KR101567438B1 - Method for Preparing of Crystalline Form I of Clopidogrel Bisulphate - Google Patents

Abstract

The present invention relates to a process for preparing clopidogrel bisulphate (CLP) crystal form I. The method of the present invention controls the polymorphic transition (phase transition) of crystal form I by using an ionic liquid as an anti-solvent, rather than a method of preparing clopidogrel sulfate (CLP) crystal form I using a general organic solvent . As a result, the stability of the clopidogrel sulfate (CLP) crystal form I was secured in the solution, and the production yield was also improved. On the other hand, a pharmaceutical composition for improving, treating or preventing platelet-related vascular diseases using the clopidogrel sulfate (CLP) crystal form I prepared by the method of the present invention as an active ingredient can be provided.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for preparing clopidogrel sulfate crystal form I,

This application is the result of the research project of the university-led cooperative university (LINC) project supported by the Ministry of Education, Science and Technology.

The present invention relates to a process for preparing clopidogrel bisulphate (CLP) crystal form I.

Most active pharmaceutical ingredients that are currently being developed or marketed are composed of the same molecules but have more than 80% of polymorphs that vary in crystal structure with different molecular arrangements and conformation . These polymorphs have different physicochemical properties such as solubility, dissolution rate, density, and crystal shape. Therefore, these materials can have a great influence on bioavailability and stability, which are characteristics to be considered in formulation.

Polymorphs have different stability at given conditions. Thus, metastable polymorphs are spontaneously transformed into stable polymorphs. FIG. 1A is a graph showing changes in nucleation energy between polymorphs. FIG. In Fig. 1A, solute molecules are first precipitated as polymorph B, which is a metastable structure during the crystallization process. This is because polymorph B has a lower critical free energy (G ^* _B ), which leads to easier nucleation. As shown in FIG. 1B, the two polymorphs having different stability have different solubilities in the solution, which causes polymorphism. That is, the solubility of the metastable polymorph is higher than that of the stable polymorph, and the stable polymorph is in a supersaturated condition even though the metastable polymorph is in an equilibrium state. Therefore, the crystallization of the metastable polymorph is stopped, while the stable polymorph is under nucleation and crystal growth under supersaturation conditions, and the supersaturated concentration is compensated by the dissolution of the metastable polymorph. This process continues and finally the crystals of the metastable polymorph are completely dissolved and disappear and the solution is in equilibrium with the crystals of the stable polymorph.

In many cases, it is the phase transition that affects the desired polymorph production in the actual polymorph control process. When a selectively stable polymorph is selected as the final formulation crystal, the metastable polymorph obtained through crystallization in the production process is phase-transformed into a stable polymorph, which takes a long time and often restricts the manufacture of polymorph. For example, in the case of an active drug substance called sulfamerazine, a stable polymorphic form II is preferred as a formulated crystal, but the polymorphic form first precipitated in the crystallization process is form-I. In this case, form-I transitions to form-II, which takes more than 14 days in actual process. To improve this, studies have been made to promote polymorphism using additives and ultrasonics. When the metastable polymorph is selected as the final formulation, the time required for the metastable polymorph to transition from a stable polymorph to the stable polymorph in the production process proceeds too fast, and there are cases where the metastable polymorph do. Typically, clopidogrel bisulphate (CLP) is the case. CLP preferentially forms the metastable polymorph form-I as a formulated crystal. The time required for the phase transition from form-I to form-II, which is a stable polymorphic form, does not exceed 5 minutes. In order to improve this, amorphous form which is more stable than form-I was prepared, and recrystallization method was adopted for phase transformation into form-I. In the salt form preparation step in which CLP free base and sulfate were reacted, form- Of the crystals are precipitated. This process also leads to the process of inducing phase transition to form-I by precipitating metastable polymorphs from form-I in salt form reaction process. Because of the unstable yield and the complexity of the crystallization process, the above-mentioned CLP form-I preparation process needs to be studied to improve it.

As described above, research on polymorph control, which is a characteristic of formulation, is gradually increasing. As a practical method for controlling the desired polymorph, there is a solvent-mediated phase transformation method in which a metastable phase is re-dissolved and a stable phase nucleus is formed, thereby forming a stable phase crystal. It is mainly used.

The key driving force that influences the kinetics of the solvent-mediated phase transfer method is the energy difference between the metastable solid and the stable solid, that is, the solubility difference between the two solids. And the factors affecting the phase transition velocity between these two solids can be classified into thermodynamic and dynamic factors. The thermodynamic factors include the temperature of the solution, the type and composition of the solvent, which affect the solubility difference of the two solids, and the dynamic factors include the stirring speed, the concentration of the suspension, the addition of seed, and the viscosity.

