WO2012055163A1

WO2012055163A1 - Letrozole type i crystal and preparation method thereof

Info

Publication number: WO2012055163A1
Application number: PCT/CN2011/001760
Authority: WO
Inventors: 唐田; 王彦青; 马春铭; 陈佳; 陈学明; 李勇; 叶冠豪; 刘碧秀
Original assignee: 深圳海王药业有限公司
Priority date: 2010-10-25
Filing date: 2011-10-24
Publication date: 2012-05-03
Also published as: CN102070541B; CN102070541A

Abstract

Disclosed is an anhydrous crystal of letrozole. The structure and characteristics of the anhydrous letrozole crystal are characterized by X-ray powder diffraction, differential scanning calorimetry, infrared spectrum and the like. The characteristic diffraction peaks of the crystal in a powder X-ray diffraction pattern at 2 θ are 13.08±0.2, 14.06±0.2, 17.04±0.2, 21.44±0.2 and 29.24±0.2 degrees. Also disclosed are a method for preparing the anhydrous letrozole crystal by using an anhydrous and pure organic solvent as a crystallization solvent, and using the crystal in a pharmaceutical formulation for antiestrogen therapy for treating menopausal patients with advanced breast cancer.

Description

Letrozole type I crystal and preparation method thereof

The present invention relates to letrozole type I crystals, a process for the preparation thereof, and a pharmaceutical composition comprising letrozole type I crystals. Background technique

Letrozole, English name Letrozole, chemical name 1-[bis(4-aminophenyl)indolyl]-1,2,4-triazole, is a new generation of aromatase inhibitor, synthetic benzyl Triazole derivatives. Letrozole reduces estrogen levels by inhibiting aromatase, thereby eliminating the stimulating effects of androgens on tumor growth. In vitro and in vivo studies have shown that letrozole can effectively inhibit the conversion of androgens to estrogen, while estrogen in postmenopausal women is mainly derived from the aromatization of androgen precursors in peripheral tissues, so it is particularly suitable for the treatment of postmenopausal Breast cancer patients.

The preparation of the patents and literature (see table below) and the like are described. However, there are large differences in the physical and chemical parameters of letrozole reported in different literatures, such as:

No. Patent or literature Melting point (°C) Crystallizing solvent

1 CN 200610028697.9 184-185 Acetate Acetate

2 CN 200710068474.X 183-185 Chloroform and ethanol

EP 0,236,940; US 4,749,713; US 4,937,250; US

3 181-183 Isopropanol: B (5: 2)

4,978,672; US 5,352,795

Dichlorodecane and sterols and water

4 US 20,070,100,149 180-183

(21 : 75: 280) Zhou Jinpei, Zhu Fengjun, Huang Wenlong. Synthesis of the anticancer drug letrozole Ethyl acetate: petroleum ether (2:

5 180-182

[J]. Journal of China Pharmaceutical University, 2003, 34(4), 375-376. 1) He Guodong, Zhou Zhiming. Synthesis of Letrozole [J]. Guangdong

6 181-183 Methanol

Worker, 2007, 34(1), 38-40.

Tang Lijuan, Zeng Yanxia, Ma Weiguang et al. Study on the synthesis of letrozole

7 181.2-181.7 95% ethanol

[J]. Journal of Huaihai Institute of Technology, 2006, 15(4), 38 40.

Xia Fan. Research on the synthesis process of the music [J]. Sichuan Chemical Industry,

8 】8 183 ethyl acetate

2005, 8(6), 8-9. The above literature reports that there is a great difference in the melting point of the compound letrozole compound. There is no systematic study and/or explanation for the difference in the physicochemical shield of letrozole reported in different literatures. The present inventors have found for the first time that letrozole has a complicated polymorphic phenomenon, and that the letrozole crystals prepared conventionally in the literature are mostly a mixture of replicating polymorphic crystals and/or amorphous powders, and thus the measured melting point. And the melting range is different.

The crystalline form of the drug is known to affect the solubility of the drug, biological absorption, and the biological activity of the drug. Therefore, the drug crystal form may have a significant influence on the drug activity, particularly on the oral solid preparation, including the therapeutic activity of the drug, adverse reactions, and the like. In addition, the crystalline form of the drug may also affect the formulation process of the drug, the shelf life, and the like that are closely related to the drug application.

