AMLODIPINE MESYLATE MONOHYDRATE PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Amlodipine mesylate monohydrate, a preparation method therefor and a use thereof. The described amlodipine mesylate monohydrate has high purity, has good fluidity and compressibility, and is suitable for direct tableting processing by a high-speed tablet press.

Claims

1. An amlodipine mesylate monohydrate, wherein said monohydrate is in crystal form, the crystal has a particle size distribution of D.sub.10: 20-40 μm, D.sub.50: 55-85 μm, D.sub.90: 95-140 μm, a carr index of 10-25%, an angle of repose (α) of 15-35°, a bulk density of 0.25-0.45 g/mL, and a purity of more than 99.5%.

2. The amlodipine mesylate monohydrate according to claim 1, wherein, said crystal has a crystal form which is consistent with that of APIs prepared in CN1263093A, and both of them are the crystal form B (a crystal form of amlodipine mesylate monohydrate) reported in EP1221438A2.

3. The amlodipine mesylate monohydrate according to claim 1, wherein, said crystal has a particle size distribution of D.sub.10: 28-40 μm, D.sub.50: 65-80 μm, D.sub.90: 100-130 μm; preferably, said crystal has a carr index of 10-20%; preferably, said crystal has an angle of repose (α) of 15-25°; preferably, said crystal has a bulk density of 0.30-0.45 g/mL.

4. A method for preparing the amlodipine mesylate monohydrate according to claim 1, wherein said method comprises following steps: dissolving an amlodipine free base in a water-containing organic solvent and adding methanesulfonic acid dropwise under low temperature condition to give a saturated solution, stirring and adding a seed crystal of amlodipine mesylate monohydrate thereto, adding methanesulfonic acid dropwise continuously under stirring to give crystals, growing the crystals, centrifuging, washing and vacuum drying before obtaining.

5. The method according to claim 4, wherein, the organic solvent is one or more selected from the group consisting of ethyl acetate, acetone, acetonitrile and isopropanol, preferably ethyl acetate or acetone; preferably, a molar ratio between the water contained in the organic solvent and the amlodipine free base is 1.0-10.0, preferably 1.0-5.0; preferably, a ratio (m:v) between the organic solvent and the amlodipine free base is 1:3-1:15, preferably 1:4-1:10, more preferably 1:4-1:6.

6. The method according to claim 4, wherein, the added seed crystal of amlodipine mesylate monohydrate has a crystal form which is consistent with that of APIs prepared in CN1263093A, and both of them are the crystal form B (a crystal form of amlodipine mesylate monohydrate) reported in EP1221438A2; preferably, an amount of the added seed crystal of amlodipine mesylate monohydrate is 0.5%-10%, preferably 1% by weight of the amlodipine free base; preferably, a total amount of methanesulfonic acid added is 0.9 to 2.0 equivalents, preferably 0.9 to 1.2 equivalents of amlodipine free base; preferably, an amount of methanesulfonic acid added before adding the seed crystal of amlodipine mesylate monohydrate is 10%-30%, preferably 15%-25% (mass percentage) of the total amount of methanesulfonic acid added.

7. The method according to claim 4, wherein, the low temperature condition refers to a condition where the temperature is 0-30° C., preferably 0-25° C.; preferably, the growing of the crystals is conducted under a temperature of −10° C.-30° C., preferably 0-10° C., more preferably 0-5° C.; preferably, the growing of the crystals is conducted for 0.5-24 hours, preferably 2-4 hours.

8. The method according to claim 4, wherein, a stirring rate used before adding the seed crystal is 150-200 rpm/min, a stirring rate used after adding the seed crystal is 100 rpm/min-60 rpm/min; preferably, the vacuum drying is conducted under a vacuum degree of −0.04˜0.07 MPa and a drying temperature of 20-45° C., preferably 20-30° C.

9. The method according to claim 4, wherein, said amlodipine free base can be a solid raw material or a solution of amlodipine free base without separation.

