Abstract:
Provided are revaprazan hydrochloride polymorphs and a preparation method thereof. The method comprises a step of dissolving revaprazan hydrochloride in ethanol or aqueous solutions of ethanol having different proportions to perform recrystallization.

Description:
TECHNICAL FIELD 
       [0001]    The present invention belongs to the field of pharmaceuticals, relates to pharmaceutical compound crystalline forms and preparation methods thereof, and particularly relates to a reversible proton pump inhibitor pharmaceutical revaprazan hydrochloride polymorph and a preparation method thereof. 
       BACKGROUND ART 
       [0002]    Revaprazan hydrochloride is a new generation of reversible proton pump inhibitor, and also is the world&#39;s only marketed potassium competitive acid pump inhibitor. Since the onset of effect is rapid, generally achieving maximum plasma concentration at about 1 h, revaprazan hydrochloride is used for rapid relief of symptoms caused by gastric acid. And it has clinical significance in meeting treatment demand and controlling gastrointestinal bleeding of patients. Its efficacy has a linear relationship with the oral dosage, which means that the gastric acid can be controlled at the best level by adjusting pharmaceutical dosage, thus meeting individualized treatment of different patients. It is used for treating peptic ulcer and other diseases relating to excessive secretion of gastric acid. 
         [0003]    Revaprazan hydrochloride was marketed in 2007. Although there are several documents reporting its synthesis process, the reports about a refining method and crystalline forms of revaprazan hydrochloride have not been seen. Document (WO9742186; WO9818784 ; Chinese Journal of Pharmaceuticals  2008, 39 (5), 321-324 ; Chinese Journal of Synthetic Chemistry  2008, 16 (4), 490-492 ; Chinese Journal of New Drugs  2013, 22 (14), 1694-1696) reported that the melting point of revaprazan hydrochloride is 255-256° C., while WO9605177 and MERCK indexing reported that the melting point of revaprazan hydrochloride is 205-208° C. We studied its refining method and crystalline forms, and found that recrystallizing the revaprazan hydrochloride using ethanol aqueous solutions with different proportions could obtain products exhibiting different crystalline forms, and the melting point is between 210-226° C. 
       SUMMARY OF THE INVENTION 
       [0004]    To solve the above technical problems, the present invention provides a revaprazan hydrochloride polymorph which particularly comprises 5 crystalline forms. 
         [0005]    The present invention also provides a preparation method of above-mentioned 5 crystalline forms. 
         [0006]    Disclosed is a revaprazan hydrochloride polymorph of the present invention, characterized in that its melting point is 210-226° C. 
         [0007]    Disclosed is also a revaprazan hydrochloride crystalline form I, the melting point of the polymorph I being 221-226° C. 
         [0008]    In the powder X-ray diffraction pattern of the crystalline form I, 2θ, which is represented in degree with the characteristic diffraction peaks at 10.24±0.2, 21.92±0.2, 17.54±0.2, 26.70±0.2, and 20.72±0.2. 
         [0009]    The powder X-ray diffraction peaks of further preferred crystalline form I are shown in Table 21. The thermogravimetric-differential thermal analysis atlas TG-DTA of the crystalline form I shows that there is an endothermic peak at 223° C. 
         [0010]    The infra-red spectrogram of the crystalline form I shows that there are characteristic absorption peaks at 3429.20, 3263.33, 2979.82, 2914.24, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1218.93, 1155.28, 1114.78, 1064.63, 1039.56, 972.06, 862.12, 833.19, 773.40, 757.97, and 514.96 cm −1 . 
         [0011]    Disclosed is also a revaprazan hydrochloride crystalline form II of the present invention, the melting point of the crystalline form II being 218-222° C. 
         [0012]    In the powder X-ray diffraction pattern of the polymorph II, 2θ, which is represented in degree with the characteristic diffraction peaks at 10.26±0.2, 24.48±0.2, 7.62±0.2, 21.94±0.2, 26.76±0.2, and 28.00±0.2. 
         [0013]    The powder X-ray diffraction peaks of further preferred crystalline form II are shown in Table 22. The thermogravimetric-differential thermal analysis atlas TG-DTA of the polymorph II shows that there is an endothermic peak at 220° C., and an exothermic peak at 137° C. 
         [0014]    The infra-red spectrogram of the crystalline form II shows that there are characteristic absorption peaks at 3431.13, 3056.96, 2979.82, 2931.60, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1415.65, 1340.43, 1305.72, 1213.14, 1155.28, 1114.78, 1064.63, 1041.49, 972.06, 862.12, 833.19, 773.40, 757.97, and 514.96 cm −1 . 
         [0015]    Disclosed is also a revaprazan hydrochloride crystalline form III of the present invention, the melting point being 216-220° C. 
         [0016]    In the powder X-ray diffraction pattern of the crystalline form III, 2θ, which is represented in degree with the characteristic diffraction peaks at 7.74±0.2, 24.42±0.2, 13.80±0.2, 7.38±0.2, and 25.62±0.2. 
         [0017]    The powder X-ray diffraction peaks of further preferred crystalline form III are shown in Table 23. The thermogravimetric-differential thermal analysis atlas TG-DTA of the crystalline form III shows that there is an endothermic peak at 218° C. and an exothermic peak at 140° C. 
         [0018]    The infra-red spectrogram of the crystalline form III shows that there are characteristic absorption peaks at 3421.48, 3265.26, 3043.46, 2979.82, 2931.60, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1218.93, 1155.28, 1114.78, 1064.63, 1039.56, 972.06, 862.12, 833.19, 773.40, 757.97, and 514.96 cm −1 . 
         [0019]    Disclosed is also a revaprazan hydrochloride crystalline form IV of the present invention, the melting point being 215-219° C. 
         [0020]    In the powder X-ray diffraction pattern of the crystalline form IV, 2θ, which is represented in degree with the characteristic diffraction peaks at 7.70±0.2, 10.34±0.2, 24.52±0.2, 20.04±0.2, and 13.78±0.2. 
         [0021]    The powder X-ray diffraction peaks of further preferred crystalline form IV are shown in Table 24. The thermogravimetric-differential thermal analysis atlas TG-DTA of the polymorph IV shows that there is an endothermic peak at 217° C. and an exothermic peak at 130° C. 
         [0022]    The infra-red spectrogram of the crystalline form IV shows that there are characteristic absorption peaks at 3473.56, 3407.98, 3269.12, 3060.82, 2981.74, 2933.53, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1433.01, 1415.65, 1340.43, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42, 966.27, 833.19, 771.47, 757.97, and 518.82 cm −1 . 
         [0023]    Disclosed is a revaprazan hydrochloride crystalline form V of the present invention, the melting point being 210-218° C. 
         [0024]    In the powder X-ray diffraction pattern of the crystalline form V, 2θ, which is represented in degree with the characteristic diffraction peaks at 7.68±0.2, 24.52±0.2, 13.74±0.2, 8.06±0.2, and 19.54±0.2. 
         [0025]    Powder X-ray diffraction peaks of further preferred crystalline form V are shown in Table 25. 
         [0026]    The thermogravimetric-differential thermal analysis atlas TG-DTA of the crystalline form V shows that there is an endothermic peak at 216° C. and an exothermic peak at 143° C. 
         [0027]    The infra-red spectrogram of the crystalline form V shows that there are characteristic absorption peaks at 3471.63, 3411.84, 3267.19, 3060.82, 2981.74, 2931.60, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1433.01, 1415.65, 1338.51, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42, 966.27, 833.19, 771.47, 757.97 and 518.82 cm −1 . 
         [0028]    A formulation containing revaprazan hydrochloride polymorphs of the present invention is composed of any one of the revaprazan hydrochloride crystalline form s I-V and pharmaceutically acceptable auxiliary materials. 
         [0029]    In the formulation, the weight percentage of revaprazan hydrochloride polymorphs can be 0.1-99.9%, and the balanced is pharmaceutically acceptable carrier. 
         [0030]    The formulation of the present invention is in a form of unit dosage, the unit dosage form refers to the unit of the formulation, such as a tablet for tablets, a capsule for capsules, a bottle for oral liquid, a sachet for granules and the like. 
         [0031]    The form of the present invention can be any pharmaceutically acceptable dosage form, and the dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquid, buccal formulations, granules, electuaries, pills, powders, ointments, sublimed formulations, suspensions, pulvis, solutions, injections, suppositories, soft ointments, hard ointments, creams, sprays, drops and patches. Preferable oral dosage forms are present as follows: capsules, tablets, oral liquid, granules, pills, powders, sublimed formulations, ointments and the like. 
         [0032]    The oral formulation of the present invention may include frequently-used excipients, such as binding agents, filling agents, diluting agents, tableting agents, lubricants, disintegrating agents, colorants, flavoring agents and wetting agents, and tablets can be coated if necessary. 
         [0033]    Applicable filling agents include cellulose, mannitol, lactose and other similar filling agents. Suitable disintegrating agents include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. The suitable lubricants include, for example magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium dodecylsulfate, polyoxyethylene hydrogenated castor oil, Tween 80, polyoxyethylene 35 castor oil and sucrose fatty acid ester. 
         [0034]    Solid oral compositions can be prepared by conventional methods such as blending, filling, tabletting and the like. By means of repeated blending, the active pharmaceutical ingredient (API) is distributed in those compositions where generally a large amount of filling agents are employed. The form of the oral liquid formulation can be, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be a dry product capable of being reconstituted with water or other suitable carriers before clinical use. The liquid formulation can contain conventional additives, such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fat, and emulsifiers, for example lecithin, sorbitan monooleate or arabic gum; the non-aqueous carriers (which may comprises edible oil), such as almond oil and fractionated coconut oil, for example glyceride oily ester, propylene glycol or ethanol; and preservatives, such as paraben or propyl p-hydroxybenzoate or sorbic acid, and if necessary, conventional flavoring agents or colouring agents can be contained. 
         [0035]    As for injections, the prepared liquid unit dosage form contains API and sterile carriers of the present invention. According to the carriers and concentrations, the compound can be suspended or dissolved. The solution is generally prepared by dissolving API in a carrier, filtering and sterilizing the carrier before being loaded into a suitable vial or an ampoule, and then sealing the vial or the ampoule. The auxiliary material, such as a local anesthetic, preservative and buffering agent, also can be dissolved in such carrier. In order to improve the stability, the composition is frozen after being loaded into the vial, and water is removed under vacuum. 
         [0036]    A suitable pharmaceutically acceptable carrier is selectively added when preparing the medicament in the present invention, the pharmaceutically acceptable carrier is selected from: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, hydrochloric acid cysteine, mercaptoacetic acid, methionine, vitamin C, EDTA disodium, EDTA calcium disodium, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyethylene pyrrolidone, glycerin, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactant, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipids material, kaolin, talc, calcium stearate, magnesium stearate and the like. 
         [0037]    When in use, usage and dosage are determined depending on the condition of the patient, 1-20 dosages may be taken every time and one to three times a day, such as: 1-20 sachets or pellets or tablets. 
         [0038]    The preparation method of the revaprazan hydrochloride polymorph of the present invention, which is characterized by comprising the following steps: 
         [0000]    (1) dissolving revaprazan hydrochloride with aqueous alcohol;
 