In general, in pharmaceutical applications, especially when applied to pharmaceuticals in solid form, the active substance should have a defined physical form and definitive physical and chemical properties. The physical form and/or physicochemical properties of the active substance are inconsistent, which may cause difficulty in formulation molding techniques of solid preparations and even liquid preparations, and may cause the final product of the preparation to be difficult to be applied to the clinic due to uneven properties. It can be seen that the stable availability of letrozole with certain physicochemical properties has important application value and theoretical significance for the preparation of its preparations, especially solid preparations. Summary of the invention

It is an object of the present invention to provide a novel crystalline form of letrozole which is characterized by its melting point,

X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and infrared spectroscopy (IR) were characterized, which have the properties required for the preparation of solid pharmaceutical preparations.

Another object of the present invention is to provide a process for the preparation of a new crystalline form of letrozole.

Still another object of the present invention is to provide a use of a new crystal form of letrozole in a pharmaceutical preparation, in particular, a pharmaceutical composition containing such a new crystalline form of letrozole.

In the process of preparing the crystals of letrozole, the present inventors have found that an anhydrous organic solvent such as anhydrous isopropanol, anhydrous chloroform, a pure solvent of anhydrous acetone or a mixture thereof is used as a crystallization solvent by a method of recrystallization. The crude crystal form of letrozole of the present invention can be obtained by crystallizing the crude letrozole. By measuring and analyzing the melting point of the crystal, X-ray powder diffraction, DSC, IR spectrum, etc., it was confirmed that the obtained crystal is a novel crystal of letrozole, which is called letrozole type I crystal.

The letrozole type I crystal of the present invention can be characterized by its X-ray powder diffraction pattern. When X-ray powder diffraction is performed with a Cu radiation source, the crystal is characterized by a characteristic diffraction peak at 13.8±0.2, 14.06±0.2, 17·04±0·2, 21.44±0.2, 29.24±0.2 (Α) at 2Θ. , the relative intensity of these peaks (Μ ₀ ) All are greater than or equal to 35%. Further, the crystal may further comprise, in X-ray powder diffraction, at 16.14±0.2, 19.64±0.2, 22.10±0.2, 23.30±0.2, 25.66±0.2, 26.02±0.2, 266.96±0.2, 29.64. Characteristic diffraction peaks of ±0.2 30.96±0.2, 40.20±0.2, 47.30±0,2 (A), the relative intensities of these peaks are all greater than or equal to 15% (see Figure 1).

The present invention also uses a differential scanning calorimetry (DSC) technique to characterize letrozole type I crystals (see figure

2), wherein the maximum endothermic value with differential scanning calorimetry is 186.3 ° C, the endothermic process appears as a sharp endothermic peak on the DSC spectrum; for the sufficiently dried sample, the endothermic peak is DSC The only significant endothermic peak on the spectrum, there is no obvious exothermic peak on the spectrum.

It was confirmed by XRD pattern that the present invention obtained a crystalline product, and it was confirmed by combining DSC spectrum that the letrozole type I crystal had a single crystal form.

The melting point range of the letrozole type I crystal of the present invention is: 183.6 to 187.8 °C.

The infrared spectrum of the letrozole type I crystal of the present invention is shown in Figure 3, wherein at 2122, 1608, 1504, 1435, 1409, 1271, 1200, 1139, 1004, 955, 868, 858, 791, 678, 658, 569, 555, 548 and 494cm have strong absorption peaks.

The letrozole type I crystal of the present invention is an anhydrous crystal having a low hygroscopicity, and after 10 days at 25 ° C and a relative humidity of 92.5%, the Karl Fischer method has a water content of not more than 0.1%. In the future, the oxazole type I anhydrous crystalline material was sealed in an aluminum foil bag and placed at a temperature of 40 ° C and a relative humidity of 75% for 6 months, and its appearance, melting point, water content and content did not change significantly. In the future, the triazole type I anhydrous crystalline drug substance was sealed in an aluminum foil bag, and it was left at a temperature of 25 ° C and a relative humidity of 60% for 12 months, and its appearance, melting point, water content and content did not change significantly.

According to another aspect of the present invention, there is provided a process for preparing a sample of letrozole type I crystal. Studies have shown that the aqueous crystallization solvent can affect the purity of the letrozole crystalline product to varying degrees, and a mixture of polymorphic crystals and/or amorphous powders appears. The present invention uses recrystallized anhydrous pure organic solvent as a crystallization solvent. The method was prepared to obtain the letrozole type I crystal. Specifically, in the future, crude trazodone is dissolved in an anhydrous organic solvent, filtered, and the filtrate is concentrated under reduced pressure and dried to give a letrozole type I crystal. The anhydrous organic solvent may be anhydrous isopropyl alcohol, anhydrous chloroform, a pure solvent of anhydrous acetone or a mixed solution thereof.