10. A tablet comprising the amlodipine mesylate monohydrate according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Hereinafter, the embodiments of the present invention will be described with reference to the accompanying drawings in detail, in which:

[0053] FIG. 1 shows a particle size distribution of the product prepared in Example 1;

[0054] FIG. 2 shows an X-ray powder diffraction spectrum of the product prepared in Example 1;

[0055] FIG. 3 shows a differential thermal analysis spectrum of the product prepared in Example 1;

[0056] FIG. 4 shows a particle size distribution of the product prepared in Example 2;

[0057] FIG. 5 shows an X-ray powder diffraction spectrum of the product prepared in Example 2;

[0058] FIG. 6 shows a differential thermal analysis spectrum of the product prepared in Example 2;

[0059] FIG. 7 shows a particle size distribution of the product prepared in Example 3;

[0060] FIG. 8 shows an X-ray powder diffraction spectrum of the product prepared in Example 3;

[0061] FIG. 9 shows a differential thermal analysis spectrum of the product prepared in Example 3;

[0062] FIG. 10 shows a particle size distribution of the product prepared in comparative example 1;

[0063] FIG. 11 shows an X-ray powder diffraction spectrum of the product prepared in comparative example 1;

[0064] FIG. 12 shows a differential thermal analysis spectrum of the product prepared in comparative example 1;

[0065] FIG. 13 shows a particle size distribution of the product prepared in comparative example 2;

[0066] FIG. 14 shows an X-ray powder diffraction spectrum of the product prepared in comparative example 2;

[0067] FIG. 15 shows a differential thermal analysis spectrum of the product prepared in comparative example 2.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0068] The following provided examples are only used to illustrate the present invention, rather than limiting the scope of the present invention in any way.

[0069] The amlodipine free base used in the following examples is commercially available, which can also be synthesized by reference to literatures in the prior art.

[0070] Determination of parameters of API of amlodipine mesylate monohydrate regarding quality such as the content and related substances and the like, is conducted through methods for determining amlodipine mesylate described in “National Drug Standard” [WS.sub.1-(X-497)-2003Z-2017]. The chromatographic conditions are as follows: chromatographic column: Phenomenex Luna C18 column filled with octadecylsilane chemically bonded silica (4.6 mm×250 mm, 5 μm) or columns with performance comparable to that of Phenomenex Luna C18 column; mobile phase: a solution of methanol-acetonitrile-0.7% triethylamine (35:15:50), wherein the 0.7% triethylamine can be obtained through taking 7.0 mL triethylamine and diluting it to 1000 mL with water, adjusting pH of the dilution to 3.0±0.1 with phosphoric acid; detection wavelength: 239 nm.

[0071] Determination of parameters of tablets of amlodipine mesylate monohydrate regarding quality such as the content, related substances, content uniformity, dissolution rate and the like, is conducted through methods for determining amlodipine mesylate tablets described in “National Drug Standard” [WS.sub.1-(X-262)-2004Z-2017]. The chromatographic conditions for the determination of the content, related substances, content uniformity of the tablets are the same as that used for the determination of the API. Determination of the dissolution rate can be conducted as follows: 500 mL of hydrochloric acid solution (0.9 mL of hydrochloric acid added to 1000 mL of water) was served as a dissolution medium, the rotation speed was 75 rmp/min and a dissolution was conducted for 30 minutes, a proper amount of the obtained solution was taken, filtered, and the obtained filtrate was used as the test solution; the reference substance of amlodipine mesylate accurately was weighed, dissolved with an appropriate amount of methanol before being diluted with the dissolution medium to give a solution containing about 10 μg of amlodipine per 1 mL, the obtained solution was served as a reference solution; the absorbance of the above two solutions was measured by ultraviolet-visible spectrophotometry at a wavelength of 239 nm (General Rule 0401, Volume IV, Pharmacopoeia of the People's Republic of China (2015 edition)), and then the dissolution rate was calculated according to the external standard method.

[0072] Determination of other parameters of API or tablets of amlodipine mesylate monohydrate regarding quality such as water content, angle of repose, carr index, particle size, bulk density, and the like, is conduct with conventional methods well known to those skilled in the art.

