Process for the preparation of trenbolone acetate having a defined particle size distribution and irregular hexagonal platelet habit

Abstract

The object of the present invention is an improved process for the preparation of Trenbolone Acetate of formula (I) by means of crystallization, having irregular hexagonal plate-like crystal habit and / or being comprised in a particle size distribution median value (D50) ranging from 50 pm to 80 pm, or from 60 pm to 90 pm, or from 90 pm to 250 pm, wherein seed crystals having a particle size distribution median value (D50) comprised in the range from 8 pm to 15 pm, or from 15 pm to 20 pm, or from 20 pm to 90 pm, respectively, are added to a solution of Trenbolone Acetate in a solvent, wherein the solvent is a C2-C5 alkyl alcohol or a mixture thereof.

Description

Technical Field

[0001] This invention relates to an improved method for preparing trenbolone acetate. Furthermore, it also relates to the solid form and / or PSD of trenbolone acetate. Background Technology

[0002] Trenbolone acetate is a small molecule marketed under brand names such as Finajet and Finaplix. It is an androgen and anabolic steroid (AAS) drug used in veterinary medicine, particularly to improve livestock profitability by promoting muscle growth in cattle.

[0003] This drug is a synthetic androgen and anabolic steroid, and therefore an agonist of the androgen receptor (AR), which is a biological target of androgens such as testosterone and dihydrotestosterone (DHT). It exhibits potent anabolic and hyperandrogenic effects, as well as strong progestogenic and weak glucocorticoid effects. Trenbolone acetate is an androgen ester and serves as a long-acting prodrug of trenbolone in vivo.

[0004] Trenbolone acetate was discovered in 1963 and introduced for veterinary applications in the early 1970s.

[0005] Trenbolone acetate, or trenbolone 17β-acetate, is a synthetic derivative of estanzanol and nandrolone (19-nortestosterone). It is the C17β-acetate of trenbolone, which itself is δ9,11-19-nortestosterone (δ9,11-19-NT) or estradiol-4,9,11-trien-17β-ol-3-one. Other trenbolone esters include heptacyanate, hexahydrobenzyl carbonate, and undecanoate.

[0006] Trenbolone acetate has the following chemical formula (I):

[0007]

[0008] And its chemical name is 17β-acetoxy-estr-4,9,11-trien-3-one.

[0009] The synthetic route for the described compound (I) is lengthy, and some reactions have extremely low yields, making the crystallization of the final product very difficult.

[0010] Zhang et al. (Fudan Journal of Medical Sciences, 2002, 29(3), 211-212) disclosed a method for preparing trenbolone acetate. The method comprises the following steps: using estradiol-4,9-diene-3,17-dione (VI) as a starting material, protecting the carbonyl group at the 3-position with methanol and p-toluenesulfonic acid as catalysts, and then reducing the carbonyl group at the 17-position to a hydroxyl group with sodium borohydride. The resulting product (IV) is deprotected under acidic conditions to restore the carbonyl group at the 3-position. The obtained (17β)-17-hydroxyestradiol-5,9-diene-3-one (III) is converted to trenbolone (II) by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In the final step, the hydroxyl group at the 17-position of trenbolone is esterified with acetic anhydride to obtain trenbolone acetate (I), the specific route of which is as follows:

[0011]

[0012] The described pathway involves numerous and lengthy steps and a variety of byproducts, yields no solid product, has low quality and low yield, requires the highly toxic solvent benzene, and is not conducive to industrial production.

[0013] According to the route disclosed in Chinese Patent CN102399253, (17β)-17-hydroxyestradiol-4,9-dien-3-one (VII) was used as a starting material. Acetylation with acetyl chloride and acetic anhydride yielded diacetylenol ester (VIII). Subsequently, hydrolysis and oxidative dehydrogenation of the acetyl group at position 3 were carried out to obtain trenbolone acetate, and the specific route is as follows:

[0014]

[0015] This approach first involves esterification of the 17-hydroxyl group, followed by enol esterification of the carbonyl group at the 3-position, which is challenging and yields low conversion rates. Continuous selective hydrolysis of the 3-enol ester is difficult, and excessive hydrolysis of the acetyl group at the 17-position is prone to occur. The resulting intermediate (IX) is difficult to purify, and process scale-up is challenging.

[0016] Chinese patent CN102924553 describes the optimized process of Zhang et al. In this method, the acidic catalyst protecting the carbonyl group at the 3-position was changed from p-toluenesulfonic acid to acetyl chloride / methanol. This approach uses a large amount of the acidic reagent, acetyl chloride, which implies significant corrosion and places high demands on production equipment, requiring corrosion-resistant equipment. Consequently, the amount of waste is large, and the overall yield is not significantly improved.

[0017] The route disclosed in Chinese patent CN108017682 begins with a compound having a 4,9-ring open ring. Reduction with potassium borohydride followed by acid-catalyzed condensation yields (17β)-17-hydroxyestradiol-5,9-dien-3-one(III). Next, oxidative dehydrogenation with DDQ and esterification give trenbolone acetate, as detailed below:

[0018]

[0019] Potassium borohydride reduction is nonselective and difficult to control; moreover, acid-catalyzed ring-closing condensation has low yields. Finally, the intermediates and products require purification due to their low quality.

[0020] The approach disclosed in Chinese patent CN110437294 is very similar to that disclosed by Zhang et al. (Fudan Journal of Medicine, 2002, 29(3), 211-212). The difference between the two approaches lies in the protecting group used to protect the carbonyl group at position 3, which is changed from methanol ketal to ethylene dioxy ketal.

[0021]

[0022] These prior art methods for preparing compound (I) do not describe a preparation method involving the use of alcohol to crystallize thibol acetate, nor do they describe the PSD of the resulting product.

[0023] None of these existing technical methods for preparing trenbolone acetate describe a method for the crystallization preparation of trenbolone acetate with a specified PSD of the resulting product.

[0024] Gheorghe Borodi et al. described the XPRD of threnbrom acetate in Journal of Molecular Structure 1212(2020)128127.

[0025] These existing techniques for preparing trenbolone acetate do not allow for the preparation of trenbolone acetate with an irregular hexagonal plate crystal habit; in fact, crystallization by means of alcohol or mixtures thereof does not provide a crystalline solid with an irregular hexagonal plate shape.

[0026] Furthermore, existing methods have drawbacks related to the method and the differential reproducibility of the resulting solid form.

[0027] Furthermore, these existing techniques for preparing threnol acetate describe methods with low yields and require a final purification step to obtain a high-purity product.

[0028] Therefore, a method is needed to prepare the intermediate trenbolone and the final product trenbolone acetate in high yield and quality. Summary of the Invention

[0029] Therefore, the problem solved by the present invention is to provide a better method for crystallizing thibol acetate, which overcomes the shortcomings of the prior art reports mentioned above.

[0030] Furthermore, the present invention therefore provides a method for preparing trenbolone acetate by means of a reproducible method, wherein the trenbolone acetate has a median particle size distribution (D50) contained in the range of 50 μm to 130 μm.

[0031] Furthermore, the present invention therefore provides a method for preparing thibol acetate with an irregular hexagonal plate-like crystal habit by means of a reproducible method.

[0032] Moreover, the present invention therefore provides a method for preparing thibol acetate by means of a reproducible method, wherein the thibol acetate has an irregular hexagonal plate-like crystal habit.

[0033] This problem is solved by the crystallization method of threnbromine acetate as outlined in the appended claims, the definition of which is an integral part of this specification.

[0034] Specifically, the present invention provides a method for preparing trenbolone acetate of formula (I) by crystallizing trenbolone acetate (I) with C2-C5 alkyl alcohols or mixtures thereof:

[0035]

[0036] The thibol acetate has an irregular hexagonal plate-like crystal habit.

[0037] In another aspect, the method provides an improved solid form of trenbolone acetate, which is trenbolone acetate with an irregular hexagonal plate-like crystal habit, exhibiting the following properties:

[0038] - It is more thermodynamically stable.

[0039] - and / or in the form of only irregular hexagonal plates and homogeneous solids.

[0040] As another aspect, threnbrom acetate with a specific average particle size contained in the range of 20 to 200 micrometers is provided.

[0041] Finally, the present invention provides a method for preparing trenbolone acetate of formula (I), wherein the trenbolone acetate has a median value (D50) of a particle size distribution in the range of 50 μm to 130 μm, the method being achieved by adding seed crystals having a median value (D50) of a specified particle size distribution through the crystallization of trenbolone acetate.

[0042] In another aspect, the method provides an improved solid form of trenbolone acetate, which is trenbolone acetate with a specified PSD, a feature that allows the product to be arranged in a more compact manner and thus have a higher solid density, thereby allowing more compound in a unit volume; that is, for the same volume of pharmaceutical composition, trenbolone acetate of formula (I) with a specified PSD may have more active ingredient.

[0043] Other features and advantages of the method and solid form according to the invention will arise from the description of the implementation embodiments of the invention provided as effects of the invention, reported below. Attached Figure Description

[0044] Figure 1 The XPRD spectra of compounds of formula (I) obtained by the method of the present invention according to Examples 2 and 6 are shown.

[0045] Figure 2 The DSC curves of the compounds of formula (I) obtained by the method of the present invention according to Examples 2 and 6 are shown.

[0046] Figure 3 The SEM images of the compounds of formula (I) obtained by the method of the present invention according to Examples 2 and 6 are shown.

[0047] Figure 4 The DSC curve of compound (I) obtained in Example 11 is shown.

[0048] Figure 5 The SEM image of compound (I) obtained in Example 11 is shown.

