Crystal form ii of letrozole, process for its preparation and pharmaceutical compositions and uses thereof

Abstract

The application discloses a crystal II type substance of letrozole compound (chemical name: 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole, English name: Letrozole), a preparation method of the crystal II type substance, and a pharmaceutical composition and application of the crystal II type substance. Specifically, the application discloses a crystal II type solid substance state of the letrozole compound, a preparation method of a crystal II type solid substance sample, and application of the letrozole crystal substance as an active ingredient in preparation of an anti-hormone antitumor drug.

Description

Technical Field

[0001] This invention relates to the discovery of a crystal form II of letrozole compounds in the solid state; to the invention of a method for preparing letrozole crystal form II; to the invention of a pharmaceutical composition containing letrozole crystal form II and a mixed crystal form containing any proportion of crystal form II; and to the application of letrozole crystal form as an active pharmaceutical ingredient in the preparation of anti-hormonal antitumor drugs. Background Technology

[0002] Letrozole (chemical name: 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole; English name: Letrozole)

[0003]

[0004] Chinese patent CN 1754876A (publication number) describes "A method for preparing high-purity letrozole" invented by Liu Kun et al. [1] One of the methods involves preparing high-purity letrozole, which involves separating a mixture of compounds (1) and (2) in a solvent to form a salt, obtaining essentially pure compound (1) or its salt, and then reacting the essentially pure compound (1) or its salt with compound (3) to prepare high-purity letrozole. The patent uses ethanol recrystallization to obtain the letrozole sample.

[0005] Chinese patent CN 101033214A (publication number) describes a method for preparing letrozole invented by Chen Shiyao. [2] This invention relates to a mild, easy-to-operate, economical method for preparing high-purity letrozole, suitable for large-scale production. The advantage of using sodium ethoxide as a catalyst in this letrozole preparation is that sodium ethoxide is relatively weakly alkaline, resulting in a milder reaction, and the reaction conditions are easy to meet and control both in the laboratory and in production. The patent uses recrystallization from ethyl acetate to obtain the letrozole sample.

[0006] Chinese patent CN 101253160A (publication number) describes an "improved method for preparing letrozole" invented by PL McDonald et al. [3] This invention relates to a high-yield method for preparing high-purity letrozole, which eliminates the need for intermediate stage removal of 4-[1-(1,3,4-triazolyl)methyl]benzylnitrile impurities. A method for synthesizing letrozole is also provided, wherein the formation of the 4-[1-(1,3,4-triazolyl)methyl]benzylnitrile impurity is minimized in the first stage. In this inventive method, 4-(halomethyl)benzylnitrile is reacted with a salt of 1H-1,2,4-triazole, thereby reducing impurity formation.

[0007] Chinese patent CN 102070541A (publication number) describes the invention of "letrozole type I crystals and its preparation method" by Tang Tian et al. [4] This patent relates to an anhydrous letrozole crystal, the structure and characteristics of which are characterized by X-ray powder diffraction, differential scanning calorimetry, and infrared spectroscopy. It also provides a method for preparing anhydrous letrozole crystals using anhydrous pure organic solvents as crystallization solvents, and the application of these crystals in pharmaceutical formulations for treating postmenopausal patients with advanced breast cancer undergoing anti-estrogen therapy. In this patent, crude letrozole is dissolved in anhydrous organic solvents (anhydrous isoacetone, anhydrous chloroform, anhydrous acetone, or any combination thereof), filtered, the filtrate is concentrated under reduced pressure, and dried to obtain type I letrozole crystals.

[0008] The Chinese Journal of Medical Practice records the clinical application of aromatase inhibitors in advanced breast cancer published by Gu Bei et al. [5] Among them, the study involved observing the efficacy and adverse reactions of letrozole (Fure) in treating postmenopausal advanced breast cancer, demonstrating that letrozole can effectively treat advanced breast cancer with mild adverse reactions and good patient tolerance.

