TWI243816B - Polymorphs of donepezil hydrochloride and process for production - Google Patents

Abstract

Donepezil hydrochloride, 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride, is provided here in the form of four polymorphs which are stable against heat and humidity in the pharmaceutical use. They can be industrially produced. They are specified by peaks in X-ray powder diffraction pattern and absorption peaks in infrared absorption spectra in potassium bromide.

Description

1243816 A7 B7 V. Description of the invention (,) [Field of the invention] The present invention is pseudo-related to Donepezil hydrochloride, which is shown in the implementation of US-A 4,895,841 or EP-A 296560. Example 4 of 1-benzyl-4-[(5,6-dimethylamino-1-indanone) -2-yl] methylhexahydropyridine phosphonium chloride, a stable polymorph, as翳 Pharmaceuticals have excellent work efficiency and industrial processes for manufacturing them. [Background of the Invention] Dunapal Hydrogenate shows inhibitory activity on acetoesterase and can be used to treat various and all kinds of the elderly. Treatment of dementia can be used to prevent, treat and alleviate Alhambra's disease. Dunapal hydrochloride is commonly administered orally and can be stored for a period of time before distribution and storage. Based on the characteristics of the target disease, it can be stored in a patient's home for up to a month. The stability of the drug to heat and humidity is important during storage. Therefore, there is a need for a more stable Dunabel helium drug system. However, the existence of polymorphs of Dunabel Hydrochloride has not yet been known. Nor was dunapal hydrochloride drugs sufficiently stable. [Prior art]

Printed by the Central Standards Bureau of the Ministry of Economic Affairs of the Shellfish Consumer Cooperatives (please read the precautions on the back before filling this page) US-A No. 4,895,841 Example 4 of the patent case shows that the crude mixture of Dunabel gas chloride is replaced by Recrystallization from methanol / isopropyl ether can provide purified dunapar hydrochloride. The existence of a more stable crystalline form of Dunapal hydrogen hydride over a long period of time will be more practical in terms of its distribution and storage. [Inventive summary] -3-This paper size is in accordance with Chinese National Standard (CNS) Λ4 叱 (210X297 mm) 1243816 A7 B7 V. Description of the invention (2) In view of the foregoing problems, the inventor of this case has conducted thorough research . As a result, it was found that the novel polymorphs (I) to (IV) and (V) of dunapar hydrochloride can be produced with excellent stability, and the present invention was established. The present invention provides five novel polymorphs of dunapar hydrochloride and excellent industrial processes for making them. In detail, the present invention relates to five polymorphs (I) to (V) of dunapar hydrochloride represented by the following chemical formulas, which are based on powder X-ray diffraction The peak K and the infrared absorption spectrum in potassium bromide are defined. 〇

(Please read the precautions on the back before filling in this page) HCI · Conditional measurement of each 100 mg sample piece Target Cu m Mirror monochrome voltage 40KV Current 2 0 ra A Narrow DS 1, RS Scanning speed 2 deg / nin. Range 5-3 Order 0 / Sample 0. 02d eg -4- (Method and conditions for measuring X-ray diffraction spectrum) ⑴ Measurement method M is as follows: 条件 Measurement conditions are printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 1243816 A7 B7 V. Description of the invention (5 pieces and the French side of the absorption line measuring the red outside the red potassium potassium bromide in the measuring method Recipes of the general formula 1 * Codex. The light spectrum receipt of the pharmacopoeia is outside the line (please read the precautions on the back before filling this page)-binding and ordering _ hard copy of the Ministry of Economic Affairs Central Standards Bureau employee consumer cooperative Paper size is applicable to Chinese National Standard (CNS) A4 specification (2Ι〇χ M7 mm) 1243816 A7 B7 V. Description of the invention (4) ⑴ Polymorph (I) for powder X-ray The peak value of the diffraction pattern is: diffraction angle intensity (20,.) (1 / I 〇) 90233345667789991222333689 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 1 2 2 2 2 2 2 2 2 2 2 40626626860828042048082620 96616892085542892059679405 49954097544207550219658357 21654441333422440334577323 (Please read the precautions on the back before filling this page) -pack-

IX The wave number of the infrared absorption spectrum (C · 4) printed on the potassium bromide in the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs · 463, 502, 563, 539, 604, 701, 750, 759, 799, 860 , 922, 947, 972, 1012, 1038, 1104, 1120, 1128, 1175, 1192, 1218, 1250, 1267, 1316, 1368, 1410, 1433, 1440, 1455, 1472, 1502, 1591, 1606, 1644, 1684 , 2412, 2530, 2559, 2595, 2620, 2717, 2840, 2858, 2924, 3004, 3074, 3259, 3373, 3547, 3589 cm " 1. This paper scale meets Chinese national standards (CNS > A4 size (210X297 Mm) 1243816

V. Description of the invention (5) The peak of ⑵ polymorphism (I) in powder X-ray diffraction form is: m-angle (2Θ 9 °) intensity (1 / I 〇) 7.40 8 9.88 100 12.36 13 15.54 40 16 · 10 38 16.22 38 16.48 35 17 · 30 17 18 · 04 20 18.44 17 18 · 84 19 19.34 19 19 · 84 47 21.16 24 22.40 19 23.18 33 24 · 02 22 24. 92 25 25.72 27 26.40 18 27,22 14 (Please (Please read the notes on the back before filling out this page)

、 1T-The wave number of the infrared absorption spectrum (ciT1) printed in the potassium bromide for the consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: 699, 748, 762, 845, 947, 1009, 1035, 1067, 1103, up 118, 1193, 1206, 1222, 1247, 1267, 1317, 1365, 1422, 1436, 1502, 1592, 1607, 1688, 2412, 2489, 2627, 2846, 2868, 3435 cm'1. 1129, 1174, 1456, 1465, 2913 , 2928, This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 1243816 A7 B7 V. Description of the invention (6) (3) Polymorphic form (B) Peak of powder X-ray diffraction For: Diffraction angle (20 ·.) Intensity (I / I〇) 6. 56 30 9.94 8 13 · 00 17 15.00 47 15-26 -14 15.74 6 16 · 48 35 17-42 4 18 · 10 21 18 · 50 56 19 · 50 17 20 · 10 32 20.94 21 21 · 66 100 22 · 32 25 22 · 92 17 23.92 19 24.68 17 26.00 44 27.20 23 28.02 29 28.22 40 28.60 13 Wave number of infrared absorption spectrum in potassium bromide ( C ·· 1): 559, 641, 648, 702, 749, 765, 786, 807, 851, 872, 92J · 949, 966, (Please read the precautions on the back before filling this page) Ministry of Economic Affairs Central Standard Printed by local shellfish consumer cooperatives 9 7 5, 982, 1007, 1034, 10 71, 1080, 1111, 1119, 1131, 11111 1190, 1205, 1217, 1230, 1250, 1265, 1292, 1313, 1367, 1389, 1420 , 1438, 1453, 1461, 1470, 1500, 1589, 1605, 1697, 2407, 2419, 2461, 2624, 2641, 2651, 2667, 2837, 2848, 2873, 2924, 2954, 2961, 2993, 3007, 3377, 3433 cm " 1. —8— This paper has a standard of Chinese Standard (sCNS) A4 (210X 297 mm) 1243816 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (7) ⑷ Polymorphs ( VI) The peak value in the form of powder X-ray diffraction is: the intensity of the incident angle (2Θ r) (ΐ / ι 〇) 6.24 9. 66 11.04 12 · 12 12.54 12 · 76 13-98 14.42 14.88 16-34 17 · 46 18 · 12 18 · 60 19-06 19 · 98 20 · 42 20 · 62 21.30 21.80 21.80 22.. 23.23 24.00 24.54 25,14 25,36 26 · 06 28.10 28.58 29. 30 29 · 44 90 52247175120525414 ^ 386290941918 112266211102317434674349934332 ( Please read the notes on the back before filling this page) Wave number of infrared absorption spectrum in potassium bromide (c ηΤ1): 401, 43 1, 459, 46 7, 490, 506, 518, 561, 586, 606, 631, 651, 709, 758, 766, 857, 944, 1009, 1041, 1106, 1119, 1132, 1213, 1225, 1265, 1304 , 1318, 1429, 1458, 1470, 1500, 1589, 1605, 1630, 1647, 1683, 2562, 2577, 2608, 2634, 2689, 2717, 2836, 2924, 2949, 2989, 3007, 3032, 3061, 3322, 3376 , 3422 cm'1. One q — This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1243816 A7 B7 V. Description of the invention (8) Additional analysis data of polymorphs (I) to (V) Shown below.峰值 The peak of polymorphism (I) in powder X-ray diffraction form is the diffraction angle (2Θ 9 °) intensity (I / I〇) 9. 82 13 10 · 48 18 12.52 93 13 · 02 69 13.52 34 13 · 74 37 14.78 31 16.00 45 16.76 37 17 · 46 34 19.18 26 19.66 32 21.04 100 21-16 82 22. 92 52 23.82 72 24.14 32 (Please read the notes on the back before filling out this page) ▼ Central Ministry of Economic Affairs Wave number of infrared absorption spectrum (cirT1) printed on potassium bromide by the Consumer Cooperative of Standards Bureau. 562.7, 603.2, 700.4, 749.6, 798.1, 859.2, 896.0, 921.3, 946.3, 971.8, 1038.0, 1119.3, 1216.8, 1266 0, 1315 · 4, 1367.7, 1454.1, 1501.5, 153 7.8, 1555.9, 1590.7, 1643.7, 1681.9, 2350.9, 2534.0, 2922.1, 3381.8, 3585.2 cm " 1. -10- This paper is applicable to "W 家 螵Feng (CNS) A4g (210X297 mm) 1243816 A7 B7 V. Description of the invention (9) The peak value of the polymorphic form (I) in the powder X-ray bin form is: Diffraction angle (20,) Intensity (1 / I 〇) 10.10 76 12.64 14 15.74 85 15.82 86 16.20 100 16.46 87 17 · 40 50 17.50 48 17 · 88 31 1 8.36 28 18 · 58 51 18.66 46 19.48 42 20 · 18 81 20.80 36 22 · 26 45 23.38 86 23.52 59 24.06 34 24. 32 55 25.14 44 25 * 44 50 25.72 39 25.96 35 26 · 14 25 28 · 06 25 28 · 20 34 28.38 34 (Please read the precautions on the back before filling out this page). Packing: Wave number of infrared absorption spectrum (ciT1) printed on potassium bromide printed by Shelley Consumer Cooperative of Central Standard Bureau of Ministry of Economic Affairs: 560.1, 698.9, 749.1 , 846 · 2, 947.6, 1036.1, 1119 · 3, 1222.7, ί 1266 · 4 χ 1318.7, 1364.1, 1458.3, 1500.9, 1522.3, 1534.0, 1542.6, 1560.2, 1570. ^ 3, 1592.0, 1637.0, 1647.9, 1654.4, 1689.5 , 1718.3, 1734.7, 1751.7, 1773.9, 1793.8, 1830.7, 1846.0, 1870.1, 2345.1, 2489.9, 2927.9, 3448.1 cm'1. -11- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1243816 A7 B7 V. Description of the invention (10) ⑶ The peak of the polymorphic (in) powder X-ray diffraction form is: diffraction angle (20, °) intensity (I / I〇) 6 · 48 21 9 · 84 7 12 96 19 14.94 45 15.20 13 1 6 4 4 31 18.04 20 18.46 55 19.44 17 20.02 30 20.86 20 21.02 13 21 · 58 100 22.22 23 22 · 90 15 23.92 13 24 · 64 15 25.92 40 26.18 17 27.14 21 28.14 37 28 · 56 11 29.94 12 (Please read the precautions on the back before filling out this page)-Installation · Wave number of infrared absorption spectrum in potassium bromide (CIT1): Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 558.3, 64Ϊ.1, 702.4, 748.5, 765.0, 786.1, 807.3, 850.8, 872.0, 926.8, 974.9, ring 1034.1, 1071.5, 1111.6, 1190.1, 1216.6, 1265.4, 1291.9, 1312.9 t 1364.4, 1420.2, 1438.1, 1458.8, 1499.1, 1522.2, 1542.6. 1560.1, 1570.2, 1589.1, 1638.8, 1647.8, 1654.3, 1697.3, 1718.1 , 1734.5, 1751.4, 1773.7, 1793.5, 1845.8, 2345.3, 2461.6, 2924.2, 3447-9 cm'1. This paper size applies the Chinese National Standard (CNS) A4 (210X297 mm) 1243816 B7 V. Description of the invention (11 ) The peak of ⑷ polymorphic form (IV) in the powder X-ray diffraction form is: diffraction angle (2 Θ, °) intensity (Ι / Ι〇) 9. 64 11 10 · 92 11 12.46 63 12 · 72 17 13.86 27 14.42 12 17.36 100 18.54 39 19.90 37 21.18 35 21.74 39 22 * 48 60 22 · 96 36 24. 10 17 25.28 70 28.00 27 28.50 27 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Infrared absorption in potassium bromide Spectral wave number (CBT1): 561.5, 709.0, 766.2, 786.3, 804.9, 857.0, 944.3, 979.3, 1041.5, 1118.7, 1264.6, 1318.7, 1364.1, 1458 · 1, 1499.2, 1542.5, 1560 · 1, 1588.1, 1636.6, 1647.8, 1654.3, 1684.3, 1718 · 2, 1734 · 4, 1751 · 4, 1773 · 7, 1793.5, 1830.5, 1845.8, 1870.1, 2344 · 8, 2369 · 3, 2719.2, 2922.9, 3324.0 cm'1 -13--This paper size applies the Chinese National Standard (CNS) A4 ^ (210 × 297 mm) 1243816 A7 B7 V. Description of the invention (l2 ⑸ polymorphic form (V) The peak value of the powder X-ray emission form is Diffraction angle (20, ° Intensity (1 / I 〇) 66022357899990011244566778999 111111111112222222222222222 86240482460440606606426642260866 58159652483673419226318592567 72334792959597502360544593 23346267121211103696142141 7 1 7 (Please read the notes on the back and fill in this page)