(2) adding active carbon, refluxing, decolorizing, filtering and the filtrate is obtained;
 
(3) cooling the filtrate, stirring, crystallizing, filtering, washing, obtaining solid, drying, and the polymorph is obtained.
 
         [0039]    The revaprazan hydrochloride is dissolved completely by adopting a mode of stirring, heating and dissolving in the above step (1). The heating and dissolving can also be carried out under the protection of argon or nitrogen, preferably the nitrogen. 
         [0040]    The temperature reduction in the above step (2) can use ice-salt water bath or ice-water bath, preferably the ice-salt bath. 
         [0041]    The aqueous alcohol in the above step (1) includes but not limited to ethanol, methanol, preferably the ethanol. The concentration of the aqueous alcohol is 45-98%. 
         [0042]    88-98% of ethanol of the aqueous alcohol is further preferably used, and the polymorph obtained is polymorph I. 
         [0043]    Specifically, placing the revaprazan hydrochloride in a reaction flask, adding 3-20 times (preferably 5-10 times of the amount, weight ratio, w/w) of 88-98% (preferably 90%) ethanol aqueous solution, stirring and heating until it is dissolved completely, slightly cooling, adding active carbon, refluxing, and decolorizing for 5-15 minutes, filtering while hot and cooling to 0-15° C., stirring, crystallizing, filtering, and washing with 88-98% (preferably 90%) aqueous ethanol, filtering, drying, and polymorph I is obtained. 
         [0044]    85% of ethanol of aqueous alcohol is further preferably used, and the polymorph obtained is crystalline form II. 
         [0045]    Specifically: placing revaprazan hydrochloride in a reaction flask, adding 3-20 times (preferably 5-10 times of the amount, weight ratio, w/w) of 85% ethanol aqueous solution, stirring and heating until it is dissolved completely, slightly cooling, adding active carbon, refluxing and decolorizing for 5-15 minutes, filtering while hot and cooling to 0-15° C., stirring, crystallizing, filtering, washing and drying, and crystalline form II is obtained. 
         [0046]    75% of ethanol of aqueous alcohol is further preferably used, and the polymorph obtained is crystalline form III. 
         [0047]    Specifically: placing revaprazan hydrochloride in a reaction flask, adding 3-20 times (preferably 5-10 times of the amount, weight ratio, w/w) of 75% ethanol aqueous solution, stirring and heating until it is dissolved completely, slightly cooling, adding active carbon, refluxing and decolorizing for 5-15 minutes, filtering while hot and cooling to 0-15° C., stirring, crystallizing, filtering, washing and drying, and crystalline form III is obtained. 
         [0048]    70% ethanol of aqueous alcohol is further preferably used, and the polymorph obtained is polymorph IV. 
         [0049]    Specifically: placing revaprazan hydrochloride in a reaction flask, adding 3-20 times (preferably 5-10 times of the amount, weight ratio, w/w) of 70% ethanol aqueous solution, stirring and heating until it is dissolved completely, slightly cooling, adding active carbon, refluxing, and decolorizing for 5-15 minutes, filtering while hot and cooling to 0-15° C., stirring, crystallizing, filtering, washing and drying, and crystalline form IV is obtained. 
         [0050]    50% ethanol of aqueous alcohol is further preferably used, and the polymorph obtained is crystalline form V. 
         [0051]    Specifically: placing revaprazan hydrochloride in a reaction flask, adding 3-20 times (preferably 5-10 times of the amount, weight ratio, w/w) of 50% ethanol aqueous solution, stirring and heating until it is dissolved completely, slightly cooling, adding active carbon and refluxing, decolorizing for 5-15 minutes, filtering while hot and cooling to 0-15° C., stirring and crystallizing, filtering, washing and drying, and crystalline form V is obtained. 
       Beneficial Effects 
       [0052]    In order to better illustrate beneficial effects of the revaprazan hydrochloride polymorphs of the present invention, the following describes beneficial effects by using stability tests. 
       Testing Examples: Stability 
     1. Stability of Revaprazan Hydrochloride Crystal Form I 
     Revaprazan Hydrochloride Crystalline Form I (Embodiment 1) 
     1.1 Light Illumination Test 
       [0053]    Revaprazan hydrochloride crystalline form I is irradiated under such a condition that the light intensity is 4500±500 Lx, and is sampled on the 5 th  day and 10 th  day for detection, and the results are shown in Table 1. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Results of intense light illumination test of revaprazan 
               
               
                 hydrochloride crystalline form I 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Days) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.27 
                 99.96 
                 Not detected 
               
               
                  5 th  day 
                 White powder 
                 0.28 
                 99.92 
                 Not detected 
               
               
                 10 th  day 
                 White powder 
                 0.30 
                 99.94 
                 Not detected 
               
               
                   
               
             
          
         
       
     