Ionic liquids (IL), which are generally defined as salts composed of separated cations and anions with a melting point below 100 ° C, are a class of complexes that form unique shapes, but have not been studied in depth for a long time. In recent years, IL research has attracted a new interest, which is an interesting substitute for volatile organic compounds (VOCs) due to their nonvolatility and liquid properties at high temperatures, This is because of the social pressures on Ionic liquids are structurally unique and differ from conventional organic solvents in that they have both cationic and anionic components that can be individually and independently adapted to a variety of applications while maintaining their unique properties. A common characteristic of IL is a wide liquid range, which is present as a solution in a wide range of temperatures and in some cases exceeding 400 ° C. It has the characteristics of high bipolarity, negligible vapor pressure, stability of air and water, high ionic conductivity and thermal stability. It can be designed according to the purpose of use and can freely change the solubility, hydrophobicity and polarity, and is called designer solvent .

Clopidogrel bisulphate has antiplatelet activity and is useful for the treatment of platelet related vascular diseases such as angina pectoris, arrhythmia, peripheral arterial occlusion, stroke, cerebral artery sclerosis and myocardial infarction. The chemical name is (+) - 5- [4,5,6,7-tetrahydro- [3,2-c] thienopyridyl] - (2-chlorophenyl) acetate hydrogensulphate ((+ , 6,7-tetrahydro- [3,2-c] thienopyridyl] - (2-chlorophenyl) acetate hydrogensulphate,

Formula 1

The polymorphs of clopidogrel sulfate are now identified in a total of six. Forms I and II of the polymorph are optionally used for formulation. Forms I and II are not only qualitatively distinguishable by Fourier transform infrared spectroscopy (FT-IR) analysis (US Pat. No. 6,504,030), but also form-I and II (Acta. Pharm. 54 (2004) 193-204) has been reported to be capable of qualitative and quantitative determination through a characteristic absorbance band. Form-I has characteristic absorption bands at 841, 1175, and 2987 cm ^-1 , and form-II has characteristic absorption bands at 1029, 1187, and 1497 cm ^-1 , (Acta. Pharm. 54 (2004) 193-204).

It is known that form-I has a monoclinic structure with higher density (I type: 1.505 g / cm 2, II type: 1.462 g / cm 2) and higher solubility than the quadriceps form of form-II (U.S. Patent No. 6,429,210 ).

Form-II is a stable polymorph at room temperature, but its solubility is significantly lower than that of form-I, so we prefer form-I in the domestic and overseas pharmaceutical industry. However, in the case of form-I, the time required for the phase transition to form-II in the solvent is not less than 5 minutes when it is prepared by using a common solvent. Therefore, it is urgent to study how much the form-I is maintained in the present solvent and how much the phase transition speed can be slowed down.

In this study, the stability of form-I in the solvent was obtained by slowly inhibiting the phase transition speed of form-I and form-II through a new solvent environment called ionic liquid, .

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have sought to develop a method capable of designing a crystallization method that is easier and reproducible by controlling the polymorphic transition time of clopidogrel sulphate (CLP) crystal form I through a new solvent environment and improving the production yield. As a result, it has been found that by using an ionic liquid as an anti-solvent, it is possible to control the polymorphic transition (phase transition) phenomenon of the crystalline Form I more than that of the clopidogrel sulphate (CLP) crystalline Form I using a general organic solvent, (CLP) crystal type I can be stably developed by securing the stability of the crystalline form I and improving the production yield, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a method for producing clopidogrel bisulphate (CLP) crystal form I.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a process for preparing clopidogrel bisulphate (CLP) crystal form I comprising the steps of: (a) clopidogrel sulfate (CLP) Dissolving; (b) adding an ionic liquid to the result of (a); And (c) inducing crystallization of the resultant product of (b) to obtain clopidogrel sulfate (CLP) crystal form I.

The present inventors have sought to develop a method capable of designing a crystallization method that is easier and reproducible by controlling the polymorphic transition time of clopidogrel sulphate (CLP) crystal form I through a new solvent environment and improving the production yield. As a result, it has been found that by using an ionic liquid as an anti-solvent, it is possible to control the polymorphic transition (phase transition) phenomenon of the crystalline Form I more than that of the clopidogrel sulphate (CLP) crystalline Form I using a general organic solvent, (CLP) crystal type Ⅰ can be developed in a stable manner by securing the stability of the crystalline form Ⅰ and improving the yield of the product.

