TW201319042A - Carvedilol sulfate crystals, preparation methods and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to carvedilol sulfate crystals, preparation methods and pharmaceutical use thereof, particularly relates to form A, form B, form C and form D crystals of carvedilol sulfate for treating hypertension, congestive heart failure and angina pectoris, preparation methods and pharmaceutical use thereof. The preparation methods comprise crystallizing random crystal form or amorphous form of carvedilol sulfate solid with conventional polar organic solvents and their aqueous solution to obtain form A, form B, form C or form D crystal. The present invention disclosed carvedilol sulfate crystals have good crystal morphology, and the used solvent for crystallization are low toxicity and low residue. Carvedilol sulfate crystals prepared by the present invention can be used in the clinical treatment better.

Description

Crystallization of carvedilol sulfate, its preparation method and its application in medicine

The present invention relates to Carvedilol sulfate type A, B, C and D crystals, a process for the preparation thereof and use thereof for the preparation of a medicament for the treatment of hypertension, congestive heart failure and angina pectoris.

Carvedilol is chemically named (±)-1-(9H-carbazolyl-4-oxy)-3-[[2-(2-methoxyphenoxy)ethyl]amine ]-2-propanol, developed by the German company Boehringer Mannhei, the FDA was first approved for listing in the United States on September 14, 1995. The trade name is DilatrendTM (Dali). Carvedilol is a racemic mixture of two stereoisomers, a non-selective beta blocker, and also has the properties of alpha blockers, which synergistically cause heart failure. Patients benefit from the treatment of hypertension, congestive heart failure and angina pectoris, which is superior to traditional beta blockers.

Carvedilol contains α-hydroxyl secondary amine functional group, Pka value is 7.8, carvedilol is soluble in neutral or alkaline medium, ie when the pH value is greater than 9, the solubility of carvedilol is relatively low (less than 1 ug/mL), about 23 ug/mL at pH=7, and about 100 ug/mL at pH=5. Therefore, it is desirable to synthesize the salt of carvedilol in order to increase its water solubility and increase chemical stability for use in the composition of the drug.

The hydrochloride salt of carvedilol is reported in International Patent Application WO 0200216 A1. However, the salt has poor solubility under the acid conditions of the simulated gastric juice, so the composition for the drug does not have an advantage. Chinese patent application CN1678305A reported the phosphate, dihydrogen phosphate and its solvate of carvedilol, which was found to have good water solubility compared with the corresponding hydrochloride salts of carvedilol and carvedilol. . The international patent application WO200808310 mainly describes the preparation of the amorphous carvedilol phosphate and its pharmaceutical composition. The preparation of carvedilol sulfate has been reported in the international patent application WO2005051325, but there is no research on the relevant pharmaceutical composition, crystal form and its crystal form preparation method. In view of the fact that the drug crystal form itself may have a special effect on the solubility, stability and formulation characteristics of the drug, it is of great significance for the study of the crystal form of carvedilol sulfate.

The technical problem to be solved by the present invention is to provide a stable crystal form of carvedilol sulfate and a preparation method thereof.

In the process of salt formation, we have surprisingly found that the sulfate of carvedilol is comparable to the dihydrogen phosphate in the drug evaluation index and can be used for the composition of the drug, but carvedilol sulfate is the hydrochloride salt. Dihydrogen phosphate and hydrogen sulfate are more stable, so carvedilol sulfate has its own advantages for drug composition. Although the international patent application WO2005051325 reports on the preparation of carvedilol sulfate, there is no research on the related crystal form and its crystal form preparation method, and the inventors have experimentally verified that the salt is formed according to the method reported by the present invention. Pure crystalline product. The present inventors conducted extensive and intensive studies on the crystal form and preparation method of carvedilol sulfate in view of the possibility that the crystal form of the drug may have an influence on the solubility, stability and formulation characteristics of the drug.

Carvedilol is a white or off-white crystalline powder, slightly soluble in water or methanol, almost insoluble in ethanol, chloroform or acetone. Water or alcohol aqueous solution is an ideal refining solvent. Whether or not polymorphism exists under different crystallization conditions, we use methanol, ethanol, isopropanol, acetone, acetonitrile and their aqueous solutions as crystallization solvents, and the obtained crystallized product of carvedilol sulfate is vacuum dried and heated. After drying, X-ray diffraction measurement was performed.

