mixtures thereof; and (b) the solvate is removed from the solvent to form quinoid crystallinity The sputum-type crystalline ipproxone has an orthorhombic system and has a light powder diffraction pattern at a wavelength of 1.54056 angstroms, the X-ray powder diffraction pattern comprising 12 〇±〇 2 degrees, 8 3 ± 〇 2 degrees 2 0 and 7·0 ± 0 · 2 degrees 20 saki; wherein the ♦ agent or / granule mixture is used before or during the crystallization step using Η type crystalline ipproxone The method of claim 40, wherein the solvated crystalline form is selected from the group consisting of: lv propanol, 2_戍嗣, acetic acid, butyl acetate, gas imitation , isobutyl ketone, isobutyl acetate, methyl acetate, ethyl propionate, n-butanol, n-octanol, propyl acetate, propylene glycol, tert-butanol, tetrahydrofuran, toluene, methanol and acetic acid third butyl vinegar Solvates, and mixtures of them. 67790-960703.DOC _8_ This paper scale applies to China National Standard (CNS) Α4 Specifications (21〇X297 公羞) A 'A8 B8 C8 1290558 Patent Application Fan Park 42. ^申 4 Patent Peripheral Method 4, wherein the crystal form of the lypodexone contains one Or a plurality of solvate forms selected from the group consisting of an isobutyl crystalline solvate and an ethanol crystalline solvate. 43. The method of claim 4G, wherein the solvated crystalline form is - Chloroformate solvate, methylene chloride / diethyl ether solvate, diethyl ether solvate - dichloro decane / isopropanol solvate and ethyl acetate solvate. 44. The method of claim 4G, wherein the solvated crystalline form is in addition to the methylene chloride solvate, the second gas smoldering/6ar solvate, the sulphur solvate, the second gas smoldering/different A propanol solvate, an acetic acid 6 vinegar solvate, a different solvate, an ethanol solvate, and an acetone solvate. 45. A method for promoting crystallization of a liquid crystal from a solution of a ketone in a solvent or a solvent mixture, the method comprising: incorporating an effective amount of a dopant compound into the solution, wherein the dopant compound is The crystal phase is essentially equivalent to the Η-type ipproxone structure. 46. The method of claim 45, wherein the doped compound is selected from the group consisting of: (a) 7-methylhydroxyl-17-hydroxy-3-oxo-17α-pregnane. 7α,2ΐ-dicarboxylate, lactone; (b) 7-methylhydrogen ια, 12α_epoxy]7-hydroxy·3_oxy_17 heart pregnancy _4_ene-7 〇:, 21_ Dicarboxylate, r lactone, and (c) 7-methylhydrogen 17_hydroxy-3-oxy-1 17 alpha-pregna-4,9(11)-diene-7,21-dicarboxylate , r•内格, and their mixture. 47. Preparation of a condition or disease for the treatment or prevention of aldosterone in an individual 67790-960703 .DOC A8 Βδ C8 A method for the pharmaceutical composition of 1290558, which comprises (4) preparing a bisprofenone from a solvent or a mixture of solvents, wherein the solvent Μ-曰曰田T绍i W is selected from the group consisting of Group: isobutyl ketone, 1-propanol, 2 _ 戍嗣 戍嗣, acetic acid, propylene _, butyl vinegar, milk imitation, ethanol, isobutanol, isobutyl vinegar, methyl acetate, ethyl acetonate, n-Butanol 'n-octanol, isopropanol, propyl acetate, propionate' third butanol, tetrahydrofuran, toluene, methanol and tert-butyl acetate, and mixtures thereof; (b) shrinking the type a crystalline particle size of the crystalline Epstein, wherein the final Dpo particle size ranges from about 4 μm to about 4 μm; and (c) mixing the therapeutically effective amount of the reduced particle size H crystal And the at least one pharmaceutically acceptable excipient to form the pharmaceutical composition, wherein step (a) is by (1) using a low purity ipprox starting material in place of the high purity ipprox starting material, (ii) using a pure phase 晶体 type crystal seeding solvent system or (iii) a combination of (1) and (ii). 48. The method of claim 47, wherein the method comprises: (a) crystallizing η-type crystalline ipproxone from a solvent or solvent mixture to form a solvate form, wherein the solvent Is selected from the group consisting of: isobutyl 3 with '1-propanol, 2-pentanone, acetic acid 'acetone' acetate, chloroform, ethanol, isobutanol, isobutyl acetate, methyl acetate , ethyl propionate, n-butanol, n-octanol, isopropanol, propyl acetate, propylene glycol, tert-butanol, tetrahydrofuran, toluene, methanol and tert-butyl acetate' and mixtures thereof ; -10- 67790-960703.DOC This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 1290558 A8 B8 C8 D8 VI. Application for patent garden (b) Desolvation of the solvate to form Η-type crystalline Epson _, the Η-type crystalline ipproxone has an orthorhombic system, and an X-ray powder diffraction pattern at a wavelength of U4056 angstroms, the luminescent private diffraction pattern includes 12·0±〇·2 degrees 2 0,8·3±〇·2 degrees 2 0 and 7 ·〇±〇.2 degrees 2 0 of the peak; (c) reduce the type a crystalline particle size of the crystalline ipproxone, wherein the final D 9 〇 particle size ranges from about 4 Å to about 4 μm; and (d) a mixed therapeutically effective amount of the reduced particle size Indole-type crystalline Epson is combined with at least one pharmaceutically acceptable excipient to form the pharmaceutical composition. 49. Use of a pharmaceutical composition of a urethral dosage form according to claim 1 of the patent application for the manufacture of a medicament for the treatment or prevention of a condition or disorder of aldosterone. 50. The use of claim 49, wherein the condition or condition is selected from the group consisting of hypertension, heart failure, cirrhosis, collagen overdose, fibrosis, benign prostate hypertrophy And depression. 51. The use of the fifth aspect of the patent application, wherein the condition or condition is high. 52. The use of the fifth aspect of the patent application, wherein the condition or condition is heart failure. 53. A sputum-type crystalline ipproxone for use in the treatment or prevention of a condition or disorder of aldosterone, characterized in that it has an X-ray powder diffraction pattern at a wavelength of h54 〇 56 angstroms, The calender powder diffraction pattern contains 7·0±0·2 degrees 20,8·3±0·2 degrees 20 and 12.0±0.2 degrees 20 peaks. 67790-960703.DOC j ^ This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 public) 1 &quot;