Preparation method of irbesartan granules

Abstract

The invention discloses irbesartan granules and a preparation method thereof. The method comprises the following steps: pulping an irbesartan raw material medicine with an organic solvent or a mixed solution of the organic solvent and water, centrifuging or filtering to obtain a wet product, drying the wet product for the first time, crushing and granulating the wet product for the first time, drying the wet product for the second time, and optionally crushing and granulating the wet product for the second time to obtain irbesartan spherical particles. In addition, the invention also provides a pharmaceutical composition containing the particle.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a spherical irbesartan with large particles and good flowability, and also provides a method for preparing the large spherical particles and a pharmaceutical composition containing the large particles. Background Technology

[0002] Irbesartan, chemically known as 2-butyl-3-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-1,3-diazaspiro-[4,4]non-1-en-4-one, with the chemical formula C25H28N6O, is mainly used as an antihypertensive drug.

[0003] European Patent EP708103 discloses that irbesartan crystallizes from solvents with a water content of less than 10% (volume ratio) to obtain crystal form A, which has main characteristic diffraction peaks at the following 2θ: 4.72°, 9.42°, 12.48°, 13.33°, 17.05°, 18.97°, 19.46°, 21.15°, 22.68°, 23.20°, 23.67°; and crystallizes from solvents with a water content of more than 10% (volume ratio) to obtain crystal form B, which has main characteristic diffraction peaks at the following 2θ: 7.95°, 11.23°, 11.81°, 14.22°, 15.93°, 16.42°, 17.60°, 18.52°, 19.29°, 19.80°, 23.75°, 26.22°. Patent EP708103 states that crystal form A is a needle-like crystal, exhibiting stability, non-hygroscopicity, and high electrostatic properties. Patent CN99807707 discloses a "brick-like crystal" of crystal form A, characterized by an aspect ratio between 1:1 and 10:1 and a bulk density of approximately 0.5 kg / m³. 3 The method for obtaining this crystal involves shearing with a shearing machine or ultrasonic oscillation using an ultrasonic device under temperature oscillation. As the number of oscillation cycles increases, the particle size of the obtained crystal decreases while the aspect ratio decreases. This method uses new equipment in production operations and employs cyclic heating and cooling, resulting in high energy consumption and relatively complex operation, which is not conducive to industrialization. Furthermore, the crystal form A obtained by the above patent still has poor flowability, which cannot adequately meet the good flowability requirements of current formulations requiring dry tableting and wet granulation. Summary of the Invention

[0004] This invention provides a method for preparing large-particle irbesartan that is easy to produce, produces large-particle samples with good flowability, and has a simple production process.

[0005] The first aspect of this invention provides irbesartan particles, which are large spherical particles with an aspect ratio not greater than 2. The D90 is 150-450 μm, preferably 200-350 μm.

[0006] In some embodiments of the present invention, the irbesartan particles have a D10 of 1-10 μm, a D50 of 30-120 μm, and a D90 of 150-450 μm.

[0007] In some embodiments of the present invention, the irbesartan particles have a D10 of 2-6 μm, a D50 of 40-80 μm, and a D90 of 200-350 μm.

[0008] In some embodiments of the present invention, the bulk density of the irbesartan particles is 0.35 to 0.40 g / mL, preferably 0.38 to 0.39 g / mL.

[0009] In some embodiments of the present invention, the tap density of the irbesartan particles is 0.45–0.60 g / mL, preferably 0.57–0.58 g / mL.

[0010] In some embodiments of the present invention, the repose angle of the irbesartan particles is 30 to 40°, preferably 32 to 35°, for example 32°, 33°, 34°, 35° or any value or range thereof.

[0011] In some embodiments of the present invention, the aspect ratio of the irbesartan particles is 1 to 1.5, for example, 1, 1.1, 1.2, 1.3, 1.4, 1.5 or any value or range thereof.