The crystallization solvent selected includes methanol, methanol/water, water, 95% ethanol, ethanol/water, isopropanol/water, acetone/water, acetonitrile/water, and the like. The crystal samples obtained from the above solvents were subjected to X-ray diffraction and DSC detection, respectively. The experimental results show that carvedilol sulfate crystallizes in an aqueous solution of a conventionally used polar organic solvent, and a crystal form containing semi-molecule crystal water, that is, a type A crystal, is obtained, and crystallized in a conventionally used aqueous methanol solution to obtain a weak bond. Synthetic crystal water B crystal form; crystallized in a conventionally used low water content methanol, obtained is a semi-molecule crystal water of carvedilol C crystal form; crystallized in a conventionally used aqueous acetonitrile solution, obtained Carvedilol D crystal form without crystal water. The X-ray diffraction patterns of these crystal forms indicate that they have respective diffraction characteristics.

The stability of carvedilol sulfate A crystal form is strong. The most readily available crystals in different solvents are A crystal form, such as in crystallization solvent: acetone/water, 95% ethanol, ethanol/water, isopropanol/ In the solvent such as water and water, the same crystal form (X-ray) spectrum is shown, and the characteristic peaks in the X-ray powder diffraction pattern are at 2θ=5.86, 6.3, 13.9, 17.7, 24.1, 25.3±0.2° (the first 1 picture).

In the case of methanol/water as the crystallization solvent, another crystal form (X-ray) pattern was shown. We define it as the B crystal form. The characteristic peaks in the X-ray powder diffraction pattern are at 2θ = 6.8, 13.2, 13.6, 18.0, 19.9, 24.0, 25.1, 30.0 ± 0.2° (Fig. 3).

In the case of methanol having a low water content as a crystallization solvent, another crystal form (X-ray) pattern was obtained. We define it as the C crystal form. The characteristic peaks in the X-ray powder diffraction pattern are at 2θ = 6.5, 7.4, 10.0, 11.8, 13.1, 14.8, 16.3, 18.3, 19.6, 20.8, 24.3, 25.9 ± 0.2° (Fig. 5).

When acetonitrile/water was used as the crystallization solvent, another crystal-free type was obtained. We define it as the D crystal form. The characteristic peak in the X-ray powder diffraction pattern is at 2θ = 6.4 ± 0.2° (Fig. 7).

It was found that under the same solvent conditions, the stirring mode had no effect on the selectivity of Form A. Under the conditions of mechanical stirring, magnetic stirring or static crystallization, the solvent system of ethanol/water was used as an example to obtain a stable A. Type crystal.

During the crystal form research, we found that the crystal form has a close relationship with water. Crystallization in an aqueous solvent, such as crystal form A in acetone/water (Fig. 1), drying the sample obtained by crystallization to a constant weight under vacuum drying at 60 ° C, and measuring the water content. Between 2.0 and 2.8%, in the DSC spectrum (Fig. 2), the presence of crystal water is shown. According to the water calculation formula: % water = [n × 18 / (2 [M] + H ₂ SO ₄ + n × 18)] × 100% (where M is the molecular weight of carvedilol), we can calculate us The product should be a hemihydrate: two molecules of carvedilol + one molecule of sulfuric acid + one molecule of water. Since the water has an influence on the crystal form, we control the crystallization product to dry at a temperature of 20 to 80 ° C for a suitable period of time, that is, drying until the water loss slowly tends to a constant weight, and the water can be stably obtained at 2.0 to 3.0. A crystal form sample between %.

Similarly, the crystal form B (Fig. 3) obtained by crystallizing carvedilol sulfate in an aqueous methanol solution can be stably obtained at a temperature of 20 to 60 ° C for a suitable period of time to obtain a water content of 2.0 to 3.0%. A sample of Form B between. The DSC spectrum (Fig. 4) shows that the B crystal form has a weak bonding force of crystal water. Compared with the A crystal sample, the crystal water of the B crystal sample is too long to dry at a temperature above 60 ° C. There is a possibility that the crystal water will be further removed. The experimental results show that under the condition of vacuum drying at 80 ° C, the moisture content of the obtained sample may be less than 2.0%.