Due to the stable crystalline morphology and clear physical and chemical properties of letrozole type I crystals, it is suitable for the preparation of tablets or other solid preparations or even liquid preparations. The application range of letrozole type I crystals in the field of pharmaceutical preparations The presence of the letrozole compound in the art is consistent, and the application value expected of letrozole is ensured. Therefore, the present invention simultaneously provides the use of letrozole type I crystal in a pharmaceutical preparation, specifically Is a pharmaceutical composition comprising letrozole type I crystals, the pharmaceutical composition comprising an effective amount of letrozole type I crystals and optionally a pharmaceutically acceptable carrier and/or excipient, which can be used for therapeutic treatment Postmenopausal patients with advanced breast cancer treated with estrogen. The "therapeutically effective amount" means that at this dose, the letrozole type I anhydrous crystal of the present invention can ameliorate or alleviate the symptoms of the disease, or can inhibit or block the progression of the disease.

The above pharmaceutical composition may be further formulated into a form for administration according to a conventional preparation method, and includes an oral or parenteral administration form, for example, a tablet, a gelatin, a powder, a granule, a lozenge, a suppository, a patch. , gelling agent. Preferred formulations are in the form of tablets and capsules. These compositions for administration can also be prepared as a sustained release preparation or a targeted preparation as needed.

The dosage forms for oral administration may be tablets and capsules, which may contain conventional excipients such as binders, including syrup, dextrin, starch syrup, gum arabic, gelatin, sorbitol, tragacanth, hydroxypropyl group a cellulose or polyvinylpyrrolidone or the like; a filler such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, mannitol, microcrystalline cellulose, sulfuric acid, or glycine; a tableting lubricant such as magnesium stearate; Disintegrating agents such as croscarmellose sodium, starch, polyvinylpyrrolidone, crospovidone, sodium hydroxyethyl starch, low-substituted sodium hydroxypropylcellulose or microcrystalline cellulose and/or pharmaceutically acceptable Wetting agents such as sodium lauryl sulfate, water, ethanol, and the like. In addition, any pharmaceutically acceptable colorant can be used to color to improve their appearance, and/or to facilitate patient identification of the product and unit dosage levels.

Those skilled in the art can readily select and determine the amounts of the various carriers and/or excipients described above based on experience and consideration of standard methods and references in the art.

The letrozole type I crystal prepared by the invention has stable morphology and determined melting point and good chemical stability. The form of letrozole has the properties required for preparing a solid preparation, and has good compressibility during preparation. Easy to form, the raw material cost is greatly reduced when the medicine is prepared in the industry, and the storage is convenient, the production operation is simpler, and the quality is easier to control.

The obtained letrozole type I anhydrous crystalline drug substance can be used to prepare the letrozole particles by a conventional formulation technique, and is further used for preparing solid preparations such as tablets and capsules. In the future, after chlorination of the modified azole I type, with a diluent (such as lactose, pregelatinized starch or starch) and a disintegrant (such as corn starch, low-substituted hydroxypropyl cellulose or crospovidone), etc. The auxiliary materials are uniformly mixed, and a soft material made of a binder (such as microcrystalline cellulose, gum tragacanth or gelatin or hydroxypropylmethylcellulose) is added, and the wet particles are filtered, dried, and sieved to obtain an I crystal form. Anhydrous letrozole bulk drug granule. The above granules are uniformly mixed with a lubricant (e.g., magnesium stearate) to compress the letrozole tablet; and the granules are filled into an empty capsule to prepare a tropazole capsule.

A solid preparation prepared using letrozole type I anhydrous water in a dissolution medium having a pH of 4.5 for 30 minutes The post-dissolution is greater than 85%. In the future, after the solid preparation of the modified azole was placed at 25 ° C and the relative humidity of 92.5% for 10 days, the appearance, related substances, dissolution and content did not change significantly. In the future, the solid preparation of the azole was sealed in an aluminum foil bag at a temperature of 40 ° C. After being placed at a relative humidity of 75% for 6 months, there was no significant change in appearance, dissolution and content. In the future, the solid preparation of the letrozole was sealed in an aluminum foil bag and left at a temperature of 25 ° C and a relative humidity of 60% for 12 months, and the appearance, related substances, dissolution and content did not change significantly. DRAWINGS

Figure 1 is a powder X-ray diffraction spectrum of letrozole type I anhydrous crystals.