       1.2 High Temperature Test 
       [0054]    Revaprazan hydrochloride crystalline form I is placed in a 60° C. incubator, and is sampled on the 5 th  day and 10 th  day for detection, and the results are shown in Table 2. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Results of high temperature test of revaprazan 
               
               
                 hydrochloride crystalline form I 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Days) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.21 
                 99.96 
                 Not detected 
               
               
                  5 th  day 
                 White powder 
                 0.23 
                 99.95 
                 Not detected 
               
               
                 10 th  day 
                 White powder 
                 0.24 
                 99.98 
                 Not detected 
               
               
                   
               
             
          
         
       
     
       1.3 High Humidity Test 
       [0055]    Revaprazan hydrochloride crystalline form I is placed in an incubator of 25° C. (relative humidity of 75±5%), and is sampled on the 5 th  day and 10 th  day for detection. The results are shown in Table 3. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Results of high humidity test of revaprazan 
               
               
                 hydrochloride crystalline form I 
               
             
          
           
               
                   
                   
                 Weight gain 
                   
                   
               
               
                   
                 Appearance 
                 upon moisture 
                   
                 Relevant 
               
               
                 Time (Days) 
                 color 
                 absorption (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
             
          
           
               
                 Day 0 
                 White powder 
                 0 
                 99.96 
                 Not detected 
               
               
                  5 th  day 
                 White powder 
                 0.42 
                 99.93 
                 Not detected 
               
               
                 10 th  day 
                 White powder 
                 0.63 
                 99.95 
                 Not detected 
               
               
                   
               
             
          
         
       
     
       1.4 Accelerated Test 
       [0056]    Revaprazan hydrochloride crystalline form I is sealed in a polyethylene film bag, is placed for 6 months under the conditions that the temperature is 40±2° C. and the relative humidity is 75±5%, and is respectively sampled at the end of the 1 st  Month, the 2 nd  Month, the 3 rd  Month and the 6 th Month for detection; and the results are shown in Table 4. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Results of accelerated test of revaprazan 
               
               
                 hydrochloride crystalline form I 
               
             
          
           
               
                   
                   
                 Appearance 
                   
                 Relevant 
               
               
                   
                 Test time 
                 color 
                 Purity (%) 
                 substances 
               
               
                   
                   
               
               
                   
                 Month 0 
                 White powder 
                 99.96 
                 Not detected 
               
               
                   
                 1 st  month 
                 White powder 
                 99.97 
                 Not detected 
               
               
                   
                 2 nd  month 
                 White powder 
                 99.92 
                 Not detected 
               
               
                   
                 3 rd  month 
                 White powder 
                 99.96 
                 Not detected 
               
               
                   
                 6 th  month 
                 White powder 
                 99.95 
                 Not detected 
               
               
                   
                   
               
             
          
         
       
     
         [0057]    The results indicate that: revaprazan hydrochloride crystalline form I is stable under the conditions of intense light illumination, high temperature, high humidity and accelerated tests, without obvious changes in appearance color, loss on drying, purity and relevant substances, and has a slight weight gain upon moisture absorption under the condition of high humidity. 
       2. Stability of Revaprazan Hydrochloride Crystalline Form II 
     Revaprazan Hydrochloride Crystalline Form II (Embodiment 2) 
     2.1 Light Illumination Test 
       [0058]    Revaprazan hydrochloride crystalline form II is irradiated under the condition that the light intensity is 4500±500Lx, and is sampled on the 5 th  day and 10 th  day for detection. The results are shown in Table 5. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Results of intense light illumination test of revaprazan 
               
               
                 hydrochloride crystalline form II 
               
             
          
           
               
                   
                 Appearance 
                 Loss on 
                   
                 Relevant 
               
               
                 Time (Days) 
                 color 
                 drying (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.25 
                 99.94 
                 Not detected 
               
               
                  5 th  day 
                 White powder 
                 0.26 
                 99.97 
                 Not detected 
               
               
                 10 th  day 
                 White powder 
                 0.28 
                 99.94 
                 Not detected 
               
               
                   
               
             
          
         
       
     
       2.2 High Temperature Test 
       [0059]    Revaprazan hydrochloride crystalline form II is placed in a 60° C. incubator, and is sampled on the 5 th  day and 10 th  day for detection, and the results are shown in Table 6. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Results of high temperature test of revaprazan 
               
               
                 hydrochloride crystalline form II 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Days) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White 
                 0.23 
                 99.94 
                 Not detected 
               
               
                   
                 powder 
               
               
                  5 th  day 
                 White 
                 0.27 
                 99.97 
                 Not detected 
               
               
                   
                 powder 
               
               
                 10 th  day 
                 White 
                 0.29 
                 99.95 
                 Not detected 
               
               
                   
                 powder 
               
               
                   
               
             
          
         
       
     
       2.3 High Humidity Test 
       [0060]    Revaprazan hydrochloride crystalline form II is placed in an incubator of 25° C. (relative humidity of 75±5%), and is sampled on the 5 th  day and 10 th  day for detection. The results are shown in Table 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Results of high humidity test of revaprazan 
               
               
                 hydrochloride crystalline form II 
               
             
          
           
               
                   
                   
                 Weight gain 
                   
                   
               
               
                   
                 Appearance 
                 upon moisture 
                   
                 Relevant 
               
               
                 Time (Days) 
                 color 
                 absorption (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
             
          
           
               
                 Day 0 
                 White powder 
                 0 
                 99.94 
                 Not detected 
               
               
                  5 th  day 
                 White powder 
                 0.42 
                 99.93 
                 Not detected 
               
               
                 10 th  day 
                 White powder 
                 0.64 
                 99.95 
                 Not detected 
               
               
                   
               
             
          
         
       
     
       2.4 Accelerated Test 
       [0061]    Revaprazan hydrochloride crystalline form II is sealed in a polyethylene film bag and is placed for 6 months under the conditions that the temperature is 40±2° C. and the relative humidity is 75±5%, and is respectively sampled at the end of the 1 st  Month, the 2 nd  Month, the 3 rd  Month and the 6 th  Month for detection; and the results are shown in Table 8. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Results of accelerated test of revaprazan 
               
               
                 hydrochloride crystalline form II 
               
             
          
           
               
                 Test time 
                 Appearance color 
                 Purity (%) 
                 Relevant substances 
               
               
                   
               
               
                 Month 0 
                 White powder 
                 99.94 
                 White powder 
               
               
                 1 st  month 
                 White powder 
                 99.93 
                 White powder 
               
               
                 2 nd  month 
                 White powder 
                 99.95 
                 White powder 
               
               
                 3 rd  month 
                 White powder 
                 99.96 
                 White powder 
               
               
                 6 th  month 
                 White powder 
                 99.95 
                 White powder 
               
               
                   
               
             
          
         
       
     
         [0062]    The results indicate that: revaprazan hydrochloride crystalline form II is stable under the conditions of intensive light illumination, high temperature, high humidity and accelerated test, without obvious changes in appearance color, loss on drying, purity and relevant substance, and has slight weight gain upon moisture absorption under high humidity condition. 
       3. Stability of Revaprazan Hydrochloride Crystalline Form III 
     Revaprazan Hydrochloride Polymorph III (Embodiment 3) 
     3.1 Light Illumination Test 
       [0063]    Revaprazan hydrochloride polymorph III is irradiated under such a condition that the light intensity is 4500±500Lx, and is sampled on the 5 th  day and 10 th  day for detection. The results are shown in Table 9. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Results of intensive light illumination test of revaprazan 
               
               
                 hydrochloride polymorph III 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Day) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.28 
                 99.95 
                 Undetected 
               
               
                  5 th  day 
                 White powder 
                 0.25 
                 99.92 
                 Undetected 
               
               
                 10 th  day 
                 White powder 
                 0.29 
                 99.95 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       3.2 High-Temperature Test 
       [0064]    Revaprazan hydrochloride polymorph III is placed in an incubator of 60° C., and is sampled on the 5 th  day and the 10 th  day for detection. The results are shown in Table 10. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Stability results of high-temperature test of revaprazan 
               