[0049] Figure 6 The DSC curve of compound (I) obtained in Example 10 is shown.

[0050] Figure 7 The SEM image of compound (I) obtained in Example 10 is shown.

[0051] Figure 8 The typical PSD distribution of the compound of formula (I) obtained by the method of the present invention is shown.

[0052] Description of the implementation plan

[0053] This invention relates to a method for preparing threnone acetate of formula (I):

[0054]

[0055] It includes crystallizing threnbromine acetate of formula (I) with C2-C5 alkyl alcohols or mixtures thereof.

[0056] According to a preferred embodiment of the method of the present invention, the term C2-C5 alkyl alcohol, the components of the above-mentioned mixture, refers to alkyl alcohols selected from the group comprising the following members: ethanol; 1-propanol (i.e., propanol); 2-propanol (i.e., isopropanol); allyl alcohol; 1-butanol (i.e., butanol); 2-butanol (i.e., sec-butanol); 2-methyl-1-propanol (i.e., isobutanol); 1-pentanol; 3-methyl-1-butanol; 2-methyl-1-butanol; 2-methyl-2-butanol; 2-pentanol; 3-pentanol; 3-methyl-2-butanol.

[0057] In a more preferred embodiment of the method according to the invention, the C2-C5 alkyl alcohol is selected from the group consisting of ethanol, propanol, isopropanol, isobutanol, n-butanol, sec-butanol, and tert-butanol.

[0058] In a more preferred embodiment of the method according to the invention, the C2-C5 alkyl alcohol is isopropanol.

[0059] In another embodiment, the present invention covers a method for preparing trenbolone acetate (I), the method comprising the following steps:

[0060] a) Provide a solution of threnbrom acetate in C2-C5 alkyl alcohols or mixtures thereof;

[0061] b) Optionally, the solution is seeded with trenbolone acetate seeds having a median (D50) particle size distribution in the range of 8 μm to 15 μm, or 15 μm to 20 μm, or 20 μm to 90 μm.

[0062] c) Cool until a suspension is obtained;

[0063] d) Filter the suspension;

[0064] e) Suspend the solid obtained in step d) in C5-C 10 In alkane or aromatic solvents;

[0065] f) Filter the resulting suspension to obtain thibolone acetate (I).

[0066] According to a preferred embodiment of the present invention, the method for preparing threnolol acetate (I) comprises the following steps:

[0067] a) Provide a solution of threnbrom acetate in C2-C5 alkyl alcohols or mixtures thereof;

[0068] b) Inoculate the solution with trenbolone acetate seeds, the seeds having a median (D50) particle size distribution in the range of 8 μm to 15 μm, or 15 μm to 20 μm, or 20 μm to 90 μm.

[0069] c) Cool until a suspension is obtained;

[0070] d) Filter the suspension;

[0071] e) Suspend the solid obtained in step d) in C5-C 10 In alkane or aromatic solvents;

[0072] f) Filter the resulting suspension to obtain thibolone acetate (I).

[0073] According to a preferred embodiment, the method of the present invention includes the following steps:

[0074] a) Provide a solution of threnbrom acetate in C2-C5 alkyl alcohols or mixtures thereof;

[0075] b) Inoculate the solution with trenbolone acetate seeds, the seeds having a median (D50) particle size distribution in the range of 8 μm to 15 μm, or 15 μm to 20 μm, or 20 μm to 90 μm.

[0076] c) Cool until a suspension is obtained;

[0077] d) Filter the suspension;

[0078] e) Suspend the solid obtained in step d) in C5-C 10 In alkane or aromatic solvents;

[0079] f) Filter the resulting suspension to obtain trenbolone acetate of formula (I) having a median particle size distribution (D50) that is contained in the range of 50 μm to 80 μm, or 60 μm to 90 μm, or 90 μm to 250 μm.

[0080] According to a more preferred embodiment, the method of the present invention includes the following steps:

[0081] a) Provide a solution of threnbrom acetate in C2-C5 alkyl alcohols or mixtures thereof;

[0082] b) Inoculate the solution with trenbolone acetate seeds, the seeds having a median (D50) particle size distribution in the range of 8 μm to 15 μm, or 15 μm to 20 μm, or 20 μm to 90 μm.

[0083] c) Cool until a suspension is obtained;

[0084] d) Filter the suspension;

[0085] e) Suspend the solid obtained in step d) in C5-C 10 In alkane or aromatic solvents;

[0086] f) Filter the resulting suspension to obtain trenbolone acetate of formula (I) having a median particle size distribution (D50) that is contained in the range of 50 μm to 80 μm, or 60 μm to 90 μm, or 90 μm to 250 μm.

[0087] According to a preferred embodiment of the method of the present invention, the C2-C5 alkyl alcohol in step c) is selected from the group consisting of ethanol, propanol, isopropanol, isobutanol, n-butanol, sec-butanol, and tert-butanol.

[0088] In a preferred embodiment of the method according to the present invention, the C2-C5 alkyl alcohol in step c) is isopropanol.

[0089] According to a preferred embodiment of the method of the present invention, the seed crystals in step b) have a median value (D50) of a particle size distribution that is included in the range of 8 μm to 15 μm, or 15 μm to 20 μm, or 20 μm to 90 μm.

[0090] According to a preferred embodiment of the method of the present invention, the seed crystals in step b) have a median value (D50) of a particle size distribution that is contained in the range of 8 μm to 40 μm.

[0091] The amount of trenbolone acetate seed crystals of formula (I) is 0.50% w / w to 1.5% w / w relative to the total amount of trenbolone acetate (I).

[0092] The amount of seed crystals of trenbolone acetate of formula (I) with irregular hexagonal plate-like crystals is 0.50% w / w to 1.5% w / w relative to the total amount of trenbolone acetate (I).

[0093] According to a preferred embodiment of the method of the present invention, step b) is inoculated at a temperature between 20°C and 30°C.

[0094] In a more preferred embodiment of the method according to the invention, step b) is inoculated at a temperature between 20°C and 25°C.

[0095] According to a preferred embodiment of the method of the present invention, the temperature in the cooling process of step c) is reduced from a temperature range of 20°C to 40°C to a temperature range of -20°C to 0°C.

[0096] In a more preferred embodiment of the method according to the invention, the temperature during the cooling process in step c) is reduced from a temperature in the range of 20°C to 30°C to a temperature in the range of -20°C to -10°C.

[0097] In a more preferred embodiment of the method according to the invention, the temperature during the cooling process in step c) is reduced from a temperature in the range of 20°C to 26°C to a temperature in the range of -18°C to -10°C.

[0098] In a more preferred embodiment of the method according to the invention, the temperature during the cooling process in step c) is reduced from a temperature in the range of 20°C to 40°C to a temperature in the range of -20°C to -10°C.

[0099] According to a preferred embodiment of the method of the present invention, the temperature during the crystallization process of trenbolone acetate of formula (I) is reduced from a temperature in the range of 20°C to 40°C to a temperature of -20°C within 8 hours.

[0100] According to a preferred embodiment of the method of the present invention, step e) C5-C 10 The alkane or aromatic solvent is selected from the group containing the following members: 2-methylbutane (i.e., isopentane), cyclopentane, pentane, cyclohexane, hexane, 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane, 2,2-dimethylbutane, a mixture of hexane isomers, heptane, 2-methylhexane, 3-methylhexane, 2,2-dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, methylcyclohexane, octane, methylheptane, 3-methylheptane, nonane, decane, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, a mixture of xylene isomers.

[0101] According to a preferred embodiment of the method of the present invention, step e) C5-C 10 The alkane or aromatic solvent is selected from the group consisting of the following members: 2-methylbutane, cyclopentane, pentane, cyclohexane, hexane, mixtures of hexane isomers, heptane, methylcyclohexane, octane, toluene, ethylbenzene, xylene isomers.

[0102] According to a more preferred embodiment of the method of the present invention, step e) C5-C 10 The alkane or aromatic solvent is heptane.

[0103] According to a preferred embodiment of the method of the present invention, the threnbrom acetate of formula (I) has a median value (D50) of particle size distribution in the range of 50 μm to 130 μm.

[0104] According to a preferred embodiment of the method of the present invention, the threnbrom acetate of formula (I) obtained has a median value (D50) of particle size distribution in the range of 50 μm to 130 μm.

[0105] According to a preferred embodiment of the method of the present invention, the threnbrom acetate of formula (I) obtained has a median value (D50) of particle size distribution that is respectively contained in the range of 50 μm to 80 μm, or 60 μm to 90 μm, or 90 μm to 250 μm.

[0106] According to a preferred embodiment of the method of the present invention, the obtained thibol acetate of formula (I) has an irregular hexagonal plate-like crystal habit.

[0107] According to a preferred embodiment of the method of the present invention, trenbolone acetate of formula (I) having irregular hexagonal plate-like crystals is inoculated with a C2-C5 alkyl alcohol at a temperature between 20°C and 25°C to crystallize trenbolone acetate (I).

[0108] According to a preferred embodiment of the method of the present invention, the crystallization of trenbolone acetate of formula (I) is carried out in an amount of C2-C5 alkyl alcohol contained in between 3 and 10 volumes, relative to the amount of trenbolone acetate (I).

[0109] The above-mentioned volume of the mixture of C2-C5 alkyl alcohols and water is relative to the amount of trenbolone acetate (I). The amount of trenbolone acetate can be the weight of the starting material trenbolone acetate, or it can be determined by stoichiometric calculations, where it is assumed that all trenbolones of formula (II) are converted to trenbolone acetate.