Jm • Refilling, binding and binding-printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs «. Wave number of infrared absorption spectrum in potassium bromide (c IT1): 506.5, 559.7, 594.4, 698.0, 740.8, 805.1, 861.9, 948.5, 972.1, 1039.9, 1120.8, 1220.7, 1264.8, 1314.6, 1364.1, 1458.0, 1499.5, 1542.5, 1560.2, 1592.1, 1692.9, 2500, 1, 2924.2, 2998.9, 3422.1 cnT1 Standard (CNS) A4 (2 丨 (> X 297 mm)) ¾ All year old jealousy licked Feng Mabei M Consumption Coupling • Social Seal 空 evasion (e bp ty) 5 eC / swollen i η 0 · 7 sec · 3 0 0 ° C Room temperature K43816 A7 B7 V. Description of the invention (〇) The melting points of the novel polymorphs (I) to (V) shown in the present invention are different from US-A4, 8 9 5 The melting point of Example 4 in No. 8, 41. The melting point in US-A4,895,841 is 211-212 X! (Decomposition). The melting point of the polymorph (I) is 2 2 5-2 2 6 eC (decomposition). The melting point of polymorph (II) is 2 2 4-2 2 6 ° C (decomposed). The melting point of polymorph (II) is 229-231 ° C (decomposed). The melting point of polymorph (IV) is 226-228 ° C (decomposition). The melting point of the polymorph (V) is 218-220 ° C (decomposition). [The melting point of the amorphous is 220-222 ° C (decomposition).] Furthermore, the polymorphs are The results of thermogravimetric analysis and differential thermal analysis (TG-DTA) measured under the following conditions show patterns different from the prior art. Based on this, it can be known that these crystal types are completely different from the prior art. {Pyrogravimetric analysis And differential thermal analysis (TG-DTA) methods and conditions} Take a sample of about 3-6ng and accept thermal analysis under the following conditions β Reference Reference (scan) Detailed method to limit the preparation of novel polymorphs under the upper limit of scanning speed sampling In these methods, " Dunapar " means the free base of the Dunapar hydrogen hydride, i.e. 1-benzyl-4-[(5,6-dimethylamino-buindacin) Keto) -2-yl] methylhexahydropyridine. (1) Method for preparing polymorph (I) (1-Π recrystallizing Dunabel's hydrogenated atmosphere from methanol, 0 -1 5-paper size Applicable to China National Standard (CNS) Α4 specification (21〇 × 297 mm) (Please read the precautions on the back before filling this page). Thread_ 1243816 A7 B7 V. Description of the invention (14) Chlorinated hydrogen chloride, pallazonide or diethyl ether in lympa KK Μ Du hydrogen ethane and chlorine 0 or acid salt into methyl alcohol After the solution is dissolved, the alcohol and ether propyl are added in order, followed by alcohol or hydrogen; The hydrogenated hydrogenated pachlor B. S 0 ^ Duric acid will be printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Salt Economy (1-5 ) Dissolve dunapar in ethanol, then add hydrochloric acid or hydrogen chloride, and isopropyl ether sequentially, and then crystallize immediately after separation. Methods (1-5) are preferred. The method is shown in Example 7. (2) Method for preparing polymorph (H) (2-1) Dissolving dunapar hydrochloride in ethanol, and then add diethyl ether or isopropyl ether, (2-2) Diunapar hydro The chloride was dissolved in ethanol, followed by the addition of isopropyl ether, and crystals were decanted from the separation solution after 10-30 minutes. (2-3) Dissolving dunapar and hydrochloric acid or hydrogen chloride in ethanol, and then add diethyl ether, (2-4) Dissolving dunapar and ethanol or hydrochloric acid or hydrogen chloride, and then concentrate, (2-5) Dissolving Dunabel in ethanol and then sequentially adding hydrochloric acid or hydrogen chloride and isopropyl ether; or (2-6) Dissolving dunapar in ethanol and then sequentially adding hydrochloric acid or hydrogen chloride and isopropyl ether, After 10 to 60 minutes of hydrocarbons, preferably 10 to 30 minutes of hydrocarbons, crystals are decanted from the separation solution. Method (2-6) is better. This method is shown in Example 14. (3) Method id for preparing polymorph (1Π). (Please read the precautions on the back before filling this page)