               
                 hydrochloride polymorph III 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Day) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.22 
                 99.95 
                 Undetected 
               
               
                  5 th  day 
                 White powder 
                 0.26 
                 99.94 
                 Undetected 
               
               
                 10 th  day 
                 White powder 
                 0.26 
                 99.92 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       3.3 High-Humidity Test 
       [0065]    Revaprazan hydrochloride polymorph III is placed in an incubator of 25° C. (relative humidity of 75±5%), and is sampled on the 5 th  day and the 10 th  day for detection. The results are shown in Table 11. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Stability results of high humidity test of revaprazan 
               
               
                 hydrochloride crystalline form III 
               
             
          
           
               
                   
                   
                 Weight gain 
                   
                   
               
               
                   
                 Appearance 
                 upon moisture 
                   
                 Relevant 
               
               
                 Time (Day) 
                 color 
                 absorption (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
             
          
           
               
                 Day 0 
                 White powder 
                 0 
                 99.95 
                 Undetected 
               
               
                  5 th  day 
                 White powder 
                 0.47 
                 99.92 
                 Undetected 
               
               
                 10 th  day 
                 White powder 
                 0.59 
                 99.94 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       3.4 Accelerated Test 
       [0066]    Revaprazan hydrochloride crystalline form III is sealed in a polyethylene film bag, is placed for 6 months under the conditions that the temperature is 40±2° C. and the relative humidity is 75±5%, and is sampled at the end of the 1 st  Month, the 2 nd  Month, the 3 rd  Month and the 6 th  Month for detection. The results are shown in Table 12. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 Results of accelerated test of revaprazan hydrochloride crystalline form III 
               
             
          
           
               
                 Test time 
                 Appearance color 
                 Purity (%) 
                 Relevant substances 
               
               
                   
               
               
                 Month 0 
                 White powder 
                 99.95 
                 Undetected 
               
               
                 1 st  month 
                 White powder 
                 99.92 
                 Undetected 
               
               
                 2 nd  month 
                 White powder 
                 99.91 
                 Undetected 
               
               
                 3 rd  month 
                 White powder 
                 99.93 
                 Undetected 
               
               
                 6 th  month 
                 White powder 
                 99.95 
                 Undetected 
               
               
                   
               
             
          
         
       
     
         [0067]    The results indicate that: revaprazan hydrochloride crystalline form III is stable under the conditions of intensive light illumination, high temperature, high humidity and accelerated test, without obvious changes in appearance color, loss on drying, purity and relevant substance, and has slight weight gain upon moisture absorption under high humidity condition. 
       4. Stability of Revaprazan Hydrochloride Crystalline Form IV 
     Revaprazan Hydrochloride Crystalline Form IV (Test Example 4) 
     4.1 Light Illumination Test 
       [0068]    Revaprazan hydrochloride crystalline form III is irradiated under such a condition that the light intensity is 4500±500Lx, and is sampled on the 5 th  day and the 10 th  day for detection. The results are shown in Table 13. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 Results of intensive light illumination test 
               
               
                 of revaprazan hydrochloride crystalline form IV 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Day) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.27 
                 99.93 
                 Undetected 
               
               
                 5 th  day 
                 White powder 
                 0.29 
                 99.95 
                 Undetected 
               
               
                 10 th  day 
                 White powder 
                 0.31 
                 99.92 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       4.2 High-Temperature Test 
       [0069]    Revaprazan hydrochloride crystalline form IV is placed in an incubator of 60° C., and is sampled on the 5 th  day and the 10 th  day for detection. The results are shown in Table 14. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 Stability results of high-temperature test 
               
               
                 of revaprazan hydrochloride crystalline form IV 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Relevant 
               
               
                 Time (Day) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.25 
                 99.93 
                 Undetected 
               
               
                 5 th  day 
                 White powder 
                 0.27 
                 99.91 
                 Undetected 
               
               
                 10 th  day 
                 White powder 
                 0.27 
                 99.92 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       4.3 High-Humidity Test 
       [0070]    Revaprazan hydrochloride crystalline form IV is placed in an incubator of 25° C. (relative humidity of 75±5%), and is sampled on the 5 th  day and the 10 th  day for detection The results are shown in Table 15. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 Stability results of high-humidity test 
               
               
                 of revaprazan hydrochloride crystalline form IV 
               
             
          
           
               
                   
                   
                 Weight gain 
                   
                   
               
               
                   
                 Appearance 
                 upon moisture 
                 Purity 
                 Relevant 
               
               
                 Time (Day) 
                 color 
                 absorption (%) 
                 (%) 
                 substances 
               
               
                   
               
             
          
           
               
                 Day 0 
                 White powder 
                 0 
                 99.93 
                 White powder 
               
               
                 5 th  day 
                 White powder 
                 0.44 
                 99.96 
                 White powder 
               
               
                 10 th  day 
                 White powder 
                 0.62 
                 99.93 
                 White powder 
               
               
                   
               
             
          
         
       
     
       4.4 Accelerated Test 
       [0071]    Revaprazan hydrochloride crystalline form IV is sealed in a polyethylene film bag, is placed for 6 months under the conditions that the temperature is 40±2° C. and the relative humidity is 75±5%, and is sampled at the end of the 1 st  Month, the 2 nd  Month, the 3 rd  Month and the 6 th  Month for detection. The results are shown in Table 16. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 Results of accelerated test of revaprazan hydrochloride crystalline form IV 
               
             
          
           
               
                 Test time 
                 Appearance color 
                 Purity (%) 
                 Relevant substances 
               
               
                   
               
               
                 Month 0 
                 White powder 
                 99.93 
                 Undetected 
               
               
                 1 st  month 
                 White powder 
                 99.91 
                 Undetected 
               
               
                 2 nd  month 
                 White powder 
                 99.90 
                 Undetected 
               
               
                 3 rd  month 
                 White powder 
                 99.95 
                 Undetected 
               
               
                 6 th  month 
                 White powder 
                 99.94 
                 Undetected 
               
               
                   
               
             
          
         
       
     
         [0072]    The results indicate that: revaprazan hydrochloride crystalline form IV is stable under the conditions of intense light illumination, high temperature, high humidity and acceleration tests, without obvious changes in appearance colour, loss on drying, impurity and related substances, and has a slight weight gain upon moisture absorption. 
       5. Stability of Revaprazan Hydrochloride Crystalline Form V 
     Revaprazan Hydrochloride Crystalline Form V (Test Example 5) 
     5.1 Light Illumination Test 
       [0073]    Revaprazan hydrochloride crystalline form V is irradiated under the light intensity condition of 4500±500Lx; and is sampled on the 5 th  day and 10 th  day for detection. The results are shown in Table 17. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 Results of intense light illumination test 
               
               
                 of revaprazan hydrochloride crystalline form 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Related 
               
               
                 Time (Days) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.24 
                 99.94 
                 Undetected 
               
               
                 5 th  Day 
                 White powder 
                 0.27 
                 99.95 
                 Undetected 
               
               
                 10 th  Day 
                 White powder 
                 0.30 
                 99.95 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       5.2 High Temperature Test 
       [0074]    Revaprazan hydrochloride crystal form 4 is placed in an incubator of 60° C.; and is sampled on the 5 th  day and the 10 th  day for detection, and the results are shown in Table 23. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 Results of stability of high temperature test 
               
               
                 of revaprazan hydrochloride crystalline form V 
               
             
          
           
               
                   
                 Appearance 
                 Loss on drying 
                   
                 Related 
               
               
                 Time (Days) 
                 color 
                 (%) 
                 Purity (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0.29 
                 99.94 
                 Undetected 
               
               
                 5 th  Day 
                 White powder 
                 0.30 
                 99.95 
                 Undetected 
               
               
                 10 th  Day 
                 White powder 
                 0.32 
                 99.92 
                 Undetected 
               
               
                   
               
             
          
         
       
     
       5.3 High Humidity Test 
       [0075]    Revaprazan hydrochloride crystal form 4 is placed in an incubator of 25° C. (the relative humidity is 75±5%), and is sampled on the 5 th  day and the 10 th  day for detection. The results are shown in Table 19. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 Results of stability of high humidity test 
               