[0073] The seed crystal of amlodipine mesylate monohydrate added in the following examples has a crystal form which is consistent with that of APIs prepared in CN1263093A, and both are the crystal form B (a crystal form of amlodipine mesylate monohydrate) reported in EP1221438A2.

Experimental Example 1: Preparation of Amlodipine Mesylate Monohydrate Using Amlodipine Free Base as Starting Material

[0074] 100 g of amlodipine free base (245.1 mmol), ethyl acetate (500 mL) and purified water (5.29 mL, 1.2 eq) were sequentially added to a 2000 mL three-necked flask, and then stirred for 15 minutes to dissolve. At room temperature, 5.88 g of methanesulfonic acid (61.3 mmol) was weighted firstly, and then was quickly added into the obtained reaction solution through a constant-pressure dropping funnel under stirring to give a clear solution, the dropping rate was controlled at 5 mL/min and the stirring rate was controlled at 160 rpm/min. At room temperature, 1.25 g of seed crystals of amlodipine mesylate monohydrate was added to the clear solution to give a suspension under stirring with a stirring rate of 70 rpm/min. 17.6 g of methanesulfonic acid (183.9 mmol) was weighted secondly, and then was slowly added into the suspension through a constant-pressure dropping funnel under stirring by controlling the dropping rate at 0.5 mL/min. When the addition of the methanesulfonic acid was completed, the obtained mixture was incubated continuously at room temperature and stirred for growing the crystals for 3 hours, filtered, and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 30° C. for 3 hours to give 88.3 g of product, i.e white crystals in solid form (yield 69%). The purity of the product determined through HPLC was 99.90%, the water content of the product determined through Karl Fischer method was 3.49%. The product has a particle size distribution of D.sub.10: 43 μm, D.sub.50: 92 μm and D.sub.90: 151 μm.

[0075] It can be seen that a significant decrease in product yield, low salt-forming rate and serious sample loss will be resulted in if the crystallization is carried out at room temperature.

Experimental Example 2: Preparation of Amlodipine Mesylate Monohydrate Using Amlodipine Free Base as Starting Material

[0076] 100 g of amlodipine free base (245.1 mmol), ethyl acetate (500 mL) and purified water (5.29 mL, 1.2 eq) were sequentially added to a 2000 mL three-necked flask, and then stirred for 15 minutes to dissolve. At room temperature (25° C.), 5.88 g of methanesulfonic acid (61.3 mmol) was weighted firstly, and then was quickly added into the obtained reaction solution through a constant-pressure dropping funnel under stirring to give a clear solution, the dropping rate was controlled at 5 mL/min and the stirring rate was controlled at 160 rpm/min. At room temperature, 1.25 g of seed crystals of amlodipine mesylate monohydrate was added to the clear solution to give a suspension under stirring with a stirring rate of 70 rpm/min. 17.6 g of methanesulfonic acid (183.9 mmol) was weighted secondly, and then was slowly added into the suspension through a constant-pressure dropping funnel under stirring by controlling the dropping rate at 0.5 mL/min. When the addition of the methanesulfonic acid was completed, the obtained mixture was incubated continuously at low temperature (0° C.) and stirred for growing the crystals for 3 hours, filtered, and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 30° C. for 3 hours to give 122.8 g of product, i.e white crystals in solid form (yield 96%). The purity of the product determined through HPLC was 99.90%, the water content of the product determined through Karl Fischer method was 3.54%. The product has a particle size distribution of D.sub.10: 32 μm, D.sub.50: 68 μm and D.sub.90: 117 μm.