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1243816 A7 B7 5. Description of the invention (15) (3-1) Paraffin hydrochloride is dissolved in ethanol, followed by ether, (3-2) Dunaparr hydrochloride is dissolved in dioxane, then n-hexane is added, and (3-3) Duraparr Soluble in acetone, then add hydrochloric acid or hydrogen chloride, (3_4) Dissolve dunapar in ethyl acetate, then add hydrochloric acid or hydrogen chloride, (3-5) Dissolve dunapar in ethanol, then add hydrochloric acid or Hydrogen chloride, and then add at least one solvent selected from the group consisting of ether, isopropyl ether and n-hexane, (3-6) following the method of (3-5), wherein the selected solvent is isopropyl ether after 1 hour, preferably It is 2 hours, more preferably 6 hours after the crystals are decanted from the separation solution, or (3-7) the polymorph (I) or (E) is heated. Methods (3-5) and (3-6) are preferred. These methods are shown individually in Examples 23 and 1δ. (4) A method for preparing the polymorph (F) is: (4-1) humidifying effect of the polymorph (Π). Method (4-1) is shown in Example 24. The aforementioned methods (1-5), (2-6) and (3-6) include dissolving Dunabel in ethanol, followed by adding hydrochloric acid or hydrogen chloride, and then adding isopropyl ether. Any of these methods can produce polymorphs (I), (H), and (I) by controlling the interval from recrystallization to separation of crystals from perylene. The amount of time delay varies with crystallization conditions such as temperature, search speed, and solvent volume. The following methods can usually be adopted. -17- This paper size applies to China National Standard (CNS) 8 4 ^ (210 × 297 mm) (please read the precautions on the back before filling this page). 1T 1243816 A7 B7 Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Cooperative print 5. Description of the invention (i6) (1) Immediately after separation, «crystals to form polymorphs u) · (2) 10-60 minutes after separation, preferably 10-30 minutes after filtration To form polymorphs UI) · (3) 1 hour after separation, preferably 2 hours, more preferably 6 hours to pass through the crystals to form polymorphs (11 workers) · Preparation of novel polymorphs The detailed method is as follows: (¾ The method for preparing the polymorph (I) is:-(1 -6) dissolving dunapar in methanol, then adding hydrochloric acid or hydrogen chloride, (1-7) dissolving dunapal In methanol, then sequentially add hydrochloric acid or hydrogen chloride, and add the third butyl methyl ether, isopropyl ether or ethyl acetate, (1 -8) dissolve dunapar in ethanol, tetrahydrofuran or acetonitrile, and then add hydrochloric acid or Hydrogen chloride, (1-9) Dissolve dunapar hydrochloride in methanol, then add the third butyl methyl ether, ethyl acetate And n-hexane, (1-10) recrystallizing dunapar hydrochloride from ethanol, (1-11) dissolving dunapar hydrochloride in ethanol, and then adding a third butyl methyl ether, method ( 1-7) is better. This method is shown in Examples 30, 31 and 32. Method (1-9) is also good. This method is shown in Examples 39, 40 and 41. (2) Preparation of polymorph (H) Method (2-7) dissolving dunapar in ethanol, then sequentially adding hydrochloric acid or hydrogen chloride and adding a third butyl methyl ether, (2-8) dissolving dunapar in isopropanol, acetone or Tetrahydrofuran, then add hydrochloric acid or hydrogen chloride, ~ 1 8-(Please read the notes on the back before filling out this page). Binding · Binding-The size of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1243816 A7 B7 V. Description of the invention (17) (2-9) Dissolve dunapar in dichloromethane, then add hydrochloric acid or hydrogen chloride and isopropyl ether in sequence, (2-10) dunapar hydrochloride Dissolve in acetic acid, then add the third butyl methyl ether or isopropyl ether and search under 101. (2-11) Dissolve dunapar hydrochloride in dichloromethane , And then add a third butyl methyl ether or isopropyl ether; or (2-12) heating the polymorph (I) or hydrazone crystal form dunapar hydrochloride. Method (2-7) is preferred. This method is shown in Example 45. Method (2-10) is also preferred. This method is shown in Examples 52, 53 and 54. (3) Method (3-8) for preparing polymorph (B) Dissolving Dunamol in methanol Then, add the salt series in sequence or (please read the precautions on the back before filling this page)-install the chloride or acid salt in the order of addition, and then follow the ether., Base., Alcohol methyl ethyl ethyl propyl Dissolve Sangardi and Pardin in Ding, mix Nagadol and Chlorine. Mix hydrogen, or acid salt with water, and add ketones, followed by ketones, amines, ketones, and acetonitrile N-Soluble H, Pyrene or Paran β, Dihydrogen will add tetra \ 1 / or acid salt in the order of addition and then 0 esters of ethyl acetate and ethyl acetate. Rol, Parhydronadol chloride will be ordered · Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperatives or acidified by acid esters, followed by ether, t-methyl, ¾, ¾, ¾, ¾, Η. _. Ding San dissolved into Calgary and Pa and hydrogen Hydrogenation 1 will condense chlorohydrogen and then re-chlorinated alcohol or formic acid will be added to the salt and V will be added to 10 and then will be lower. Zhang Jiye uses the Chinese National Standards (CNS) today 4 specifications (210X297 mm). The seal of the Bayer Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1243816 A7 B7 V. Description of the invention (18) (3-15) Dissolve the chloride in methanol, then add the third butyl methyl ether or acetonitrile, (3-16) Dissolve the dunapar hydrochloride in ethanol, and then add the third butyl methyl ether or acetone. Search and mix, (3-17) dissolve dunapar hydrochloride in N, Η-dimethylformamide or dimethyl asus, and then add a third butyl methyl ether, (3-18) Napal hydrochloride is recrystallized from isopropanol, and (3-19) is converted into a polymorph (I), (I), (¥), (V) or amorphous dunapar hydrochloride in a solvent. Or (3-20) according to the production method (3-19), wherein the solvent is selected from the group consisting of methanol, ethanol, ethyl ethoxylate or acetone. The method (3-11) is better. This method is shown in Example 59. Method (3-16) is also good. This method is shown in Example 72. Method (3-19) is better. This method is shown in Examples 76-95. (4) Method for preparing polymorph (W) (4-2) Dissolving dunapar in hydrochloric acid, and then filtering the separated crystal, (4-3) Dissolving dunapar in hydrochloric acid, and then adding Tetrahydrofuran, (4-4) dissolving dunapar in water and a mixture of tetrahydrofuran, followed by adding hydrochloric acid or hydrogen chloride, (4-5) dissolving dunapar in methanol, toluene or n-hexane, and then adding hydrochloric acid, ( 4-6) Dissolve dunapar in a mixture of formazan and hydrochloric acid, (4-7) Dissolve dunapar in water, and then add hydrochloric acid or hydrogen chloride. -20- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 丨 7 Γ ---- (Please read the precautions on the back before filling this page) Line 1243816 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Invention Description (is) ( 4-8) recrystallizing dunapar hydrochloride from water, (4-9) humidifying the polymorph (H) of dunapar hydrochloride; or (4-10) amorphous Dunapal hydrochloride humidifies. Method (4-4) is better. The method is shown in Example 101. Method (4-8) is also good. This method is shown in Example 106, (5) Method for preparing polymorph (V) t (5-1) heating polymorph of dunapar hydrochloride (IV) Method (5-1) is shown in Example 109. The aforementioned method (3-6) for obtaining polymorphs includes dissolving dunapar in ethanol, then adding hydrochloric acid or hydrogen chloride, and then adding isopropyl ether. The preferred crystallization time depends on the mixing speed. Dissolve volume and so on. However, high temperatures shorten the crystallization time. These changes are seen in Examples 96-98. The present invention provides a method for treating diseases related to acetylcholinesterase activity, by inhibiting acetylcholine esters in human patients by administering a pharmacologically effective amount of a polymorph of dunapar hydrochloride M Enzyme activity. The present invention further provides a therapeutic composition, which comprises a pharmacologically effective amount of the above-mentioned polymorphs of Dunapal Hydrogen. Chloride and a pharmaceutically acceptable carrier. The compound in the polymorphic form of the present invention is suitable for different kinds of senile dementia, especially Alhammer type senile dementia; cerebral stroke accompanied by cerebrovascular disease, such as cerebral hemorrhage or cerebral infarction, cerebral vascular sclerosis, head injury, etc. Treatment of encephalitis and cerebral palsy associated with inability (concentration), language disorder, weakened will, altered mood, attention deficit / hyperactivity disorder, short-term memory impairment, hallucinations-paranoid syndrome, behavior change, etc. (please first Read the notes on the back and fill in this page again)-Binding, binding-Thread paper size is applicable to China W furniture ratio (CNS) A4 specification (210 × 29; 7 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1243816 A7 B7 V. Description of the invention (20) Treatment, prevention, reduction and improvement are very effective. Furthermore, the compound in the form of a polymorph of the present invention has a strong and highly selective action on acetylcholinesterase, which causes the compound of the present invention to also be used as a drug based on this action. In detail, the compound in the form of a polymorph according to the present invention is non-Ammohan type such as Huntington, chores, Pick's disease, and delayed dyskinesia or tardive dyskinesia. Alzheimer's disease is effective. When the compound in the form of a polymorph of the present invention uses K as a drug for such diseases, it can be administered orally or parenterally. Generally, parenteral administration may be in the form of injections, such as intravenous, subcutaneous or intramuscular injections, suppositories or tongues; tablets. The dosage usually depends on the symptoms; the age, sex, weight, and sensitivity of the patient; the method of administration; the time and interval and characteristics of the administration, the type of pharmaceutical and pharmaceutical preparations; the type P of the active ingredient, etc., which are extremely different. There is no particular limitation on the dosage. Generally, the compound can be administered at a dose of 1.0 to 3 00 "per adult per day, preferably 1 to 100" per day. Pharmaceutical formulations such as injections, suppositories, sublingual tablets, capsules and capsules are prepared according to methods generally accepted in the art. In the preparation of injections, the active ingredients are mixed with: Ph regulators, elemental solutions, suspensions, solubilizers, stabilizers, penetrants, preservatives, etc., if needed, and then a vein, subcutaneous or muscle is prepared according to common methods injection. In this case, if necessary, they can be used as usual. See methods to freeze-dry these preparations. This paper size applies Chinese National Standard (CNS) Α4 specification (210X 297 mm) ----- ^ ---: --ΙΡΊ-- (Please read the precautions on the back before filling this page),?!- Line 1243816 ¾ Qilang Zhongli licking Mabeigong Cooperative Co., Ltd. Printing A7 B7 V. Description of the invention (> 1) Examples of the suspending agent include methyl mineral vitamin, polysorbate 80, hydroxyethylclavidin, Gum arabic, carrageenan powder, sodium carboxymethyl cellulose, and polyoxyethylene polysorbate monolaurate. Examples of the solubilizing agent include polygas ethylene hydrogenated sesame oil, polysorbate 80, nicotinamide, polygas polyethylene polysorbate monolaurate, polyethylene glycol (Macrogol), and ethyl ester of castor oil fatty acid. Examples of the stabilizer include sodium sulfite, sodium metabisulfite, and the like, and examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and phenoxycresol . [Brief Description of the Drawings] FIG. 1 is a powder X-ray diffraction pattern of the polymorph (I). _ Figure 2 shows the powder X-ray diffraction pattern of polymorph (II). FIG. 3 is a powder X-ray diffraction pattern of a polymorph (ffl). No. 4 is a powder X-ray diffraction pattern of the polymorph (VI). Fig. 5 is a powder X-ray diffraction pattern of an amorphous material. Number 6 is the infrared absorption effect of polymorph (I) on potassium bromide. Figure 7 shows the infrared absorption effect of polymorph (II) on potassium bromide. Figure 8 shows the infrared absorption effect of polymorph (m) on potassium bromide. Figure 9 shows the infrared absorption effect of polymorph (VI) on potassium bromide. Figure 10 shows the infrared absorption effect of amorphous substance on potassium bromide. Figure 11 shows the results of the pyrolysis weight and differential thermal analysis (TG-D T A) of the polymorph (I). Fig. 12 shows the results of pyrolysis weight and differential thermal analysis (TG-DTA) of the polymorph (II). -23- I-- · --L ———— (Please read the precautions on the back before filling this page), 1T

JL line · This paper size applies Chinese National Standard (CNS) A4 * t grid (2 丨 0 X 297 mm) 1243816 A7 B7 V. Description of the invention (22) Figure 13 shows the pyrolytic weight of the polymorph (set) And differential thermal analysis (TG-DTA) results. Figure 14 shows the results of the pyrolysis weight and differential thermal analysis (TG-DTA) of the polymorph (VI). FIG. 15 shows the results of pyrolysis weight and differential thermal analysis (TG-DT A) of the amorphous material. Fig. 16 is a graph showing the change of the impurity content when the polymorphs and amorphouss are stored at -20o. Figure 17 shows the changes in the impurity content of each polymorph and amorphous when stored at 40o. Figure 1δ shows the change in impurity content when each polymorph and amorphous are stored at 60ti. Figure 19 shows the change in impurity content when each polymorph and amorphous are stored at 80t. Figure 20 shows the changes in the water content of each polymorph and amorphous stored at 25 Π under different relative humidity conditions. Fig. 21 is a clear powder X-ray diffraction pattern of the polymorph (I). Fig. 22 is a clear powder X-ray diffraction pattern of the polymorph (I). Figure 23 is a clear powder X-ray diffraction pattern of polymorph (HI). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Figure 24 shows the clear powder X-ray diffraction pattern of polymorphs (VI). Figure 25 shows a clear powder X-ray diffraction pattern of the polymorph (V). Fig. 26 is a clear powder X-ray diffraction pattern of amorphous objects. Figure 27 shows the clear infrared absorption of polymorph (I) in potassium bromide. The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 1243816 A7 B7 5. Description of the invention (25) Figure 28 shows the clear infrared absorption effect of polymorph (H) on potassium bromide. Figure 29 shows the clear infrared absorption effect of polymorph (H) on potassium bromide. Figure 30 shows the clear infrared absorption effect of polymorph (VI) on potassium bromide 0 Figure 31 shows the clear infrared absorption effect of polymorph (V) on potassium bromide 0 Figure 32 is amorphous matter on bromide Clear infrared absorption effect of potassium. Figure 33 shows the results of clear pyrolysis weight and differential thermal analysis (TG-DTA) of the polymorph (Ί). Figure 34 shows the clear pyrolysis weight and differential thermal analysis (TG-DTA) results of the polymorph (E). Figure 35 shows the clear pyrolysis weight and differential thermal analysis (TG-DTA) results of the polymorph (M). Figure 36 shows the clear pyrolysis weight and differential thermal analysis (TG-DTA) results of the polymorph (VI). Figure 37 shows the clear pyrolysis weight and differential thermal analysis (TG-DTA) results of the polymorph (V). Figure 38 shows the clear pyrolysis weight and differential thermal analysis (TG-DTA) results of the amorphous material. The products shown in Figures 1-15 were again determined by experimentally obtaining a clearer shape. [Detailed description of the best embodiment] The paper size is in accordance with the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the precautions on the back before filling this page).

, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1243816 A7 B7 V. Description of the Invention (24) The present invention will now be described in more detail with reference to the following examples. Needless to say, the technical field of the present invention is not limited to these embodiments. Examples 1-8 relate to a method for producing the polymorph (I). Examples 9-15 relate to a method for producing a polymorph (E). Examples 16-27 relate to a method for producing a polymorph (S). Example 28 relates to a method for producing a polymorph (IV). Reference Example 1 relates to a method for manufacturing amorphous dunapar hydrochloride. 0 Example 1: Polymorph of dunapar hydrochloride (I). 1 g of dunapar hydrochloride was dissolved. In 5.1 methanol. 10 * 1 isopropyl ether was added and the mixture was stirred in an ice water bath. The separated crystals were filtered and dried in the atmosphere to give 0.9 g of the title compound. Example 2 • Polymorph of Dunapal Hydrochloride (I) 1 g of Dunapal hydrochloride was heated and dissolved in 5 * 1 methanol. After cooling to room temperature, 10.1 isopropyl ether was added. The mixture was stirred at room temperature for 30 minutes, and then the separated crystals were filtered and dried under the atmosphere to give 0.9 g of the title compound. Example 3: Polymorph of Dunapal Hydrochloride (I) 1 g of Dunapal hydrochloride was heated and dissolved in 5 nl of methanol. After the cooling solution started, the crystallization began to separate at an internal temperature of 15t. After 10 minutes, 10b1 isopropyl ether was added. The mixture was stirred at room temperature for 1 hour, and the isolated crystals were dried and dried in the atmosphere to give 0.9 g of the title compound. Example 4: Polymorph (I) of Dunapal Hydrogenate 5 grams of Dunapal hydrochloride were heated and dissolved in 25β1 of methanol, -2 6-This paper standard is applicable to Chinese National Standards (CNS ) Α4 size (210X297mm) ^ Γ--install ------- order ----- line (please read the notes on the back before filling this page) Cooperative printed A7 B7 V. Description of the invention (4) The mixture is then cooled in an ice water bath. The separated crystals were filtered and dried under the atmosphere to give 4.6 g of the title compound. Example 5: Polymorph (j) of Dunapal Argon Chloride 0.3 g of Dunapal was dissolved in 1.5 ml of methanol. Next, 0.997βιβ1 10 × -hydrochloric acid was added to a methanol mixture, and the separated crystals were dropped and dried under the atmosphere to give 0.2 g of the title compound. Example 6 · Polymorph of Dunapal Hydrogenated Aqueous Solution (1) 0.3 g of Dunapal was heated and dissolved in 3 * 1 ethanol. Then, 3 ml of isopropyl ether and 0.79 ml of 10% -hydrochloric acid in a methanol mixture were added, and the separated crystals were filtered and dried under the atmosphere to produce 0.2 g of the title compound. Example 7: Polymorph (I) of Dunapyr Hydrogenate 10 g of Dunapal was heated to dissolve in 100ial of ethanol. When mixing, add a mixture of concentrated hydrochloric acid (3.1g) and ethanol (28il), and then add 150al isopropyl ether. After 10 seconds of separation, it was crystallized and dried in the atmosphere to give 9.36 g of wedge-shaped compound with a yield of 85.4 ×, a water content of 5.17% and a melting point of 225-226 eC (decomposition). Example 8: Polymorph of Dunapal Hydrochloride (I) 10 g of Dunapal hydrochloride was dissolved in methanol by heating. In a cold water bath, add 600β1 ether. Stir for 1 hour under the same conditions, then filter the crystals and dry in the air to give the title compound. Example 9: Polymorph of Dunapar Hydrogenate (氛) 13.7 g of Dunapar and 4.411 | 1 hydrochloric acid were heated and dissolved in 1 () 0 »1 ethanol. After searching at room temperature, add 200 · 1 isopropyl®❶filter crystal-27- (Please read the precautions on the back before filling in this page) • Packing | Binding-Threaded paper Λ degree applies Chinese national standard ( CNS) Eight 4 ^ grids (210 × 29? Mm) 1243816 The Qilang order clip sample bureau cooper consumer cooperation Du Yin »A7 B7 5. Description of the invention (4) and dried under vacuum to produce 11.2 g of the title compound. Example 1 Polymorph of Dunabel Hydrochloride (I) 50 grams of Dunabel was heated to dissolve in 200 «1 ethanol. After cooling to room temperature, 27.3 g of 18 × hydrogen chloride in ethanol solution was added, and after standing still for 1 hour calmly, the mixture was concentrated under vacuum, and then the resulting crystals were dried in the atmosphere to give 55.0 g of the title compound. Example 11 1: Polymorph (II) of Dunapal Hydrochloride 0.5 g of Dunapal was heated and dissolved in 5 nl of ethanol. With stirring at room temperature, 10 × concentrated hydrochloric acid 1.31β1 was added to ethanol, followed by 5ϋ1 isopropyl ether. After 10 minutes, the crystals were filtered from the isolate and dried in the atmosphere to give 0.4 g of the title compound. Example 12 Polymorph (II) of Dunabel Hydrochloride 5.6 grams of Dunabel Hydrochloride was dissolved in 30b1 ethanol, and IGObI isopropyl ether was added. The mixture was cooled in an ice-water bath. The crystals were then filtered and dried at 50 ° C for three days to yield 4.9 g of the title compound. Example 13: Polymorph (Π) of Dunapyr hydrochloride 23.3 g of Dunapal hydrochloride was heated and dissolved in ethanol at 250 bl. After stirring in an ice water bath, 600 ml of diethyl ether was added, and after standing for 3 hours, the crystals were filtered and dried at 85 ° C for 22 hours to give 22.7 g of the title compound. Example 14 · Polymorph (II) of Dunabel Hydrochloride 10 g of Dunapar was heated and dissolved in 10 GmI of ethanol. With stirring, add 150b1 of concentrated hydrochloric acid (3.1g) and diethyl ether (28b1), followed by 15Gil isopropyl ether. After 15 minutes, the crystals were filtered and separated from the isolate, and at -28- (please read the precautions on the back before filling this page). Binding and binding paper; Applicable to China National Standard (CNS) 8 4 specifications (210X297 mm) ) 1243816 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (27) Dry drying under gas produces 9 g of the title compound with a yield of 82. IX and a melting point of 224-226 t! (Decomposition). Example 15: Polymorph of Dunapal Hydrochloride (H) 40 g of Dunapal hydrochloride was heated and dissolved in 700 b1 of ethanol. In an ice-water bath, add 50 ml of isopropyl ether. Flask K was removed by scraping with a spatula to complete crystallization, then the crystals were dried and dried at 50 ° for 12 hours to yield 31.4 g of the title compound. Example 16: Polymorph of Dunapal Hydrochloride (I) 16 g of Dunapal hydrochloride was heated and dissolved in 2000 β1 ethanol. After cooling to room temperature, 5000 ml of ether was added with stirring. It was crystallized and dried at 35t for 12 hours to produce 120 g of the title compound in a yield of 74.5. ≫: and a water content of 0.15X. Example 17: Polymorph (I) of Dunapal Hydrochloride 308 grams of Dunapal were dissolved in 700 b 1 ethanol. Under stirring, add 230al of 103 in sequence; hydrogen chloride in ethanol solution and 5000ml of ether. The crystals were filtered and dried at 50 ° C for 1 hour, then at 60t: for 30 minutes, and then at 85 ° F for 12 hours to yield 269 g of the title compound. Example 18 Polymorph (B) of Dunapal Argon Chloride 59 g of Dunapal was dissolved in 590 ml of ethanol. Under cooling in an ice-water bath, 17.8 g of concentrated hydrochloric acid and 885 a of isopropyl ether were sequentially added. After overnight searching at room temperature, the crystals were filtered and dried at 55TC for 22 hours to yield 62 g of the title compound. Example 19: Polymorph of Dunapal hydrochloride (melon) 5 grams of Dunapal hydrochloride are heated and dissolved in 100ml of ethanol-29- (Please read the precautions on the back before filling in this Page). Binding and binding of paper. The size of the paper meets the Chinese National Standard (CNS) A4 specification (210X297 mm) 1243816 A7 B7. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (28). After cooling to room temperature, 100 bI of n-hexane was added, followed by cooling in an ice water bath. Stirring was continued for 1 hour. It was crystallized and dried at room temperature to give 4 g of the title compound. Cell Example 20: Polymorph (H) of Dunapal Hydrochloride 1 g of Dunapal Hydrochloride was heated and dissolved in 15 nl of dichloromethane. After cooling to room temperature, 15 nl of hexane was added with stirring, followed by cooling in an ice-water bath. Stir for 1 hour. It was crystallized and dried at room temperature to give 0.9 g of the title compound. Example 2 1. Polymorph (B) of Dunapyr hydrochloride 0.5 g of Dunapal was heated to dissolve in 10 * 1 acetone. After cooling to room temperature, 0.13nl of concentrated hydrochloric acid was added. Stir for 30 minutes. Crystals were passed through and dried at 85 ° F for 16 hours to give 0.5 g of the title compound. Example 22: Polymorph of dunapar hydrochloride U) 0.3 g of dunapar was heated to dissolve in 3b1 ethyl acetate. At room temperature, add 0.79ml of 105; hydrogen chloride in ethanol. It was crystallized and dried at 85 t for 3 hours, and then dried at 70 for 16 hours to yield 0.3 g of the title compound. Example 23: Polymorph of Dunapal Hydrochloride (I) 10 g of Dunapal was heated to dissolve in 100 «1 of ethanol. Under agitation, a mixture of 3. U concentrated hydrochloric acid and 28b1 diethyl ether was sequentially added, followed by 150 m 1 isopropyl ether. Stir for 1 hour to separate crystals. The crystals were filtered and dried at room temperature to give 9.86 g of the title compound with a yield of 90X water content of 0 · 2 6 X and melting point of 2 2 9-2 3 1 t! (Decomposition). Example 24: Polymorphs of Dunapal Hydrochloride (B) -30-(Please read the precautions on the back before filling out this page) One pack. Order a line The paper size is applicable to Chinese National Standard (CNS) A4 Specifications (210X 297 mm) 1243816 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (29) 5.0 g of polymorph of dunapar hydrochloride (I) is coated on a test dish (Schale) and allowed to stand for 7 days under the aeration of 85? Air to obtain 4.9 g of the title compound. Example 25: Polymorph (S) of Dunapal hydrochloride 5.0 g of polymorph (I) of Dunapal hydrochloride was coated on a test dish (Schale) and contained δ5υ air It was allowed to stand for 2 days under aeration, and then allowed to stand for 3 days under aeration of 105 t: to obtain 4.8 g of the title compound. Example 26: Polymorph of Dunapal Argon Chloride (Li) 5.0 g of polymorph (I) of Dunapal hydrochloride was coated on a test dish (Schale) and ventilated at 851C After standing for 5 days, 4.9 g of the title compound was obtained. Example 27: Polymorph of dunapar hydrochloride U) 5.0 g of polymorph (I) of dunapar hydrochloride was coated on a test dish (Schple) at 105 t! Air It was allowed to stand for 3 days under aeration to obtain 4.9 g of the title compound. Example 28: Polymorph (IV) of Dunapal Hydrochloride 15.0 g of polymorph (I) of Dunapal hydrochloride was coated on a test dish (Schale) and compared with An atmospheric volume of 100X humidity was allowed to stand for 2 times, and 14.8 g of the title compound was obtained with a melting point of 226-228 ^! (Decomposed). Reference Example 1: Amorphous dunapar hydrochloride 15.0 g of dunapar hydrochloride was dissolved in 300 ml of water. The solution was frozen in a dry ice and acetone bath and lyophilized for 4 days at -82C. 14.8 g of the title compound were obtained.一 31- (Please read the precautions on the back # | Fill this page first) Binding. Binding-line paper size is applicable to Chinese National Law (('NS) A4) (210 parent 297 / > cent) 1243816 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards ^-A7 B7 V. Description of the Invention (50) The present invention will be described in more detail with reference to the following examples. Examples 29-44 are for manufacturing polymorphs (I). Methods. Examples 45-57 are methods for producing polymorph (H) by rhenium. Examples 58-98 are methods for making polymorph (U). Examples 99-108 are a method for producing polymorph (IV) by rhenium. Example 109 relates to a method for producing a polymorph (V). Example 2 9: Polymorph (I) of Dunapal hydrochloride 1.0 g of Dunapal was dissolved in 4b1 methanol under heating at 40t. The solution was cooled in an ice-water bath. 0.31 g of concentrated hydrochloric acid was added to IbI methanol at an internal temperature of 10C. Hold in a cold water bath for 90 minutes. Belian crystals and then dried to give 0.43 g of the title compound (water content: 5.3 3X). Example 30 · Polymorph (I) of Dunapal Hydrochloride 1.0 g of Dunapal was dissolved in 4 ml of methanol under heating at 40 TC. The solution was cooled in an ice-water bath. 0.31 g of 10S: concentrated hydrochloric acid in 1.1 methanol was added. After 5 minutes, 30 nl of a third butyl methyl ether (hereinafter, referred to as TBME) was added at an internal temperature of 3TC. Stir in an ice-water bath for 30 minutes. Crystallization and subsequent drying yielded 1.10 g of the title compound (water content: 5.60%). Example 31: Polymorph of dunapar hydrochloride (I) 1.0 g of dunapar was heated to 40 υ Dissolve in 4nl of methanol. The solution was cooled in an ice-water bath. 0.31 g of concentrated hydrochloric acid was added to lnl methanol. After 5 minutes, 30 ml of isopropyl ether (hereinafter, referred to as IPE) was added at an internal temperature of 3C. Stir for 30 minutes in an ice-water bath. Filter crystals and -32- (Please read the precautions on the back before filling out this page). Binding · Binding-Thread paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1243816 Employees of Central Bureau of Standards, Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention (Η) Then dried to produce 1.13 g of the title compound (water content: 5.50 ί). Example 32 2: Polymorph of Dunapal Hydrochloride (I) 1.0 g of Dunapal was dissolved in 4 ml of methanol with heating at 40 ° C. The solution was cooled in an ice-water bath. Sequentially, 0.31 g of concentrated hydrochloric acid was added to 1 ml of methanol at an internal temperature of 12C. After 7 minutes, 30 ml of ethyl acetate was added at an internal temperature of 3 °. Stir for 30 minutes in an ice-water bath. The crystals were filtered and then dried to yield 0.71 g of the title compound (water content: 5.223!). Example 33: Polymorph (I) of Dunapal hydrochloride 1.0 g of Dunapal was dissolved in 4 nl of G alcohol under heating at 4 Ot. The solution was cooled in an ice-water bath. After cooling for 5 minutes, 0.31 g of concentrated hydrochloric acid was added to 1 ml of ethanol. Hold in a water bath for 30 minutes. To this was added a small amount of the polymorph (I) of dunapar hydrochloride. Incubate for 30 minutes in an ice-water bath. The crystals were separated by filtration and then dried to give 0.70 g of the title compound (water content: 5.33¾). Example 34 4: Polymorph (I) of Dunapal Hydrochloride 1.0 g of Dunapal was dissolved in 4nl of tetrahydrofuran (hereinafter simply referred to as THF) at 24 * 0. The solution was cooled in an ice-water bath. To this was added 0.31 g of concentrated hydrochloric acid in IbI THF. Hold in a cold water bath for 40 minutes. The crystals were separated by centrifugation and then dried to give 1.00 g of the title compound (water content: 5, 67%). Example 35 5: Polymorph of Dunapal Hydrochloride (I) 1.0 g of Dunapal was dissolved in 9b1 of acetonitrile under heating at 40 ° C. The solution was cooled in an ice-water bath. After cooling for 2 minutes, 0.31 g of concentrated hydrochloric acid was added to 1 ml of acetonitrile. Hold Myanmar search and mix for 50 minutes in an ice water bath -33- (Please read the precautions on the back before filling this page) Packing, 11-line paper size applies Chinese National Standard (CNS) grid (210 X 297 mm) 1243816 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (52) minutes. The crystals were separated over time and then dried to yield 0.63 g of the title compound (water content: 5 · 5 9 X). Example 36: Polymorph of Dunapal Hydrochloride (I) 4.0 g of Dunapal was dissolved in 20 ml of methanol under heating at 40 t !. The solution was cooled in an ice-water bath. Blow in hydrogen chloride gas at 3t: internal temperature until the atmosphere becomes acidic. Stir in an ice-water bath for 20 minutes. The crystals were separated by centrifugation and then dried to yield 3.40 g of the title compound (aqueous solution: 5.19X). Example 3 7 · Polymorph (I) of dunapar hydrochloride 10.0 g of dunapar was added to Dissolved in 60 liters of methanol under reflux. Stop heating. Add 120B1 IPE at an internal temperature of 60¾. Hold in a cold water bath and search for 20 minutes. The crystals were separated by filtration and then dried to give 9.80 g of the title compound. (Water content: 5.87¾). Example 38: Polymorph (I) of dunapar hydrochloride 3.0 g of dunapar hydrochloride was dissolved in 18b1 methanol under reflux. Stop heating. At 54t: 36.1 IPE was added at an internal temperature. Search for 20 minutes in an ice-water bath. The crystals were separated by centrifugation and then dried to yield 2.95 g of the title compound (water content: 5.55! 0. Elemental analysis: CΗN C1 measurement (X) 65.55 7.53 3.05 8.16 Example 3 9: Dunapar hydrochloride Crystal (I) Dissolve 1.0 g of dunapar hydrochloride in 5 ml of methanol under reflux. Cool the solution in an ice-water bath. Add 30 ml at an internal temperature of 3 * -34- (Please read first (Notes on the back then fill out this page).