[0012] In some embodiments of the present invention, when the irbesartan particles are irradiated with Cu-Kα, their X-ray powder diffraction patterns have characteristic peaks at 2θ angles of 4.72±0.2°, 12.48±0.2°, and 18.97±0.2°.

[0013] In some embodiments of the present invention, when the irbesartan particles are irradiated with Cu-Kα, their X-ray powder diffraction patterns exhibit characteristic peaks at 2θ angles of 4.72±0.2°, 9.42±0.2°, 12.48±0.2°, 13.33±0.2°, 17.05±0.2°, 18.97±0.2°, 19.46±0.2°, 21.15±0.2°, 22.68±0.2°, 23.20±0.2°, and 23.67±0.2°.

[0014] The second aspect of the present invention provides a method for preparing irbesartan granules as described in the first aspect of the present invention, comprising the following steps: slurrying irbesartan raw material with an organic solvent or a mixture of organic solvent and water, centrifuging or filtering, drying the obtained wet product for the first time, pulverizing and granulating it for the first time, drying it for the second time, and optionally pulverizing and granulating it for the second time to obtain irbesartan spherical granules.

[0015] In some embodiments of the present invention, the irbesartan active pharmaceutical ingredient is used in crystal form A.

[0016] In some embodiments of the present invention, irbesartan active pharmaceutical ingredient is used as irbesartan granules of crystal form A with needle-like crystals.

[0017] In some embodiments of the present invention, the particle size of the irbesartan active pharmaceutical ingredient is D90≤40μm, preferably D90≤20μm, and more preferably D90 is 6 to 10μm, for example 6μm, 7μm, 8μm, 9μm, 10μm or any value or range thereof.

[0018] In some embodiments of the present invention, the organic solvent is an alcohol, preferably a C1-C6 monohydric alcohol, and more preferably methanol, ethanol, isopropanol, n-butanol or isobutanol.

[0019] In some embodiments of the present invention, the volume-to-mass ratio of the organic solvent or the mixture of organic solvent and water to the irbesartan active pharmaceutical ingredient is 15 to 2:1 mL / g, preferably 8 to 3:1 mL / g.

[0020] In some embodiments of the present invention, the mass ratio of organic solvent to water in the mixed solution of organic solvent and water is 20 to 5:1, preferably 10 to 5:1.

[0021] In some embodiments of the present invention, the pulping temperature is -10 to 30°C, preferably 0 to 10°C; and the pulping time is 0.5 to 6 hours, preferably 1 to 3 hours.

[0022] In some embodiments of the present invention, the pulverizer for crushing and granulating has a screen aperture of 0.5-3 mm, preferably 0.8 mm-2.0 mm, for example 0.8 mm, 1.0 mm, 1.2 mm, 1.5 mm, 1.8 mm, 2.0 mm or any value or range thereof; the pulverizer speed is 1500-4000 rpm, preferably 1500-3000 rpm, more preferably 2000-2500 rpm.

[0023] The pulverizer used in this invention can be a mechanical pulverizer, such as a cone granulator or a hammer mill.

[0024] In some embodiments of the present invention, the temperature of the first drying is 30–50°C, preferably 40–45°C, and the drying is carried out until the loss on drying is controlled at 20–30%, preferably 20–28%.

[0025] In some embodiments of the present invention, the temperature of the second drying is 60-90°C, preferably 70-80°C, and the drying is carried out until the dry loss ratio is controlled at 0-20%, preferably 0-10%, and more preferably 0-5%.

[0026] A third aspect of the present invention provides a pharmaceutical composition comprising irbesartan granules of the first aspect of the present invention and one or more pharmaceutically acceptable carriers.

[0027] This invention is easy to operate, highly safe, and meets the requirements of industrial production. The resulting irbesartan particles are large and have good flowability, which can meet the needs of formulation. Attached Figure Description

[0028] Figure 1 Microscopic photograph of spherical large particles of irbesartan after granulation in Example 1.

[0029] Figure 2 The particle size distribution of spherical large-particle irbesartan after granulation in Example 1 is shown.