Experimental Example 3: Preparation of Amlodipine Mesylate Monohydrate Using Amlodipine Free Base as Starting Material

[0077] 210 g of amlodipine free base (514.7 mmol), ethyl acetate (1000 mL) and purified water (11.1 mL, 1.2 eq) were sequentially added to a 3000 mL three-necked flask, and then stirred for 15 minutes to dissolve. At low temperature (5° C.), 12.3 g of methanesulfonic acid (128.7 mmol) was weighted firstly, and then was quickly added into the obtained reaction solution through a constant-pressure dropping funnel under stirring to give a clear solution, the dropping rate was controlled at 5 mL/min and the stirring rate was controlled at 160 rpm/min. At room temperature, 2.6 g of seed crystals of amlodipine mesylate monohydrate was added to the clear solution to give a suspension under stirring with a stirring rate of 270 rpm/min. 37.1 g of methanesulfonic acid (386.0 mmol) was weighted secondly, and then was slowly added into the suspension through a constant-pressure dropping funnel under stirring by controlling the dropping rate at 0.5 mL/min. When the addition of the methanesulfonic acid was completed, the obtained mixture was incubated continuously at low temperature (5° C.) and stirred for growing the crystals for 3 hours, filtered, and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 30° C. for 3 hours to give 257.9 g of product, i.e white crystals in solid form (yield 95%). The purity of the product determined through HPLC was 99.92%, the water content of the product determined through Karl Fischer method was 3.63%. The product has a particle size distribution of D.sub.10: 34 μm, D.sub.50: 69 μm and D.sub.90: 120 μm.

Example 1: Preparation of Amlodipine Mesylate Monohydrate with High Fluidity Using Amlodipine Free Base as Starting Material

[0078] 100 g of amlodipine free base (245.1 mmol), ethyl acetate (500 mL) and purified water (5.29 mL, 1.2 eq) were sequentially added to a 2000 mL three-necked flask, stirred for 15 minutes to dissolve and then the obtained reaction solution was cooled down to 0° C. to 5° C. 5.88 g of methanesulfonic acid (61.3 mmol) was weighted firstly, and then was quickly added into the obtained reaction solution through a constant-pressure dropping funnel under stirring to give a clear solution, the dropping rate was controlled at 5 mL/min and the stirring rate was controlled at 160 rpm/min. The temperature of the clear solution was kept at 0° C. to 5° C., then 1.25 g of seed crystals of amlodipine mesylate monohydrate was added thereto to give a suspension under stirring with a stirring rate of 100-60 rpm/min. 17.6 g of methanesulfonic acid (183.9 mmol) was weighted secondly, and then was slowly added into the suspension through a constant-pressure dropping funnel under stirring by controlling the dropping rate at 0.5 mL/min. When the addition of the methanesulfonic acid was completed, the obtained mixture was incubated continuously at 0° C. and stirred for growing the crystals for 3 hours, filtered, and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 30° C. for 3 hours to give 122.5 g of product, i.e white crystals in solid form (yield 96%). The purity of the product determined through HPLC was 99.92%, the water content of the product determined through Karl Fischer method was 3.51% (the theoretical value is 3.44%). The product has a particle size distribution of D.sub.10: 33.9 μm, D.sub.50: 70.2 μm and D.sub.90: 121 μm; a carr index of 23%, an angle of repose of 29°, and a bulk density of 0.32 g/mL. The particle size distribution of the product was shown in FIG. 1, the X-ray powder diffraction spectrum of the product was shown in FIG. 2, and the differential thermal analysis spectrum of the product was shown in FIG. 3. It can be seen the product has a uniform particle size distribution, and a bulk density and a particle size which are similar to that of the type 102 microcrystalline cellulose. The carr index and the angle of repose of the product indicated that the crystals have good fluidity and stability (see table-1).

TABLE-US-00001 TABLE 1 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Average Water Related particle Bulk content substance Content size density Carr Time Character (%) (%) (%) (μm) (g/mL) index(%) 0 month White solid 3.51 0.07 99.92 70.2 0.32 23 3 months White solid 3.49 0.07 99.78 70.6 0.31 23 6 months White solid 3.50 0.08 99.71 69.5 0.33 24

Example 2: Preparation of Amlodipine Mesylate Monohydrate with High Fluidity Using Amlodipine Besylate as Starting Material