[0009] This invention discovers a type II solid state of letrozole crystals and a method for its preparation that differs from the content reported in the aforementioned patents or literature.

[0010] The purpose of this invention is to start with the study of the crystalline solid form of letrozole, and through crystal form screening technology and crystal form bioactivity evaluation technology, to find and discover the types and state characteristics of crystalline solid forms at the level of active pharmaceutical ingredients. By combining crystalline substances with pharmacodynamic studies, this invention provides basic scientific data for finding, discovering, and developing advantageous pharmaceutical crystalline solid forms of letrozole with the best clinical efficacy. At the same time, it also provides a scientific basis for applying for national or international intellectual property invention patent protection based on letrozole solid pharmaceutical raw materials. Summary of the Invention

[0011] One of the objectives of this invention is to provide a crystalline solid state and description method for letrozole crystal type II.

[0012] The second objective of this invention is to provide a method for preparing a crystalline solid substance of letrozole type II.

[0013] The third objective of this invention is to provide solid pharmaceutical products and their compositions containing pure letrozole type II crystals or mixed crystal forms containing any non-zero proportion of type II crystals.

[0014] The fourth objective of this invention is to provide a daily dosage of letrozole crystalline solid as the active pharmaceutical ingredient in the range of 0.1 to 100 mg.

[0015] The fifth objective of this invention is to provide various tablets, capsules, pills, powder injections, injectable preparations, sustained-release or controlled-release preparations for clinical use, prepared and developed using letrozole crystalline solid as the active pharmaceutical ingredient.

[0016] The sixth objective of this invention is to provide a letrozole crystalline substance that, during the treatment of diseases, increases the blood drug concentration in the organism due to the crystalline substance, thereby exerting an effective therapeutic effect.

[0017] The seventh objective of this invention is to provide the application of letrozole crystal type II and mixed crystal type II solid substances as raw materials for the preparation of anti-hormonal anti-tumor drugs.

[0018] This patent discloses a crystal type II solid state of letrozole compounds and a method for preparing such a crystal sample. Furthermore, this invention discovers the application of letrozole crystal type II solid in the preparation of anti-hormonal antitumor drugs.

[0019] Technical features

[0020] 1. Morphological characteristics of letrozole type II crystal samples:

[0021] 1.1 The letrozole crystal type II solid material of the present invention is characterized in that when CuK is used for powder X-ray diffraction analysis... α Under radiation experimental conditions, the diffraction peak position is represented by the 2-Theta value. or d value The relative intensity of diffraction peaks: solid substances with the following characteristic peak values ​​(Table 1) are defined as follows: peak height (Height%) or peak area (Area%). Figure 1 ):

[0022] Table 1. Powder X-ray diffraction peak values ​​of letrozole type II crystal samples.

[0023]

[0024] 1.2 The letrozole crystal type II solid sample of the present invention is characterized by the following properties when analyzed by infrared spectroscopy: 3119, 3054, 2993, 2916, 2851, 2231, 2087, 1941, 1912, 1811, 1743, 1704, 1607, 1503, 1434, 1408, 1371, 1334, 1315, 1270, 1222, 1199, 1184, 1138, 1016, 1003, 976, 954, 880, 867, 858, 821, 806, 789, 764, 753, 717, 697, 677, 656 cm⁻¹ -1 ±2cm -1The absorption peak is the position of the characteristic infrared spectral peak of letrozole crystal type II solid material. Figure 2 ).

[0025] 1.3 The letrozole crystal type II solid material of the present invention is characterized by, when analyzed using differential scanning calorimetry, exhibiting an endothermic peak at 184℃±3℃ in the DSC spectrum at a heating rate of 10℃ per minute. Figure 3 ).

[0026] 1.4 Letrozole crystal type II solid substance, sample analysis was performed using a melting point apparatus, the melting point value was 186℃±2℃ when the heating rate was 1℃ per minute.

