CN1634921A - Crystalline anticholinergic tiotropium bromide - Google Patents

Abstract

The invention relates to crystal unhydrous (1R,2R,4S,5S,7S)-7-[2-hydroxy-2,2-bis(2-thienyl) acetoxy]-9,9-dimethyl-3-oxa-9-azo cation tricyclo octane [3.3.1.02.4] nonane bromide, clinic use of tiotropium bromide anhydrous crystal as anti-cholinergic medicines, and preparation process of tiotropium bromide anhydrous crystal.

Description

Crystalline anticholinergic tiotropium bromide

technical field

The present invention relates to crystalline anhydrous (1R, 2R, 4S, 5S, 7S)-7-[2-hydroxy-2,2-bis(2-thienyl)acetoxy]-9,9-dimethyl- 3-oxa-9-aza-cation tricyclooctane [3.3.1.0 ^2.4 ] nonane bromide crystal, commonly known as tiotropium bromide (Tiotropium Bromide), its preparation method and pharmaceutical composition, can be used as anticholinergic It can be used clinically to treat asthma and COPD (chronic obstructive pulmonary disease). Its chemical structural formula is as follows:

Background technique

The crystalline anhydrous (1R, 2R, 4S, 5S, 7S)-7-[2-hydroxy- Preparation of 2,2-bis(2-thienyl)acetoxy]-9,9-dimethyl-3-oxa-9-azation tricyclooctane[3.3.1.0 ^2.4 ]nonane bromide crystals method. The method is as follows: take tiotropium bromide monohydrate as the starting material, carefully dry under reduced pressure at above 50°C, preferably 60-100°C or store it on a suitable desiccant for 12-96 hours to obtain crystalline Tiotropium bromide water, crystal unit lattice parameters are respectively a=10.4336 (2) , b=11.3297 (3) , c=17.6332 (4) , α=90 °, β=105.158 (2) °, γ=90°, the patent lists the X-ray powder diffraction analysis data of anhydrous tiotropium bromide crystalline structure, but does not provide test results such as infrared and DSC. For comparison, we prepare tiotropium bromide monohydrate crystal according to the method in CN1469877A (publication number), then dry and dehydrate according to the method in CN1520294A and prepare into anhydrous tiotropium bromide crystal, carry out infrared, DSC and X-ray Powder diffraction test, compared with the anhydrous tiotropium bromide crystal of the present invention, there is a significant difference between the results, which proves that due to the difference in preparation methods and conditions, the present invention produces a crystal different from that in the CN1520294A patent , New crystalline anhydrous tiotropium bromide crystals.

The method of the invention can refine the tiotropium bromide crude product (anhydrous), can be used as a purification method of the tiotropium bromide medicine, and can also convert the tiotropium bromide monohydrate crystal into anhydrous crystal simultaneously.

Contents of the invention

The object of the invention is to provide a new, single stable anhydrous crystal form of tiotropium bromide, and it has been confirmed through experiments that the powder mist capsules prepared by micronization are compared with tiotropium bromide monohydrate crystals, and the quality of the preparation is not obvious. difference.

Another object of the present invention is to provide a process for preparing crystalline anhydrous tiotropium bromide crystals.

Another object of the present invention is to provide a pharmaceutical composition comprising crystalline anhydrous tiotropium bromide crystals.

In addition, another object of the present invention is that the composition containing crystalline anhydrous tiotropium bromide crystals can be used as an anticholinergic drug for the clinical treatment of asthma and COPD.

Characteristics of crystalline anhydrous tiotropium bromide crystals:

The present invention provides crystalline anhydrous tiotropium bromide crystals, using Cu-Ka radiation, its X-ray powder diffraction pattern is shown in Fig. There are absorption peaks at 17.92, 18.60, 19.06, 19.46, 22.58, 23.22, 25.26, 26.20, 27.26, 28.06, 28.42, 29.96, 31.78, and 34.86. With respect to the anhydrous crystalline tiotropium bromide reported in patent CN1520294A, its typical feature is that there are strong absorption peaks at 13.52, 14.16, 14.68, 17.92, 18.60, 19.06, 22.58, 23.22, 28.42, while the crystal in patent CN1520294A There are strong absorption peaks at positions 15.62 and 17.56, and the tiotropium bromide crystal of the present invention has no absorption peaks at these positions.