[0079] 200 g of amlodipine besylate (352.7 mmol), ethyl acetate (750 mL) and purified water (75 mL) were sequentially added to a 2000 mL three-necked flask, stirred for 15 minutes. 16.9 g of sodium hydroxide (1.2 eq, 423.3 mmol) was weighted and dissolved in 211 mL purified water to give a sodium hydroxide solution. The sodium hydroxide solution was then added dropwise under a cooling condition with water bath for about 10 min. When the addition of the NaOH aqueous solution was completed, the reaction solution was continued to be stirred for about 30 min before terminating the reaction. The obtained reaction solution was allowed to stand for phase separation, the aqueous phase was extracted twice with 200 mL of ethyl acetate, the combined organic phases were then washed with purified water to obtain an ethyl acetate layer with a volume of 1100 mL (the density measured was 0.98 g/mL). The water content of the ethyl acetate layer determined through Karl Fischer method was 1.0%, i.e. the amount of water contained in the ethyl acetate layer was 10.8 g, which meant there was no need to further make up the amount of water as the theoretical amount of water required was 6.35 g. The ethyl acetate layer was cooled down to 0° C. to 5° C., and then 8.46 g of methanesulfonic acid (88.2 mmol) was weighted and quickly added thereto through a constant-pressure dropping funnel under stirring to give a clear solution, the dropping rate was controlled at 5 mL/min and the stirring rate was controlled at 175 rpm/min. The temperature of the clear solution was kept at 0° C. to 5° C., then 1.84 g of seed crystals of amlodipine mesylate monohydrate was added thereto to give a suspension under stirring with a stirring rate of 100-60 rpm/min. 25.4 g of methanesulfonic acid (264.3 mmol) was weighted secondly, and then was slowly added into the suspension through a constant-pressure dropping funnel under stirring by controlling the dropping rate at 1.0 mL/min. When the addition of the methanesulfonic acid was completed, the obtained mixture was incubated continuously at 0° C. and stirred for growing the crystals for 3 hours, filtered, and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 30° C. for 3 hours to give 165.7 g of product in white solid (yield 90%). The purity of the product determined through HPLC was 99.95%, the water content of the product determined through Karl Fischer method was 3.51% (the theoretical value is 3.44%). The product has a particle size distribution of D.sub.10: 34.8 μm, D.sub.50: 72.1 μm and D.sub.90: 126 μm; a carr index of 23%, an angle of repose of 31°, and a bulk density of 0.33 g/mL. The particle size distribution of the product was shown in FIG. 4, the X-ray powder diffraction spectrum of the product was shown in FIG. 5, and the differential thermal analysis spectrum of the product was shown in FIG. 6. It can be seen the product has a uniform particle size distribution, and a bulk density and a particle size which are similar to that of the type 102 microcrystalline cellulose. The carr index and the angle of repose of the product indicated that the crystals have good fluidity and stability (see table-2).

TABLE-US-00002 TABLE 2 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Average Water Related particle Bulk content substance Content size density Carr Time Character (%) (%) (%) (μm) (g/mL) index(%) 0 month White solid 3.51 0.06 99.95 72.1 0.33 23 3 months White solid 3.52 0.07 99.81 71.8 0.32 24 6 months White solid 3.49 0.08 99.73 72.4 0.32 24

Example 3: Scaled-Up Preparation of Amlodipine Mesylate Monohydrate with High Fluidity