[0110] Volume refers to the volume of solvent per unit of product (i.e., the weight of trenbolone acetate). Thus, for example, 1 volume is 1 liter / 1 kilogram, or 1 milliliter / 1 gram, or 1 microliter / 1 milligram. Therefore, 10 volumes means, for example, 10 microliters per milligram of substance (in this case, the compound of formula (I)).

[0111] In step f), the threnbromine acetate of formula (I) is separated, for example, by filtration or centrifugation.

[0112] The molar yield of the method according to the invention, starting with threnbromine of formula (II), is between 75% and 90%.

[0113] The molar yield of the method according to a more preferred embodiment of the invention, starting with threnbromine of formula (II), is between 80% and 87%.

[0114] The molar yield of thibol acetate from formula (I) according to the method of the present invention is between 85% and 95%.

[0115] The molar yield of the method according to a more preferred embodiment of the present invention, starting from trenbolone acetate of formula (I), is between 90% and 95%.

[0116] According to a preferred embodiment, the method of the present invention provides trenbolone acetate (I) with high chemical purity (i.e., more than 99.50% A / A%).

[0117] Therefore, another aspect is threnbromine acetate of formula (I) with an irregular hexagonal plate-like crystal habit:

[0118]

[0119] Therefore, another aspect is threnbromine acetate of formula (I) with an irregular hexagonal plate-like crystal habit:

[0120]

[0121]

[0122] The thibol acetate (I) therein is in the form of only plate-like crystals.

[0123] In another embodiment, the present invention covers a method for preparing threnbrolon acetate of formula (I), which has an irregular hexagonal plate-like crystal habit.

[0124] In fact, the method of the present invention allows for the production of threnbrolon acetate with an irregular hexagonal plate-like crystal habit, existing only in the form of plate-like crystals. This means that the solid form does not contain crystals of different morphologies, but only plate-like crystals.

[0125] Therefore, threnbromine acetate, which has an irregular hexagonal plate-like crystal habit and exists only in the form of plate-like crystals, does not contain any soft agglomerates or any other crystals with different morphologies.

[0126] Furthermore, threnbromine acetate, which has an irregular hexagonal plate-like crystal habit, is a homogeneous solid.

[0127] Trenbolone acetate, which has an irregular hexagonal plate-like crystal habit and exists only in plate-like crystal form, can be appropriately used to prepare pharmaceutical compositions.

[0128] According to a preferred embodiment, the thibol acetate (I) has an average particle size contained in the range of 20-200 micrometers.

[0129] According to a preferred embodiment, the threnbroline acetate (I) has a melting point (starting point) of 95.8°C as measured by DSC.

[0130] According to a preferred embodiment, threnbrolon acetate (I), which has an irregular hexagonal plate-like crystal habit and is in the form of only plate-like crystals, has a mean square weight contained in the range of 20-200 μm (i.e., micrometers).

[0131] Average particle size refers to a measure of the average diameter determined by laser diffraction.

[0132] The solid form also exhibits the same favorable behavior in terms of thermal stability, hygroscopicity, and solubility.

[0133] As another advantage of the method of the present invention, it is noted that the method provides threnbrolon acetate with irregular hexagonal plate-like crystals of large size and / or length, specifically having a mean square weight contained in the range of 20 μm to 200 μm.

[0134] The method of the present invention provides threnbrolon acetate of formula (I) having an irregular hexagonal plate-like crystal habit. Specifically, the method of the present invention provides threnbrolon acetate of formula (I) having an irregular hexagonal plate-like crystal habit, having a mean square weight contained in the range of 20-200 μm and / or being in the form of plate-like crystals only.

[0135] The mean square weight was determined by the chord length distribution analysis of threnbroline acetate according to formula (I), specifically by scanning electron microscopy (SEM).

[0136] The method of the present invention advantageously provides threnbrolon acetate with plate-like crystals of large size and / or length, specifically, as determined by chord length distribution analysis, containing a particle size distribution in the range of 20 μm to 200 μm.

[0137] Examples 10 and 11 provide clear comparative evidence of the effects of the invention. In fact, trenbolone acetate of formula (I), prepared by crystallizing it with a solvent different from that of C2-C5 alkyl alcohols, does not produce plate-like crystals because it exhibits a distinctly different crystal morphology (see...). Figure 3 Compared to Figure 5 , 7 ).

[0138] The different crystal habits of the three solid forms are actually evident through microscopic analysis. Two of them were obtained by crystallization with a mixture of AcOEt / heptane and diisopropyl ether (DIPE) (non-plate-like crystals), while the other was obtained by crystallization with C2-C5 alkyl alcohols (plate-like crystals).

[0139] Specifically, obtained through microscopic analysis Figure 3 The images in Figure 5 and 7 The comparison of the images provides further evidence for the three different crystal habits.

[0140] also, Figure 3The plate-like crystal habit of trenbolone acetate obtained by crystallizing trenbolone acetate of formula (I) with C2-C5 alkyl alcohols is clearly shown.

[0141] Furthermore, trenbolone acetate of formula (I) with irregular hexagonal plate-like crystal habit has this characteristic, which allows the product to be arranged in a more compact manner and thus have a higher solid density, thereby allowing more compound per unit volume unit; that is, for the same volume of pharmaceutical composition, trenbolone acetate of formula (I) with irregular hexagonal plate-like crystal habit may have more active ingredient.

[0142] Contrary to the results observed in existing methods, the method and product of the present invention offer another remarkable advantage through easy control of precipitation and also through the non-aggregation of the crystalline products (i.e., no agglomerates are observed in the products).

[0143] The solid form exhibits the same favorable behavior in terms of stability.

[0144] According to a preferred embodiment of the invention, trenbolone acetate, having an irregular hexagonal plate-like crystal habit and a mean square weight contained in the range of 20-200 μm, is in the form of plate-like crystals only. This solid form has the advantage of being a homogeneous solid and is therefore very suitable (especially in terms of processability) for the preparation of pharmaceutical compositions containing trenbolone acetate.

[0145] The method of the present invention provides threnbrolon acetate of formula (I) having an irregular hexagonal plate-like crystal habit. The threnbrolon acetate (I) is further described by the following parameters.

[0146] The solid form of trenbolone acetate, obtained by crystallizing it with C2-C5 alkyl alcohols or mixtures thereof, exhibits an irregular hexagonal plate-like crystal habit and has a melting point of 95.8°C as measured by DSC (see [reference]). Figure 2 ).

[0147] Specifically, as measured by DSC, record the values ​​of the DSC start and DSC peak.

[0148] DSC begins to correspond to the melting point recorded by DSC analysis, the method of which is better described in the experimental section.

[0149] Furthermore, threnbromine acetate, which has an irregular hexagonal plate-like crystal habit, exhibits a peak at 97.59 °C as measured by DSC.

[0150] Therefore, trenbolone acetate with an irregular hexagonal plate-like crystal habit has a melting point of 95.8 °C, which is higher than that of trenbolone acetate with a non-irregular hexagonal plate-like crystal habit (approximately 93 °C), both measured by DSC (start) (see respective references). Figure 2 and Figure 4 , 6 ).

[0151] The different peaks in the DSC analysis also confirmed these different thermal behaviors: threnbromine acetate with irregular hexagonal plate-like crystal habit showed a peak at 97.59 °C, which is a higher temperature compared to the peak at about 95 °C for threnbromine acetate with non-irregular hexagonal plate-like crystal habit.

[0152] The aforementioned DSC comparative study thus demonstrates that the crystallization habit of threnol acetate as an irregular hexagonal plate crystal is thermodynamically more stable than that of a non-irregular hexagonal plate crystal, because the former has a higher melting point than the latter (97.59 °C relative to about 95 °C (peak) and 95.8 °C relative to about 93 °C (start)).

[0153] Figure 4 , 6 and Figure 2 The comparison of the DSC curves clearly demonstrates the different thermal behaviors of the three solid forms of threnbrom acetate with three different crystal habits: non-plate and plate crystals, which may belong to the same polymorphic form.

[0154] Specifically, threnbrom acetate, which has an irregular hexagonal plate-like crystal habit, has a characteristic X-ray powder diffraction pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, and 20.9, each ±0.2.

[0155] More specifically, threnbromine acetate, which has an irregular hexagonal plate-like crystal habit, has a characteristic X-ray powder diffraction pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, 16.1, 19.5, 20.9, 22.3, each ±0.2.

[0156] More specifically, threnbromine acetate, exhibiting an irregular hexagonal plate-like crystal habit, displays a characteristic X-ray powder diffraction pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, 16.1, 18.2, 19.5, 20.9, 22.3, 23.8, and 24.2, each ±0.2 (see [link to relevant documentation]). Figure 1 ).

[0157] In the case of threnbromine acetate with irregular hexagonal plate-like crystal habit, this difference in intensity comes from the orientation preference of the crystal caused by the plate-like shape.

[0158] It has been surprisingly discovered that crystallizing trenbolone acetate of formula (I) using C2-C5 alkyl alcohols or mixtures thereof is a highly reproducible and robust method for obtaining trenbolone acetate with a median (D50) particle size distribution ranging from 50 μm to 130 μm and an irregular hexagonal plate-like crystal habit.

[0159] It has been surprisingly discovered that crystallizing trenbolone acetate of formula (I) with a C2-C5 alkyl alcohol (which is isopropanol) is a highly reproducible and robust method for obtaining trenbolone acetate with a median (D50) particle size distribution in the range of 50 μm to 130 μm and an irregular hexagonal plate-like crystal habit.