[0030] Figure 3 The crystal structure of the spherical large particles of irbesartan after granulation in Example 1 is shown in the image.

[0031] Figure 4 Microscopic photograph of spherical large particles of irbesartan after granulation in Example 5.

[0032] Figure 5 This is a particle size distribution of the spherical large-particle irbesartan after granulation in Example 5.

[0033] Figure 6 Microscopic image of irbesartan prepared for Comparative Example 1. Detailed Implementation

[0034] Terms and definitions:

[0035] In the specification and claims of this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the invention, definitions and explanations of some related terms are provided below. Furthermore, in the event of any discrepancy between the definitions and explanations of terms provided herein and their commonly understood meanings by those skilled in the art, the definitions and explanations provided herein shall prevail.

[0036] Unless otherwise specified, the "irbesartan active pharmaceutical ingredient" in this invention can be irbesartan in any form, including but not limited to: amorphous, any crystal form, any hydrate or solvate, such as irbesartan crystal form A, crystal form B, or a mixture thereof. In a preferred embodiment of this invention, irbesartan active pharmaceutical ingredient uses crystal form A, which has a needle-like crystal habit. EP 708103 indicates that this needle-like crystal form A exhibits stable, non-hygroscopic needle-like shape and high electrostatic properties. CN1127499C indicates that this needle-like crystal is difficult to filter and dry, and has poor flowability. CN1127499C discloses "brick-like crystals" of crystal form A. In Example 2, three types of "brick-shaped crystals" were generated based on the increase in the number of oscillation cycles: those with a length of 300-500 μm, a width of 20-50 μm, and a ratio of 25:1-6:1; those with a length of 40-110 μm, a width of 5-40 μm, and a ratio of 8:1-1:1, which also showed many fine particles; and those with a relative average length of 30 μm, an average width of 5 μm, and a ratio of 6:1. It can be seen that the crystal particles with a low aspect ratio are small particles with a wide particle size distribution.

[0037] The term "loss to dryness ratio" refers to the percentage of mass lost after drying to constant weight.

[0038] The term "C1-C6 monohydric alcohol" refers to alcohols with 1-6 carbon atoms in the main chain and containing only one hydroxyl group.

[0039] The specific testing instruments and methods used in this invention are as follows:

[0040] X-ray powder diffraction detection method:

[0041] Instrument: Aeris

[0042] Light tube type: Empyrean XRD tube Cu LFF HR

[0043] Voltage and current: 40kV, 7.5mA

[0044] Goniometer: radius 145mm

[0045] Detector: PIXcel1D-Medipix3 detector

[0046] Scanning mode: Continuous scan

[0047] Scan range (2θ): 3.0 -50.0°

[0048] Microscope: OLYMPUSBX43;

[0049] Particle size analysis method: The sample was dispersed in water and analyzed using a Malvern MS2000 laser particle size analyzer;

[0050] Angle of repose measurement:

[0051] 1) Fix the lower outlet of the glass funnel in the measuring device 100mm above the glass base plate with a diameter of 100mm, centered; 2) Add the sample to be tested from the funnel of the device. When material flows out of the cone formed on the glass base plate below, stop adding the sample. Measure the height H of the cone with the movable scale on the device, and calculate the angle of repose according to the formula θ=arctan(H / 50); 3) Repeat the measurement 5 times and take the average value.

[0052] The pulverizer used in this embodiment of the invention is model HM-CM-lab.

[0053] For example, using a mechanical pulverizer 1.0#-1800rpm for granulation means that the pulverizer has a screen aperture of 1.0mm and the pulverizing speed is set to 1800rpm.

[0054] The following specific embodiments illustrate the content of this article, but these specific embodiments are not intended to limit the scope of this article.

[0055] In the examples, the irbesartan used as a starting material is crystal form A, and its crystal habit is needle-like.