Figure 2 is a differential scanning calorimetry (DSC) spectrum of letrozole type I anhydrous crystals.

Figure 3 is an infrared spectrum of the letrozole type I anhydrous crystal.

Fig. 4 is a powder X-ray diffraction spectrum of a conventional letrozole crystal form.

Figure 5 is a DSC spectrum of a conventional letrozole crystal form. Detailed ways

The invention will be further described below in conjunction with the drawings and embodiments. However, the examples do not constitute any limitation to the invention.

Testing instruments and conditions:

1, X-ray powder diffraction

Instrument: RIGAKU X-ray diffractometer (D/Max-IIlA, Cu target)

Nai: divergence (1.), acceptance gap (0.3 mm), color chromaticity (1.), tube pressure 40 kV, tube flow 60 mA.

2, differential scanning calorimetry

Instrument: NETZSCH DSC204 Differential Scanning Calorimeter

Conditions: Temperature range 25~210°C, heating rate 10.00°C/min

3, infrared spectrum

Instrument: Nicolet Magna 550 Infrared Spectrometer

Conditions: Potassium bromide tablets.

[Example 1] 1-[Bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) control crystal form Preparation of control crystal form 1- [double (4 The crude cyanophenyl)methyl]-1,2,4-triazole compound can be prepared by the method described in U.S. Patent No. 20,070,100,149: In the future, 20 g of crude trazole is added to 140 ml of dichloro Oxane was then added to 500 ml of sterol. After stirring for 10 min, some of the solvent was removed by rotary evaporation at a temperature of 40 ° C or less until 105-120 ml of the mixed solvent remained, and 350 ml of water was added, and the mixture was stirred for 1 h. A large amount of white solid was formed to be filtered, washed with 140 ml of water, and filtered under reduced pressure at 55 to 60 ° C for 4 hours to obtain 15.2 g of a white crystalline powder, yield 76%. Its XRD spectrum and DSC spectrum are referred to US Patent No. 20,070,100,149, see Figure 4, Figure 5.

[Example 2] 1- [Bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) Preparation of Form I crystals Solvent acetone was added to anhydrous potassium carbonate, shaken After refluxing for 4 hours, the flask was placed in a 4A Linde molecular sieve to obtain an anhydrous acetone solvent. 50g of letrozole crude, added to about 1.5L of anhydrous acetone solvent, dissolved and filtered, the filtrate was concentrated under reduced pressure (O.lMpa, 50 ° C), concentrated to dry weight (O.lMpa, room temperature), obtained 43 g of a white crystalline solid in a yield of 86%.

The XRD spectrum is shown in Figure 1. The DSC is shown in Figure 2. The infrared language is shown in Figure 3. The main diffraction peaks of the XRD spectra are shown in Table 1.

Table 1

[Example 3] 1-[Bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) Preparation of type I crystals Solvent isopropanol was added to calcium oxide (200 g/ L) After refluxing for 3 hours, it is then distilled, and the distillate is further distilled by adding calcium hydride to obtain an anhydrous isopropanol solvent. 50 g of letrozole, added to about 1.5 L of anhydrous isopropanol solvent, dissolved and filtered, the filtrate was concentrated under reduced pressure (O.lMpa, 50 ° C), concentrated to dry weight (O.lMpa, room temperature). 40 g of a white crystalline solid were obtained in a yield of 80%. [Example 4] 1- [Bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) Preparation of Form I crystal Solvent Chloroform added anhydrous potassium carbonate Thousands of 24 After an hour, add anhydrous pentoxide to reflux and distill. Anhydrous chloroform solvent was obtained. 50 g of letrozole, added to about 1.5 L of anhydrous chloroform solvent, dissolved, filtered, and concentrated under reduced pressure (O.lMpa, 50 ° C), concentrated to dry weight (O.lMpa, room temperature), 42 g White crystalline solid, yield 84%.

[Example 5] 1-[Bis(4-cyanophenyl)indenyl]-1,2,4-triazole (letrozole) Preparation of Form I crystal 50 g of letrozole crude, added to about 1.0 L anhydrous chloroform and 0.5 L of anhydrous isopropanol mixed solvent, dissolved and filtered, the filtrate was concentrated under reduced pressure (O.lMpa, 50 ° C), concentrated to dry weight (O.lMpa, room temperature), 41g white Crystalline solid, yield 82%.