[0160] According to a preferred embodiment of the method of the present invention, threnolol acetate of formula (I):

[0161]

[0162] It has a median (D50) particle size distribution that is contained in the range of 50 μm to 130 μm.

[0163] In another embodiment, the present invention covers a method for preparing trenbolone acetate (I) having a median particle size distribution (D50) in the range of 50 μm to 130 μm.

[0164] According to a preferred embodiment of the method of the present invention, threnbrolon acetate (I) has a median value (D50) of particle size distribution contained in the range of 70 μm to 100 μm.

[0165] According to a preferred embodiment of the method of the present invention, the threnbroline acetate of formula (I) has a D10 with a particle size distribution of less than 40 μm.

[0166] According to a preferred embodiment of the method of the present invention, threnbrolon acetate (I) has a median value (D10) of particle size distribution contained in the range of 15 μm to 40 μm.

[0167] According to a preferred embodiment of the method of the present invention, the threnbroline acetate of formula (I) has a D90 with a particle size distribution of less than 300 μm.

[0168] In a more preferred embodiment of the method according to the invention, the threnbroline acetate of formula (I) has a D90 with a particle size distribution of less than 200 μm.

[0169] The trenbolone acetate solid form has a median particle size distribution (D50) ranging from 50 μm to 130 μm and a melting point of 95.8 °C as measured by DSC (see [reference]). Figure 1 ).

[0170] Specifically, trenbolone acetate has a median particle size distribution (D50) encompassing a range of 50 μm to 130 μm, and a characteristic X-ray powder diffraction pattern (i.e., XPRD) with characteristic peaks at positions represented by 2-θ values ​​(2θ): 6.5, 13.2, and 20.9, each ±0.2.

[0171] More specifically, trenbolone acetate has a median (D50) of particle size distribution encompassing the range of 50–130 μm, and a characteristic XPRD pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, 16.1, 19.5, 20.9, and 22.3, each ±0.2.

[0172] More specifically, trenbolone acetate has a median particle size distribution (D50) encompassing the range of 50 μm to 130 μm, exhibiting a characteristic X-ray powder diffraction pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, 16.1, 18.2, 19.5, 20.9, 22.3, 23.8, and 24.2, each ±0.2 (see [link to relevant documentation]). Figure 1 ).

[0173] According to a preferred embodiment of the method of the present invention, threnbrolon acetate of formula (I) having an irregular hexagonal plate-like crystal habit:

[0174]

[0175] It can be obtained by the method of the present invention.

[0176] According to a preferred embodiment of the method of the present invention, threnbromide acetate of formula (I) having a median particle size distribution (D50) in the range of 50 μm to 130 μm is used.

[0177]

[0178] It can be obtained by the method of the present invention.

[0179] In another embodiment, the present invention covers a method for preparing trenbolone acetate (I), comprising the prior step of preparing compound (I) by acetylation of trenbolone of formula (II):

[0180]

[0181] According to a preferred embodiment of the method of the present invention, the acetylation step of trenbolone and the crystallization of trenbolone acetate of formula (I) are carried out in one pot.

[0182] Specifically, the method of the present invention can be carried out in one pot, that is, starting from the acetylation step of trenbolone of formula (II) and continuing with the crystallization step to produce solid trenbolone acetate (I), wherein the compound of trenbolone acetate of formula (I) obtained in the acetylation step is retained in solution, that is, it is not separated into solid form.

[0183] Specifically, at the end of acetylation, the solvent is switched to isopropanol, thus carrying out the entire process in one pot.

[0184] This invention relates to a method for preparing threnone acetate of formula (I):

[0185]

[0186] The thilbone acetate has a median particle size distribution (D50) in the range of 50 μm to 80 μm, or 60 μm to 90 μm, or 90 μm to 250 μm. The method is achieved by adding seed crystals to a solution of thilbone acetate in a solvent, the seed crystals having a median particle size distribution (D50) in the range of 8 μm to 15 μm, or 15 μm to 20 μm, or 20 μm to 90 μm, respectively.

[0187] By adding seed crystals having a median D50 particle size distribution in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, trenbolone acetate in solid form having a median D50 particle size distribution in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm has a melting point of 95.8 °C as measured by DSC (starting point) (see See). Figure 2 ).

[0188] Specifically, as measured by DSC, record the values ​​of the DSC start and DSC peak.

[0189] DSC begins to correspond to the melting point recorded by DSC analysis, the method of which is better described in the experimental section.

[0190] Furthermore, the thibol acetate (I) of the present invention exhibits a peak at 97.9°C as measured by DSC.

[0191] Specifically, by adding seed crystals having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, threnbrolon acetate having a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks at positions represented by 2-θ values ​​(2θ): 6.5, 13.2, and 20.9, each ±0.2.

[0192] More specifically, by adding seed crystals having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, threnbrolon acetate with a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, 16.1, 19.5, 20.9, 22.3, each ±0.2.

[0193] More specifically, by adding seed crystals having a median (D50) particle size distribution in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, threnbrolon acetate with a median (D50) particle size distribution in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks at the following positions, expressed in 2-θ values ​​(2θ): 6.5, 13.2, 16.1, 18.2, 19.5, 20.9, 22.3, 23.8, and 24.2, each ±0.2 (see [link to relevant documentation]). Figure 1 ).

[0194] Another object of the present invention is a pharmaceutical composition comprising trenbolone acetate of formula (I) prepared according to the method of the present invention:

[0195]

[0196] And one or more pharmaceutically acceptable excipients.

[0197] According to a preferred embodiment, the method for preparing threnbrolon acetate of formula (I) provides a compound of formula (I) having an irregular hexagonal plate-like crystal habit.

[0198] According to a preferred embodiment, the method for preparing threnone acetate of formula (I) provides a compound of formula (I) in the form of only plate-like crystals, the solid being a homogeneous solid.

[0199] According to a preferred embodiment, the method for preparing trenbolone acetate of formula (I) provides a compound of formula (I) having a median value (D50) of a particle size distribution contained in the range of 50 μm to 130 μm.

[0200] Another object of the present invention is a pharmaceutical composition comprising trenbolone acetate of formula (I) having a median (D50) particle size distribution in the range of 50-130 μm:

[0201]

[0202]

[0203] And one or more pharmaceutically acceptable excipients.

[0204] According to a preferred embodiment of the invention, the pharmaceutical composition comprises trenbolone acetate of formula (I) having a particle size distribution of D10 of less than 40 μm and one or more pharmaceutically acceptable excipients.

[0205] According to a preferred embodiment of the invention, the pharmaceutical composition comprises trenbolone acetate of formula (I) having a particle size distribution of less than 300 μm and one or more pharmaceutically acceptable excipients.

[0206] Another object of the present invention is a pharmaceutical composition comprising threnol acetate of formula (I) having an irregular hexagonal plate-like crystal habit:

[0207]

[0208] And one or more pharmaceutically acceptable excipients.

[0209] Examples of suitable pharmaceutical compositions comprising trenbolone acetate according to the invention are those disclosed in WO 2001043748A2, WO 9930685 A1, WO 9947073 A1, WO 2000025743A2, WO 2001043749 A2, WO 2019217203 A1 or WO 2020061550 A1, differing in that trenbolone acetate having an irregular hexagonal plate-like crystal habit is used instead of the disclosed trenbolone acetate having a non-irregular hexagonal plate-like crystal habit, and / or differing in that trenbolone acetate has a median (D50) particle size distribution contained in the range of 50 μm to 130 μm.

[0210] Pharmaceutical compositions can be in various dosage forms, including, for example, capsules, tablets, powders, suspensions, or any other suitable dosage form. In such dosage forms, trenbolone acetate (I), having an irregular hexagonal plate-like crystal habit, can be combined with one or more pharmaceutically acceptable excipients, carriers, or diluents (such as, for example, mannitol, silicon derivatives, or sugars).

[0211] As described above, trenbolone acetate of formula (I), which has an irregular hexagonal plate-like crystal habit obtained by crystallizing trenbolone acetate of formula (I) with C2-C5 alkyl alcohols, can be used to prepare pharmaceutical compositions.

[0212] Trenbolone acetate of formula (I) with irregular hexagonal plate-like crystal habit obtained by crystallizing trenbolone acetate of formula (I) with C2-C5 alkyl alcohol as described above, or the aforementioned pharmaceutical composition, can be used as a medicine or for use in medicine or in veterinary medicine.

[0213] Trenbolone acetate of formula (I), which has an irregular hexagonal plate-like crystal habit, obtained by crystallizing trenbolone acetate of formula (I) with C2-C5 alkyl alcohols as described above, or the aforementioned pharmaceutical compositions, can be used as an androgen stimulant and / or to increase the muscle mass of cattle.

[0214] Trenbolone acetate of formula (I), exhibiting an irregular hexagonal plate-like crystal habit, effectively provides a drug with better bioavailability. According to a preferred embodiment, trenbolone acetate has an average particle size contained in the range of 20 to 200 μm.

[0215] According to a preferred embodiment, trenbolone acetate with an average particle size in the range of 20 to 200 micrometers exhibits an irregular hexagonal plate-like crystal habit. In such cases, particularly where the crystal habit is unfavorable to the manufacturing process of the pharmaceutical product, the small particle size distribution provides a very positive effect, thereby balancing the two effects and providing the product as a more stable solid form of trenbolone acetate.

[0216] According to a preferred embodiment, trenbolone acetate, having an average particle size in the range of 20 to 200 micrometers, is in the form of only plate-like crystals. This product is particularly homogeneous and therefore appears to be the easiest to use in the manufacturing process for preparing pharmaceutical products. Furthermore, it allows for better control over the amount of active ingredient applied during the preparation of pharmaceutical products.