               
                 of revaprazan hydrochloride crystalline form V 
               
             
          
           
               
                   
                   
                 Weight gain 
                   
                   
               
               
                   
                 Appearance 
                 upon moisture 
                 Purity 
                 Related 
               
               
                 Time (Days) 
                 color 
                 absorption (%) 
                 (%) 
                 substances 
               
               
                   
               
               
                 Day 0 
                 White powder 
                 0 
                 99.94 
                 White powder 
               
               
                 5 th  Day 
                 White powder 
                 0.42 
                 99.94 
                 White powder 
               
               
                 10 th  Day 
                 White powder 
                 0.66 
                 99.96 
                 White powder 
               
               
                   
               
             
          
         
       
     
       5.4 Acceleration Test 
       [0076]    Revaprazan hydrochloride crystalline form V is sealed in a polyethylene film bag and is placed for 6 months under the condition that the temperature is 40±2° C. and the relative humidity is 75±5%, and is sampled at the end of the 1 st  month, the 2 nd  month, the 3 rd  month and the 6 th  month for detection, and the results are shown in Table 20. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 20 
               
             
             
               
                   
               
               
                 Results of acceleration test of revaprazan hydrochloride crystalline form V 
               
             
          
           
               
                 Test time 
                 Appearance color 
                 Purity (%) 
                 Related substances 
               
               
                   
               
               
                 Month 0 
                 White powder 
                 99.94 
                 Undetected 
               
               
                 1 st  Month 
                 White powder 
                 99.98 
                 Undetected 
               
               
                 2 nd  Month 
                 White powder 
                 99.95 
                 Undetected 
               
               
                 3 rd  Month 
                 White powder 
                 99.97 
                 Undetected 
               
               
                 6 th  Month 
                 White powder 
                 99.94 
                 Undetected 
               
               
                   
               
             
          
         
       
     
         [0077]    The results indicate that: revaprazan hydrochloride crystalline form V is stable under the conditions of intense light illumination, high temperature, high humidity and accelerated tests, without obvious changes in appearance color, loss on drying, purity and relevant substances, and has a slight weight gain upon moisture absorption under the condition of high humidity. 
         [0078]    The five crystal forms of revaprazan hydrochloride prepared by using the method of the present invention have high product purities which are more than 99.9%; moreover, they have high yields which are about 90%. Besides, the five crystal forms are stable during light illumination, high temperature, high humidity and acceleration tests, and their impurities show no significant changes. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0079]      FIG. 1  Powder X-ray diffraction pattern of crystal form I 
           [0080]      FIG. 2  TG-DTA diagram of crystal form I 
           [0081]      FIG. 3  Infra-red spectrogram of crystal form I 
           [0082]      FIG. 4  Powder X-ray diffraction pattern of crystal form II 
           [0083]      FIG. 5  TG-DTA diagram of crystal form II 
           [0084]      FIG. 6  Infra-red spectrogram of crystal form II 
           [0085]      FIG. 7  Powder X-ray diffraction pattern of crystal form III 
           [0086]      FIG. 8  TG-DTA diagram of crystal form III 
           [0087]      FIG. 9  Infra-red spectrogram of crystal form III 
           [0088]      FIG. 10  Powder X-ray diffraction pattern of crystal form IV 
           [0089]      FIG. 11  TG-DTA diagram of crystal form IV 
           [0090]      FIG. 12  Infra-red spectrogram of crystal form IV 
           [0091]      FIG. 13  Powder X-ray diffraction pattern of crystal form V 
           [0092]      FIG. 14  TG-DTA diagram of crystal form V 
           [0093]      FIG. 15  Infra-red spectrogram of crystal form V 
       
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       [0094]    The present invention is further described below in detail through embodiments, but it is not intended to further define the present invention. 
       Product Embodiments 
     Embodiment 1 Revaprazan Hydrochloride Crystalline Form I 
       [0095]    For revaprazan hydrochloride crystalline form I, in its powder X-ray diffraction pattern, 2θ, which is represented in degree, the characteristic diffraction peaks at 10.24±0.2, 21.92±0.2, 17.54±0.2, 26.70±0.2 and 20.72±0.2. Its powder X-ray diffraction data is shown in Table 21, and its powder X-ray diffraction pattern is shown in  FIG. 1 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 21 
               
             
             
               
                   
               
               
                 Parameters of characteristic peaks of powder X-ray diffraction pattern 
               
               
                 of revaprazan hydrochloride crystalline form I 
               
             
          
           
               
                   
                   
                   
                   
                 Relative 
               
               
                   
                 Number 
                 2θ 
                 d value 
                 intensity I/I 0   
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 7.300 
                 12.0996 
                 15 
               
               
                   
                 2 
                 10.240 
                 8.6314 
                 100 
               
               
                   
                 3 
                 12.160 
                 7.2725 
                 28 
               
               
                   
                 4 
                 13.240 
                 6.6816 
                 17 
               
               
                   
                 5 
                 14.660 
                 6.0374 
                 5 
               
               
                   
                 6 
                 16.300 
                 5.4335 
                 29 
               
               
                   
                 7 
                 16.840 
                 5.2605 
                 19 
               
               
                   
                 8 
                 17.540 
                 5.0521 
                 42 
               
               
                   
                 9 
                 18.240 
                 4.8597 
                 4 
               
               
                   
                 10 
                 19.580 
                 4.5301 
                 25 
               
               
                   
                 11 
                 20.720 
                 4.2833 
                 32 
               
               
                   
                 12 
                 21.920 
                 4.0515 
                 45 
               
               
                   
                 13 
                 22.200 
                 4.0010 
                 25 
               
               
                   
                 14 
                 22.480 
                 3.9518 
                 10 
               
               
                   
                 15 
                 23.220 
                 3.8275 
                 17 
               
               
                   
                 16 
                 24.240 
                 3.6687 
                 14 
               
               
                   
                 17 
                 25.440 
                 3.4983 
                 24 
               
               
                   
                 18 
                 25.920 
                 3.4346 
                 13 
               
               
                   
                 19 
                 26.700 
                 3.3360 
                 33 
               
               
                   
                 20 
                 27.980 
                 3.1862 
                 31 
               
               
                   
                 21 
                 29.440 
                 3.0315 
                 17 
               
               
                   
                 22 
                 31.160 
                 2.8679 
                 7 
               
               
                   
                 23 
                 31.920 
                 2.8014 
                 7 
               
               
                   
                 24 
                 33.040 
                 2.7089 
                 5 
               
               
                   
                 25 
                 34.600 
                 2.5903 
                 6 
               
               
                   
                 26 
                 36.300 
                 2.4728 
                 6 
               
               
                   
                 27 
                 37.620 
                 2.3890 
                 7 
               
               
                   
                 28 
                 39.680 
                 2.2696 
                 6 
               
               
                   
                   
               
             
          
         
       
     
         [0096]    The thermogravimetry-differential thermal analysis atlas (TG-DTA) shows that crystalline form I has endothermic peaks at the temperature of 223° C., which is shown in  FIG. 2 . The infra-red spectrogram of crystalline form I shows that there are characteristic absorption peaks at 3429.20, 3263.33, 2979.82, 2914.24, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1218.93, 1155.28, 1114.78, 1064.63, 1039.56, 972.06, 862.12, 833.19, 773.40, 757.97 and 514.96. Its infra-red spectrogram is shown in  FIG. 3 . 
       Embodiment 2 Revaprazan Hydrochloride Crystalline Form II 
       [0097]    In the powder X-ray diffraction pattern of revaprazan hydrochloride crystalline form II, 2θ which is represented in degree, the characteristic diffraction peaks at 10.26±0.2, 24.48±0.2, 7.62±0.2, 21.94±0.2, 26.76±0.2 and 28.00±0.2. The specific powder X-ray diffraction data is shown in Table 22, and its powder X-ray diffraction pattern is shown in  FIG. 4 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 22 
               
             
             
               
                   
               
               