The DSC spectrum of the crystalline anhydrous tiotropium bromide crystal of the present invention is shown in Fig. 2, with the speed of 10 DEG C/min heating, its endothermic transition is at 227 DEG C.

The infrared absorption spectrum of tiotropium bromide crystal of the present invention measured by KBr tablet is shown in Fig. 3, which is characterized in that there are absorption peaks at 3435cm ^-1 , 3187cm ^-1 , 1750cm ^-1 and 736cm ^-1 . However, the crystal in patent CN1520294A has absorption peaks at 3571cm ^-1 , 3413cm ^-1 , 3146cm ^-1 , 1732cm ^-1 , and 712cm ^-1 .

The thermal gravimetric analysis (TGA) spectrum of the tiotropium bromide crystal of the present invention is shown in Fig. 4, and the DSC and TGA test results all show that the crystal does not contain a crystallization solvent.

According to literature ^{(1) (2)} report, when tetropine bromide (i.e. tiotropium bromide) was purified, the conditions for selection were different, and different crystal forms appeared in tetropine bromide, such as monohydrate crystal and anhydrous Crystals, in combination with the present invention, it can be confirmed that different anhydrous crystals can be produced by intentionally selecting different conditions. In patent CN1520294A, the monohydrate of tetropine bromide is used as the starting material, and the method of drying and dehydration is different. In the present invention, the anhydrous crude product of tetropine bromide is used as the starting material, and monohydrate can also be used. Recrystallize with a mixed solvent containing water and an organic solvent to obtain anhydrous crystals different from those invented in CN1520294A.

The preparation method of crystalline anhydrous tiotropium bromide crystal:

Method 1: Take an appropriate amount of crude tiotropium bromide, add ternary mixed solvent A-B-C, the volume ratio of A, B and C is 30:30:1-5, heat to dissolve, cool and crystallize, filter, wash with acetone, and let it air dry Dry or dry under reduced pressure at low temperature to obtain tiotropium bromide crystals. Moisture content <0.5% as measured by Fischer method. Detected by HPLC method, the purity reaches above 99.0%.

Among them, A is a ketone solvent, including acetone, butanone, 2-pentanone, 3-pentanone, cyclopentanone, cyclohexanone, methyl acetophenone, etc., preferably acetone; B is an alcohol solvent, including methanol , ethanol, propanol, isopropanol, n-butanol, etc., preferably methanol; C is water. The amount of solvent added is 3 to 20 times (V/W) of the input amount of the crude product of tiotropium bromide, preferably 8 to 10 times. Heat to dissolve. The cooling temperature is -15°C to -4°C, preferably -10°C to -5°C. The cooling time is 24-48 hours, and it is placed at 20-25°C for 8-24 hours or dried under reduced pressure at 60-30°C, preferably at 50°C.

Method 2: Take an appropriate amount of tiotropium bromide crude product, add ternary mixed solvent A-B-C, the volume ratio of A, B and C is 30:30:1～5, heat to dissolve, evaporate part of the solvent, cool and crystallize, filter, Wash with acetone, dry naturally or dry under reduced pressure at low temperature to obtain tiotropium bromide crystals. Moisture content <0.5% as measured by Fischer method. Detected by HPLC method, the purity reaches above 99.0%.

Method 3: Take an appropriate amount of tiotropium bromide monohydrate (more than 99.0% in purity), add ternary mixed solvent A-B-C, the volume ratio of A, B and C is 30:30:1～5, heat to dissolve, cool and crystallize , filtered, washed with acetone, and dried naturally or at low temperature and reduced pressure to obtain tiotropium bromide crystals, with a water content <0.5% as measured by the Fischer method (monohydrate theoretical water content is about 3.7%).

The amount of solvent added is 3 to 20 times (V/W) of the input amount of the crude product of tiotropium bromide, preferably 8 to 10 times. When the solvent ratio is larger, for example, more than 10 times, part of the solvent can be evaporated, and then cooled and analyzed. Crystal, heated to dissolve. The cooling temperature is -15°C to -4°C, preferably -10°C to -5°C. The cooling time is 24-48 hours, and it is placed at 20-25°C for 8-24 hours or dried under reduced pressure at 60-30°C, preferably at 50°C.

