WO2012013118A1

WO2012013118A1 - Carvedilol sulfate crystals, preparation method thereof, and pharmaceutical use thereof

Info

Publication number: WO2012013118A1
Application number: PCT/CN2011/077150
Authority: WO
Inventors: 孙飘扬; 武乖利; 吴玉霞; 陈永江
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2010-07-26
Filing date: 2011-07-14
Publication date: 2012-02-02
Also published as: CN102336701B; HK1164883A1; CN102336701A

Abstract

Disclosed are a carvedilol sulfate form A, form B, form C or form D crystalline medicament for the treatment of hypertension, congestive heart failure, and angina pectoris, a preparation method thereof, and a pharmaceutical application thereof. The preparation method comprises: crystallizing carvedilol sulfate solid in random crystal forms or an amorphous form with common polar organic solvents and aqueous solutions thereof to obtain form A, form B, form C or form D crystals. The disclosed carvedilol sulfate crystals have strong crystal morphology, and the crystallization solvent employed is of low toxicity and low residue.

Description

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

The present invention relates to Carvedilol sulfate type A, B, C and D crystals, a preparation method thereof and use thereof for preparing medicines for treating hypertension, congestive heart failure and angina pectoris

Background technique

Carvedilol Chemical name (±)-1-(9Η-oxazolyl-4-oxy:)-3-[[2-(2-methoxyphenoxy:)ethyl] Amino]-2-propanol, developed by the German company Boehringer Mannhei, was first approved for listing in the US 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 work synergistically. Patients with heart failure benefit from 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 lug /mL), about 23 ug/mL at pH=7, about 100 ug/mL at pH=5. Therefore, people have synthesized the salt of carvedilol in order to improve its water solubility and increase chemical stability for 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 condition of simulating gastric juice, so the composition for the drug is not advantageous. 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 is reported in the international patent application WO2005051325, but there is no research related to 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. Summary of the invention

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, but does not involve the study of the relevant crystal form and its crystal form preparation method, the inventors have experimentally verified that the salt is formed according to the reported method, and it is impossible to obtain 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. An aqueous solution of water or alcohol is an ideal refining solvent. Whether 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 are separately X-ray diffraction and DSC detection were performed. The experimental results show that carvedilol sulfate crystallizes in an aqueous solution of a conventionally used polar organic solvent, mainly obtaining a crystal form containing semi-molecule crystal water, that is, type A crystal; crystallizing in a conventionally used aqueous methanol solution, resulting in weak B crystal form of bonding force crystal water; crystallized in a conventional low-moisture methanol to obtain a crystal form of carvedilol C in a semi-molecule of crystal water; crystallized in a conventionally used aqueous solution of acetonitrile, 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 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° (Fig. D o

In the case of methanol/water as the crystallization solvent, another crystal form (X-ray) pattern is shown. We define it as the B crystal form. The characteristic peaks in the X-ray powder diffraction pattern are 2 Θ = 6.8, 13.2, 13.6, 18.0, 19.9, 24.0, 25. Κ 30·0 ± 0·2. At (Figure 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 2 Θ = 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 ^ο (Fig. 5).

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

It was found that under the same solvent conditions, the stirring mode did not produce a shadow orientation for the selectivity of the twin crystal. Under the conditions of mechanical stirring, magnetic stirring or static crystallization, the solvent system of ethanol/water was taken as an example. Stable A-type crystals.

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), the sample obtained by crystallization is dried to constant weight under vacuum drying at 60 ° C, and the water is measured. 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: moisture%=[1^

18): ^ 100% (where M is the molecular weight of carvedilol), we can calculate that our product should be a hemihydrate: two molecules carvedilol + - molecular sulfuric acid + - molecular water. Since moisture has an effect on the crystal form, we control The crystallized product is dried at a temperature of 20 to 80 ° C for a suitable period of time, that is, drying until the water loss is slow to a constant weight, and a sample of the A crystal form having a water content of between 2.0 and 3.0% can be stably obtained.

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

Further, carvedilol sulfate is crystallized under the condition of crystallization of methanol with low water content.