Further, the crystallized carvedilol sulfate C crystal form (Fig. 5) is crystallized under low-moisture methanol crystallization conditions, and the obtained sample is dried to a constant weight under vacuum drying at 40 to 80 °C. The water content was found to be between 2.0 and 2.8%. In the DSC spectrum (Fig. 6), it was shown that the carved form of carvedilol sulfate C had a strong bonding force of crystal water. The moisture calculation results indicate that the C crystal form product should be a hemihydrate. The crystallized product is dried at a temperature of 20 to 80 ° C for a suitable period of time, and dried until the water loss slowly approaches a constant weight, so that a C crystal form sample having a water content of between 2.0 and 3.0% can be stably obtained.

As an alternative crystallization solvent, the inventors used acetonitrile aqueous solution as a crystallization solvent to obtain crystallized product of carvedilol sulfate D crystal form (Fig. 7), and the sample was obtained under vacuum drying at 40 to 80 ° C. The sample was dried for 3 hours, and the DSC pattern (Fig. 8) showed the presence of the crystallized water of Carvedilol D crystal form. The crystallized product is dried at a temperature of 20 to 80 ° C for a suitable period of time, and the adsorbed water is removed to obtain a D crystal sample having a water content of 1.0% or less.

The form of the form of carvedilol sulfate which can be used as a raw material in the method of the present invention is not particularly limited, and may be a crystal of any crystal form or an amorphous solid.

The method of the present invention is characterized in that a lower organic solvent is used, preferably a polar organic solvent such as an alcohol, a nitrile or a ketone which has a carbon number of less than 3 and which can be volatilized and can be used as a crystallization solvent, or a mixture thereof An aqueous solution thereof; more preferably ethanol or methanol or a mixture thereof, or a mixture thereof with water as a recrystallization solvent for carvedilol sulfate crystals. The crystallization may be carried out using pure water or a pure organic solvent, a mixed solvent of an alcohol and another polar organic solvent, or an aqueous solution of a polar organic solvent. The ratio of the polar organic solvent to water is not particularly limited and may be arbitrary, but such a ratio may often affect the type and purity of the crystal form.

The present invention provides a process for preparing Carvedilol Form A crystals. The method includes the following steps:

(1) heating or dissolving any crystalline or amorphous calveridol sulfate in an appropriate amount of a polar organic solvent or an aqueous solution thereof, and cooling or crystallization, the polar organic solvent is selected from one or more of the following solvents; : ethanol, isopropanol or acetone;

(2) Filtration, washing; drying under vacuum at 40 to 80 °C.

The present invention also provides a method of preparing Carvedilol Form B sulfate. The method includes the following steps:

(1) heating any crystal form or amorphous calveridol sulfate in an aqueous methanol solution, and cooling and crystallization;

(2) Filtration, washing; drying under vacuum at 20 to 60 °C.

The present invention also provides a process for preparing Carvedilol Form C crystals. The method includes the following steps:

(1) calcining any crystalline or amorphous form of carvedilol sulfate in methanol, and cooling and devitrifying;

(2) Filtration, washing; drying under vacuum at 20 to 80 °C.

The process for preparing Form B of the present invention is characterized by using an aqueous methanol solution as a crystallization solvent. For the crystallization process itself, the ratio of the methanol solvent to the water is not particularly limited and may be arbitrary, but the research results also show that when the methanol ratio is less than 40%, it is possible to obtain an impure mixed crystal form. When the proportion of methanol is further lowered and the proportion of water tends to 100, it actually means pure water as a solvent, and the crystal obtained at this time is type A crystal. Therefore, the ratio of alcohol to water is generally limited to 40:60 to 90:10, and the crystal form of carvedilol sulfate B can be obtained. If the proportion of the methanol solvent is further increased by more than 10%, an impure mixed crystal form may be obtained. When the methanol content tends to be 100% and contains water for crystallization, the carvedilol C crystal form containing the semi-molecule of crystal water can be obtained. Generally, the moisture content can be adjusted from 2% to 0.2%.