[0080] 7.0 kg of amlodipine free base (17.16 mol), ethyl acetate (35 L) and purified water (370.66 mL, 1.2 eq) were sequentially added to a 100 L reaction still, stirred for 30 minutes to dissolve and then the obtained solution of amlodipine free base in ethyl acetate was cooled down to −5° C. to 5° C. 296.2 g of methanesulfonic acid (3.09 mol) was weighted firstly, and then was quickly added into the solution through a constant-pressure dropping funnel under stirring to give a clear solution, the dropping rate was controlled at 10-15 mL/min and the stirring rate was controlled at 200 rpm/min. The temperature of the clear solution was kept at 0° C. to 5° C., then 90 g of seed crystals of amlodipine mesylate monohydrate was added thereto to give a suspension under stirring with a stirring rate of 100 rpm/min. 1.236 kg of methanesulfonic acid (12.87 mol) was weighted secondly, and then was slowly added into the suspension through a constant-pressure dropping funnel under stirring by controlling the dropping rate at 5 mL/min. When the addition of the methanesulfonic acid was completed, the obtained mixture was incubated continuously at 0° C. and stirred for growing the crystals for 4 hours, filtered, and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 25-35° C. for 2-4 hours to give 8.51 kg of white solid product (yield 95%). The purity of the product determined through HPLC was 99.93%, the water content of the product determined through Karl Fischer method was 3.50% (the theoretical value is 3.44%). The product has a particle size distribution of D.sub.10: 32.9 μm, D.sub.50: 70.1 μm and D.sub.90: 124 μm; a carr index of 24%, an angle of repose of 33°, and a bulk density of 0.30 g/mL. The particle size distribution of the product was shown in FIG. 7, the X-ray powder diffraction spectrum of the product was shown in FIG. 8, and the differential thermal analysis spectrum of the product was shown in FIG. 9. It can be seen the product has a uniform particle size distribution, and a bulk density and a particle size which are similar to that of the type 102 microcrystalline cellulose. The carr index and the angle of repose of the product indicated that the crystals has good fluidity and stability (see table-3).

TABLE-US-00003 TABLE 3 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Water Related Average Bulk content substance Content particle density Carr Time Character (%) (%) (%) size (μm) (g/mL) index(%) 0 month White solid 3.50 0.07 99.93 70.1 0.30 24 3 months White solid 3.48 0.08 99.82 69.5 0.31 23 6 months White solid 3.49 0.10 99.71 71.4 0.32 25

Example 4: Preparation of Tablets of Amlodipine Mesylate Monohydrate Through Direct Compression

(1) Formulation

[0081]

TABLE-US-00004 Nos. Name for the API and excipients 800,000 tablets 1 Amlodipine mesylate prepared in Example 3 5.12 kg 2 Type 102 microcrystalline cellulose 108.24 kg 3 Pregelatinized starch 46.4 kg 4 Magnesium stearate 0.24 kg Total 160 kg

(2) Preparation

[0082] Magnesium stearate, pregelatinized starch, type 102 microcrystalline cellulose and amlodipine mesylate prepared in Example 3 were accurately weighed in the order of excipients before the API and then were placed in clean, sealable stainless-steel barrels respectively. Then, the amlodipine mesylate was passed through 80 mesh firstly following by passing ⅓ of the feed amount of pregelatinized starch through the same mesh. The obtained mixture of amlodipine mesylate and pregelatinized starch was then put into a SBH-1200 Three-Dimensional Oscillating Mixer and mixed for 10 min. Afterwards, the remaining pregelatinized starch was put into the Mixer and mixed for 30 min. ½ of the feed amount of microcrystalline cellulose was put into the Mixer and mixed for 25 min following by putting the remaining microcrystalline cellulose into the Mixer for mixing 35 min. Finally, the magnesium stearate was put into the Mixer and mixed for 10 min to give an intermediate in a form of mixed powder. The intermediate has an angle of repose of 26°, a carr index of 23%, and a bulk density of 0.37 g/mL, as well as good fluidity. The content of the intermediate was determined through HPLC. The intermediate was then compressed by ZP129 Rotary High Speed Tablet Press Machine to produce tablets with following compression parameters: 6.4 mg per tablet (equivalent to 5.0 mg amlodipine), 38 rpm/min and a hardness of 4.0-12.0 kg. The obtained tablets were packaged using an Aluminum Plastic Blister Packaging Machine to give end products of the amlodipine mesylate. During the process of producing the tablets of amlodipine mesylate, smoothly compressing process can be achieved and tablets with small tablet weight variation, smooth appearance, qualifying hardness and friability, and good content uniformity and stability can be obtained. Results are shown in table-4 and table-5.