[0027] 2. Characteristics of the preparation method for letrozole crystal type II samples:

[0028] The present invention relates to a method for preparing letrozole crystal type II as described in claim 1, characterized in that a single solvent system or a mixed solvent system of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, and dichloromethane is used to completely dissolve the letrozole sample, and then hexane, cyclohexane, diethyl ether, petroleum ether, benzene, and toluene are added to precipitate and obtain a letrozole crystal type II solid sample.

[0029] 3. Crystallographic composition, dosage, and pharmaceutical formulation characteristics of letrozole:

[0030] 3.1 A mixed-crystal solid substance of letrozole compound, containing any non-zero proportion of letrozole type II crystals.

[0031] 3.2 The pharmaceutical composition of the present invention is characterized by containing an effective dose of letrozole crystal type II, or containing letrozole mixed crystal solids and a pharmaceutically acceptable carrier.

[0032] 3.3 The pharmaceutical composition of the present invention uses letrozole crystalline solid as the active pharmaceutical ingredient, and the daily dosage is in the range of 0.1 to 100 mg.

[0033] 3.4 The pharmaceutical composition of the present invention is characterized in that the pharmaceutical composition is a tablet, capsule, pill, powder for injection, injectable preparation, sustained-release preparation, or controlled-release preparation.

[0034] 3.5 This invention relates to the use of letrozole type II crystals or mixed crystals containing any non-zero proportion of letrozole type II crystals in the preparation of anti-hormonal antitumor drugs.

[0035] This invention relates to pharmaceutical compositions using the letrozole crystal type II component and the letrozole mixed crystalline solids of this invention as active ingredients. These pharmaceutical compositions can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the letrozole crystal type II component and the letrozole mixed crystalline solids of this invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the letrozole crystal type II component and the letrozole mixed crystalline solids of this invention in their pharmaceutical compositions is typically 0.1-95% by weight.

[0036] The letrozole crystal type II component of the present invention, the letrozole mixed crystal solid substance of the present invention, or the pharmaceutical composition containing it can be administered in unit dose form, and the route of administration can be enteric or non-enteric, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0037] The preferred dosage form for administration in this invention is a solid dosage form. Solid dosage forms can be tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, sprays, etc.

[0038] The letrozole crystal type II component and the letrozole mixed crystal solid substance of the present invention can be made into ordinary preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0039] In order to formulate the letrozole crystal type II component and the letrozole mixed crystal solid material of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0040] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0041] To formulate the drug delivery unit into capsules, the active ingredient, letrozole crystal type II component or letrozole mixed crystalline solid substance of the present invention, can be mixed with a diluent and a flow aid, and the mixture can be directly placed into hard capsules or soft capsules. Alternatively, the active ingredient, letrozole crystal type II component or letrozole mixed crystalline solid substance of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and flow aids used to prepare tablets of letrozole crystal type II component or letrozole mixed crystalline solid substance of the present invention can also be used to prepare capsules of letrozole crystal type II component or letrozole mixed crystalline solid substance of the present invention.

[0042] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0043] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0044] The dosage of the letrozole crystal type II component and the letrozole mixed crystal solid pharmaceutical composition of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. The above dosage can be administered as a single unit or divided into several units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0045] The letrozole crystal type II component, the letrozole mixed crystalline solid substance, or the composition thereof of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the letrozole crystal type II component or the letrozole mixed crystalline solid substance of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0046] 4. Beneficial technical effects of the present invention: Advantages of oral administration of letrozole crystal type II component in terms of absorption and blood drug concentration characteristics:

[0047] This invention relates to pharmaceuticals and pharmaceutical compositions using letrozole crystal type II as active ingredients, and their biological absorption after oral administration. It is characterized by the advantageous effects and applications of using letrozole crystal type II as an active ingredient to rapidly reach maximum concentrations in the gastrointestinal tract or bloodstream for disease prevention and treatment. Figure 4The letrozole crystal type II solid substance of the present invention increases the blood drug concentration in organisms, thereby exerting a more effective therapeutic effect. Attached Figure Description