Hereinafter, the method of the present invention for producing clopidogrel bisulphate (CLP) crystal form I will be described step by step in detail as follows:

(a) Clopidogrel sulfate (CLP) Crystalline Form II is dissolved in an organic solvent

First, the method of the present invention comprises dissolving Clopidogrel Sulfate (CLP) crystalline Form II in an organic solvent.

The clopidogrel sulfate (CLP) crystal form II used in the present invention can be prepared by various methods known in the art and commercially available.

According to a preferred embodiment of the present invention, the clopidogrel sulfate (CLP) crystalline form II of step (a) is 50-150 (weight / volume)% based on the organic solvent, more preferably 70-120 ), And even more preferably 80-100 (weight / volume)%.

According to another preferred embodiment of the present invention, the organic solvent of step (a) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane, hexane, heptane, cyclohexane, toluene, acetone, methyl acetate, methylene chloride, An organic solvent selected from the group consisting of ether, petroleum ether, benzene, ethylene glycol, propylene glycol and butylene glycol, more preferably an organic solvent selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane and hexane Solvent, more preferably methanol or ethanol, and most preferably ethanol.

According to another preferred embodiment of the present invention, the dissolution of step (a) is carried out at a temperature of from 20 to 25 占 폚, that is, at room temperature.

(b) adding an ionic liquid to the resultant product (a)

The process of the present invention then involves the step of adding an ionic liquid to the result of (a).

According to a preferred embodiment of the present invention, the cation constituting the ionic liquid used in the present invention is at least one selected from the group consisting of ammonium cations, imidazolium cations, oxazolium cations, piperidinium cations, pyrazinium cations, pyrazolium cations, A pyridinium cation, a pyridinium cation, a pyrimidinium cation, a pyrrolidinium cation, a pyrrolinium cation, a pyrrolinium cation, a sulfonium cation, and a triazolium cation, more preferably an imidazolium cation, A sulfonium cation or a pyridinium cation, and most preferably an imidazolium cation.

According to another preferred embodiment of the present invention, the anion constituting the ionic liquid used in the present invention is selected from the group consisting of an ethylsulfate anion, a tetrafluoroborate anion, a tosylate anion and a methanesulfonate anion, Is an ethylsulfate anion or a tetrafluoroborate anion, and most preferably a tetrafluoroborate anion.

According to a more preferred embodiment of the present invention, the ionic liquid used in the present invention is 1-ethyl-3-methylimidazolium ethylsulfate, 1-ethyl-3-methylimidazolium tetrafluoroborate, 1- Ethyl-3-methylimidazolium methosulfonate, 1-ethyl-3-methylimidazolium free plate, 1-ethyl-3-methylimidazolium dicyanamide Butyl-3-methylimidazolium bis (trifluormethylsulfonyl) imide, 1-butyl-3-methylimidazolium dicyanamide, 1-butyl- Butyl-3-methylimidazolium methanesulfonate, 1,3-didecyl-2-methylimidazolium bis (trifluormethylsulfonyl) imide, 1-butyl- 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1- (2-hydroxyethyl) -3-methylimidazolium 3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylpyridinium tetrafluoroborate, 1-butyl-4-methylpyridinium tetrafluoroborate, 1- 3-ethylimidazolium tetrafluoroborate (AEImBF ₄ ), 1-methyl-1-propylpiperidinium bis (trifluoromethylsulfonyl) imide, methyltrioctylammonium bis (trifluoromethylsulfonyl) ) Imide, butyltrimethylammonium bis (trifluoromethylsulfonyl) imide, triethylsulfonium bis (trifluoromethylsulfonyl) imide and diethylmethylsulfonium bis (trifluoromethylsulfonyl) imide Ethyl-3-methylimidazolium tetrafluoroborate, 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1- (2- Lt; / RTI > ethyl) -3-methylimidazolium tetra 3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylpyridinium tetrafluoroborate, 1-butyl-4-methylpyridinium tetrafluoroborate or 1-allyl- 3 is an ethyl borate (AEImBF ₄₎ as imidazolium tetrafluoroborate, and in the most preferably a compound of 1-allyl 3-ethyl represented by the formula (2) imidazolium tetrafluoroborate (AEImBF _4).

(2)

In the process of the present invention, the ionic liquid acts as an antisolvent to precipitate dissolved solutes.