[0056] Example 1

[0057] 100g of irbesartan (D90: 8μm) was added to a 500ml glass autoclave, along with 400ml of 90% ethanol. The mixture was stirred at 10℃-15℃ for 1 hour, filtered, and the wet product was dried at 40℃ until the loss on drying was 24.7%. The product was then granulated using a mechanical pulverizer (1.0#-1800rpm). After granulation, the material was placed in an oven at 80℃ for further vacuum drying for 12 hours until the loss on drying was <0.5%. The particle size was determined as D10: 5μm, D50: 58μm, and D90: 222μm. Microscopic images of the samples are shown below. Figure 1 As shown, the particle size distribution is as follows: Figure 2 As shown, the crystal form spectrum is as follows Figure 3 As shown.

[0058] Example 2

[0059] 100g of irbesartan with a D90 of 8μm was added to a 500ml glass autoclave, along with 500ml of 90% ethanol. The mixture was stirred at 10℃-15℃ for 2 hours, filtered, and the wet product was dried at 40℃ to a dry loss ratio of 22.3%. The product was then granulated using a mechanical pulverizer at 1.0#-2000rpm. After granulation, the material was placed in an oven at 80℃ for further vacuum drying for 12 hours until the dry loss was <0.5%. The particle size was then measured: D10: 3μm, D50: 49μm, and D90: 282μm.

[0060] Example 3

[0061] 500g of irbesartan with a D90 of 8μm was placed in a 5000ml glass autoclave, and 3500ml of 90% ethanol was added. The mixture was stirred at 5℃-10℃ for 3 hours, filtered, and the wet product was dried at 40℃ to a dry loss ratio of 23.5%. The product was then granulated using a mechanical pulverizer at 1.2#-3000rpm. After granulation, the material was placed in an oven at 80℃ for further vacuum drying for 12 hours until the dry loss was <0.5%. The particle size was measured as D10: 6μm, D50: 109μm, and D90: 392μm.

[0062] Example 4

[0063] 5 kg of irbesartan with a D90 of 8 μm was placed in a 50 L glass reactor, and 30 L of 90% ethanol was added. The mixture was pulped at 5-10 °C for 3 hours, filtered, and the wet product was dried at 40 °C until the dry loss ratio was 26.2%. The product was then granulated using a mechanical pulverizer at 1.0#-3000 rpm. After granulation, the material was placed in an oven at 80 °C for vacuum drying for 12 hours until the dry loss was <0.5%. The product was then granulated again at 1.0#-2000 rpm. The particle size was measured to be D10: 3 μm, D50: 54 μm, and D90: 240 μm.

[0064] Example 5

[0065] 200 kg of irbesartan with a D90 of 8 μm was added to a 2000 L reactor, along with 1400 L of 90% ethanol. The mixture was stirred at 0-5 °C for 4 hours, centrifuged, and the wet product was dried at 40 °C until the loss on drying was 21.1%. The product was then granulated using a mechanical pulverizer at 1.5#-3000 rpm. After granulation, the material was placed in an oven at 80 °C for further vacuum drying for 16 hours until the loss on drying was <0.5%. Granulation was then repeated once more using a 1.2#-2200 rpm pulverizer. The particle size was measured as D10: 2 μm, D50: 87 μm, and D90: 292 μm. Microscopic images of the samples are shown below. Figure 4 As shown, the particle size distribution is as follows: Figure 5 As shown.

[0066] Comparative Example 1

[0067] Add 100g of irbesartan to a 1000ml crystallizer, add 740ml of 90% ethanol, heat to 75-80℃ and reflux to dissolve. Slowly cool to 5℃ for 6-7 hours, maintain the temperature and stir for 1 hour, filter, dry the wet product in a vacuum oven at 80℃ for 12 hours, and then pulverize with a mechanical powder at 1.0#-1800rpm. Analyze the particle size: D10: 2μm, D50: 11μm, D90: 36μm. See the microscopic photograph of the sample. Figure 6 As shown.