[0048] Figure 1 Powder X-ray diffraction pattern of letrozole type II solid material

[0049] Figure 2 Infrared absorption spectrum of letrozole type II solid material

[0050] Figure 3 DSC spectrum of letrozole type II solid material

[0051] Figure 4 Plasma concentration-time curves of letrozole crystal type I and crystal type II samples in rats after oral absorption Detailed Implementation

[0052] To better illustrate the technical solution of the present invention, the following embodiments are provided, but the present invention is not limited thereto.

[0053] Example 1

[0054] Preparation method 1 for letrozole crystal type II sample:

[0055] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 150 ml Erlenmeyer flask, adding 5 ml of methanol, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 100 ml of n-hexane is added under stirring, and the mixture is allowed to stand at room temperature for one day. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 160 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0056] Preparation method 2 for letrozole crystal type II samples:

[0057] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 150 ml Erlenmeyer flask, adding 5 ml of methanol, and heating the sample completely at 60 °C in a water bath. Then, 120 ml of toluene is added under stirring. After standing at room temperature for 2 days, the sample is filtered and dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0058] Preparation method 3 for letrozole crystal type II samples:

[0059] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 150 ml Erlenmeyer flask, adding 10 ml of ethanol, and heating in a water bath at 60 °C to completely dissolve the sample. Then, 120 ml of benzene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 170 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0060] Preparation method 4 for letrozole crystal type II samples:

[0061] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 150 ml Erlenmeyer flask, adding 10 ml of n-propanol, and heating the sample completely in a water bath at 60 °C. Then, 120 ml of diethyl ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 168 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0062] Preparation method 5 for letrozole crystal type II samples:

[0063] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 150 ml Erlenmeyer flask, adding 12 ml of n-butanol, and heating the sample completely in a water bath at 60 °C. Then, 120 ml of cyclohexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 164 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0064] Preparation method 6 for letrozole crystal type II samples:

[0065] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 150 ml Erlenmeyer flask, adding 12 ml of acetone, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 120 ml of cyclohexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 146 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0066] Preparation method 7 for letrozole crystal type II samples:

[0067] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 12 ml of acetone, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 250 ml of benzene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 159 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0068] Preparation method of letrozole crystal type II sample 8:

[0069] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of acetonitrile, and heating the sample completely in a water bath at 60 °C. Then, 150 ml of petroleum ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 138 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0070] Preparation method of letrozole crystal type II sample 9:

[0071] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of acetonitrile, and heating the sample completely in a water bath at 60 °C. Then, 150 ml of toluene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 140 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0072] Preparation method 10 for letrozole crystal type II samples:

[0073] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 15 ml of chloroform, and heating the sample completely in a water bath at 60 °C. Then, 250 ml of petroleum ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 145 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0074] Preparation method 11 for letrozole crystal type II sample:

[0075] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 15 ml of chloroform, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 250 ml of cyclohexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 159 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0076] Preparation method 12 for letrozole crystal type II samples:

[0077] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 15 ml of dichloromethane, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 250 ml of benzene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0078] Preparation method 13 for letrozole crystal type II samples:

[0079] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of methanol and 5 ml of n-propanol, and heating the sample completely in a water bath at 60 °C. Then, 200 ml of n-hexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0080] Preparation method 14 for letrozole crystal type II samples:

[0081] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of ethanol and 5 ml of isopropanol, and heating in a water bath at 60 °C to completely dissolve the sample. Then, 200 ml of petroleum ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0082] Preparation method of letrozole crystal type II sample 15:

[0083] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of n-propanol and 5 ml of n-butanol, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of benzene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0084] Preparation method of letrozole crystal type II sample 16:

[0085] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of methanol and 5 ml of acetone, and heating the sample completely in a water bath at 60 °C. Then, 200 ml of petroleum ether is added under stirring. After standing at room temperature for 2 days, the sample is filtered and dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0086] Preparation method of letrozole crystal type II sample 17:

[0087] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of acetone and 5 ml of isopropanol, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of diethyl ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0088] Preparation method of letrozole crystal type II sample 18:

[0089] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of acetone and 5 ml of n-butanol, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of cyclohexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0090] Preparation method of letrozole crystal type II sample 19:

[0091] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of ethanol and 5 ml of acetonitrile, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of petroleum ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0092] Preparation method of letrozole crystal type II sample 20:

[0093] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of n-propanol and 5 ml of ethyl acetate, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of cyclohexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0094] Preparation method of letrozole crystal type II sample 21:

[0095] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of tetrahydrofuran and 5 ml of isopropanol, and heating the sample completely in a water bath at 60 °C. Then, 200 ml of diethyl ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0096] Preparation method of letrozole crystal type II sample 22:

[0097] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of methanol and 5 ml of chloroform, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of benzene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0098] Preparation method of letrozole crystal type II sample 23:

[0099] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of n-propanol and 5 ml of dichloromethane, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of toluene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0100] Preparation method of letrozole crystal type II sample 24:

[0101] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of n-butanol and 5 ml of ethyl acetate, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of petroleum ether is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0102] Preparation method of letrozole crystal type II sample 25:

[0103] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of n-propanol and 5 ml of acetonitrile, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of toluene is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a type II solid substance of letrozole crystals.

[0104] Preparation method of letrozole crystal type II sample 26:

[0105] A method for preparing letrozole crystal type II samples is characterized by placing 200 mg of letrozole sample in a 500 ml Erlenmeyer flask, adding 5 ml of n-butanol and 5 ml of dichloromethane, and heating in a water bath at 60 °C until the sample is completely dissolved. Then, 200 ml of cyclohexane is added under stirring, and the mixture is allowed to stand at room temperature for 2 days. After filtration, the sample is dried under reduced pressure at room temperature for 4 hours to obtain 150 mg of letrozole solid. Powder X-ray diffraction analysis is performed on the obtained sample, and its diffraction pattern is consistent with... Figure 1 The consistency indicates that the obtained sample is a letrozole crystal type II solid substance.

[0106] Example 2

[0107] Preparation method 1 of combination drug formulation (tablets):

[0108] A method for preparing a combination drug tablet, characterized by using letrozole type II pure product or mixed crystalline solid substance containing any proportion of type II crystals as the active pharmaceutical ingredient (API) of the combination drug, and using several excipients as excipients for preparing the combination drug tablet, and preparing tablet samples with a drug content of 0.5-20 mg per tablet according to a certain ratio. Table 2 gives the tablet formulation ratio:

[0109] Table 2. Formulation for the preparation of letrozole combined with drug tablets

[0110]

[0111] The method for preparing trazodone type II pure product or mixed crystal raw material containing any proportion of type II crystals into tablet formulation is as follows: several excipients are mixed evenly with the raw material, an appropriate amount of 1% sodium carboxymethyl cellulose solution is added to make a soft material, which is then granulated by sieving, the wet granules are dried, sieved and sized, magnesium stearate and talc are added and mixed evenly, and then tableted to obtain the final product.

[0112] Preparation method 2 of combination drug formulation (capsule):

[0113] A method for preparing a combination drug capsule, characterized by using letrozole type II pure product or mixed crystalline solid substance containing any proportion of type II crystals as the active pharmaceutical ingredient (API) of the combination drug, and using several excipients as excipients for preparing the combination drug capsule, and preparing capsule samples with a drug content of 0.5-20 mg per capsule according to a certain ratio. Table 3 gives the capsule formulation ratio:

[0114] Table 3. Active pharmaceutical ingredients and excipients formulations for letrozole crystal type II combination drug capsules.