[0217] Pharmaceutical compositions can be prepared comprising thibol acetate of formula (I) having an irregular hexagonal plate-like crystal habit and one or more pharmaceutically acceptable excipients.

[0218] The pharmaceutical composition containing trenbolone acetate of formula (I) having an irregular hexagonal plate-like crystal habit can have the same route of administration and dosage form as previously described with respect to pharmaceutical compositions containing trenbolone acetate having a non-irregular hexagonal plate-like crystal habit.

[0219] Trenbolone acetate of formula (I) having a median particle size distribution (D50) in the range of 50 μm to 130 μm, and / or a particle size distribution of less than 40 μm (D10), and / or a particle size distribution of less than 300 μm (D90) as described above can be used to prepare pharmaceutical compositions.

[0220] As described above, by adding seed crystals having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, trenbolone acetate of formula (I) having a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm can be used to prepare pharmaceutical compositions.

[0221] Trenbolone acetate of formula (I) having a particle size distribution median value (D50) in the range of 50 μm to 130 μm, and / or a particle size distribution D10 of less than 40 μm, and / or a particle size distribution D90 of less than 300 μm, or the aforementioned pharmaceutical compositions, may be used as a medicine or for use in medicine or in veterinary medicine.

[0222] As described above, trenbolone acetate of formula (I) having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, or the aforementioned pharmaceutical composition, can be used as a medicine or for use in medicine or in veterinary medicine by adding seed crystals having a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm, respectively.

[0223] As described above, trenbolone acetate of formula (I) having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, or the aforementioned pharmaceutical composition, can be used to promote androgen production and / or increase bovine muscle mass by adding seed crystals having a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm, respectively.

[0224] According to a preferred embodiment, trenbolone acetate of formula (I) has a median particle size distribution (D50) comprising a particle size distribution in the range of 50-130 μm, and / or a particle size distribution of less than 40 μm (D10), and / or a particle size distribution of less than 300 μm (D90). In such cases, particularly where crystals are unfavorable for the manufacturing process of pharmaceutical products, the small particle size distribution provides a very positive effect, thus balancing the two effects and providing a product as a more stable solid form of trenbolone acetate.

[0225] According to a preferred embodiment, trenbolone acetate has a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm by adding seed crystals having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively. In such cases, especially where crystals are detrimental to the manufacturing process of the pharmaceutical product, a small particle size distribution provides a very positive effect, thereby balancing the two effects and providing a product as a more stable solid form of trenbolone acetate.

[0226] According to a preferred embodiment, trenbolone acetate of formula (I) has a median particle size distribution (D50) comprising a particle size distribution in the range of 50 μm to 130 μm, and / or a D10 for a particle size distribution less than 40 μm, and / or a D90 for a particle size distribution less than 300 μm. Such a product is particularly homogeneous and therefore appears to be the easiest to use in the manufacturing process for preparing pharmaceutical products. Furthermore, it allows for better control of the amount of active ingredient applied during the preparation of pharmaceutical products.

[0227] According to a preferred embodiment, trenbolone acetate has a median particle size distribution (D50) in the ranges of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm by adding seed crystals having a median particle size distribution (D50) in the ranges of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively. Such a product is particularly homogeneous and therefore appears to be the easiest to use in the manufacturing process of pharmaceutical products. Furthermore, it allows for better control of the amount of active ingredient applied during the preparation of the pharmaceutical product.

[0228] Pharmaceutical compositions can be prepared comprising trenbolone acetate of formula (I) having a median particle size distribution (D50) in the range of 50 μm to 130 μm, and / or a particle size distribution of less than 40 μm (D10), and / or a particle size distribution of less than 300 μm (D90), and one or more pharmaceutically acceptable excipients.

[0229] A pharmaceutical composition can be prepared comprising trenbolone acetate of formula (I) having a median particle size distribution (D50) in the range of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm, obtained by adding seed crystals having a median particle size distribution (D50) in the range of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, and one or more pharmaceutically acceptable excipients.

[0230] The pharmaceutical composition containing trenbolone acetate of formula (I) having a median value (D50) of a particle size distribution in the range of 50 μm to 130 μm, and / or a D10 of a particle size distribution less than 40 μm, and / or a D90 of a particle size distribution less than 300 μm, may have the same route of administration and dosage form as previously described with respect to pharmaceutical compositions containing trenbolone acetate of the prior art.

[0231] The pharmaceutical composition comprising trenbolone acetate of formula (I) having a median particle size distribution (D50) in the range of 50 μm to 80 μm, 60 μm to 90 μm, or 90 μm to 250 μm, obtained by adding seeds having a median particle size distribution (D50) in the range of 8 μm to 15 μm, 15 μm to 20 μm, or 20 μm to 90 μm, respectively, may have the same route of administration and dosage form as previously described with respect to pharmaceutical compositions comprising trenbolone acetate of the prior art.

[0232] Another object of the present invention is the preparation of the pharmaceutical composition, the method comprising the following steps:

[0233] a) Provided the thibol acetate of the present invention;

[0234] b) Mix the trenbolone acetate from step a) with one or more pharmaceutically acceptable excipients;

[0235] c) Packaging the mixture obtained in step b).

[0236] Trenbolone acetate, which has a plate-like crystal habit, is a thermodynamically more stable solid form, thus exhibiting better storage stability and being easier to formulate into pharmaceutical compositions.

[0237] The method of the present invention is carried out by means of crystallization of trenbolone acetate of formula (I). In this case, crystallization is the process of forming solid crystals from a solution of trenbolone acetate of formula (I) that has been prepared in advance and / or dissolved therein. In particular, the term crystallization in the method of the present invention means crystallization or recrystallization.

[0238] Recrystallization is a technique used to purify compounds and / or to obtain different solid forms (e.g., polymorphs). Specifically, a solid compound is dissolved in a suitable solvent and then, by means of heating and then cooling, or by dissolving in a suitable solvent and adding an antisolvent, the compound is restored to a solid, typically a solid crystal.

[0239] Therefore, the method of the present invention can be carried out, for example, starting with trenbolone acetate and recrystallizing it by heating / cooling treatment, or alternatively, by obtaining a trenbolone acetate solution and then crystallizing the product (e.g., by cooling or by adding an antisolvent, or by other means).

[0240] Trenbolone acetate of formula (I) having a median particle size distribution (D50) in the range of 50 μm to 130 μm, and / or a particle size distribution of less than 40 μm (D10), and / or a particle size distribution of less than 300 μm (D90) can be more easily formulated into a pharmaceutical composition.

[0241] Trenbolone acetate, obtained by adding seed crystals having a median particle size distribution (D50) in the ranges of 8-15 μm, 15-20 μm, or 20-90 μm, can be more easily formulated into pharmaceutical compositions having a median particle size distribution (D50) in the ranges of 50-80 μm, 60-90 μm, or 90-250 μm.

[0242] The method of the present invention is carried out by means of crystallization of trenbolone acetate of formula (I). In this case, crystallization is the process of forming solid crystals from a solution of trenbolone acetate of formula (I) that has been prepared in advance and / or dissolved therein. In particular, the term crystallization in the method of the present invention means crystallization or recrystallization.

[0243] Recrystallization is a technique used to purify compounds and / or to obtain different solid forms (e.g., polymorphs). Specifically, a solid compound is dissolved in a suitable solvent and then, by means of heating and then cooling, or by dissolving in a suitable solvent and adding an antisolvent, the compound is restored to a solid, typically a solid crystal.

[0244] Therefore, the method of the present invention can be carried out, for example, starting with trenbolone acetate and recrystallizing it by heating / cooling treatment, or alternatively, by obtaining a trenbolone acetate solution and then crystallizing the product (e.g., by cooling or by adding an antisolvent, or by other means).

[0245] Furthermore, the improved method for preparing trenbolone acetate of formula (I) having a median particle size distribution (D50) contained in the range of 50 μm to 130 μm, and / or a particle size distribution of less than 40 μm (D10), and / or a particle size distribution of less than 300 μm (D90) makes it possible to prepare trenbolone acetate with high chemical purity (i.e., more than 99.90%, by HPLC A / A%).

[0246] Furthermore, by adding seed crystals having a median particle size distribution (D50) in the ranges of 8-15 μm, 15-20 μm, or 20-90 μm, respectively, the improved method for preparing trenbolone acetate with a median particle size distribution (D50) in the ranges of 50-80 μm, 60-90 μm, or 90-250 μm makes it possible to prepare trenbolone acetate with high chemical purity (i.e., more than 99.90%, by HPLC A / A%).

[0247] It has been surprisingly discovered that crystallization of trenbolone acetate (I) with a median particle size distribution (D50) in the range of 50-80 μm, 60-90 μm, or 90-250 μm is achieved by adding seed crystals having a median particle size distribution (D50) in the range of 8-15 μm, 15-20 μm, or 20-90 μm, respectively. This is a highly reproducible and robust method for obtaining trenbolone acetate with a median particle size distribution (D50) in the range of 50 μm to 130 μm.

[0248] Furthermore, trenbolone acetate of formula (I) has a median particle size distribution (D50) in the range of 50 μm to 130 μm, a feature that allows the product to be arranged in a more compact manner and thus has a higher solid density, thereby allowing more compound per unit volume; that is, for the same volume of pharmaceutical composition, trenbolone acetate of formula (I) with a median particle size distribution (D50) in the range of 50 μm to 130 μm may have more active ingredient.