[0068] Table 1 Solid-state characterization data of irbesartan products

[0069] Sample source Bulk density Tap density Angle of repose Comparative Example 1 0.26g / ml 0.43g / ml 52° Example 3 0.38g / ml 0.57g / ml 34° Example 4 0.39g / ml 0.57g / ml 33° Example 5 0.38g / ml 0.58g / ml 33°

Claims

1. An irbesartan granule, characterized in that, Its D90 is 150-450μm, preferably 200-350μm.

2. The irbesartan granules according to claim 1, characterized in that, D10 is 1-10μm, D50 is 30-120μm, and D90 is 150-450μm.

3. The irbesartan granules according to claim 1, characterized in that, D10 is 2-6μm, D50 is 40-80μm, and D90 is 200-350μm.

4. The irbesartan granules according to claim 1, characterized in that, The aspect ratio of the irbesartan particles is 1 to 2, preferably 1 to 1.

5.

5. The irbesartan granules according to claim 1, characterized in that, The bulk density is 0.35–0.40 g / mL, preferably 0.38–0.39 g / mL; and / or The tap density is 0.45–0.60 g / mL, preferably 0.57–0.58 g / mL; and / or The angle of repose is 30–40°, preferably 32–35°.

6. The irbesartan granules according to claim 1, characterized in that, When Cu-Kα radiation is used, its X-ray powder diffraction pattern shows characteristic peaks at 2θ angles of 4.72±0.2°, 12.48±0.2°, and 18.97±0.2°; or When Cu-Kα radiation is used, the X-ray powder diffraction pattern shows characteristic peaks at 2θ angles of 4.72±0.2°, 9.42±0.2°, 12.48±0.2°, 13.33±0.2°, 17.05±0.2°, 18.97±0.2°, 19.46±0.2°, 21.15±0.2°, 22.68±0.2°, 23.20±0.2°, and 23.67±0.2°.

7. A method for preparing irbesartan granules according to any one of claims 1 to 5, characterized in that, The process includes the following steps: irbesartan raw material is pulped with an organic solvent or a mixture of organic solvent and water, centrifuged or filtered, the resulting wet product is dried for the first time, pulverized and granulated for the first time, dried for the second time, and optionally pulverized and granulated for the second time to obtain irbesartan spherical granules. The irbesartan active pharmaceutical ingredient has a crystal form of crystal form A. Further, the irbesartan active pharmaceutical ingredient is irbesartan particles of crystal form A with needle-like crystals. Even further, the particle size of the irbesartan active pharmaceutical ingredient is D90≤40μm, preferably D90≤20μm, and more preferably D90 is 6~10μm. The organic solvent is an alcohol, preferably a C1-C6 monohydric alcohol, and more preferably methanol, ethanol, isopropanol, n-butanol or isobutanol; The volume-to-mass ratio of the organic solvent or the mixture of organic solvent and water to irbesartan active pharmaceutical ingredient is 15-2:1 mL / g, preferably 8-3:1 mL / g. More preferably, the mass ratio of organic solvent to water in the mixture of organic solvent and water is 20-5:1, preferably 10-5:

1. The pulping temperature is -10 to 30°C, preferably 0 to 10°C; the pulping time is 0.5 to 6 hours, preferably 1 to 3 hours. The pulverizer for crushing and granulating has a screen aperture of 0.5-3mm, preferably 0.8mm-2.0mm; the pulverizer speed is 1500-4000rpm, preferably 1500-3000rpm, and more preferably 2000-2500rpm. The temperature of the first drying is 30-50°C, preferably 40-45°C, and the drying is carried out until the dry loss ratio is controlled at 20-30%, preferably 20-28%. The temperature for the second drying is 60–90°C, preferably 70–80°C, and the drying is carried out until the dry loss ratio is controlled at 0–20%, preferably 0–10%, and more preferably 0–5%.

8. A pharmaceutical composition comprising irbesartan granules as described in any one of claims 1 to 6 and one or more pharmaceutically acceptable carriers.

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