                 Parameters of characteristic peaks of powder X-ray diffraction 
               
               
                 pattern of revaprazan hydrochloride crystalline form II 
               
             
          
           
               
                   
                 Serial 
                   
                   
                 Relative 
               
               
                   
                 Number 
                 2θ 
                 d value 
                 intensity I/I 0   
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 7.300 
                 12.0996 
                 25 
               
               
                   
                 2 
                 7.620 
                 11.5922 
                 55 
               
               
                   
                 3 
                 8.020 
                 11.0149 
                 32 
               
               
                   
                 4 
                 10.260 
                 8.6146 
                 100 
               
               
                   
                 5 
                 12.200 
                 7.2487 
                 29 
               
               
                   
                 6 
                 13.280 
                 6.6616 
                 20 
               
               
                   
                 7 
                 13.740 
                 6.4396 
                 42 
               
               
                   
                 8 
                 15.620 
                 5.6685 
                 15 
               
               
                   
                 9 
                 16.040 
                 5.5210 
                 20 
               
               
                   
                 10 
                 16.320 
                 5.4269 
                 32 
               
               
                   
                 11 
                 16.880 
                 5.2481 
                 21 
               
               
                   
                 12 
                 17.560 
                 5.0464 
                 42 
               
               
                   
                 13 
                 18.240 
                 4.8597 
                 14 
               
               
                   
                 14 
                 18.480 
                 4.7972 
                 14 
               
               
                   
                 15 
                 18.840 
                 4.7063 
                 15 
               
               
                   
                 16 
                 19.580 
                 4.5301 
                 35 
               
               
                   
                 17 
                 19.960 
                 4.4447 
                 30 
               
               
                   
                 18 
                 20.760 
                 4.2752 
                 44 
               
               
                   
                 19 
                 21.940 
                 4.0478 
                 49 
               
               
                   
                 20 
                 22.220 
                 3.9974 
                 30 
               
               
                   
                 21 
                 22.520 
                 3.9449 
                 15 
               
               
                   
                 22 
                 23.320 
                 3.8113 
                 37 
               
               
                   
                 23 
                 24.480 
                 3.6333 
                 58 
               
               
                   
                 24 
                 25.440 
                 3.4983 
                 36 
               
               
                   
                 25 
                 26.020 
                 3.4216 
                 24 
               
               
                   
                 26 
                 26.760 
                 3.3287 
                 46 
               
               
                   
                 27 
                 27.260 
                 3.2687 
                 20 
               
               
                   
                 28 
                 28.000 
                 3.1840 
                 46 
               
               
                   
                 29 
                 29.060 
                 3.0702 
                 14 
               
               
                   
                 30 
                 29.560 
                 3.0194 
                 24 
               
               
                   
                 31 
                 30.020 
                 2.9742 
                 22 
               
               
                   
                 32 
                 30.800 
                 2.9006 
                 16 
               
               
                   
                 33 
                 31.200 
                 2.8644 
                 13 
               
               
                   
                 34 
                 31.540 
                 2.8342 
                 12 
               
               
                   
                 35 
                 31.900 
                 2.8031 
                 13 
               
               
                   
                 36 
                 33.240 
                 2.6931 
                 12 
               
               
                   
                   
               
             
          
         
       
     
         [0098]    The thermogravimetry-differential thermal analysis atlas (TG-DTA) shows that crystalline form II has an endothermic peak at 220° C., and has an exothermic peak at 137° C., which are shown in  FIG. 5 . The infra-red spectrogram of crystalline form II shows that it has characteristic absorption peaks at 3431.13, 3056.96, 2979.82, 2931.60, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1415.65, 1340.43, 1305.72, 1213.14, 1155.28, 1114.78, 1064.63, 1041.49, 972.06, 862.12, 833.19, 773.40, 757.97 and 514.96 cm −1 . The infra-red spectrogram is shown in  FIG. 6 . 
       Embodiment 3 Revaprazan Hydrochloride Crystalline Form III 
       [0099]    In the powder X-ray diffraction pattern of revaprazan hydrochloride crystalline form III, 2θ, which is represented in degree, the characteristic diffraction peaks at 7.74±0.2, 24.42±0.2, 13.80±0.2, 7.38±0.2 and 25.62±0.2. The specific powder X-ray diffraction data is shown in Table 23, and its powder X-ray diffraction pattern is shown in  FIG. 7 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 23 
               
             
             
               
                   
               
               
                 Parameters of characteristic peaks of powder X-ray diffraction pattern 
               
               
                 of revaprazan hydrochloride crystalline form III 
               
             
          
           
               
                   
                 Serial 
                   
                   
                 Relative 
               
               
                   
                 Number 
                 2θ 
                 d value 
                 intensity I/I 0   
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 7.380 
                 11.9687 
                 77 
               
               
                   
                 2 
                 7.740 
                 11.4128 
                 100 
               
               
                   
                 3 
                 8.120 
                 10.8795 
                 68 
               
               
                   
                 4 
                 10.360 
                 8.5317 
                 55 
               
               
                   
                 5 
                 11.400 
                 7.7556 
                 35 
               
               
                   
                 6 
                 11.820 
                 7.4809 
                 32 
               
               
                   
                 7 
                 12.300 
                 7.1900 
                 24 
               
               
                   
                 8 
                 13.800 
                 6.4117 
                 79 
               
               
                   
                 9 
                 14.680 
                 6.0293 
                 28 
               
               
                   
                 10 
                 15.660 
                 5.6541 
                 38 
               
               
                   
                 11 
                 16.060 
                 5.5142 
                 59 
               
               
                   
                 12 
                 16.940 
                 5.2296 
                 38 
               
               
                   
                 13 
                 17.540 
                 5.0521 
                 33 
               
               
                   
                 14 
                 18.340 
                 4.8335 
                 38 
               
               
                   
                 15 
                 18.880 
                 4.6964 
                 40 
               
               
                   
                 16 
                 19.540 
                 4.5392 
                 45 
               
               
                   
                 17 
                 20.060 
                 4.4227 
                 60 
               
               
                   
                 18 
                 20.520 
                 4.3246 
                 52 
               
               
                   
                 19 
                 21.000 
                 4.2268 
                 53 
               
               
                   
                 20 
                 22.040 
                 4.0297 
                 44 
               
               
                   
                 21 
                 22.840 
                 3.8903 
                 41 
               
               
                   
                 22 
                 23.440 
                 3.7921 
                 53 
               
               
                   
                 23 
                 24.420 
                 3.6421 
                 98 
               
               
                   
                 24 
                 25.620 
                 3.4741 
                 70 
               
               
                   
                 25 
                 26.120 
                 3.4088 
                 52 
               
               
                   
                 26 
                 26.740 
                 3.3311 
                 57 
               
               
                   
                 27 
                 27.580 
                 3.2315 
                 49 
               
               
                   
                 28 
                 27.940 
                 3.1907 
                 47 
               
               
                   
                 29 
                 29.160 
                 3.0599 
                 31 
               
               
                   
                 30 
                 30.120 
                 2.9646 
                 38 
               
               
                   
                 31 
                 30.860 
                 2.8951 
                 32 
               
               
                   
                 32 
                 31.540 
                 2.8342 
                 27 
               
               
                   
                   
               
             
          
         
       
     
         [0100]    The thermogravimetry-differential thermal analysis atlas (TG-DTA) shows that crystalline form III has an endothermic peak at 218° C., and has an exothermic peak at 140° C., which are shown in  FIG. 8 . The infra-red spectrogram of crystalline form III shows that it has characteristic absorption peaks at 3421.48, 3265.26, 3043.46, 2979.82, 2931.60, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1218.93, 1155.28, 1114.78, 1064.63, 1039.56, 972.06, 862.12, 833.19, 773.40, 757.97 and 514.96 cm −1 . The infra-red spectrogram is shown in  FIG. 9 . 
       Embodiment 4 Revaprazan Hydrochloride Crystalline Form IV 
       [0101]    In the powder X-ray diffraction pattern of revaprazan hydrochloride crystalline form IV, 2θ, which is represented in degree, the characteristic diffraction peaks at 7.70±0.2, 10.34±0.2, 24.52±0.2, 20.04±0.2, 13.78±0.2. The specific powder X-ray diffraction data is shown in Table 24, and its powder X-ray diffraction pattern is shown in  FIG. 10 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 24 
               