The present invention also provides a method of preparing Carvedilol Form D sulfate. The method includes the following steps:

(1) heating any crystal form or amorphous calveridol sulfate in an aqueous solution of acetonitrile, and cooling and devitrifying;

(2) Filtration, washing; drying under vacuum at 20 to 80 °C.

The process for preparing Form D of the present invention is characterized by using an aqueous acetonitrile solution as a crystallization solvent. For the crystallization process itself, the ratio of the acetonitrile solvent to water is not particularly limited and may be arbitrary, but the results of the study indicate that when the acetonitrile ratio is too low, an impure mixed crystal form is obtained, and when the proportion of acetonitrile is too high, At the time, the solubility of the crystallization solvent is too low, and a satisfactory yield cannot be obtained. Generally, the ratio of acetonitrile to water can be limited to 30:70 to 90:10, more preferably 40:60 to 80:20, and the above procedure can be used to obtain Carvedilol D crystal form.

The method of recrystallization is not particularly limited and is carried out in accordance with a usual recrystallization operation method. For example, calveridol sulfate is first dissolved in an organic solvent or a mixed solvent of an organic solvent and water, and then cooled and crystallized, filtered, and the obtained crystal is dried under vacuum at 40 to 80 ° C to be removed. The effect of recrystallization solvent.

The carvedilol sulfate crystals prepared according to the process of the present invention contain no or only a low level of solvent residue. Ethanol, methanol, isopropanol and acetone are the third type of low-toxic solvents among the residual solvents of pharmaceutical products prescribed by the National Pharmacopoeia. Therefore, the crystal of the present invention can be preferably used as a pharmaceutical active ingredient. The crystal of the present invention exhibits good properties both in stability and solubility.

The above and other objects and features of the present invention will become apparent from the accompanying drawings.

The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical solutions of the invention and not to limit the nature of the invention.

Test instrument used in the experiment

X-ray diffraction spectrum

Instrument model: D/Max-RA Japan Rigaku X-ray powder diffractometer

Ray: Monochrome Cu-Kα ray (λ=1.5418 )

Scanning method: θ/2θ, scanning range: 3 to 40°

Voltage: 30KV current: 50mA

Comparative Example: Synthesis of carvedilol sulfate (synthesized according to patent WO2005051325):

38 ml of acetone was added to a 250 ml three-necked flask, and 10.25 g of carvedilol and 6 ml of water were added and dissolved by heating. To the reaction system, 25.2 ml of a 1 N sulfuric acid solution was added, and the temperature of the reaction mixture was maintained at 25. °C, solid precipitation was stirred for 20 hours, filtered, and the filter cake was washed with 20.5 ml of a mixture of acetone and water, and then the solid was added to 44 ml of a mixed solution of acetone and water (10:1) at 20 to 35 ° C. The slurry was filtered for 30 hours, and the cake was filtered and dried under vacuum to dryness to give a white solid, 4.95 g. Yield: 43.1%, moisture: 2.83%. The X-ray diffraction spectrum characteristic absorption and DSC spectra of the solid sample are shown in Figures 11 and 12. It is judged to be mixed crystal.

Example 1

25 g (0.062 mol) of carvedilol (synthesized according to US Pat. No. 4,503,067 (1983)) was dissolved in 250 ml of ethanol, dissolved by heating, and sulfuric acid (0.031 mol, 3.04 g, 1.68 ml of 98% concentrated sulfuric acid) was diluted. 30ml of water. Slowly dropwise added to the carvedilol ethanol solution, a white solid precipitated and stirring was continued overnight. The next day, suction filtration was carried out, and dried under reduced pressure at 60 ° C for 3 hours to obtain 25.8 g of a white solid of carvedilol sulfate and a water content of 2.29%. The molar yield was 92.1%.