According to another preferred embodiment of the present invention, the organic solvent of step (a) and the ionic liquid of step (b) have a volume ratio of 0.2-3: 1, more preferably 0.7-1.5: , And most preferably a volume ratio of 1: 1.

(c) inducing crystallization of the resultant product of (b) and obtaining clopidogrel sulfate (CLP) crystal form I

Finally, inducing crystallization of the resultant of (b) to obtain clopidogrel sulfate (CLP) crystal form I.

According to a preferred embodiment of the present invention, the crystallization induction of the step (c) is carried out at a crystallization temperature of 25 to 50 캜.

One of the characteristics of the present invention is that the retention time and yield of the obtained clopidogrel sulphate (CLP) crystal form I are improved by using an ionic liquid as an anti-solvent and adopting a crystallization temperature of 25 to 50 캜.

According to another preferred embodiment of the present invention, the phase transition time of the clopidogrel sulfate (CLP) crystal form I to the crystal form II of the step (c) is 2 to 5 hours.

According to another preferred embodiment of the present invention, the yield of clopidogrel sulphate (CLP) crystalline form I of step (c) is 60-95%.

As can be seen from the following examples, in order to prolong the holding time of the clopidogrel sulfate (CLP) crystal form I, the holding time is prolonged at a temperature in the range of the crystallization temperature of 25 to 50 캜, and the clopidogrel sulfate (CLP) crystal form I In order to improve the yield, it was found that the lower the temperature in the range of the crystallization temperature of 25 to 50 캜, the better the yield.

For this reason, the induction of the crystallization in the step (c) is preferably carried out at a crystallization temperature of 25 to 40 ° C, more preferably at a crystallization temperature of 25 to 30 ° C.

In this way, a clopidogrel sulfate (CLP) crystal form I having a prolonged phase transition time to clopidogrel sulfate (CLP) crystal form I type crystal form II, that is, an elongation time of the clopidogrel sulfate (CLP) .

According to another aspect of the present invention, there is provided a pharmaceutical composition for improving, treating or preventing platelet-related vascular diseases comprising clopidogrel bisulphate (CLP) crystal form I prepared by the above-described method of the present invention as an active ingredient Lt; / RTI >

Since the composition of the present invention is produced by the above-described method of producing Clopidogrel Sulfate (CLP) crystal form I of the present invention described above, the common content between the two is that, in order to avoid the excessive complexity of the specification according to the repeating substrate, do.

The clopidogrel bisulphate (CLP) crystal form I, an active ingredient of the present invention, has an effect of improving, treating or preventing platelet-related vascular diseases.

Platelet-related vascular diseases to which the present invention can be applied include angina pectoris, arrhythmia, peripheral arterial atresia, stroke, cerebral arterial sclerosis or myocardial infarction.

The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans in various routes such as oral or parenteral routes. In the case of parenteral administration, intravenous injection, subcutaneous injection, Injection, transdermal administration, and the like.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in any form suitable for pharmaceutical preparations including oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations such as ointments and creams, suppositories and sterile injectable solutions, , Dispersants, or stabilizers.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides a method for producing clopidogrel bisulphate (CLP) crystal form I.

(b) The method of the present invention is more effective than the method of producing clopidogrel sulfate (CLP) crystal form I using a general organic solvent by using an ionic liquid as an anti-solvent. Respectively.

(c) This ensures the stability of clopidogrel sulphate (CLP) crystal form I in solution and also improves production yield.

Figures 1a and 1b show thermodynamic diagrams for polymorphic crystallization. FIG. 1A is a graph showing a polymorphic nucleation according to free energy change. FIG. Figure 1B is a graph of equilibrium concentration (solubility) between polymorphs.
FIG. 2 shows the results of calibration of two solids in a proportional manner after confirming specific peaks of the clopidogrel bisulphate (CLP) crystal type I and II types using FT-IR. As a result, the R ² value (slope value) showed a reliable value of 0.993. FT-IR was calculated by calculating the specific peak area _II / area _I + area _II , and the percentage of phase I transition from crystalline type I to crystalline type II was calculated.
FIG. 3 illustrates the use of an ionic liquid 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF ₄ ) as an organic solvent with ethanol (EtOH) and an antisolvent according to an embodiment of the present invention 2 is a photograph showing the crystal form of clopidogrel sulfate (CLP) crystal form I at a crystallization temperature of 25 캜 and 2 hours after the phase transition time.
FIG. 4 is a graph showing the retention time of clopidogrel sulfate (CLP) crystal form I at a crystallization temperature of 25 ° C. using an ionic liquid AEImBF ₄ as an organic solvent as an organic solvent and an anti-solvent as an organic solvent according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Throughout this specification, "%" used to denote the concentration of a particular substance is intended to include solids / solids (wt / wt), solid / liquid (wt / The liquid / liquid is (vol / vol)%.