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm). Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 1243816 A7 B7. 5. Description of the invention (yet) TBME〇 Continuous blending under ice water After 30 minutes, the crystals were separated and then dried to give 1.00 g of the title compound (water content: 5.40X). Example 40: Polymorph of Dunapal Hydrochloride (I) 1.0 g of Dunapal hydrochloride was dissolved in 5 μl of methanol under reflux. The solution was cooled in an ice-water bath. After cooling for 2 minutes, crystals began to separate. One minute after the start of the separation, 30 liter of ethyl acetate was added thereto. Stir for 30 minutes in an ice-water bath. The crystals were separated by filtration and then dried to give 1.00 g of the title compound (water content: 5.60!). Example 4 1. Polymorph (I) of Dunapal Hydrochloride 1.0 g of Dunapal Hydrochloride Dissolve in 5nl of methanol under reflux. Cool the solution in an ice-water bath. Add 30 il n-hexane at an internal temperature of 3¾. Search and stir in an ice-water bath for 70 minutes. After "isolating the crystals and drying to produce 0.89 g The title compound (water content: 5.6650. Example 42: Polymorph of Dunapal hydrochloride (I) 1.0 g of Dunapal hydrochloride was dissolved in 20 »1 ethanol under reflux. The solution was cooled in an ice-water bath. The mixture was searched and held in an ice-water bath for 70 minutes. The crystals were separated and dried to give 0.48 g of the title compound (water content: 5 · 7 250. Example 43: Dunapal Hydrogen) Polymorph (I) of chloride Dissolve 1.0 g of dunapar hydrochloride in 25nl of ethanol under reflux. Cool the solution in an ice-water bath. Add 50ml IPE at an internal temperature of 3υ. In an ice-water bath Hold and stir for 5 minutes. The crystals are separated by filtration and then dried to yield 0.86. Title compound (moisture content: 5.32X). Example 44: Polymorphs of Dunapal Hydrochloride (I) -35- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 cm) (please (Please read the notes on the back before filling this page). Packing-Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1243816 A7 B7 V. Description of the invention (54) Dissolve 1.0 g of dunapar hydrochloride under reflux In 20 Hi ethanol. The solution was cooled in an ice-water bath. 30b1 TBME was added at an internal temperature of 3C. The mixture was stirred for 30 minutes in an ice-water bath. The crystals were separated by drying and then dried to give 1.00 g of the title compound (water content : 5.33¾). Example 4 5: Polymorph (H) of Dunapal Hydrochloride 1.0 g of Dunapal is dissolved in 4iel's ethanol under heating for 40 t. The solution is placed in an ice-water bath Cool. After cooling for 4 minutes, add 0.31g of concentrated hydrochloric acid to linl ethanol. After 3 minutes, add 30ϋ1 of TBME. Hold in a ice-water bath and stir for 50 minutes. The crystals are separated by filtration and then dried to produce I. Οδg of the title compound (water content: 1.78! Π Example 46: Polymorph (E) of Dunapal Hydrochloride ^ 1.0 g of Dunapal was dissolved in 9 ml of isopropyl alcohol (hereinafter referred to as IPA) under heating for 40 t. The solution was Cool in an ice-water bath. Add 0.31 g of concentrated hydrochloric acid to 1 ml of IPA. Continue stirring for 30 minutes in the ice-water bath. The crystals are separated by filtration and then dried to produce 0.87 g of the title compound (water content: 1 · 10¾). Example 4 7. Polymorph of Dunapal Hydrochloride U) 1.0 g of Dunapal was dissolved in 9 ml of acetone at 19v. To this was added 0.31 g of concentrated hydrochloric acid in 1 ml of acetone. Continue to search for 5 minutes at room temperature. The crystals were separated by centrifugation and then dried to give 0.87 g of the title compound (water content: 0.833;). Example 48: Polymorph (I) of Dunapal hydrochloride 1.0 g of Dunapal was dissolved in 9 ml of propidium at 24C. To this was added 0.31 g of concentrated hydrochloric acid to lei acetone. Hold 缜 -36 in an ice-water bath. The size of this paper is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297 mm). I ^ Μ--pack ------ order ----- line (please read first Note on the back, please fill out this page again) 1243816 Printed A7 B7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (55) Mix for 30 minutes. It is difficult to crystallize when it meets the points, and then dried to produce 0.92 g of the title compound (water content: 0.61 ×). Example 4 9: Polymorph of dunapar hydrochloride (IT) 1.0 g of dunapar was dissolved in 9 ml of THF at 24 t !. To this was added 0.31 g of concentrated hydrochloric acid to lffil THF. Hold in a cold water bath for 30 minutes. The crystals were separated by filtration and then dried to give 1.09 g of the title compound (water content: 0 · 7 8 X). Example 50: Polymorph (I) of Dunapal Hydrochloride 3.0 g of Dunapal is dissolved in 30b1 of acetone at 2 °. Blow in hydrogenated hydrogen gas at room temperature until the atmosphere becomes acidic. After 3 minutes of incubation. The crystals were separated by centrifugation and then dried to give 2.80 g of the title compound (water content: 2 · 7 8 J;). Example 5 1: Polymorph (E) of Dunapal Hydrochloride 4.0 g of Dunapal was dissolved in 20 * 1 dichloromethane at 18 υ. The solution was cooled in an ice-water bath. Blow in hydrogen chloride gas at an internal temperature of 4T0 until the atmosphere becomes acidic. Blow argon through it. After stirring in an ice water bath for 2 hours, the crystals were separated by centrifugation and then dried to give 4.09 g of the title compound (water content: 0.81X). Example 5 2: Polymorph (E) of Dunapal hydrochloride 1.0 g of Dunapal hydrochloride was dissolved in 20 nl of ethanol under reflux. The solution was cooled in an ice-water bath. Add 30 »1 TB ME at an internal temperature of 20 °. Stir for 3 hours in an ice water bath. The crystals were separated by filtration and then dried to give 0.92 g of the title compound (water content: 0.79X). Example 53: Polymorph (E) of Dunapal Hydrochloride (Please read the precautions on the back before filling this page).