Form C (Fig. 5), dry the sample to a constant weight under vacuum drying at 40 to 80 ° C, and measure the moisture, which is found between 2.0 and 2.8%, in the DSC spectrum (Figure 6). In the case, it is shown that the crystal form of carvedilol sulfate C has a strong bonding force of crystal water. The moisture calculation results indicate that the C crystal form product should be a hemihydrate. The crystallization product is controlled to dry at a temperature of 20 to 80 ° C for a suitable period of time, and dried until the dehydration slowly approaches a constant weight, so that a C crystal 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 spectrum (Fig. 8) showed the presence of the crystallized water of carvedilol sulfate D crystal form. Controlling the crystallized product to be dried at a temperature of 20 to 80 ° C for a suitable period of time, and removing the adsorbed water, thereby obtaining a D crystal form having a water content of 1.0% or less. Carvedilol can be used as a raw material in the method of the present invention. The type of the form 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; 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 stirring or placing a cooling and crystallization, wherein the polar organic solvent is selected from the following solvents; One or more: ethanol, isopropanol or acetone;

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

The present invention also provides a process for 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 devitrifying;

(2) Filtration, washing; drying under vacuum at 20~60 °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 calveridol sulfate in methanol, leaving it to be cooled and devitrified;

(2) Filtration, washing; drying under vacuum at 20~80 °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 results of the study 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 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 controlled from 2% to 0.2%.

The present invention also provides a process for 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 placing it for cooling and crystallization;

(2) Filtration, washing; drying under vacuum at 20~80 °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 ratio of acetonitrile is excessive When it is high, the solubility of the crystallization solvent is too low, and a satisfactory yield is not obtained. In general, 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 obtain a vacuum. The effect of removing the recrystallization solvent.

The carvedilol sulfate crystals prepared according to the process of the present invention contain no or only a relatively low level of solvent residue. Ethanol, methanol, isopropanol and acetone are the third class of low toxic solvents in the residual solvents of medical 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. DRAWINGS

The above and other objects and features of the present invention will become apparent from the accompanying drawings in which <RTIgt; <RTIgt; </RTI> Figure 1 is an X-ray powder diffraction pattern of Carvedilol Form A crystal (20081121). 2 is the DSC spectrum 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 spectrum of carvedilol sulfate type B crystal (20081125).

Figure 5 is an X-ray powder diffraction pattern of carvedilol sulfate type C crystal (20081129). Figure 6 is a DSC spectrum of carvedilol sulfate type C crystal (20081129).

Figure 7 is an X-ray powder diffraction pattern of carvedilol sulfate D-type crystal (20090503). Figure 8 is a DSC spectrum of carvedilol sulfate D-type crystal (20090503).

Figure 9 is an X-ray powder diffraction pattern of carvedilol sulfate amorphous crystal (20090421). Figure 10 is a DSC spectrum of carvedilol sulfate amorphous crystal (20090421).

Figure 11 is an X-ray powder diffraction pattern of carvedilol sulfate (20090422) Figure 12 is a DSC spectrum of carvedilol sulfate (20090422) (synthesized according to patent WO2005051325)

The invention is explained in more detail below with reference to the embodiments, which are merely intended to illustrate the technical solutions of the invention and not to limit the essence 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-Κα ray (λ=1·5418 Α)

Scanning method: Θ/2Θ, scanning range: 3-40θ

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 thereto, 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. Then, the solid was added to 44 ml of a mixed solution of acetone and water (10:1) at 20-35 °. C was paddle for 30 hours, the paddle was filtered, and the filter cake was dried to constant weight under vacuum 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 Fig. 11 and Fig. 12. It is judged to be mixed crystal. Example 1

Carvedilol (synthesized according to patent US4503067 (1983)) 25g (0.062mol) was dissolved in 250ml of ethanol, heated to dissolve, sulfuric acid (0.031mol, 3.04g, 1.68ml)