             
             
               
                   
               
               
                 Parameters of characteristic peaks of powder X-ray diffraction pattern 
               
               
                 of revaprazan hydrochloride crystalline form IV 
               
             
          
           
               
                   
                 Serial 
                   
                   
                 Relative 
               
               
                   
                 Number 
                 2θ 
                 d value 
                 intensity I/I 0   
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 7.700 
                 11.4720 
                 100 
               
               
                   
                 2 
                 8.100 
                 10.9063 
                 37 
               
               
                   
                 3 
                 10.340 
                 8.5481 
                 76 
               
               
                   
                 4 
                 13.100 
                 6.7527 
                 6 
               
               
                   
                 5 
                 13.780 
                 6.4210 
                 42 
               
               
                   
                 6 
                 14.340 
                 6.1714 
                 5 
               
               
                   
                 7 
                 15.360 
                 5.7638 
                 11 
               
               
                   
                 8 
                 15.700 
                 5.6398 
                 11 
               
               
                   
                 9 
                 16.120 
                 5.4938 
                 16 
               
               
                   
                 10 
                 16.480 
                 5.3746 
                 7 
               
               
                   
                 11 
                 17.520 
                 5.0578 
                 9 
               
               
                   
                 12 
                 18.280 
                 4.8492 
                 9 
               
               
                   
                 13 
                 18.560 
                 4.7767 
                 9 
               
               
                   
                 14 
                 18.880 
                 4.6964 
                 11 
               
               
                   
                 15 
                 19.560 
                 4.5347 
                 13 
               
               
                   
                 16 
                 20.040 
                 4.4271 
                 45 
               
               
                   
                 17 
                 20.460 
                 4.3372 
                 10 
               
               
                   
                 18 
                 21.020 
                 4.2229 
                 21 
               
               
                   
                 19 
                 21.940 
                 4.0478 
                 7 
               
               
                   
                 20 
                 22.280 
                 3.9868 
                 7 
               
               
                   
                 21 
                 22.700 
                 3.9140 
                 6 
               
               
                   
                 22 
                 23.440 
                 3.7921 
                 27 
               
               
                   
                 23 
                 24.060 
                 3.6957 
                 13 
               
               
                   
                 24 
                 24.520 
                 3.6274 
                 56 
               
               
                   
                 25 
                 25.460 
                 3.4956 
                 13 
               
               
                   
                 26 
                 26.240 
                 3.3934 
                 16 
               
               
                   
                 27 
                 26.860 
                 3.3165 
                 13 
               
               
                   
                 28 
                 27.340 
                 3.2594 
                 18 
               
               
                   
                 29 
                 27.980 
                 3.1862 
                 15 
               
               
                   
                 30 
                 28.760 
                 3.1016 
                 8 
               
               
                   
                 31 
                 29.180 
                 3.0579 
                 9 
               
               
                   
                 32 
                 30.080 
                 2.9684 
                 16 
               
               
                   
                 33 
                 30.860 
                 2.8951 
                 14 
               
               
                   
                 34 
                 31.620 
                 2.8273 
                 8 
               
               
                   
                 35 
                 32.120 
                 2.7844 
                 7 
               
               
                   
                 36 
                 33.260 
                 2.6915 
                 11 
               
               
                   
                 37 
                 33.680 
                 2.6589 
                 8 
               
               
                   
                 38 
                 34.320 
                 2.6108 
                 6 
               
               
                   
                 39 
                 35.160 
                 2.5503 
                 5 
               
               
                   
                 40 
                 37.340 
                 2.4062 
                 8 
               
               
                   
                 41 
                 43.200 
                 2.0924 
                 6 
               
               
                   
                 42 
                 44.940 
                 2.0154 
                 6 
               
               
                   
                   
               
             
          
         
       
     
         [0102]    The thermogravimetry-differential thermal analysis atlas (TG-DTA) shows that crystalline form IV has an endothermic peak at 217° C., and has an exothermic peak at 130° C., which are shown in  FIG. 11 . The infra-red spectrogram of the crystalline form IV shows that there are characteristic absorption peaks at 3473.56, 3407.98, 3269.12, 3060.82, 2981.74, 2933.53, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1433.01, 1415.65, 1340.43, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42, 966.27, 833.19, 771.47, 757.97 and 518.82 cm −1 . The infra-red spectrogram is shown in  FIG. 12 . 
       Embodiment 5 Revaprazan Hydrochloride Crystalline Form V 
       [0103]    In the powder X-ray diffraction pattern, 2θ, which is represented in degree, the characteristic diffraction peaks at 7.68±0.2, 24.52±0.2, 13.74±0.2, 8.06±0.2, 19.54±0.2. The specific powder X-ray diffraction data is shown in Table 25, and its powder X-ray diffraction pattern is shown in  FIG. 13 . 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 25 
               
             
             
               
                   
               
               
                 Parameters of characteristic peaks of powder X-ray diffraction pattern 
               
               
                 of revaprazan hydrochloride crystalline form V 
               
             
          
           
               
                   
                 Serial 
                   
                   
                 Relative 
               
               
                   
                 Number 
                 2θ 
                 d value 
                 intensity I/I 0   
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 7.680 
                 11.5018 
                 100 
               
               
                   
                 2 
                 8.060 
                 10.9604 
                 62 
               
               
                   
                 3 
                 10.280 
                 8.5979 
                 6 
               
               
                   
                 4 
                 13.060 
                 6.7733 
                 9 
               
               
                   
                 5 
                 13.740 
                 6.4396 
                 66 
               
               
                   
                 6 
                 14.280 
                 6.1972 
                 9 
               
               
                   
                 7 
                 14.500 
                 6.1037 
                 9 
               
               
                   
                 8 
                 15.340 
                 5.7713 
                 13 
               
               
                   
                 9 
                 15.660 
                 5.6541 
                 21 
               
               
                   
                 10 
                 16.100 
                 5.5005 
                 25 
               
               
                   
                 11 
                 18.300 
                 4.8439 
                 15 
               
               
                   
                 12 
                 18.540 
                 4.7818 
                 17 
               
               
                   
                 13 
                 18.860 
                 4.7014 
                 19 
               
               
                   
                 14 
                 19.540 
                 4.5392 
                 18 
               
               
                   
                 15 
                 20.040 
                 4.4271 
                 41 
               
               
                   
                 16 
                 20.440 
                 4.3414 
                 14 
               
               
                   
                 17 
                 21.020 
                 4.2229 
                 30 
               
               
                   
                 18 
                 22.200 
                 4.0010 
                 6 
               
               
                   
                 19 
                 22.700 
                 3.9140 
                 8 
               
               
                   
                 20 
                 23.420 
                 3.7953 
                 35 
               
               
                   
                 21 
                 24.060 
                 3.6957 
                 18 
               
               
                   
                 22 
                 24.520 
                 3.6274 
                 96 
               
               
                   
                 23 
                 25.200 
                 3.5311 
                 19 
               
               
                   
                 24 
                 25.440 
                 3.4983 
                 18 
               
               
                   
                 25 
                 26.220 
                 3.3960 
                 26 
               
               
                   
                 26 
                 26.860 
                 3.3165 
                 18 
               
               
                   
                 27 
                 27.340 
                 3.2594 
                 23 
               
               
                   
                 28 
                 27.940 
                 3.1907 
                 21 
               
               
                   
                 29 
                 28.780 
                 3.0995 
                 12 
               
               
                   
                 30 
                 29.160 
                 3.0599 
                 12 
               
               
                   
                 31 
                 30.080 
                 2.9684 
                 18 
               
               
                   
                 32 
                 30.800 
                 2.9006 
                 18 
               
               
                   
                 33 
                 31.600 
                 2.8290 
                 12 
               
               
                   
                 34 
                 32.140 
                 2.7827 
                 8 
               
               
                   