1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specification (2Ι0χ; 297 mm) 1243816 A7 B7 5. Description of the invention (4) The consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs will print 1.0 g of Duna Parr chloride was dissolved in 20.1 ethanol under reflux. The solution was cooled to room temperature in an ice water bath. 30 b1 TBHE was added at an internal temperature of 20 ° C. The mixture was stirred at room temperature for 20 minutes. The crystals were separated by filtration and then dried to yield 0.80 g of the title compound (water content: ◦ .52 ×). Example 54 : Polymorphs of Dunabel Hydrochloride (π) Dissolve 10 • 0 grams of Dunapar Hydrochloride in 100nl of ethanol under reflux. Add 0 0 1 to the solution under stirring. 1 IPE is cooled in an ice-water bath. Hold in the ice-water bath for 5 minutes. The crystals were separated by filtration and then dried to give 9.40 g of the title compound (water content: 0.19X). Elemental analysis: C 1 Η C 1 measured value (%) 6 9. 1 2 7. 2 0 3. 3 2 8.61 Example 55: Polymorph (II) of Dunapal Hydrochloride 1.0 g of Dunapal hydrochloride was added to 18. . The solution was dissolved in 20 ml of dichloromethane. The solution was cooled in an ice-water bath. 30 al TBHE was added thereto. The mixture was stirred in the ice-water bath for 3 minutes. The crystals were separated by filtration and then dried to give 0.88 g of the title compound ( Moisture content: 2.33%) 〇Example 56 • Polymorph (Π) of Dunamol Hydrochloride 2.0 g of polymorph (I) of Dunabel Hydrochloride was applied to Test m (S cha 1 e) and let stand for 16 hours 9 at 80 ° C under pressure to obtain 1.89 g of the title compound (water content: 0.22%). Example 57: Dunapa Polymorph (π) of Hydrochloride Hydrochloride Amorphous material of 2.0 g of Dunabel Hydrochloride was coated on test m (S cha 1 e) and decompressed at 80 ° C under reduced pressure. After standing for 16 hours, you can get -38- (Please read the notes on the back before filling this page): Packing. The size of each paper stack applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1243816 A7 B7 V. Description of the invention P7) 1.98 g of the title compound (water content: 1.15%) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy. Example 58 Polymorphs of Dunapal Hydrochloride (I) 1.0 g of Dunapal was dissolved in 4 ο 1 of methanol under heating 40. The solution was cooled in an ice-water bath. 0.31 g of concentrated hydrochloric acid was added to 1 m 1 of methanol at an internal temperature of 7P. After mixing for 5 minutes at m, 30 B 1 of acetone was sequentially added thereto. The mixture was stirred under an ice water bath for 1 hour. The crystals were separated by filtration and dried to produce 0.44 g of the title compound (water content: 04.1 IX). <) Example 59 · Polymorphs of Dunapal Hydrochloride (I) 1.0 g of Dunapal was dissolved in 4 hi 1 ethanol under heating at 40V. The solution was placed in an ice-water bath. After cooling to room temperature, 0.31 g of concentrated hydrochloric acid in 1 m 1 of ethanol was added thereto, followed by stirring for 5 minutes in 22 t! Under η, 30 B 1 TBME was added in order. Hold at room temperature and search overnight. The crystals were separated and dried to form 1.09 g of the title compound (water content: 0. 19X). Elemental analysis: C Η Η C 1 Measured value (X) 69 • 27 7 .23 3 • 34 8 .58 Example 60 Polymorph (®) of Dunapal Hydrogenated Aqueous 1.0 g of Dunapal was heated at 40 t The ethyl acetate solution dissolved in 9 ml of 1 was cooled to room temperature in an ice water bath. 0. 31 ε of concentrated hydrochloric acid was added to 1 b 1 of ethyl acetate. After continuous stirring at room temperature for 30 minutes. The crystals were separated by filtration and then dried to give 1.08 g of the title compound (water content: 0.21%). Example 61: Polymorph (I) of a Dunapal Hydrogenate -39- I ---- ; ---:-install ------- order ----- ^ line (please read the precautions on the back before filling this page) Zhang scale is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1243816 A7 B7 V. Description of the invention (58) Dissolve 1.0 g of dunapar at 9 ° C at 21 ° C. In the second eye. The solution was cooled in an ice-water bath. To this was added 0.31 g of concentrated hydrochloric acid in IbI acetonitrile. The solution became homogeneous. Keep track and stir overnight at room temperature. The crystals were separated by filtration and then dried to give 1.05 g of the title compound (water content: 0.05¾). Example 6 2: Polymorph of Dunapal Hydrochloride (Li) 1.0 g of Dunapal was heated. 40 t: Soluble in 9ial acetone. The solution was cooled to room temperature in an ice-water bath. To this was added 0.31 g of concentrated hydrochloric acid to IibI propionamidine. Stir overnight at room temperature. The crystals were separated by centrifugation and then dried to give 1.08 g of the title compound (water content: 0.03X). Example 63: Polymorph of Dunapal Hydrochloride (H ^ 1.0 g of Dunapal was dissolved in a mixture containing 29b1 of acetone and 1B1 ion-exchanged pure water under stirring. The solution was Cool in an ice-water bath. Add 0.31 g of concentrated hydrochloric acid to 1 ml of acetone. Hold the soil in the ice-water bath and stir for 30 minutes. The crystals are separated and dried to yield 0.83 g of the title compound (water content: 0.56! ί). Example 64: Polymorphs of Dunapal Hydrochloride (B) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1.0 g of Duna Parr was dissolved in 9 ml of THF at 2410. To this was added 0.31 g of concentrated hydrochloric acid in 1 ul of THF. Stirring was continued for 30 minutes in an ice water bath. The crystals were separated by filtration and then dried to give 1.09 g of the title compound (water content: 0.54S). ;). Example 65 5: Polymorphs of Dunapal Hydrochloride (II) 1.0 g of Dunapal was dissolved in 4ral DMF under 40 scoops of heating. The solution was cooled in an ice-water bath. Among them, 0.31 g of concentrated hydrochloric acid is added to lnl -40. Standard (CNS > A4 size (210X297 mm) 1243816 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (59) DHF. Continue mixing for 30 minutes in an ice-water bath. The crystals are separated by filtration and dried. Refining yielded 1.08 g of the title compound (water content: 0.723 :). Cell Example 66: Polymorph of Dunapal Hydrochloride (B) 1.0 g of Dunapal was almost soluble at 20¾ 9nl of DMS0. To this was added 0.31g of concentrated hydrochloric acid to lal DMS0. Stir for 1 hour at room temperature, add 30b1TBME to it. Stir overnight at room temperature. Isolate and crystallize at room temperature and then dry. 0.97 g of the title compound was produced (water content: 0.25X). Example 6 7: Polymorph of Dunapal Hydrochloride (I) 2.0 g of Dunapal was dissolved in 20b1 ethanol under 40t heating! The solution was cooled to room temperature in an ice-water bath. At 24t: at room temperature, hydrogen chloride gas was blown into the g until the atmosphere became acidic. After 10 minutes of incubation, 50alTBHE was added. Overnight. Crystals were separated by drying and then dried to yield 2.11 g of the title. Compound (water content: 0.07: 1;). Example 68: Dunapar hydrochloride is polycrystalline, (m) 2.0 g of dunapar is dissolved in 30nl at 20 * C Blow hydrogen chloride gas into toluene at room temperature until the atmosphere becomes acidic. Blow argon gas into it. After stirring for 30 minutes, crystals are separated by filtration and then dried to give 2.21 g of the title compound (containing Water volume: 0.65¾). Example 6 9: Polymorph (EI) of Dunapal hydrochloride 1.0 g of Dunapal hydrochloride was dissolved in 5 ml of methanol under rolling. Stop heating. Hold Burmese stir overnight at room temperature, and stir in an ice-water bath for an additional 2 hours. The crystals were separated by filtration and then dried to give 0.90 g of the title compound (water content: 0.05X). -41 A paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling out this page) Installation · -line 1243816 A7 " B7 V. Description of the invention (4〇 ) Example 70: Polymorph of Dunapal Hydrochloride (Li) 1.0 g of Dunapal Hydrochloride was dissolved in 5 Al of methanol under rolling. The solution was cooled, and 30.1TBM was added at 40 ° C. Hold Myanmar for 3 hours at 40 * 0. The mixture was cooled in an ice-water bath and maintained for 45 minutes. The crystals were separated by filtration and then dried to give 0.94 g of the title compound (water content: 0 · 13 ×). Example 71: Polymorph (H) of Dunapal hydrochloride 1.0 g of Dunapal hydrochloride was dissolved in 5 ml of methanol under reflux. The solution was cooled in an ice-water bath and crystals began to separate after 4 minutes. 30 «1 acetonitrile was added to it, and the crystals immediately dissolved. After stirring at room temperature overnight, the crystals were separated by filtration and dried to yield 0.10 g of the title compound (water content: 0.09X). Example 72: Polymorph (H) of Dunapal hydrochloride 1.0 g of Dunapal hydrochloride was dissolved in 20 nl of ethanol under reflux. The solution was cooled and 30®1TBME was added at an internal temperature of 40¾. At 40t: Hold Myanmar for 3 hours. The mixture was cooled in an ice-water bath and stirring was continued for 20 minutes. The crystals were separated by filtration and then dried to give 0.97 g of the title compound (water content: 0.14S :). Example 73: Polymorphs of Dunapal Hydrochloride (in) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before writing this page) 1.0 g of Dunapal Hydrochloride was dissolved in 12 nl IPA under reflux. Stop heating. Keep searching and mixing overnight at room temperature, and incubate in an ice-water bath for 1 hour. The crystals were separated by filtration and then dried to give 0.92 g of the title compound (water content: 0.2U). Example 74: Polymorphs of Dunapal hydrochloride U) -42- The paper size is applicable to the Chinese national standard (CNS > A4 old box (2 丨 〇 X 297 mm) 1243816 A7 B7 V. Description of the invention (U) Separate from 1 to 5B and search for 1 to maintain the lower temperature ο room 10 in. Thermal heating and chlorination to stop hydrogenation. Mekyl of Panadol Duffa ο A