[0249] Contrary to the results observed in prior art methods, the method and product of the present invention offer another surprising advantage through easy control of precipitation and also through the non-aggregation of the crystalline products (i.e., no agglomerates are observed in the products).

[0250] It has been surprisingly discovered that the crystallization of trenbolone acetate of formula (I) of the present invention is a highly reproducible and robust method for obtaining trenbolone acetate with a median (D50) particle size distribution encompassing a range of 50 μm to 130 μm.

[0251] Furthermore, those skilled in the art of organic chemistry will understand that the method of the present invention allows for increased solid density, a feature that allows products to be arranged in a more compact manner, thereby allowing more compounds per unit volume unit; that is, for the same volume of pharmaceutical composition, trenbolone acetate of formula (I) having a median (D50) particle size distribution contained in the range of 50 μm to 130 μm may have more active ingredients.

[0252] Furthermore, the improved method for preparing trenbolone acetate with irregular hexagonal plate-like crystals allows for the preparation of trenbolone acetate with high chemical purity (i.e., over 99.90%, by HPLC A / A%).

[0253] All the features and preferred embodiments of the method of the present invention given above can be combined in every possible combination to achieve the claimed method.

[0254] Those skilled in the art of organic chemistry will understand that, considering the reduction in the number of steps required to synthesize trenbolone acetate (i.e., the method does not require a recrystallization step of trenbolone acetate), the method of the present invention enables increased productivity.

[0255] Experimental Section

[0256] The starting materials trenbolone and trenbolone acetate can be prepared according to well-known existing techniques or, for example, as described in CN108017682, CN 102399253, CN 102924553 or CN 110437294, or can be purchased commercially.

[0257] A suspension is a mixture of solid material suspended in a solvent or solution, that is, a mixture of solid and solvent, which is liquid. The solvent may also contain other compounds or solids.

[0258] Room temperature (RT) refers to the temperature within the range of 20-25°C, which is defined as the comfortable indoor temperature range.

[0259] Molar equivalent refers to the amount of one substance reacting with the amount of another substance in a given chemical reaction.

[0260] The term “volume” refers to the volume of solvent per unit of product; therefore, for example, 1 volume is 1 liter per kilogram, or 1 milliliter per gram, or 1 microliter per milligram.

[0261] Example 1: Trenbolone was prepared starting with 9(10)-dehydronandrolone (DHN).

[0262]

[0263] A solution of 100 g DHN in 250 mL DCM, 50 mL MeOH, and 1.4 g PTSA was added dropwise over at least 2 h to a stirred solution of 100 mL DCM, 350 mL MeOH, and 61 mL trimethyl orthoacetate. At the end of the addition, the feeding funnel was rinsed with 33 mL DCM, and the rinse solution was transferred into the reaction mixture. IPC analysis indicated that the reaction was complete. Afterward, 500 mL of water was added to the mixture and the mixture was stirred for 0.5–2 h. The aqueous phase was discarded, and a mixture of 400 mL water and 5 g PTSA was added to the organic phase. Afterward, IPC analysis indicated that the reaction was complete. The two phases were separated, and the organic phase was neutralized by adding a solution of water (100 mL) and NaHCO3 (0.2 g) at room temperature with stirring, bringing the pH to 7–8. The phases were separated, and 200 mL DCM was added to the organic phase. The resulting solution was concentrated to approximately 200 mL under vacuum by maintaining an internal temperature below 30 °C. This addition / concentration procedure was repeated until the solution was anhydrous. After reaching this limit, the mixture was evaporated one last time until the total volume reached 300 mL. The mixture was treated with 24 mL of acetic acid and added dropwise to a stirred suspension of 96 g DDQ in 700 mL of DCM, maintaining the internal temperature between 0 and 7 °C. After the addition was complete, the addition vessel was rinsed with 50 mL of DCM, and the rinse solution was combined with the reaction mixture and stirred at 0-7 °C until complete conversion was achieved. The reaction mixture was quenched by adding a solution consisting of 38 g of Na₂S₂O₅ aqueous solution (30% by weight), 73 mL of water, and 20 mL of MeOH at 0-7 °C. The resulting slurry was warmed to room temperature and stirred for 0.5 h, then filtered, and the filter cake was washed with 2 x 100 mL DCM. The resulting two-phase mixture was separated, and the organic phase was washed with a solution of 200 mL of water, 20 mL of MeOH, and 7.7 g of NaHCO₃. After phase separation, the organic layer was washed again with a solution of 200 mL water, 60 mL MeOH, and 7.7 g NaHCO3. The phases were separated, and the organic layer was washed a final time with a solution of 200 mL water, 100 mL MeOH, and 7.7 g NaHCO3. The combined filtered solutions were concentrated to 300 mL under vacuum with stirring, maintaining an internal temperature below 30 °C. 300 mL of acetone was added to the resulting solution, and the mixture was again concentrated to 300 mL (total volume) under vacuum, maintaining an internal temperature below 30 °C. The resulting suspension was cooled to 0 °C and maintained at this temperature for 0.5 h with stirring. It was then filtered, and the filter cake was washed twice with 100 mL of acetone. The wet solid was dried under vacuum at a maximum temperature of 40 °C to produce trenbolone in 65% yield and with an A / A purity >99.0% (by HPLC).

[0264] Example 2:Starting with trenbolone, trenbolone acetate is prepared by acetylation followed by crystallization from isopropanol (IPA).

[0265]

[0266] Add 60 g of acetic anhydride to a stirred mixture of 100 g threnbolone and 2 g 4-DMAP in 250 mL DCM. Rinse the anhydride feeding funnel with 50 mL of DCM and warm the resulting solution to 30 °C with stirring. At the end of the reaction, cool the solution to 20 °C and add a suspension of 31 g NaHCO3 in 300 mL of water with stirring. Rinse the acetylation reactor with another 50 mL of DCM and add the rinsing solution to the two-phase reaction mixture, then warm it again to 30 °C with stirring and hold for 1 h. Then cool the mixture to 20 °C and discard the aqueous layer. Wash the organic layer with 100 mL of water and separate the phase. Add isopropanol (300 mL) to the resulting organic solution and concentrate the mixture to 500 mL under vacuum, maintaining the internal temperature at 30 °C. Add isopropanol (300 mL) to the mixture again and distill the solvent under vacuum to 580 mL (total volume) while maintaining the internal temperature at 30 °C. The addition / concentration regimen was repeated three times. 0.5 g of trenbolone acetate was inoculated into the solution at an internal temperature of 20–25 °C. The mixture was maintained at 20–25 °C for 30 min, and then slowly cooled to an internal temperature of -20 / -10 °C. The resulting suspension was maintained at -20 / -10 °C for 0.5 h and then filtered. The filter cake was washed with 100 mL of cold IPA, and the resulting wet solid was then milled for 0.5 h by resuspending in cold n-heptane (150 mL). The mixture was then filtered and dried under vacuum at 40 °C to produce trenbolone acetate in 83% yield and >99.0% A / A (by HPLC), with a PSD within the D50 range of 67–130 μm.

[0267] Example 3: Starting with trenbolone, trenbolone acetate was prepared by acetylation followed by crystallization from ethanol.

[0268]

[0269] Add 60 g of acetic anhydride to a stirred mixture of 100 g threnbolone and 2.2 g 4-DMAP in 250 mL DCM. Rinse the anhydride feeding funnel with 50 mL of DCM and warm the resulting solution to 30 °C with stirring. At the end of the reaction, cool the solution to 20 °C and add a suspension of 31.1 g NaHCO3 in 300 mL of water with stirring. Rinse the acetylation reactor with another 50 mL of DCM and add the rinsing solution to the two-phase reaction mixture, then warm it again to 30 °C with stirring and hold for 1 h. Then cool the mixture to 20 °C and discard the aqueous layer. Wash the organic layer with 100 mL of water and separate the phase. Add ethanol (300 mL) to the resulting organic solution and concentrate the mixture to 500 mL (total volume) under vacuum, maintaining the internal temperature at 30 °C. Add ethanol (300 mL) to the mixture again and distill the solvent under vacuum to 580 mL (total volume) while maintaining the internal temperature at 30 °C. The addition / concentration regimen was repeated three times. 0.8 g of trenbolone acetate was inoculated into the solution at an internal temperature of 20–25 °C. The mixture was maintained at 20–25 °C for 30 minutes, and then slowly cooled to an internal temperature of -20 / -10 °C. The resulting suspension was maintained at -20 / -10 °C for 0.5 h and then filtered. The filter cake was washed with 100 mL of cold ethanol, and the resulting wet solid was then milled for 0.5 h by resuspending in cold n-heptane (150 mL). The mixture was then filtered and dried under vacuum at 40 °C to produce trenbolone acetate in 70% yield and >99.0% A / A (by HPLC).

[0270] Example 4: Starting with trenbolone, trenbolone acetate was prepared by acetylation followed by crystallization from n-butanol.