TABLE-US-00005 TABLE 4 Determination results of tablets of amlodipine mesylate Tablet weight variation (average Content Total tablet weight + uniformity Content impurities Dissolution Hardness Friability RSD %) (A + 2.2 S) (%) (%) rate (%) (kg) (%) 199.7 + 0.52 4.9 99.91 0.08 98.21 7.3 0.52

TABLE-US-00006 TABLE 5 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Total Dissolution Time Character impurities (%) Content (%) rate (%) 0 month White tablet 0.08 99.91 98.21 3 months White tablet 0.10 99.87 98.69 6 months White tablet 0.10 99.82 98.81

Comparative Example 1

[0083] This comparative example was conduct with reference to the method for preparing amlodipine mesylate monohydrate disclosed by CN1263093A. Specifically, 1000 g of amlodipine free base (2.45 mol) and ethyl acetate (7.0 L) were sequentially added to a 20 L reaction still and then stirred for 15 minutes to dissolve before adding purified water (100 mL) thereto. Subsequently, under a cooling condition with water bath, 282.2 of methanesulfonic acid (2.94 mol, 1.2 eq) was slowly added dropwise through a constant-pressure dropping funnel under stirring, and the dropping rate was controlled at about 1 mL/min. A large number of crystals were precipitated, and an explosive crystallization appeared when about 101 mL of methanesulfonic acid (makes up about 53% of the total amount) was added. The remaining methanesulfonic acid was continued to drop. After completion, the obtained mixture was left at room temperature overnight to precipitate white solid which was then filtered and rinsed with ethyl acetate to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 30° C. for 4 hours to give 1151.4 g white like solid (the product) (yield 90%). The purity of the product determined through HPLC was 99.89%, the water content of the product determined through Karl Fischer method was 3.49% (the theoretical value is 3.44%). The product has a particle size distribution of D.sub.10: 1.73 μm, D.sub.50: 6.70 μm and D.sub.90: 16.4 μm. The particle size distribution of the product was shown in FIG. 10, the X-ray powder diffraction spectrum of the product was shown in FIG. 11, and the differential thermal analysis spectrum of the product was shown in FIG. 12. Furthermore, the obtained product has a carr index of 41%, an angle of repose of 46°, and a bulk density of 0.22 g/mL. It can be seen the particle size distribution of the product is not uniform, and the carr index and the angle of repose of the product indicated that the product has poor fluidity. In addition, the results of stability study showed that the impurities in the product increased quickly, and the color changed obviously (see table-6).

TABLE-US-00007 TABLE 6 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Water Related Average Bulk Carr content substance Content particle density index Time Character (%) (%) (%) size (μm) (g/mL) (%) 0 month White like 3.49 0.12 99.89 6.70 0.22 41 solid 3 months Light 3.48 0.18 99.81 5.96 0.25 42 yellow solid 6 months Yellow 3.51 0.23 99.71 6.93 0.26 43 solid

Comparative Example 2

[0084] This comparative example was conduct with reference to the method for preparing amlodipine mesylate monohydrate disclosed by EP1221438A2. Specifically, 100 g amlodipine free base (245.1 mmol) and 577 g of isopropanol were sequentially added to a 2000 mL three-necked flask, stirred for 30 minutes at 30-40° C. under nitrogen atmosphere to dissolve. The obtained solution was filtered, and the filtrate was cooled to 25-30° C. and treated by addition of purified water (12.5 mL). 24.1 g (251.2 mmol, 1.025 eq.) of methanesulfonic acid was then weighted and slowly added dropwise through a constant-pressure dropping funnel under stirring. A large number of crystals were precipitated, and an explosive crystallization appeared when about 9 mL of methanesulfonic acid (makes up about 55% of the total amount) was added. The remaining methanesulfonic acid was continued to drop until complete. The obtained mixture was left at room temperature overnight to precipitate white solid which was then filtered and rinsed with isopropanol to obtain white crystals. The obtained crystals were vacuum-dried at a drying temperature of 40° C. for 48 hours to give 111.3 g white like solid (the product) (yield 87%). The purity of the product determined through HPLC was 99.82%, the water content of the product determined through Karl Fischer method was 3.57% (the theoretical value is 3.44%). The product has a particle size distribution of D.sub.10: 1.62 μm, D.sub.50: 6.22 μm and D.sub.90: 14.1 μm. The particle size distribution of the product was shown in FIG. 13, the X-ray powder diffraction spectrum of the product was shown in FIG. 14, and differential thermal analysis spectrum of the product was shown in FIG. 15. Furthermore, the obtained product has a carr index of 42%, an angle of repose of 45°, and a bulk density of 0.26 g/mL. It can be seen the particle size distribution of the product is not uniform, and the carr index and the angle of repose of the product indicated that the product has poor fluidity. In addition, the results of stability study showed that the impurities in the product increased quickly, and the color changed obviously (see table-7).