Dissolve in V night. Add 30.1TBME at an internal temperature of 20TC. The mixture was cooled in an ice-water bath and kept under stirring for 3 hours. The crystals were separated by filtration and then dried to give 0.90 g of the title compound (water content: 0.10 ×). Example 75 · Polymorph of Dunapal Hydrochloride (I) 1.0 g of Dunapal hydrochloride was dissolved in 15 «1 1 dimethylaso (hereinafter referred to as" hereinafter abbreviated " DMS0). The solution was cooled to room temperature in an ice-water bath, and 30 μ1 ΤΒΕΕ was added at an internal temperature of 20 t !. Hold at room temperature overnight. The crystals were separated upon encountering and then dried to give 1.01 g of the title compound (water content: 0.08 ×). Examples 76-95: Polymorph (Π) of Dunapal hydrochloride 1.0 g of the substance shown in the table below was suspended at room temperature in the solvent shown in the table below. Hold at room temperature and stir overnight. The crystals were isolated by centrifugation and then dried to give the title compound. (Please read the precautions on the back before filling out this page) • Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economics and Printing -43- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 1243816 A7 B7 V. Description of the invention (42) Example of materials printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Material production 76 Polymorph (I) Methanol 0.91g 77 Polymorph (I) Ethanol 0 · 94g 78 Polymorph ( I) Ethyl acetate 0.93 g 79 polymorph (I) acetone 0.93 g 80 polymorph (I) methanol 0.93 g 81 polymorph (I) ethanol 0.95 g 82 polymorph (I) ethyl acetate Ester 0.95 g 83 polymorph (I) acetone 0.94 g 84 polymorph (IV) methanol 0.92 g 85 polymorph (IV) ethanol 0.90 g 86 polymorph (IV) ethyl acetate m 0.93 g 87 Polymorph (IV) Propane 81 0.94g 88 Polymorph (V) Methanol 0.96g 89 Polymorph (V) Ethanol 0.93g 90 Polymorph (V) Ethyl acetate 0.97g 91 polymorph (V) propylene m 0.92g 92 amorphous methanol 0.94g 93 amorphous ethanol 0.94g 94 ethyl acetate amorphous 0.92g 95 amorphous amorphous 0.94 g 4 4 -(Please read the precautions on the back before filling in itself) Binding and binding The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ¾ Printed in China Yayago Goubei Gongbo Cooperative Print 1243816 A7 B7 V. Description of the invention (〇) S Example 96: Polymorph of Dunamol hydrochloride (IE) 10.0 g of Dunapar hydrochloride was dissolved in IDObI ethanol under heating at 4G ° C. . The solution was cooled to room temperature, and 3. 3 g of concentrated hydrochloric acid was added at an internal temperature of 20 ° C. Place the solution in an ice-water bath. After stirring for 9 minutes, 150b1 of isopropyl ether was added at an internal temperature of 3 ° C. Stir for 300 minutes in an ice-water bath. The crystals were isolated by filtration and then dried to give the title compound. Example 97: Polymorph of Dunapal Hydrochloride (II) 10.0 g of Dunapal was dissolved in 100 ml of ethanol under heating at 40 ° C. The sol was cooled to room temperature, and 3.01 g of concentrated hydrochloric acid was added at 2 ° C internal temperature. After stirring for 9 minutes, 150 «il isopropyl ether was added at 20 ° C internal temperature. Stir at room temperature for 120 minutes. Minutes. The crystals were separated by filtration and then dried to give the title compound. Example 9 8: Polymorphs of Dunapal Hydrogenate (III) 10.0 g of Dunapal hydrochloride was dissolved under heating at 40 ° C IGObI in ethanol. The solution was cooled to room temperature, and 3.0 g of concentrated hydrochloric acid was added at an internal temperature of 20 ° C. The solution was placed in an oil bath and heated to an internal temperature of 40 ° C. At an internal temperature of 40 ° C Isopropyl ether of 15011 was added at 0 ° C and stirred for 2 G minutes at an internal temperature of 60 ° C. The crystals were separated by filtration and then dried to give the title compound. Example 9 9: Polymorph of Dunapal Hydrochloride (IV ) 2.0 g of Dunapal was dissolved in a mixture containing 0.65 g of concentrated hydrochloric acid and 10 ml of ion-exchanged pure water under stirring at 22 ° C. After stirring at room temperature for 1 hour, the crystals were separated by filtration and then dried to yield 1.80 g of the title. Compound (water content: 11.00X). Example 1 0 0: Polymorph (IV) of Dunabel Hydrochloride -45- Winter paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) _pack ·

1T 1243816 A7 B7 V. Description of the invention (44) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 1.0 g of dunapar was dissolved in 22 * 0 and dissolved in 0.3U concentrated hydrochloric acid and 4 η. 1 A mixture of ion-exchanged pure water. 100 η 1 THF was added thereto, and the mixture was continuously stirred at room temperature for 30 minutes. The crystals were separated and then dried to give 1.06 g of the title compound (water content: 11.14 ×). Example 101: Dunapal hydrogen Polymorph (IV) of chloride Dissolve 3.0 g of dunapar in a mixture containing 88b1THF and 3d 1 ion-exchanged pure water with stirring. 0. 93 g of concentrated hydrochloric acid is added to the mixture. 2η 1 THF. Stir in an ice-water bath for 30 minutes, separate and crystallize after being dried, and generate 3. 21 g of the title compound (water content: 1 1 · 34X) Elemental analysis • C Η Ν C 1 measured value (X) 61.30 7 .76 2 86 7 • 68 Example 102: Polymorph (IV) of Dunapal Hydrochloride 1.0 g of Dunapal was dissolved in Θβ 1 toluene at 22V. To this was added 0. 31 g of concentrated hydrochloric acid in 1.1 toluene. Overnight at room temperature, the mixture was separated and crystallized and then dried to produce 1.23 g of the title compound (water content: 1 1.40X). Example 103: Polymorphs of dunapar hydrochloride ( IV) 1.0 g of Dunapal was dissolved in 9β 1 n-hexane at 21 ° C. To this was added 0.31 g of concentrated hydrochloric acid to 1 Β1 n-hexane c > continuous stirring at room temperature overnight 0 pm to separate the crystals and then dry to give 1.23 g of the title compound (water content: 1 1.24¾). Example 104: Polymorph (IV) of Dunapal Hydrochloride 1.0 g of Dunapal was dissolved in In 1 methanol-46- at 20 V (see the reverse Note: Please fill in this page again.) This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 1243816 A7 Λ Β7 5. Description of the invention (45), 3al A mixture of ion-exchanged pure water and 0.93 g of concentrated hydrochloric acid. Search and mix at room temperature for three days. The crystals were separated by centrifugation and then dried to give 0.83 g of the title compound (water content: 11.04S :). Example 105: Polymorph (IV) of Dunapal hydrochloride 2.0 g of Dunapal was suspended in 10 * 1 ion-exchanged pure water. Blow in hydrogen chloride gas at 23 ° C until it becomes homogeneous. After 2.5 hours of stirring at room temperature, the crystals were separated and dried to yield 1.77 g of the title compound (water content: 11.10 ×). Example 106: Polymorphs (IV) of Dunapal hydrochloride 1.0 g of Dunapal hydrochloride was heated at 60 t to dissolve it in ionic water. The solution was cooled to room temperature. After stirring overnight at room temperature, the crystals were separated by filtration and then dried to give 0.92 g of the title compound (water content: 11.2 X). Example 107: Polymorph (IV) of Dunapal Hydrochloride 1.0 g of polymorph (E) of Dunapal hydrochloride was coated on a test dish (Schale) and at a relative humidity A 90 × atmosphere capacity M was left to stand for 24 hours to obtain 1.15 g of polymorph (IV) (water content: 12.33 ×). Example 108: Amorphous and Polymorph (IV) of Dunapal Hydrochloride 10.0 g of polymorph (M) of Dunapal Hydrochloride was coated on a test dish (Schale, Φ = 250πιβι) and dissolved in 300ml of ion exchange pure water at 211C. The solution was transferred to a freeze-drying unit and dried for 3 days. 0.90 g of amorphous was obtained. The material was left to stand for 24 hours in an atmosphere of a relative humidity of 90S; Obtained 11.20 grams of polymorphs (water content: 1 1 · 21X) 〇-4 7 — Paper size: Chinese Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling (This page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1243816 A7 Λ B7 V. Description of the Invention (Servo) Example 109: Polymorph of Dunapal Hydrochloride (V) 2.0 g of Dunapal Hydrochloride The polymorph (IV) was coated on a test dish (Schale, O = 250mm) and allowed to stand for 16 hours under a reduced pressure of 80 ° to obtain 1.75 g of polymorph (IV) (water content: 0.28S: ). Finally, the efficiency of the present invention is compared with the dunapar hydrochloride amorphous in terms of stability and hygroscopicity. The superior results provided by the present invention are shown below: Stability analysis (measurement analysis) The polymorphs (I) to (IV) of Dunapal Hydrogenate were taken as 10Bg each in two samples and placed in tubes . They were stored under the following conditions and the content of impurities was periodically measured. Conditional storage period 80¾ 1 case 2 case 60V 2 weeks January A0V January March -20V 1 week 2 weeks January March (method and conditions for measuring HPLC purity) Add 10b1 to each tube of the aforementioned sample as follows Mobile phase on HPLC. Then, the impurity content of each sample was measured under the following conditions. The average is calculated from two results. -4 8 ~ This paper size is in accordance with Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling out this page). · · Τ Line 1243816 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Description of the invention (47) Tubing (solid phase); Inertsi 1 0D: S-II (4, 6bub I. D · x 1 5 0 i & ship) mobile phase; CH a CM / water / 70¾ HC10 4 (V / V / V = 300: 700: 1) Detector; UV271 nm flow rate; 1.0 m 1 / ei η. Injection volume; 5 a 1 column temperature; room temperature results: Γ) stored at -2 0 t (Refer to Figure 16) Impurity (X) 0 1 week 2 weeks January March polymorph (I) 0.11 0 · 12 0.12 0.13 0.11 polymorph (I) 0 · 09 0.09 0.13 0.10 0. 09 polymorph (I) 0.15 0.14 0.13 0.13 0.15 Polymorph (IV) 0. 08 0.08 (K 08 0.08 0. 08 Amorphous 0.12 0.14 0 · 15 0 · 15 0.14 -1 49- (Please read the precautions on the back first (Fill in this page)