[0271]

[0272] Add 60 g of acetic anhydride to a stirred mixture of 100 g threnbolone and 2.2 g 4-DMAP in 250 mL DCM. Rinse the anhydride feeding funnel with 50 mL of DCM and warm the resulting solution to 30 °C with stirring. At the end of the reaction, cool the solution to 20 °C and add a suspension of 31.1 g NaHCO3 in 300 mL of water with stirring. Rinse the acetylation reactor with another 50 mL of DCM and add the rinsing solution to the two-phase reaction mixture, then warm it again to 30 °C with stirring and hold for 1 h. Then cool the mixture to 20 °C and discard the aqueous layer. Wash the organic layer with 100 mL of water and separate the phase. Add n-butanol (300 mL) to the resulting organic solution and concentrate the mixture to 500 mL (total volume) under vacuum, maintaining the internal temperature at 30 °C. Add n-butanol (300 mL) to the mixture again, and distill the solvent under vacuum to 580 mL (total volume) while maintaining the internal temperature at 30 °C. Repeat this addition / concentration process three times. Inoculate the solution with 1.5 g of trenbolone acetate at an internal temperature of 20–25 °C. Keep the mixture at 20–25 °C for 30 min, then slowly cool it to an internal temperature of -20 / -10 °C. Keep the resulting suspension at -20 / -10 °C for 0.5 h and then filter. Wash the filter cake with 100 mL of cold n-butanol, and then grind the resulting wet solid in cold n-heptane (150 mL) for 0.5 h. After that, filter the mixture and dry it under vacuum at 40 °C to produce trenbolone acetate in 75% yield and >99.0% A / A (by HPLC).

[0273] Example 5: Starting with trenbolone, trenbolone acetate was prepared by acetylation followed by crystallization from n-propanol.

[0274]

[0275] Add 60 g of acetic anhydride to a stirred mixture of 100 g threnbolone and 2.2 g 4-DMAP in 250 mL DCM. Rinse the anhydride feeding funnel with 50 mL of DCM and warm the resulting solution to 30 °C with stirring. At the end of the reaction, cool the solution to 20 °C and add a suspension of 31.1 g NaHCO3 in 300 mL of water with stirring. Rinse the acetylation reactor with another 50 mL of DCM and add the rinsing solution to the two-phase reaction mixture, then warm it again to 30 °C with stirring and hold for 1 h. Then cool the mixture to 20 °C and discard the aqueous layer. Wash the organic layer with 100 mL of water and separate the phase. Add n-propanol (300 mL) to the resulting organic solution and concentrate the mixture to 500 mL (total volume) under vacuum, maintaining the internal temperature at 30 °C. Add 300 mL of n-propanol to the mixture again, and distill the solvent under vacuum to 580 mL (total volume) while maintaining the internal temperature at 30 °C. Repeat this addition / concentration process three times. Inoculate the solution with 1 g of trenbolone acetate at an internal temperature of 20–25 °C. Keep the mixture at 20–25 °C for 30 min, then slowly cool it to an internal temperature of -20 / -10 °C. Keep the resulting suspension at -20 / -10 °C for 0.5 h and then filter. Wash the filter cake with 100 mL of cold n-propanol, and then grind the resulting wet solid in cold n-heptane (150 mL) for 0.5 h, after which filter the mixture and dry it under vacuum at 40 °C to produce trenbolone acetate in 78% yield and >99.0% A / A (by HPLC).

[0276] Example 6: This allows threnone acetate to crystallize from IPA.

[0277]

[0278] At 20°C, dichloromethane (2.5 mL) was added to a suspension of 50 g trenbolone acetate in 200 mL IPA. The mixture was heated to 30°C, after which complete dissolution was observed. The solution was cooled to 20–25°C and inoculated with 0.5% w / w trenbolone acetate. The mixture was held at 20–25°C for 30 min, and then slowly cooled to an internal temperature of -15°C. The resulting suspension was held at -15°C for 0.5 h and then filtered. The filter cake was washed with 50 mL of cold ethanol, and the resulting wet solid was then milled in cold n-heptane (75 mL) for 0.5 h, after which the mixture was filtered and dried under vacuum at a maximum temperature of 40°C to produce trenbolone acetate in 90% yield and >99.0% A / A (by HPLC).

[0279] Example 7: Trenbolone acetate is crystallized from ethanol.

[0280]

[0281] At 20°C, dichloromethane (2.5 mL) was added to a suspension of 50 g trenbolone acetate in 200 mL ethanol. The mixture was heated to 30°C, after which complete dissolution was observed. The solution was cooled to 20–25°C and inoculated with 0.8% w / w trenbolone acetate. The mixture was held at 20–25°C for 30 min, and then slowly cooled to an internal temperature of -15°C. The resulting suspension was held at -15°C for 0.5 h and then filtered. The filter cake was washed with 50 mL of cold ethanol, and the resulting wet solid was then milled for 0.5 h by resuspending in cold n-heptane (75 mL), after which the mixture was filtered and dried under vacuum at a maximum temperature of 40°C to produce trenbolone acetate in 70% yield and >99.0% A / A (by HPLC).

[0282] Example 8: Trenbolone acetate is crystallized from n-propanol.

[0283]

[0284] At 120°C, dichloromethane (2.5 mL) was added to a suspension of 50 g trenbolone acetate in 200 mL n-propanol. The mixture was heated to 30°C, after which complete dissolution was observed. The solution was cooled to 20–25°C and inoculated with 0.7% w / w trenbolone acetate. The mixture was held at 20–25°C for 30 min, and then slowly cooled to an internal temperature of -15°C. The resulting suspension was held at -15°C for 0.5 h and then filtered. The filter cake was washed with 50 mL of cold n-propanol, and the resulting wet solid was then milled for 0.5 h by resuspending in cold n-heptane (75 mL), after which the mixture was filtered and dried under vacuum at a maximum temperature of 40°C to produce trenbolone acetate in 75% yield and >99.0% A / A (by HPLC).

[0285] Example 9: Trenbolone acetate is crystallized from n-butanol.

[0286]

[0287] At 120 °C, dichloromethane (2.5 mL) was added to a suspension of 50 g trenbolone acetate in 200 mL n-butanol. The mixture was heated to 30 °C, after which complete dissolution was observed. The solution was cooled to 20–25 °C and inoculated with 1.3% w / w trenbolone acetate. The mixture was held at 20–25 °C for 30 min, and then slowly cooled to an internal temperature of -15 °C. The resulting suspension was held at -15 °C for 0.5 h and then filtered. The filter cake was washed with 50 mL of cold n-butanol, and the resulting wet solid was then milled by resuspending in cold n-heptane (75 mL) for 0.5 h, after which the mixture was filtered and dried under vacuum at a maximum temperature of 40 °C to produce trenbolone acetate in 80% yield and >99.0% A / A (by HPLC).

[0288] Example 10: Trenbolone acetate was prepared by acetylation followed by crystallization from diisopropyl ether (DIPE).

[0289]

[0290] Add a total of 30 g of acetic anhydride to a stirred mixture of 25 g threnbolone and 0.3 g 4-DMAP in 187.5 mL DCM, and stir the resulting solution at 20 °C. At the end of the reaction, treat the solution with a solution of 31.1 g NaHCO3 in 250 mL of water while stirring. Discard the aqueous layer and wash the organic layer with 125 mL of water. After phase separation, redissolve the combined aqueous washes with 125 mL DCM. Combine the organic phases and concentrate them under vacuum while maintaining an internal temperature below 30 °C. Add 125 mL of diisopropyl ether to the resulting solution and concentrate the mixture to 100 mL (total volume) under vacuum while maintaining an internal temperature of 30 °C. Add 100 mL of diisopropyl ether to the mixture again and distill the solvent under vacuum to 100 mL (total volume) while maintaining an internal temperature of 30 °C. Repeat this addition / concentration scheme three times. The mixture was cooled to -15°C and cold diisopropyl ether (100 mL) was added dropwise. At an internal temperature of -15°C, 0.5 g of trenbolone acetate was inoculated into the solution. The mixture was kept at -15°C for 8 h, after which it was filtered. The filter cake was washed with 25 mL of cold diisopropyl ether and dried under vacuum at 40°C to produce trenbolone acetate in 69% yield and >99.0% A / A (by HPLC). For morphology, see [link to morphology section]. Figure 7 .

[0291] Example 11: Trenbolone acetate was prepared by recrystallization from EtOAc / heptane.

[0292]

[0293] A stirred suspension of 50 g trenbolone acetate in 75 mL of n-heptane was heated to 60 °C. While stirring, 50 mL of EtOAc was added, maintaining the internal temperature at 60 °C. 500 mL of n-heptane was added dropwise to the resulting solution, maintaining the internal temperature at 60 °C. After stirring at this temperature for 0.5 h, the mixture was cooled to -10 °C over 3 h. Spontaneous crystallization occurred at 40–42 °C. After reaching -10 °C, the suspension was held at this temperature for 15 min, then filtered and washed with 2 x 25 mL portions of n-heptane (at -10 °C). The filter cake was dried under vacuum at a maximum temperature of 40 °C to produce trenbolone acetate in 83% yield and >99.0% A / A (by HPLC). For morphology, see [link to morphology section]. Figure 5 .

[0294] Example 12: Starting with trenbolone, trenbolone acetate is prepared by acetylation followed by crystallization from isopropanol (IPA).