2.0 g (2.2 mmol) of carvedilol sulfate obtained in the previous step was added to 65 ml of 95% ethanol solution, heated to reflux until clarification, kept for 30 minutes, stirred and cooled to room temperature to crystallize, and filtered, and the obtained crystal was at 60 ° C. It was dried under vacuum for 3 hours to obtain 1.86 g of crystals, a quality yield of 93%, and a water content of 2.63%. The X-ray diffraction spectrum of the crystal sample is shown in Fig. 1 and is type A crystal. The DSC spectrum (see Fig. 2) indicates that the type A crystal has a desorption endothermic peak at 107.2 °C, and the peak value is 113.4 ° C, starting at 147.4 ° C. A melting endotherm peak appeared with a peak of 149.4 °C.

Example 2

2.0 g (2.2 mmol) of carvedilol sulfate obtained in Example 1 was added to 250 ml of water, heated to reflux until clarification, slowly cooled to room temperature, and filtered, and the obtained crystal was vacuum dried at 60 ° C for 3 hours to obtain The crystal was 1.87 g, the water content was 2.73%, and the mass yield was 93.5%. The X-ray diffraction spectrum of the crystal sample was characteristically absorbed as the type A crystal.

Example 3

2.0 g (2.2 mmol) of carvedilol sulfate obtained in Example 1 was added to 25 ml of a 50% aqueous acetone solution, and heated to reflux for clarification, kept for 30 minutes, slowly cooled to room temperature for crystallization, and filtered, and the obtained crystal was Drying at 60 ° C in vacuo gave crystals 1.72 g, mass yield 85.9%, water: 2.59%. The X-ray diffraction spectrum characteristic of the crystal sample is the same as that of the Form A crystal.

Example 4

10.0 g (11.0 mmol) of carvedilol sulfate obtained in Example 1 was added to 30 ml of an aqueous 50% isopropanol solution, heated to reflux for clarification, kept for 30 minutes, slowly cooled to room temperature, and filtered. The crystals were dried under vacuum at 60 ° C to give crystals of 9.5 g, mass yield 95%, and water: 2.42%. The X-ray diffraction spectrum characteristic of the crystal sample is the same as that of the Form A crystal.

Example 5

10.0 g (11.0 mmol) of carvedilol sulfate obtained in Example 1 was added to 50 ml of an aqueous 50% ethanol solution, and the mixture was heated to reflux for clarification, kept for 30 minutes, cooled, and stirred under magnetic stirring at room temperature, and filtered. The crystals were dried under vacuum at 60 ° C to give crystals of 9.5 g, mass yield 95%, and water: 2.18%. The X-ray diffraction spectrum of the crystalline sample is characteristically absorbed by the same type A crystal.

Example 6

2.0 g (2.2 mmol) of carvedilol sulfate obtained in Example 1 was added to 80 ml of a 50% aqueous methanol solution, and heated to reflux for clarification, kept for 30 minutes, stirred and cooled to room temperature for crystallization, and filtered, and the obtained crystal was 40. Dry at °C to constant weight to obtain crystals of 1.8 g, mass yield of 90.0%, and water: 2.56%. The X-ray diffraction spectrum of the crystal sample is the same as that of Fig. 3, which is type B crystal. The DSC spectrum (see Fig. 4) indicates that the type B crystal has a flat desorption endothermic peak at 60 ° C, and the peak value is about 87 ° C, indicating that there is The weakly bonded crystallization water or adsorbed water is present; a sharp melting endotherm peak begins at 147.8 ° C with a peak of 150.2 ° C.

Example 7

2.0 g (2.2 mmol) of carvedilol sulfate obtained in Example 1 was added to 160 ml of methanol, heated to reflux until clarification, kept for 30 minutes, slowly cooled to room temperature, crystallized, filtered, and the obtained crystal was vacuumed at 60 ° C. Drying to constant weight gives crystals of 1.54 g, quality yield of 76.9%, water 2.24%; X-ray diffraction spectrum of the crystal sample is shown in Figure 5, which is C-type crystal, and DSC pattern (see Figure 6) shows The C-type crystal began to have a flat dehydration endothermic peak at 103 ° C, and the peak value was about 112.1 ° C, indicating the presence of crystal water having a strong bonding force; the C-type crystal showed no melting endothermic peak before 270 ° C, and gradually began to decompose after 270 ° C.