                 35 
                 33.200 
                 2.6962 
                 11 
               
               
                   
                 36 
                 33.660 
                 2.6604 
                 12 
               
               
                   
                 37 
                 34.260 
                 2.6152 
                 7 
               
               
                   
                 38 
                 35.140 
                 2.5517 
                 6 
               
               
                   
                 39 
                 37.280 
                 2.4100 
                 11 
               
               
                   
                 40 
                 38.140 
                 2.3576 
                 7 
               
               
                   
                 41 
                 43.160 
                 2.0943 
                 8 
               
               
                   
                 42 
                 44.980 
                 2.0137 
                 8 
               
               
                   
                   
               
             
          
         
       
     
         [0104]    The thermogravimetry-differential thermal analysis atlas (TG-DTA) shows that crystalline form IV has an endothermic peak at 216° C., and has an exothermic peak at 143° C., which are shown in  FIG. 14 . The infra-red spectrogram of the crystalline form V shows that there are characteristic absorption peaks at 3471.63, 3411.84, 3267.19, 3060.82, 2981.74, 2931.60, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1433.01, 1415.65, 1338.51, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42, 966.27, 833.19, 771.47, 757.97 and 518.82 cm −1 . The infra-red spectrogram is shown in  FIG. 15 . 
       Embodiments of the Preparation Method 
     Embodiment 1 Preparation of Revaprazan Hydrochloride Crystalline Form I 
       [0105]    10 g of crude product of revaprazan hydrochloride is placed in a reaction flask, 30 g of 87% ethanol aqueous solution is added, under the protection of nitrogen, the mixture is stirred and heated until completely dissolved, after slight cooling, 0.1 g of activated carbon is added, reflux-decoloration is performed for 15 min, and the solution is filtered while hot and is cooled to 15° C. for crystallization under stirring. It is filtered and washed with 87% ethanol aqueous solution, and is dried to obtain the product (8.9 g). 
       Embodiment 2 Preparation of Revaprazan Hydrochloride Crystalline Form I 
       [0106]    50 g of crude product of revaprazan hydrochloride is placed in a reaction flask, 250 g of 90% ethanol aqueous solution is added, under the protection of nitrogen, the mixture is stirred and heated until completely dissolved, after slight cooling, 0.5 g of activated carbon is added, reflux-decoloration is performed for 10 min, and the solution is filtered while hot and is cooled to 0° C. for crystallization under stirring. It is filtered and washed with 90% ethanol aqueous solution, and is dried to obtain the product (47.3 g). 
       Embodiment 3 Preparation of Revaprazan Hydrochloride Crystalline Form I 
       [0107]    20 g of crude product of revaprazan hydrochloride is placed in a reaction flask, 200 g of 95% ethanol aqueous solution is added, under the protection of nitrogen, the mixture is stirred and heated until completely dissolved, after slight cooling, 0.2 g of activated carbon is added, reflux-decoloration is performed for 5 min, and the solution is filtered while hot and is cooled to 5° C. for crystallization under stirring. It is filtered and washed with 95% ethanol aqueous solution, and is dried to obtain the product (18.9 g). 
       Embodiment 4 Preparation of Revaprazan Hydrochloride Crystalline Form I 
       [0108]    10 g of crude product of revaprazan hydrochloride is placed in a reaction flask, 150 g of 98% ethanol aqueous solution is added, the mixture is stirred and heated until completely dissolved, after slight cooling, 0.1 g of activated carbon is added, reflux-decoloration is performed for 15 min, and the solution is filtered while hot and is cooled to 10° C. for crystallization under stirring. It is filtered and washed with 98% ethanol aqueous solution, and is dried to obtain the product (9.3 g). 
       Embodiment 5 Preparation of Revaprazan Hydrochloride Crystalline Form I 
       [0109]    5 g of crude product of revaprazan hydrochloride is placed in a reaction flask, and 100 g of anhydrous alcohol aqueous solution is added, the mixture is stirred and heated until completely dissolved, 0.1 g of activated carbon is added after slight cooling, reflux-decoloration is performed for 15 min, and the solution is filtered while hot and is cooled to 15° C. for crystallization under stirring. The crystals are filtered and washed with anhydrous alcohol aqueous solution, and are dried to obtain 4.6 g product. 
       Embodiment 6 Preparation of Revaprazan Hydrochloride Crystal Form II 
       [0110]    20 g of crude product of revaprazan hydrochloride is placed in a reaction flask, and 200 g of anhydrous alcohol aqueous solution is added, the mixture is stirred and heated under the protection of nitrogen until completely dissolved, 0.2 g of activated carbon is added after slight cooling, reflux-decoloration is performed for 5 min, and the solution is filtered while hot and is cooled to 15° C. for crystallization under stirring. The crystals are filtered and washed with 85% anhydrous alcohol aqueous solution, and are dried to obtain 18.1 g product. 
       Embodiment 7 Preparation of Revaprazan Hydrochloride Crystal Form III 
       [0111]    30 g of crude product of revaprazan hydrochloride is placed in a reaction flask, and 150 g of 75% anhydrous alcohol aqueous solution is added, the mixture is stirred and heated under the protection of nitrogen until completely dissolved, 0.3 g of activated carbon is added after slight cooling, reflux-decoloration is performed for 15 min, and the solution is filtered while hot and is cooled to 15° C. for crystallization under stirring. The crystals are filtered and washed with 75% anhydrous alcohol aqueous solution, and are dried to obtain 27.6 g product. 
       Embodiment 8 Preparation of Revaprazan Hydrochloride Crystal Form IV 
       [0112]    30 g of crude product of revaprazan hydrochloride is placed in a reaction flask, and 300 g of 70% anhydrous alcohol aqueous solution is added, the mixture is stirred and heated until completely dissolved, 0.3 g of activated carbon is added after slight cooling, reflux-decoloration is performed for 5 min, and the solution is filtered while hot and is cooled to 15° C. for crystallization under stirring. The crystals are filtered and washed with 70% anhydrous alcohol aqueous solution, and is dried to obtain 27.1 g product of. 
       Embodiment 9 Preparation of Revaprazan Hydrochloride Crystal Form V 
       [0113]    30 g of crude product of revaprazan hydrochloride is placed in a reaction flask, and 180 g of 50% anhydrous alcohol aqueous solution is added, the mixture is stirred and heated until completely dissolved under the protection of nitrogen, 0.3 g of activated carbon is added after slight cooling, reflux-decoloration is performed for 5 min, and the solution is filtered while hot and is cooled to 5° C. for crystallization under stirring. The crystals are filtered and washed with 50% anhydrous alcohol aqueous solution, and are dried to obtain 27.0 g product. 
       Formulation Embodiments 
     Embodiment 1 
       [0114]    0.5 g of any one polymorph product of embodiments 1-5 is taken and is evenly mixed with 10.5 g of polyethylene glycol 6000, heating and melting are performed, the molten material is transferred into a dripper for dripping pills, the drug solution is dropwise added into 6-8° C. liquid paraffin, followed by deoiling, to obtain 400 dripping pills. 
       Embodiment 2 
       [0115]    0.5 g of any one polymorph product of embodiments 1-5, 4.5 g of glucose, 0.9 g of sodium thiosulfate and 1 mL of distilled water are taken and mixed evenly, freeze-dried, and packaged in 500 ampoules, to obtain the final products. 
       Embodiment 3 
       [0116]    0.5 g of any one polymorph product of embodiments 1-5, 5.5 g of mannitol, 0.9 g of calcium sodium edetate and 2 mL of distilled water are taken and mixed evenly, freeze-dried, and packaged in 300 ampoules, to obtain the final products. 
       Embodiment 4 
       [0117]    0.5 g of any one polymorph product of embodiments 1-5, 50 g of starch and 50 g of sucrose are taken and evenly mixed, granulated and tabletted to obtain tablets. 
       Embodiment 5 
       [0118]    0.5 g of any one polymorph product of embodiments 1-5, 50 g of starch and 50 g of sucrose are taken and mixed evenly, granulated and encapsulated to obtain capsules.