The formulation of the present invention comprises a combination of tiotropium bromide crystals and one or more pharmaceutically acceptable excipients. Put micronized anhydrous tiotropium bromide crystals (0.5-10 μm) and suitable auxiliary materials into capsules to make a powder mist for inhalation, and then place it in a special device for use. These compositions may be in the form of capsules containing about 17-27 micrograms of anhydrous tiotropium bromide crystalline.

The crystalline anhydrous tiotropium bromide crystal of the present invention can be used as an active ingredient in the preparation of anticholinergic drugs.

The crystalline anhydrous tiotropium bromide crystal of the present invention can also be used as an active ingredient in the preparation of medicines for treating asthma and COPD.

Description of drawings

Fig. 1 is the x-ray powder diffraction pattern of tiotropium bromide crystal of the present invention.

Fig. 2 is the differential scanning calorimetry diagram (DSC diagram) of tiotropium bromide crystal of the present invention.

Fig. 3 is the infrared absorption spectrogram of tiotropium bromide crystal of the present invention.

Fig. 4 is the TGA spectrum of tiotropium bromide crystal of the present invention.

Detailed ways

Example 1

Take 30g of tiotropium bromide crude product (light yellow), put it in a 500ml three-neck glass bottle, add 300ml of acetone-methanol-water (30:30:2), stir and heat up to 50°C, dissolve the solid, filter, and cool the filtrate to - Crystallize at 10～-5°C for 24 hours, precipitate colorless crystals, filter, wash with acetone, and place at room temperature for 8 hours to obtain 21.5 g of white crystals, yield 71.7%, melting point (decomposition): 218～220°C, use Fischer The moisture measured by the method is 0.20%. The purity measured by high performance liquid chromatography is 99.6% (normalized method)

Example 2

Take 15g of tiotropium bromide crude product (light yellow), put it in a 500ml three-necked glass bottle, add 230ml of acetone-methanol-water (30:30:1), stir and heat up to reflux, dissolve the solid, filter, and concentrate the filtrate to about 50ml , the filtrate was cooled to -10～-5°C to crystallize for 24 hours, filtered, washed with acetone, and dried under reduced pressure at 50°C to obtain 13.4 g of white crystals, the measured water content was 0.41%, and the yield was 89.3%. Melting point (decomposition): 218～219℃.

Example 3

Take 16g of tiotropium bromide monohydrate, put it in a 500ml three-neck glass bottle, add 130ml of acetone-methanol-water (30:30:1), stir and heat up to reflux, dissolve the solid, filter, and cool the filtrate to -10～- Crystallize at 5°C for 24 hours, precipitate colorless crystals, filter, wash with acetone, and place at room temperature for 8 hours to obtain 12.5 g of white crystals, yield 81.1%, melting point (decomposition): 218-219°C, measured by Fischer method Moisture is 0.24%.

Example 4

Take 15g of tiotropium bromide crude product (light yellow), put it in a 250ml three-necked glass bottle, add 150ml of acetone-ethanol-water (30:30:2), stir and heat up to 50°C, dissolve the solid, filter, and cool the filtrate to - Crystallize at 10～-5°C for 24 hours, precipitate colorless crystals, filter, wash with acetone, and place at room temperature for 8 hours to obtain 10.2 g of white crystals, yield 68.0%, melting point (decomposition): 218～220°C, use Fischer The moisture measured by the method is 0.22%. The purity measured by high performance liquid chromatography is greater than 99.0% (normalized method).

Example 5

Take 14g of tiotropium bromide crude product (light yellow), put it in a 250ml three-necked glass bottle, add 210ml of butanone-isopropanol-water (30:30:4), stir and heat up to reflux, dissolve the solid, filter, and concentrate the filtrate To about 100ml, the filtrate was cooled to -10～-5°C to crystallize for 24 hours, filtered, washed with acetone, and dried under reduced pressure at 50°C to obtain 11.4g of white crystals, the measured water content was 0.45%, and the yield was 81.4%. Melting point (decomposition): 218～219℃.