Example 8

10.0 g (11.0 mmol) of carvedilol sulfate obtained in Example 1 was added to 50 ml of an aqueous 50% acetonitrile solution, and heated to reflux for clarification, kept for 30 minutes, cooled to room temperature, allowed to stand for crystallization, and filtered. The obtained crystal was dried under vacuum at 60 ° C to obtain 7.9 g of crystals, a mass yield of 79.0%, and a water content: 1.73%. The X-ray diffraction spectrum of the crystal sample is shown in Fig. 7, which is a D-type crystal. The DSC spectrum (see Figure 8) shows that the D-type crystal has no desorption endothermic peak before and after 100 °C, and a sharp melting endothermic peak starts at 146.9 °C with a peak of 149.3 °C.

Example 9

2.0 g (2.2 mmol) of carvedilol sulfate obtained in Example 1 was added to 80 ml of isopropanol, heated to reflux for clarification, kept for 30 minutes, cooled to room temperature, stirred and crystallized, and filtered to obtain crystals obtained. Drying at 60 ° C for 3 hours under vacuum gave 1.73 g of crystals, 2.55% of water, and a quality yield of 86.5%. The X-ray diffraction spectrum of the crystal sample showed no characteristic absorption peak (Fig. 9), and it was judged to be amorphous crystal. The DSC spectrum (see Figure 10) indicates that the amorphous crystal begins to show a sharp melting endotherm at 179.5 °C with a peak at 182.5 °C.

Comparative Example 1:

Carvedilol base (20080903) was prepared according to the method disclosed in the patent US Pat. No. 4,503,067 (1983); the hydrochloride salt of carvedilol (batch number 20080824) was prepared according to the method disclosed in the patent WO0200216A1; the card was prepared according to the method disclosed in the patent CN1678305A. Dihydrogen phosphate of lotilol (batch No. 20080904); Carvedilol sulfate (batch 20080904) was prepared according to the method of Example 1, and the sulfuric acid was reacted with molars such as carvedilol according to the method of Example 1. Carvedilol hydrogen sulfate (batch 20080903); the above samples were tested for stability and solubility, and the results are shown in the table below.

The stability test results show that carvedilol sulfate exhibits good chemical stability under high temperature, high humidity or light conditions, and other salt related substances have different degrees of increase. Dilohydrosulphate has the worst stability.

The solubility test results showed that the solubility of carvedilol sulfate in the simulated gastric acid was comparable to that of dihydrogen phosphate, which was superior to carvedilol and hydrochloride.

Figure 1 is an X-ray powder diffraction pattern of carvedilol sulfate Form A crystal (20081121).

Figure 2 is a DSC chart of carvedilol sulfate type A crystal (20081121).

Figure 3 is an X-ray powder diffraction pattern of carvedilol sulfate type B crystal (20081125).

Figure 4 is a DSC chart of carvedilol sulfate type B crystal (20081125).

Figure 5 is an X-ray powder diffraction pattern of carvedilol sulfate Form C crystal (20081129).

Figure 6 is a DSC chart of Carvedilol Form C crystal (20081129).

Figure 7 is an X-ray powder diffraction pattern of carvedilol sulfate D-type crystal (20090503).

Figure 8 is a DSC chart of Carvedilol Form D crystal (20090503).

Figure 9 is an X-ray powder diffraction pattern of carvedilol sulfate amorphous form (20090421).

Figure 10 is a DSC chart of the amorphous crystal of carvedilol sulfate (20090421).

Figure 11 is an X-ray powder diffraction pattern of carvedilol sulfate (20090422) (synthesized according to patent WO2005051325).

Figure 12 is a DSC map of carvedilol sulfate (20090422) (synthesized according to patent WO2005051325).