98% concentrated sulfuric acid) was diluted in 30 ml of water. Slowly drip into the ethanolic solution of carvedilol, 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 for clarification, kept for 30 minutes, stirred and cooled to room temperature for crystallization, and filtered, and the obtained crystal was 60. Drying under vacuum for 3 hours gave a crystal of 1.86 g, a mass yield of 93%, and a water content of 2.63%. The X-ray diffraction spectrum of the crystal sample is shown in Fig. 1. It is a 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. A melting endotherm peak began to appear at 147.4 ° C 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. The crystal was obtained in 1.87 g, the water content was 2.73%, and the mass yield was 93.5%. The X-ray diffraction spectrum characteristic of the crystal sample was the same as that of the type A crystal. Example 3

Adding 2.0 g (2.2 mmol) of carvedilol sulfate obtained in Example 1 to 25 ml

In a 50% aqueous acetone solution, the mixture was heated to reflux to be clarified, kept for 30 minutes, slowly cooled to room temperature to crystallize, and filtered, and the obtained crystal was dried under vacuum at 60 ° C to obtain crystals of 1.72 g, mass yield: 85.9%, water: 2.59 %. The X-ray diffraction spectrum characteristic absorption of the crystal sample is the same as that of the A type 曰曰₀ .

The carvedilol sulfate lO.Og (ll.Ommol) 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 obtained crystal was dried under vacuum at 60 ° C to obtain 9.5 g of crystals, mass yield 95%, and water: 2.42%. The X-ray diffraction spectrum of the crystalline sample is characterized by absorption of the same type A crystal. Example 5

The carvedilol sulfate lO.Og (ll.Ommol) obtained in Example 1 was added to 50 ml of an aqueous 50% ethanol solution, heated to reflux for clarification, kept for 30 minutes, cooled, and stirred under magnetic stirring at room temperature, filtered. The obtained crystal was dried under vacuum at 60 ° C to obtain 9.5 g of crystals. Mass yield 95%, moisture: 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 50% aqueous methanol solution, heated to reflux for clarification, kept for 30 minutes, stirred and cooled to room temperature for crystallization, and filtered, and the obtained crystal was Drying to constant weight at 40 ° C under vacuum gave 1.8 g of crystals, mass yield 90.0%, 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 a peak value of about 87 ° C. It indicates that there is a weak bonding force of crystal water or adsorbed water; a sharp melting endothermic peak starts at 147.8 °C, and the peak value is 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 for clarification, kept for 30 minutes, slowly cooled to room temperature for crystallization, and filtered, and the obtained crystal was at 60 °. C vacuum drying to constant weight, to obtain crystals of 1.54g, mass yield of 76.9%, water 2.24%; X-ray diffraction spectrum of the crystal sample is shown in Figure 5, is C-type crystal, DSC map (see Figure 6) It indicates that the C-type crystal has a flat dehydration endothermic peak at 103 °C, and the peak value is about 112.1 °C, indicating that there is a strong bonding force of crystal water; C-type crystal has no melting endothermic peak before 270 °C. After 270 ° C began to gradually decompose. Example 8

The carvedilol sulfate lO.Og (ll.Ommol) obtained in Example 1 was added to 50 ml of an aqueous 50% acetonitrile solution, 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, mass yield: 79.0%, and water: 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 value of 149.3 °C. Example 9

Add 2.0 g (2.2 mmol) of carvedilol sulfate prepared in Example 1 to 80 ml of isopropyl In the alcohol, the mixture was heated to reflux to be clarified, kept for 30 minutes, cooled to room temperature, stirred and crystallized, filtered, and the obtained crystal was vacuum dried at 60 ° C for 3 hours to obtain crystals 1.73 g, water 2.55%, mass yield 86.5%. . The X-ray diffraction spectrum of the crystal sample showed no characteristic absorption peak (Fig. 9), and 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 card was reacted with carvedilol in the same manner as in Example 1 to obtain a card. Venodisulfate (batch number 20080903); The above samples were tested for stability and solubility, and the results are shown in the table below. Table 1. Stability of carvedilol and several salts (HPLC related substances:)

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. Carvedilol hydrogen sulfate has the worst stability with varying degrees of increase. Table 2. Solubility of carvedilol and several salts

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.