[0115]

[0116] The method for preparing trazodazole type II pure product or mixed crystal drug containing any proportion of type II crystals into tablet formulations is as follows: several excipients are mixed evenly with the drug, an appropriate amount of 1% sodium carboxymethyl cellulose solution is added, wet granules are prepared, dried, sieved and granulated, magnesium stearate is added and mixed evenly, and then inserted into capsules; or, without using the granulation step, trazodazole drug is directly mixed evenly with several excipients and excipients, sieved, and directly filled into capsules.

[0117] Example 3

[0118] Dosage of letrozole crystal form combination drugs 1 (tablets):

[0119] A pharmaceutical composition developed using crystalline letrozole samples as the active pharmaceutical ingredient is characterized by using crystalline type II letrozole as the active pharmaceutical ingredient, with a daily dose of 2.5 mg, and can be prepared as 5 ordinary tablets of 0.5 mg once daily or 1 tablet of 2.5 mg once daily.

[0120] Dosage of letrozole crystal form combination drug 2 (capsules):

[0121] A pharmaceutical composition developed using crystalline letrozole samples as the active pharmaceutical ingredient is characterized by using crystalline type II letrozole as the active pharmaceutical ingredient, with a daily dose of 10 mg, which can be prepared into two 5.0 mg capsules twice daily and one 10 mg capsule once daily.

[0122] Issues to be clarified: The dosage of the active ingredient in the letrozole crystal form pharmaceutical composition involved in this invention is affected by many factors, such as: different uses for prevention and treatment resulting in different daily dosages; different natures and severity of diseases resulting in different daily dosages; differences in patient gender, age, body surface area, route of administration, frequency of administration, and treatment purpose resulting in different daily dosages; in addition, differences in absorption and blood drug concentration between crystal forms also result in the appropriate daily dosage range of the letrozole crystal form component in this invention being 0.002-2 mg / kg body weight, preferably 0.01-0.5 mg / kg body weight. When using it, different total dosage schemes for the active ingredient of crystal form II letrozole should be formulated according to the actual needs of prevention and treatment, and it can be administered in multiple or single doses.

[0123] Example 4

[0124] Absorption and plasma concentration characteristics of letrozole type II in rats:

[0125] Twelve SD rats were randomly divided into two groups of six each. They were fasted for 12 hours prior to drug administration but allowed free access to water. The rats were weighed, and the drug was administered at a dose of 100 mg / kg.-1 To calculate the dosage of letrozole, letrozole samples of different crystal forms were loaded into solid delivery devices and administered directly into the stomach of rats via oral administration. Blood samples were collected from the inner canthus of the eye at 30 min, 1 h, 2 h, 3 h, 5 h, 6 h, 7 h, 9 h, 12 h, 14 h, 24 h, 30 h, 37 h, and 48 h post-administration and placed in heparinized tubes. The supernatant was collected by centrifugation, and 100 μL of the supernatant was collected. 100 μL of plasma was accurately measured and placed in a 1.5 mL EP tube. 800 μL of ethyl acetate was added, vortexed for 3 min, and centrifuged (13400 rpm) for 10 min. The supernatant organic phase was collected, dried under nitrogen at room temperature, and reconstituted with 100 μL of acetonitrile-water (40:60). The mixture was vortexed for 3 min, centrifuged (13400 rpm) for 5 min, and the supernatant was injected for analysis.

[0126] Detection conditions: Detection system: Aligent 1200; Column: Agilent Eclipse XDB-C18 (4.6×250mm, 5μm); Mobile phase: Acetonitrile-water (40:60, v / v); Flow rate: 1 ml·min -1 Column temperature: 25℃; Detection wavelength: 239nm; Injection volume: 20μl.

[0127] Table 4 shows the blood drug concentrations of rats at various time points after oral administration of letrozole crystal type I and crystal type II samples;

[0128] Table 5 shows the oral samples (100 mg·kg) of letrozole crystal type I and II in rats. -1 The pharmacokinetic parameters obtained after the analysis indicate that letrozole type II has the advantages of rapid absorption, high blood concentration, and long plateau of action.