Claims (19)

A type A crystal of carvedilol sulfate characterized by having a powder X-ray diffraction pattern as shown in Fig. 1, using Cu-Ka radiation, X-ray powder diffraction expressed by 2θ angle and interplanar spacing d value The characteristic peak at 13.90 (6.36) is the strongest. A method for preparing Carvedilin Form A crystal according to Item 1 of the patent application, comprising the steps of: 1) heating and dissolving any crystalline or amorphous calveridol sulfate in an appropriate amount; In an aqueous solution of a polar organic solvent, cooling and crystallization are carried out, and the polar organic solvent is selected from one or more of the following solvents: ethanol, isopropanol or acetone; 2) filtered, washed; and dried under vacuum at 20 to 80 °C. A method for preparing Carvedilol Form A crystal as described in claim 2, wherein the heat-dissolving temperature means a temperature at which the solution is refluxed. A method of preparing Carvedilol Form A crystal as described in claim 2, wherein the cooling means cooling to room temperature naturally. A type B crystal of carvedilol sulfate characterized by having a powder X-ray diffraction pattern as shown in FIG. 3, using X-ray powder diffraction represented by 2θ angle and interplanar spacing d value using Cu-Ka radiation. The characteristic peak at 18.00 (4.92) is the strongest. The invention relates to a preparation method of carvedilol sulfate type B according to item 5 of claim 5, which comprises the following steps: 1) heating and dissolving any crystalline or amorphous calveridol sulfate in an appropriate amount. In the aqueous methanol solution, it is placed under cooling and crystallization; 2) filtered, washed; and dried under vacuum at 20 to 60 °C. A method for preparing Carvedilol Form B crystal according to claim 6, wherein the heat-dissolving temperature refers to a temperature at which the solution is refluxed. A method of preparing Carvedilol Form B crystallization as described in claim 6 wherein the cooling means cooling to room temperature. A type C crystal of carvedilol sulfate characterized by having a powder X-ray diffraction pattern as shown in FIG. 5, using X-ray powder diffraction represented by 2θ angle and interplanar spacing d value using Cu-Ka radiation. The characteristic peaks at 6.52 (13.54) and 7.38 (11.97) are the strongest. A method for preparing Carvedilin Form C crystal according to Item 9 of the patent application, comprising the steps of: 1) heating and dissolving an arbitrary amount or amorphous calveridol sulfate in an appropriate amount; In methanol, place for cooling and crystallization; 2) filter, wash; vacuum dry at 20 to 80 °C. A method for preparing Carvedilol Form C crystal according to claim 10, wherein the heat-dissolving temperature means a temperature at which methanol is refluxed. A method of preparing Carvedilol Form C crystal according to claim 10, wherein the cooling means cooling to room temperature naturally. A type D crystal of carvedilol sulfate characterized by having a powder X-ray diffraction pattern as shown in Fig. 7, using Cu-Ka radiation, X-ray powder diffraction represented by 2θ angle and interplanar spacing d value The characteristic peak at 6.40 (13.80) is the strongest. A method for preparing Carvedilin D type crystal according to claim 13 of the patent application, characterized in that the method comprises the following steps: 1) heating and dissolving any crystal form or amorphous form of carvedilol sulfate in an appropriate amount In an aqueous solution of acetonitrile, cooling and crystallization are placed; 2) filtration, washing; drying at 20 to 80 ° C under vacuum. A method for preparing Carvedilol Form D sulfate as described in claim 14 wherein the heat-dissolving temperature means a temperature at which the solution is refluxed. A method of preparing Carvedilol Form D sulfate as described in claim 14 wherein the cooling means cooling to room temperature. A carved form of Carvedilol A type crystal according to the first aspect of the patent application, a carved form of Carbide sulfate type B according to claim 5, and a sulfated form of the sulfuric acid mentioned in claim 9 The use of the C-type crystal, the type 3 crystal of carvedilol sulfate according to claim 13 of the patent application, is for the preparation of a medicament for treating hypertension, congestive heart failure and angina pectoris. A pharmaceutical composition comprising one or more of the type A crystal of carvedilol sulfate according to item 1 of the patent application scope, the type B crystal of carvedilol sulfate according to item 5 of the patent application scope, and the patent application scope The carvedilol type C crystal of the above-mentioned item 9 and the carvedilol sulfate type D crystal according to claim 13 and a pharmaceutically acceptable salt. A use of the pharmaceutical composition according to claim 18, which is for use in the preparation of a medicament for the treatment of hypertension, congestive heart failure and angina pectoris.