Claims

Claims:

1. 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- represented by a 2 Θ angle and a d-value of the interplanar spacing The ray powder diffraction has the strongest characteristic peak at 13.90 (6.36).

2. A method of preparing Carvedilol Form A crystal according to claim 1, comprising the steps of:

1) calcining any crystalline or amorphous calveridol sulfate in an appropriate amount of an aqueous solution of a polar organic solvent, and cooling and devitrifying, the polar organic solvent being selected from one or more of the following solvents; Species: ethanol, isopropanol or acetone;

2) Filter, wash; vacuum dry at 20~80 °C.

A method of preparing Carvedilol Form A crystal according to claim 2, wherein said heat-dissolving temperature means a temperature at which the solution is refluxed.

A method of preparing Carvedilol Form A crystal according to claim 2, wherein said cooling means cooling to room temperature naturally.

5. A type B crystal of carvedilol sulfate characterized by having a powder X-ray diffraction pattern as shown in Fig. 3, using Cu-Ka radiation, X- represented by a 2 Θ angle and a crystal plane spacing d value. The characteristic peak of the ray powder diffraction at 18.00 (4.92) is the strongest.

6. A method of preparing a carvedilol sulfate type B according to claim 5, comprising the steps of:

1) heating any crystal form or amorphous calveridol sulfate in an appropriate amount of methanol water solution, and cooling and crystallization;

2) Filter, wash; vacuum dry at 20~60 °C.

7. A method of preparing carvedilol sulfate type B crystal according to claim 6, wherein said heated dissolution temperature means a temperature at which the solution is refluxed.

A method of preparing Carvedilol Form B crystal according to claim 6, wherein said cooling means cooling to room temperature naturally.

9. A type C crystal of carvedilol sulfate characterized by having a powder X-ray diffraction pattern as shown in Fig. 5, using Cu-Ka radiation, X-indicated by a value of 2 Θ angle and interplanar spacing d The ray powder diffraction has the strongest characteristic peak at 6.52 ( 13.54) and 7.38 ( 11.97).

10. A method of preparing Carvedilol Form C crystal according to claim 9, comprising the steps of:

1) heating or dissolving any crystal form or amorphous calveridol sulfate in an appropriate amount of methanol, and placing it for cooling and crystallization;

2) Filter, wash; vacuum dry at 20~80 °C.

A method of preparing Carvedilol Form C crystal according to claim 10, wherein said heating and dissolving temperature means a temperature at which methanol is refluxed.

A method of preparing Carvedilol Form C crystal according to claim 10, wherein said cooling means natural cooling to room temperature.

13. 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-indicated by a value of 2 Θ angle and interplanar spacing d The characteristic peak of the ray powder diffraction at 6.40 (13.80) is the strongest.

14. A method of preparing Carvedilol Form D crystals according to claim 13 comprising the steps of:

1) heating or dissolving any crystal form or amorphous calveridol sulfate in an appropriate amount of acetonitrile aqueous solution, and placing it for cooling and crystallization;

2) Filter, wash; vacuum dry at 20~80 °C.

15. A method of preparing Carvedilol Form D sulfate according to claim 14, wherein

A method of producing Carvedilol Form D sulfate according to claim 14, wherein said cooling means natural cooling to room temperature.

The carvedilol sulfate type A crystal according to claim 1, the carvedilol sulfate type B crystal according to claim 5, the carvedilol sulfate type C crystal according to claim 9, The use of carvedilol sulfate D-type crystal according to claim 13 for the preparation of a medicament for the treatment of hypertension, congestive heart failure and angina pectoris.

18. A pharmaceutical composition comprising one or more of carvedilol sulfate Form A crystals according to claim 1 and a carvedilol sulfate Form B crystal according to claim 5, as claimed The carvedilol sulfate type C crystal according to claim 9, the carvedilol sulfate type D crystal according to claim 13, and a pharmaceutically acceptable salt.

19. Use of a pharmaceutical composition according to claim 18 for the manufacture of a medicament for the treatment of hypertension, congestive heart failure and angina pectoris.