Example 6

Take 10g of tiotropium bromide monohydrate, put it in a 250ml three-necked glass bottle, add 100ml of butanone-n-butanol-water (30:30:1), stir and heat up to reflux, dissolve the solid, filter, and cool the filtrate to - Crystallize at 10～-5°C for 24 hours, precipitate colorless crystals, filter, wash with acetone, and place at room temperature for 8 hours to obtain 7.6 g of white crystals, yield 78.9%, melting point (decomposition): 217～219°C, with Fischer The moisture measured by the method is 0.29%.

Example 7

Preparation of Powder Mist Capsules

One, to the stability test investigation of crystal form of the present invention

(1) Influencing factor test

Take an appropriate amount of tiotropium bromide sample, put it in a weighing bottle, spread it into a thin layer ≤ 5mm thick, and carry out the following experiments.

1. High temperature test

The test product was placed in a weighing bottle with an opening, and placed at a temperature of 60°C for 10 days, and samples were taken on the 5th and 10th days for testing. The results are shown in Table 1.

2. High humidity test

Take an appropriate amount of samples and place them in a constant humidity desiccator, place them at 25°C and 92.5% relative humidity for 10 days, and take samples on the 5th and 10th days. The results are shown in Table 1.

3. Strong light irradiation test

The opening of the test product was placed in a light box equipped with a fluorescent lamp, and placed under the condition of an illumination of 4500lx±500lx for 10 days, and samples were taken for testing on the 5th and 10th days. The results are shown in Table 1.

Table 1 Tiotropium Bromide Influencing Factors Test Results

                                     

Conditions Properties Properties Melting Point/℃ Content %

/day Substance % Properties %

       White crystalline

                                                                                Decomposes 99.                      

           Powder, Odorless

high temperature white crystalline

                                                            Decomposes 99.                                    

(60℃) powder, odorless

       White crystalline

                                                                                                  Decomposes 99.

           Powder, Odorless

       White crystalline

                                                                                Decomposes 99.                      

           Powder, Odorless

High humidity White crystalline

                                                                                                                             

(92.5%) powder, odorless

       White crystalline

                                                                                                                               

           Powder, Odorless

       White crystalline

                                                                                Decomposes 99.                      

           Powder, Odorless

Strong light White crystalline

                                                                                                                       

Irradiated powder, odorless

       White crystalline

                                                                                                Decomposes 99.

           Powder, Odorless

(2) Accelerated test

Get 3 batches of tiotropium bromide samples, pack according to commercially available, place 6 months under the condition of temperature 40 ℃ ± 2 ℃, relative humidity 75% ± 5%. Samples were taken in the first, second, third, and sixth months for testing, and the results are shown in Table 2.

              Table 2 Tiotropium Bromide Accelerated Test Results

                        

Batch No. Characters Melting Point/℃ Content %

/month Substance%

          White crystalline

                                                                                                         

                             

          White crystalline

                                                                                                                 

                             

          White crystalline

030317 2 218.4, decomposes simultaneously during melting 99.7 0.15

                             

          White crystalline

                                                                                                

                             

          White crystalline

                                                                                                   

                             

          White crystalline

                                                                                                                       

                             

          White crystalline

                                                                                                     

                             

          White crystalline

030318 2 218.3, decomposes simultaneously when melting 99.1 0.06

                             

          White crystalline

                                                                                                                                      

                             

          White crystalline

                                                                                                     

                             

          White crystalline

030319 0 218.5, decomposes simultaneously when melting 99.8 0.07

                             

          White crystalline

                                                                                                 

                             

          White crystalline

                                                                                                         

                             

         White crystalline

                                                                                                                            

                            

     White crystalline

6 218.7, decomposed at the same time when melting 99.3 0.06

    Powder, Odorless

Influencing factors carried out to tiotropium bromide crystal of the present invention and accelerated test investigation result show that each detection item of tiotropium bromide does not appear significant change, has good stability, also carried out infrared and X-ray powder diffraction test in addition, The results show that the crystal form does not change, and the crystal form can maintain good stability.

2. Prescription:

Tiotropium bromide was formulated into capsules containing about 22 μg per tablet according to the prescription in Table 3.