TABLE-US-00008 TABLE 7 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Water Related Average Bulk content substance Content particle density Carr Time Character (%) (%) (%) size (μm) (g/mL) index (%) 0 month White like 3.57 0.11 99.82 6.22 0.26 42 solid 3 months Light yellow 3.52 0.18 99.71 5.89 0.27 41 solid 6 months Yellow solid 3.53 0.26 99.62 6.74 0.25 44

Comparative Example 3: Preparation of Tablets of Amlodipine Mesylate Monohydrate Through Direct Compression

[0085] This comparative example was conduct with reference to the method for preparing tablets of amlodipine mesylate monohydrate disclosed by CN1263093A.

(1) Formulation

[0086]

TABLE-US-00009 No. Name for the API and excipients 100,000 tablets 1 Amlodipine mesylate prepared in comparative 0.64 kg example 1 2 Type 102 microcrystalline cellulose 13.53 kg 3 Pregelatinized starch 5.8 kg 4 Magnesium stearate 0.03 kg Total 20 kg

(2) Preparation

[0087] Magnesium stearate, pregelatinized starch, type 102 microcrystalline cellulose and amlodipine mesylate prepared in comparative example 1 were accurately weighed in the order of excipients before the API and then were placed in clean, sealable stainless-steel barrels respectively. Since part of amlodipine mesylate was blocky, it should be passed through 80 mesh firstly following by passing ⅓ of the feed amount of pregelatinized starch through the same mesh. The obtained mixture of amlodipine mesylate and pregelatinized starch was then put into an SBH-1200 Three-Dimensional Oscillating Mixer and mixed for 10 min. Afterwards, the remaining pregelatinized starch was put into the Mixer and mixed for 30 min. ½ of the feed amount of microcrystalline cellulose was put into the Mixer and mixed for 25 min following by putting the remaining microcrystalline cellulose into the Mixer for mixing 35 min. Finally, the magnesium stearate was put into the Mixer and mixed for 10 min to give an intermediate in a form of mixed powder. The intermediate has an angle of repose of 32°, a carr index of 34%, and a bulk density of 0.31 g/mL, as well as slightly worse fluidity.

[0088] The content of the intermediate was determined through HPLC. The intermediate was then compressed by ZP129 Rotary High Speed Tablet Press Machine to produce tablets with following compression parameters: 6.4 mg per tablet (equivalent to 5.0 mg amlodipine), 38 rpm/min and a hardness of 4.0-12.0 kg. The obtained tablets were packaged using an Aluminum Plastic Blister Packaging Machine to give end products of the amlodipine mesylate. During the process of producing the tablets of amlodipine mesylate, less smooth compressing process can be observed and tablets with large tablet weight variation, smooth appearance, qualifying hardness and friability and poor content uniformity can be obtained. In addition, the results of stability study showed that the impurities in the tablets increased quickly and the color changed obviously (see table-8 and table-9).

TABLE-US-00010 TABLE 8 Determination results of tablets of amlodipine mesylate Tablet weight variation (average Content Total tablet weight + uniformity Content impurities Dissolution Hardness Friability RSD %) (A + 2.2 S) (%) (%) rate (%) (kg) (%) 198.6 + 1.89 12.1 99.82 0.13 97.25 7.1 0.62

TABLE-US-00011 TABLE 9 Results of accelerated test (sealed and packaged in aluminum- plastic composite film bags, 40° C., 75% RH). Total Dissolution Time Character impurities (%) Content (%) rate (%) 0 month White tablet 0.13 99.82 97.25 3 months White like 0.21 99.71 98.52 tablet 6 months White like 0.28 99.63 97.89 tablet