[0129] Table 4. Blood drug concentrations at different time points (n=6, ±SD)

[0130]

[0131]

[0132] Table 5. Pharmacokinetic parameters of letrozole polymorph (100 mg·kg⁻¹) after oral administration to SD rats.

[0133]

[0134] References

[0135] 1. Chinese Patent, Publication No. CN 1754876A.

[0136] 2. Chinese Patent, Publication No. CN 101033214A.

[0137] 3. Chinese Patent, Publication No. CN 101253160A.

[0138] 4. Chinese Patent, Publication No. CN 102070541A.

[0139] 5. Chinese Journal of Medical Practice, Gu Bei, Clinical application of aromatase inhibitors in advanced breast cancer.

Claims

1. A crystalline form II solid material of letrozole characterized by, The powder X-ray diffraction analysis was performed using Cu K α The diffraction peak positions: 2-Theta values (°) or d values and the relative intensities of the diffraction peaks: peak height values (Height %) or peak area values (Area %) have the following characteristics:

2. The solid form of letrozole Form II according to claim 1, characterized in that, The absorption peaks at 3119, 3054, 2993, 2916, 2851, 2231, 2087, 1941, 1912, 1811, 1743, 1704, 1607, 1503, 1434, 1408, 1371, 1334, 1315, 1270, 1222, 1199, 1184, 1138, 1016, 1003, 976, 954, 880, 867, 858, 821, 806, 789, 764, 753, 717, 697, 677, 656 cm"1when analyzed using infrared spectroscopy are characteristic of the infrared spectrum of Letrozole Form II solid material. -1 ± 2 cm -1 The absorption peaks at 3119, 3054, 2993, 2916, 2851, 2231, 2087, 1941, 1912, 1811, 1743, 1704, 1607, 1503, 1434, 1408, 1371, 1334, 1315, 1270, 1222, 1199, 1184, 1138, 1016, 1003, 976, 954, 880, 867, 858, 821, 806, 789, 3. The solid form of letrozole Form II according to claim 1, characterized in that, When analyzed using differential scanning calorimetry technique, it exhibits a DSC pattern containing one endothermic peak at 184℃±3℃ when the heating rate is 10℃ / min.

4. The solid form of Letrozole Form II according to claim 1, characterized in that, When analyzed using melting point apparatus, the melting point value is 186℃±2℃ when the heating rate is 1℃ / min.

5. A solid substance of a mixed crystal of letrozole compounds, characterized in that, It contains any non-zero proportion of the letrazole crystal II type solid substance as claimed in claim 1.

6. The method of claim 1, wherein the solid form II of letrozole is characterized by The letrazole crystal II type solid substance is obtained by completely dissolving a letrazole sample in a single solvent system or mixed solvent system of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, and then precipitating with n-hexane, cyclohexane, diethyl ether, petroleum ether, benzene or toluene.

7. A pharmaceutical composition, characterized by, It contains an effective dose of the letrazole crystal II type solid substance as claimed in claim 1 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition, characterized by, It contains an effective dose of the letrazole mixed crystal solid substance as claimed in claim 5 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition according to claim 7 or claim 8 characterised in that, The daily dose of the letrazole crystal type substance is in the range of 0.1-100 mg.

10. A pharmaceutical composition according to claim 7 or claim 8, characterised in that, The pharmaceutical composition is selected from tablets, capsules, pills or powder injections.

11. A pharmaceutical composition according to claim 7 or claim 8, characterised in that, The pharmaceutical composition is selected from sustained release preparations or controlled release preparations.

12. Use of the letrazole crystal II type solid substance as claimed in claim 1 or the mixed crystal solid substance as claimed in claim 5 in the preparation of anti-hormone anti-tumor drugs.

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