Example

Example 1:

Clopidogrel sulphate (CLP) Crystalline Form Ⅱ (450 mg) was dissolved in ethanol (5 ml) at room temperature (20-25 ℃) and ionic liquid 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF ₄ , Japan), the stirring speed was fixed at 300 rpm, and crystallization was induced at a crystallization temperature of 25-50 ° C to observe the phase transition time from crystalline type I to crystalline type II and the retention time of crystalline type I . After 10 to 30 minutes of crystallization induction, crystals precipitated. Then, Fourier Transform Infrared Spectroscopy (FT-IR) was measured at intervals of 30 minutes to observe the CLP polymorphic phase transition with time. Crystalline type I did not transfer to crystalline type II at a crystallization temperature of 25 ° C until 2 hours of phase transition time, and 405 mg (yield: 90%) of crystalline type I was obtained after 2 hours (FIGS.

The changes in the retention time and the yield of the crystalline Form I depending on the crystallization temperature using an ionic liquid as an anti-solvent are summarized in Table 1 below:

Temperature (℃) Retention time of crystalline type I yield(%) 25 Up to 2 hours 90 30 Up to 2 hours 30 minutes 80 40 Up to 4 hours and 30 minutes 70 50 Up to 5 hours 62

Comparative Example 1:

450 mg of clopidogrel sulfate (CLP) crystalline form II was dissolved in 5 ml of ethanol at room temperature (20-25 ° C) and 5 ml of isopropyl alcohol was added. Thereafter, crystallization was induced at a crystallization temperature of 20 to 25 DEG C with stirring speed of 300 rpm. Crystalline type II crystals were precipitated one hour after the crystallization time, and crystal type II was confirmed by FT-IR. Therefore, crystal form I was not obtained.

Comparative Example 2:

3 g of clopidogrel sulfate (CLP) amorphous was dissolved in 10 ml of ethanol at room temperature (20-25 ° C), 10 ml of isopropyl alcohol was added, and the mixture was allowed to stand at 25 ° C for 15 hours without stirring. 2.25 g of crystalline form I (yield: 75%) was obtained, but it was confirmed by FT-IR that 5 minutes after the formation of crystal form I, crystalline form II of 20% was produced.

Therefore, it is judged that the ionic liquid (IL) slowly inhibits the nucleation (crystallization seed) rate of the CLP crystal type II to result in an increase in the retention time of the crystalline type I (FIG. 4) than in the organic solvent.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (10)

CLP Crystalline Form I of Clopidogrel Bisulphate (CLP) comprising the steps of:
(a) dissolving Clopidogrel Sulfate (CLP) crystalline Form II in an organic solvent;
(b) adding an ionic liquid to the result of (a); And
(c) inducing crystallization of the resultant product of (b) to obtain clopidogrel sulfate (CLP) crystal form I; And,
Wherein the organic solvent in step (a) is selected from the group consisting of methanol, ethanol, butanol, isopropyl alcohol, pentane and hexane,
Wherein the ionic liquid of step (b) is selected from the group consisting of 1-ethyl-3-methylimidazolium tetrafluoroborate, 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1- ) -3-methylimidazolium tetrafluoroborate, 1-decyl-3-methylimidazolium tetrafluoroborate or 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4).
The method according to claim 1, wherein the clopidogrel sulfate (CLP) crystalline Form II of step (a) is 50-150 (weight / volume)% based on the organic solvent.
delete The process according to claim 1, wherein the dissolution of step (a) is carried out at a temperature of from 20 to 25 ° C.
The method of claim 1, wherein the organic solvent of step (a) and the ionic liquid of step (b) have a volume ratio of 0.2: 3: 1.
delete delete The method according to claim 1, wherein the crystallization induction of step (c) is carried out at a temperature of 25 to 50 캜.
The method according to claim 1, wherein the phase transition time of the clopidogrel sulfate (CLP) crystal form I to the crystal form II of the step (c) is 2 to 5 hours.
The method of claim 1, wherein the yield of clopidogrel sulfate (CLP) crystalline form I of step (c) is 60-95%.

Images