The physicochemical properties of the letrozole type I crystal of the present invention and the control crystal form are shown in Table 2 below:

Table 2

[Example 6] Preparation of solid pharmaceutical preparation

Prescription 1:

Ingredients

I crystal form to Qu Jun (Example 2) lOOmg

Microcrystalline cellulose 40mg

Lactose 50mg

Low substituted hydroxypropyl cellulose 8mg

Magnesium stearate 2mg

Ninja 200mg

Method of preparation: The above ingredients are mixed and directly compressed according to a conventional preparation method.

Prescription 2:

Ingredient

Form I Letrozole (Example 2) 100g Lactose 50g

Starch (120 mesh) 40g

Micronized silica gel 2g

3% HPMC

Total 200g

Method: Letrozole type I crystal is mixed with starch, lactose and dextrin by equal amount multiplication method. Pre-formed HPMC solution is added to make soft material, 20 mesh sieve granules, dried at 60 ° C for 30 minutes, 18 Mesh the whole grain, add the micro-silica gel, mix well, and put it into 2# glue Yuan.

Prescription 3:

Ingredients

Control crystal form letrozole (Example 1) lOOmg

Microcrystalline cellulose 40mg

Lactose 50mg

Low substituted hydroxypropyl cellulose 8mg

Magnesium stearate 2mg

, 3⁄4·里 200mg

[Example 7] Controlled factors of influencing factors

Three batches of samples were prepared according to the prescription 1 ~ 3 process in Example 6. After passing the basic project, the light, high temperature and high humidity tests were carried out to examine the appearance properties, content and dissolution of the samples. The results of the influencing factors indicate that the sample is stable under high temperature and light conditions and can be used as a reference formulation and process for the formulation, but the prescription 3 is easy to absorb moisture at 25 ° C, RH 75%, 25 ° C, and RH 92.5%.

table 3

The purpose of developing the crystal form is mainly to solve the problem of dissolution and increase the dissolution. According to the 2010 edition of the Pharmacopoeia The out-patient test showed that the prescription 1 ~ 2 had a dissolution rate of more than 80% in 15 minutes. The prescription 3 has a dissolution rate of less than 70% in 15 minutes. Under the premise of consistent excipients, the indicators of prescription 1 are better than prescription 3, so the products of I crystal and control crystal form are not only different in melting point, solubility, crystal solubility, etc., the stability of the latter, dissolution of the preparation The indicators of degree, compressibility, disintegration and the like were not as good as the letrozole I crystal form of the present invention. Industrial applicability

A new type of letrozole type I crystal, which has high purity and good stability, and is particularly suitable for preparation of a preparation; and the process for preparing the crystal is simple and practical, the amount of solvent used is small, the crystallization is complete and the yield is high. The above description of the preferred embodiments of the present invention is not intended to limit the invention, and various modifications and changes can be made by those skilled in the art without departing from the spirit of the invention. .

Claims

Rights request

A sample of letrozole type I, characterized in that the crystal is in Cu X-ray powder diffraction at a frequency of 13.08 ± 0.2, 14.06 ± 0 · 2, 17.04 soil 0.2, 21.44 ± 0.2, 29.24 There are characteristic peaks at 0.2 degrees.

2. The letrozole type I crystal according to claim 1, wherein the crystal is further in the range of 16.14 ± 0.2, 19.64 ± 0.2, 22.10 ± 0.2, 23.30 ± 0.22, 25.66 ± 0.2, 26.02 0.2, 266.96 ± 0.2, 29.64 ± 0.2, 30.96 ± 0.2, 40.20 ± 0.2, 47.30 ± 0.2 degrees have characteristic peaks.

The letrozole type I crystal according to claim 1, wherein the crystal has an endothermic peak by differential scanning calorimetry and has a peak at 186.3 °C.

The letrozole type I crystal according to claim 1, wherein the crystal has an infrared spectrum as shown in Fig. 3.

A process for the preparation of letrozole type I crystal according to claim 1, characterized in that the letrozole is crystallized with an anhydrous organic solvent.

The method according to claim 5, characterized by comprising the steps of: dissolving the crude koji in an anhydrous organic solvent, filtering, and concentrating the filtrate under reduced pressure to obtain a letrozole type I crystal.

7. A method according to claim 6 wherein the anhydrous organic solvent is anhydrous isopropanone, anhydrous chloroform, anhydrous acetone or any combination thereof.

The method according to claim 6, characterized in that the filtrate is concentrated under reduced pressure at 50 ° C at O.lMpa, and the drying is carried out at O.lMpa at room temperature.

A pharmaceutical composition comprising the letrozole type I crystal of claim 1.