[0295]

[0296] Add 60 g of acetic anhydride to a stirred mixture of 100 g threnbolone and 2 g 4-DMAP in 250 mL DCM. Rinse the anhydride feeding funnel with 50 mL of DCM and warm the resulting solution to 30 °C with stirring. At the end of the reaction, cool the solution to 20 °C and add it to a suspension of 31 g NaHCO3 in 300 mL of water with stirring. Rinse the acetylation reactor with another 50 mL of DCM and add the rinsing solution to the two-phase reaction mixture, then warm it again to 30 °C with stirring and hold for 1 h. Then cool the mixture to 20 °C and discard the aqueous layer. Wash the organic layer with 100 mL of water and separate the phase. Add isopropanol (300 mL) to the resulting organic solution and concentrate the mixture to 500 mL under vacuum, maintaining the internal temperature at 30 °C. Add isopropanol (300 mL) to the mixture again and distill the solvent under vacuum to 580 mL (total volume) while maintaining the internal temperature at 30 °C. Repeat the addition / concentration protocol three times. Inoculate the solution with 0.5 g of trenbolone acetate, having a PSD range of D10: 4-12 μm; D50: 12-29 μm; D90: <76 μm, at an internal temperature of 20-25 °C. Maintain the mixture at 20-25 °C for 30 minutes, then slowly cool it to an internal temperature of -20 / -10 °C. Maintain the resulting suspension at -20 / -10 °C for 0.5 h and then filter. The filter cake was washed with 100 mL of cold IPA, and the resulting wet solid was then milled for 0.5 h by resuspending it in cold n-heptane (150 mL). The mixture was then filtered and dried under vacuum at 40 °C to produce trenbolone acetate in 83% yield and >99.0% A / A (by HPLC), which had PSDs in the following ranges: D10: 15-40 μm; D50: 67-130 μm; D90: ≤350 μm.

[0297] Example 13: This allows threnone acetate to crystallize from IPA.

[0298]

[0299] At 20°C, dichloromethane (2.5 mL) was added to a suspension of 50 g trenbolone acetate in 200 mL IPA. The mixture was heated to 30°C, after which complete dissolution was observed. The solution was cooled to 20–25°C and inoculated with 0.5% w / w trenbolone acetate (PSD range D10: 2–5 μm; D50: 10–20 μm; D90: 25–51 μm). The mixture was held at 20–25°C for 30 minutes, and then slowly cooled to an internal temperature of -15°C. The resulting suspension was held at -15°C for 0.5 h and then filtered. The filter cake was washed with 50 mL of cold ethanol, and the resulting wet solid was then milled in cold n-heptane (75 mL) for 0.5 h. The mixture was then filtered and dried under vacuum at a maximum temperature of 40 °C to produce trenbolone acetate in 83% yield and >99.0% A / A (by HPLC), which had PSDs in the following ranges: D10: 15-40 μm; D50: 67-130 μm; D90: ≤300 μm.

[0300] Example 14 The following table summarizes successful experimental results of trenbolone acetate of formula (I) obtained according to the method of Example 3:

[0301]

[0302] Example 15: Analytical methods for identifying and quantifying compounds of formula (I) and determining their chemical purity using HPLC:

[0303] - Column: Hypersil-ODS, 150×4.0mm, 3.0μm, or equivalent;

[0304] - Column temperature: 25℃;

[0305] -Mobile phase A: Acetonitrile / Methanol / MilliQ water 36.5:30:33.5 v / v / v;

[0306] -Mobile phase B: Acetonitrile / Methanol 90:10v / v;

[0307] -gradient

[0308] Time (min) ％A ％B 0 100 0 6 100 0 16 0 100 26 0 100 26.1 100 0 30 100 0

[0309] - Flow rate: 1.0 mL / min;

[0310] - Ultraviolet detector: 229nm;

[0311] -Injection volume: 5 μL;

[0312] -Analysis time: 26 min;

[0313] - Diluent: ACN / MeOH / MilliQ water / acetic acid 36.5:30:33.5:0.1v / v / v / v.

[0314] Example 16: Characterization of thibol acetate solid form with irregular hexagonal plate-like crystal habit prepared according to Examples 2 and 6.

[0315] Crystal habit: Trenbolone acetate in solid form exhibits an irregular hexagonal, plate-like crystal habit. Furthermore, trenbolone acetate displays a crystallization habit as a soft polycrystalline agglomerate.

[0316] DSC: The method for characterizing the product of the present invention.

[0317] DSC analysis was recorded using a Mettler DSC822e. The compound sample was placed in a 40 μL aluminum crucible with a pinhole cap and heated from 30 °C to 300 °C at a rate of 10 °C / min under nitrogen (50 mL / min).

[0318] DSC tests were conducted in a sealed, medium-pressure stainless steel crucible. All tests were performed by heating the sample from 30°C to a maximum temperature of 300°C at a rate of 10°C / min.

[0319] DSC analysis was performed on the crystalline compounds of formula (I) obtained in the preceding examples (i.e., as in Examples 2, 6, 10, and 11).

[0320] The solid form of trenbolone acetate obtained according to the present invention is characterized by an endothermic peak, as determined by DSC analysis, corresponding to the melting point beginning at 97.59 °C (enthalpy of fusion -74.83 J / g). An endothermic peak also begins at 95.8 °C (as shown in the diagram). Figure 2 (as shown in the image).

[0321] The solid form of trenbolone acetate obtained according to Example 11 is characterized by an endothermic peak corresponding to the melting point, as determined by DSC analysis, starting at 94.87 °C (enthalpy of fusion 68.31 J / g). A broad endothermic peak begins at 93.57 °C (see [reference needed]). Figure 4 ).

[0322] The solid form of trenbolone acetate obtained according to Example 10 is characterized by an endothermic peak, as measured by DSC analysis, corresponding to the melting point beginning at 95.06 °C (enthalpy of fusion -66.78 J / g). A broad endothermic peak begins at 93.74 °C (see [reference needed]). Figure 6 ).

[0323] Microscopic analysis: The crystal habit of threnbrolon acetate (I) was identified by microscopic analysis of the solid.

[0324] Microscopic images were recorded using a Zeiss Evo MA10 scanning electron microscope. Powder samples were sputtered with gold and observed by SEM at different magnifications. Micrographs were collected under the same conditions and magnifications (20 kV, HDBSD, variable pressure). All samples were observed at the same time after the same treatment and preparation.

[0325] In fact, microscopic analysis provides further evidence of the crystal habit of thiol acetate (I) in Examples 10 and 11 (see corresponding...). Figure 5 and 7 ), which has a more irregular hexagonal plate-like crystal habit than thiol acetate (I) obtained according to Examples 2 and 6 above (see Figure 3 (More different forms)

[0326] Trenbolone acetate crystallized in solvents different from C2-C5 alkyl alcohols (as prepared in Examples 10 and 11) exhibits a crystal habit of forming soft polycrystalline agglomerates (see [link to original text]). Figure 5 and 7 Large, round particles consisting of stacked thick plates or thin sheets were present, and many long, oblique, isolated crystals were also detected in both samples.

[0327] Microscopic analysis of threnbrom acetate (prepared as in Examples 2 and 9) exhibiting irregular hexagonal plate-like crystal habit.

[0328] Trenbolone acetate (I) crystallized from C2-C5 alkyl alcohols (as prepared in Examples 2 to 9) exhibits a predominantly thin, irregular hexagonal plate-like crystal habit, ranging from 20 to 200 micrometers. A limited number of aggregates consisting of closely packed small plates exist, while the majority are larger, fragmented particles and similar structures (see [link to relevant documentation]). Figure 3 A single crystal is like a plate, especially a thin plate.

[0329] In summary, microscopic analysis shows that the crystals obtained by the method of this invention exhibit a structure formed by large / long plates.

[0330] XRPD analysis: Methods for characterizing the following products of the present invention. For the XRPD method, the instrument (Bruker D8 Advance diffractometer), instrument parameters, and other parameters used are reported in the following table:

[0331]

[0332] *It is recommended to use a cavity-free 0-background sample holder to obtain images with good peak resolution.

[0333] The thibol acetate of formula (I) prepared in Examples 2 and 6 was analyzed, and the XRPD diffraction patterns are shown below. Figure 1 middle.

[0334] Particle size distribution (PSD): Specifically, the granularity distribution was determined using Malvern Mastersizer 3000, and the other parameters used are reported in the table below:

[0335]

[0336]

[0337] The particle size distribution of threnol acetate obtained according to the method of the present invention exhibits a Gaussian distribution with a D50 value of 50-130 μm.

Claims

1. A process for preparing Trenbolone Acetate of formula (I) by crystallizing Trenbolone Acetate of formula (I) with isopropanol: wherein said Trenbolone Acetate of formula (I) has irregular hexagonal plate-like crystal habit.

2. The process according to claim 1, comprising the following steps: a) providing a solution of Trenbolone Acetate in isopropanol; b) seeding the solution with Trenbolone Acetate seeds having a particle size distribution median value (D50) comprised in the range of 8 pm to 15 pm, or 15 pm to 20 pm, or 20 pm to 90 pm; c) cooling until a suspension is obtained; d) filtering the suspension; e) suspending the solid obtained in step d) in a C5-C 10 alkane or aromatic solvent; f) filtering the obtained suspension to obtain Trenbolone Acetate of formula (I).

3. The process according to claim 2, wherein the temperature during the cooling of step c) is reduced from a temperature comprised in the range of 20 °C to 40 °C to a temperature comprised in the range of -20 °C to -10 °C.

4. The process according to claim 2, wherein the C5-C 10 The aliphatic or aromatic solvent is heptane.

5. The process according to any one of claims 1-4, wherein Trenbolone Acetate of formula (I) has a particle size distribution median value (D50) comprised in the range of 50 pm to 130 pm.

6. The process according to any one of claims 1-4, wherein the obtained Trenbolone Acetate of formula (I) has a particle size distribution median value (D50) comprised in the range of 50 pm to 80 pm, or 60 pm to 90 pm, or 90 pm to 250 pm, respectively.

7. The process according to claim 1, comprising the previous step of preparing the compound of formula (I) by acetylating Trenbolone of formula (II) 8. The process according to claim 7, wherein the steps of claim 2 and the previous step of claim 7 are carried out in one pot. ​

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