Table 3 Tiotropium bromide powder spray prescription Name of raw material Prescription dosage (g/1000 capsules) tiotropium bromide 0.0217 lactose 25

3. Craft

1. Micronization of tiotropium bromide: Weigh an appropriate amount of tiotropium bromide (about 10g) and bake at 60°C for 2 to 3 hours, weigh after cooling to room temperature, then put it into a jet mill for micronization, and take a sample to determine the particle size of the powder , the particle size is required to be 0.5-7 μm, and most of them are ≤5 μm.

2. Preparation of lactose carrier: crush lactose and pass through 100-mesh sieve, use 70% (v/v) ethanol solution to make soft material, granulate with 20-mesh sieve, bake at 60°C for 30 minutes, then granulate with 40-mesh sieve, and then bake at 60°C After 2 to 3 hours, pass through an 80-mesh sieve to obtain the lactose carrier.

3. Mixing: Weigh the prescription amount of tiotropium bromide micropowder and lactose carrier, and mix them evenly with the method of equal addition.

4. Pack 3 ^# capsules after the determination of intermediate content is qualified.

4. Prescription inspection

The investigation result of different crystal preparations of tiotropium bromide of table 4 investigation Prescription (g/1000 capsules) Crystalline anhydrous tiotropium bromide crystals 0.0217 lactose 25 Tiotropium Bromide Monohydrate 0.0225 Lactose 25g Angle of repose (°) 37.8 37.3 Empty rate (%) Compliance Compliance Loading difference qualified qualified Effective site drug deposition (%) 11.8 11.1

The investigation results show that there is no significant difference in quality between the powder mist capsule made of the crystalline anhydrous tiotropium bromide crystal of the present invention and the preparation made of tiotropium bromide monohydrate.

references:

1. EP418716A

2. CN1469877A

Claims (12)

1, a kind of tiotropium crystal, it is characterized in that described crystalline tiotropium bromide is water-free crystallization, it uses the Cu-Ka radiation, at 11.32,13.52,14.16,14.68,15.28,15.98,16.96,17.92,18.60,19.06,19.46,22.58,23.22,25.26,26.20,27.26,28.06,28.42,29.96,31.78,34.86 places the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent, heat up with 10 ℃/minute speed, its DSC endothermic transition is at 227 ℃, and infrared absorption pattern is at 3435cm ^-1, 3187cm ^-1, 1750cm ^-1, 736cm ^-1There is absorption peak at the place.

2, a kind of method for preparing the described tiotropium crystal of claim 1 is characterized in that in anhydrous tiotropium bromide crude product, adds ternary mixed solvent A-B-C, the volume ratio of A, B and C is 30: 30: 1～5, and A is a ketones solvent, and B is an alcoholic solvent, C is a water, solvent volume is 3～20 times of tiotropium bromide input amounts, and heating for dissolving is cooled to-15 ℃～4 ℃ and makes and separate out crystal, be 24-48 hour cooling time, filter, acetone is washed, and places 8～24 hours or 60-30 ℃ of drying under reduced pressure for 20～25 ℃.

3, method according to claim 2 is characterized in that ketones solvent A comprises acetone, butanone, 2 pentanone, propione, cyclopentanone, pimelinketone, methyl acetophenone.

4, method according to claim 3 is characterized in that ketones solvent A is an acetone.

5, method according to claim 2 is characterized in that alcoholic solvent B is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol.

6, method according to claim 5 is characterized in that alcoholic solvent B is a methyl alcohol.

7, method according to claim 2 is characterized in that solvent volume is tiotropium bromide input amount 8-10 times.

8, method according to claim 2 is characterized in that being cooled to-10～5 ℃ and makes and separate out crystal.

9, a kind of pharmaceutical composition, it contains the defined tiotropium crystal of claim 1 and one or more pharmaceutical excipients.

10, composition according to claim 9 is characterized in that described composition is the dust cloud capsule that contains 17～27 μ g tiotropium crystals.

11, according to the defined crystalline anhydrous tiotropium crystal of claim 1 as activeconstituents in the application of preparation in the anticholinergic agents.

12, preparing the application for the treatment of in asthma and the COPD medicine according to the defined crystalline anhydrous tiotropium crystal of claim 1 as activeconstituents.

Images