、 1T line _ This paper size is applicable to China (C, NS) A4 scale (210 × 297 mm) 1243816 A7 B7 V. Description of the invention (48) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 2) Stored in 40 * 0 (Refer to Figure 17) Impurities U) 0 January-March Polymorph (I) 0.11 0 · 12 0.13 Polymorph (E) 0. 09 0. 08 0. 08 Polymorph (H) 0.15 0.14 0- 15 Polymorph (IV) 0. 08 0.08 0 · 07 Amorphous 0 · 12 0. 20 0 · 45 3) Stored at 60 t: (refer to Figure 18)-Impurity (¾) 0 2 weeks and more in January Polymorph (I) 0.11 0.12 0.13 Polymorph (E) 0. 09 0.12 0. 09 Polymorph U) 0.15 0.14 0.14 Polymorph (IV) 0. 08 0.09 0.13 Amorphous 0,12 0.30 0.39 -50 -(Please read the notes on the back before filling in this page) ^ Packing · Ordering · Fees The paper size is applicable to China National Standard (CNS) 8 4 specifications (210 × 297 mm) 1243816 A7 B7 V. Description of the invention (49) 4 ) Stored in S0V (refer to Figure 19) Impurities (%) 0 1 Polymorphs (I) after 2 weeks 0 • 11 0 · 12 0., 19 Polymorphs (I ) 0 • 09 0. 20 0,, 11 Polymorph (I) 0 • 15 0. 14 0 ·, 14 Polymorph (IV) 0 • 08 0. 09 0., 19 Amorphous 0 • 12 0. 02 3. 29 (Please read the notes on the back before filling out this page) From the above results, it is clear that the polymorphs (I) to (IV) have better thermal stability than the amorphous ones. (2) Hygroscopicity analysis (Measurement method) The polymorphs (I) to (IV) are stored in an atmosphere with a relative humidity of 25 π as follows. The water content was measured according to the general method introduced by the Japanese Pharmacopoeia (Karl Fischer Method). The results are as follows. Order_Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs-51- This paper size applies to Chinese national standards (CNS > A4it (2 丨 0 X 297 mm) 1243816 Explanation of the invention (50) Results (refer to Section 20) Relative humidity and water content ⑴ Polymorphs (%) (Work) (II) (III) (IV) Amorphous starting 4.34 0.26 0.11 12.87 2.03 10.6 4.54 0.28 0.15 10.70 4.09 22.2 4.75 0.29 0.14 10.60 4.78 31.0 5.07 0.32 0.26 10.77 5.61 42.8 5.25 0.39 0.13 11.03 7.80 51.0 5.38 0.43 0.15 11.28 9.29 61-8 5.49 0.40 0.18 11,40 12.01 75.0 5.65 1.73 0.15 11.62 13.89 84.0 5.64 13.70 0.16 11.72 13.74 93.0 5.76 13.99 0.15 11.84 14.51 96.6 5.88 14.18 0.17 11.80 14.53 100.0 10.3 7 15.93 9.71 12.26 15.44 In the above results, the polymorphs (I) to (IV) respectively show relative humidity at 96.6X, 75.0X, 96 • 6X, and 100X relative humidity. Wetness. Amorphous dunapar hydrochloride at 10.6 »: lower and later wet The results of these experiments show that Dunapal hydrochloride polymorphs (I) to (IV) have excellent stability and low leakage. -52- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297mm) (Please read the precautions on the back before filling out this page)

Claims (1)

'1243816 VI. Application for Patent Scope No. 891 10397 "Donepezil hydrochloride polymorphs and its manufacturing method" patent (Amended on June 10, 2005) 6 Application for patent scope: 1. Polymorph (IV) of Dunapal hydrochloride, 1-benzyl hydrochloride 4-[(5,6-dimethoxy-1 -indanone) -2 -yl] methyl Hexahydropyridine polymorph (IV). This polymorph is shown in the following table. The powder X-ray diffraction form has an intensity of 1/1. In the infrared absorption spectrum, the absorption peak is defined by the reciprocal centimeter of = = 1243816 VI. The peak value of the patent-application polymorph (IV) in the form of powder X-ray latitude is: diffraction angle (2 Θ, °) intensity (I / I〇) 9.64 11 10.92 11 12.46 63 12.72 17 13.86 27 14.42 12 17.36 100 18. 5 4 39 19: 90 37 21.18 35 2 1 · .7 4 39 22 · 48 60 * 22.96 3 6 · 24.10 17 2 5 * 28 7 0 2 8,00 27 28.50 27 561., .1118 1588 1773 2922 Wave number of infrared absorption spectrum in potassium (c DT1):, 709. 0, 766-2, 786-3, 804.9, 857.0, 944.3; 979.3, 1041.5,.. 7, 1264.6, 1318.7, 1364.1, 1458.1, 1499.2, 1542.5, 1560.1, • 1, 1636-6, 1647.8, 1654.3, 1684 · 3, 1718.2, 1734.4, 1751.4, .7, 1793.5, 1830 · 5 # 1845.8, 1870.1, 2344.8, 2369.3, 2719.2, / .9, 3324.0 cm-1; 1243816 6. Application scope of patent The polymorph (IV) method of Dunapal hydrochloride according to item 1 of the patent, which comprises the step of wetting the polymorph (II) under the condition that the polymorph (IV) can be obtained. This polymorph The substance (II) is the diffraction peak 値 of the powder X-ray diffraction form with an intensity of I / 1 Q, as shown in the following table, and the absorption peak showing a reciprocal of 値 in the infrared absorption spectrum in potassium bromide as follows Defined by = = peak of polymorph (II) in powder X-ray diffraction form: diffraction angle (20, °) intensity (1 / 1〇) 10.10 7 6 12.64 14 15.74 8 5 15.82 8 6 16.20 1 0〇16.46 8 7 17.40 5 0 17.50 4 8 17.88 3 1 18.36 2 8 18.58 5 1 18.66 4 6 19.48 4 2 1243816 6.Scope of patent application 2 0.18 2 0 .80 2 2.26 2 3.38 2 3.52 2 4.06 2 4.32 2 5.14 2 5.44 2 5.72 2 5.96 2 6.14 2 8.06 2 8.20 2 8.38 In potassium bromide infrared 8 1 3 6 4 5 8 6 5 9 3 4 5 5 4 4 5 0 3 9 3 5 2 5 Wave number of the absorption spectrum (cm · 1): 5 6 0.1, 6 9 8.9, 7 4 1119.3, 1222.7, 1458.3, 1500.9, 1560.2, 1570.3, 1654.4, 1689.5, 1773.9, 1793.8, 2345.1, 2489.9, one kind of manufacturing as applied) .1, 8 4 6.2, 9 4 7.6, 1266.4, 1318.7, 1522.3, 1534.0, 1592.0, 1637.0, 1718.3, 1734.7, 1830.7, 1846.0, 1927.9, 3448.1cm · Scope of patent No. 1 1036.1, 1364.1, 1542.6, 1647.9, 1751.7 Method of polymorph (IV) of dunapar hydrochloride, 1870.1, 〇, comprising dissolving dunapar in water with or without tetrahydrofuran under conditions where polymorph (IV) is available And the salt 1243816 6. The patent application scope acid or hydrogen chloride is added to the solution step. 4. A method for manufacturing polymorph (IV) of dunapar hydrochloride as described in item 1 of the patent, which comprises dissolving dunapar in the condition that polymorph (IV) is obtained Step 05 of adding hydrochloric acid and adding tetrahydrofuran to the solution.-A method for producing a polymorph (IV) of dunapar hydrochloride as claimed in item 1 of the patent scope, which is included in obtaining the polymorph (IV) Under the conditions of dissolving dunapar in toluene and adding hydrochloric acid to the solution, step 6-making a polymorph of dunapar hydrochloride as described in the first item of the patent scope (IV) A method comprising the step of dissolving dunapar in Zhengjiyuan and adding hydrochloric acid under the condition that a polymorph (IV) can be obtained.-A method of manufacturing such as duna in the first patent scope Parr Hydrochlorination A method for polymorph (IV), which comprises the step of crystallizing dunapar in a mixture of methanol and hydrochloric acid under conditions where polymorph (IV) can be obtained. The method of polymorph (IV) of Dunapal Hydrochloride of Sundial Patent Scope No. 1 includes crystallization of Dunapal Hydrochloride L chloride in white water under conditions where polymorph (IV) is available Step 〇1243816 VI. Application for patent scope 9. A method for manufacturing polymorph (IV) of dunapar hydrochloride as described in the scope of patent application item 1, which is included in the conditions for obtaining polymorph (IV) Step of humidifying Dunapar hydrochloride amorphous.