JPH1053576A - Polymorphic crystal of donepezil hydrochloride and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially obtain five kinds of new polymorphic crystal of donepezil hydrochloride with excellent storage stability, useful as a therapeutic agent for various kinds of senile dementia. SOLUTION: The production method for three kinds of new polymorphic crystal (I) to (III) of donepezil hydrochloride shown by the formula is as follows: the compound of the formula is dissolved in ethanol, and hydrochloric acid or hydrogen chloride is then added to the resultant solution followed by addition of isopropyl ether to effect crystallization; although the means for collecting the resultant crystal after filtration depends on the type of crystal, it is general that polymorphic crystal (I) is collected just after deposited; crystal (II) is collected 10-60 (pref. 10-30)min after deposited; while crystal (III) is collected one hour or longer (pref. 24h or longer) after deposited. The other two kinds of polymorphic crystal (IV) and (V) are obtained by humidifying the polymorphic crystal (II) and by heating the polymorphic crystal (IV) respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to Donepezil Hydrochloride (Chemical name: 1-benzyl-4-one) having excellent action as a medicament disclosed in Example 4 of JP-A-64-79151. [(5,6-dimethoxy-1-indanone) -2
(I)-(IV)-(IV) and (V) and their industrial production process.

[0002]

BACKGROUND OF THE INVENTION Donepezil hydrochloride is a remedy for various senile dementias having acetylcholinesterase inhibitory activity, and is extremely highly useful as a preventive, therapeutic and ameliorating agent for Alzheimer-type senile dementia. Donepezil hydrochloride is usually used as an oral preparation, but there is a distribution / storage process after formulation and before it is actually taken.In addition, due to the nature of the target disease,
It is prescribed together for a maximum of one month and stored further at home. Therefore, storage stability of the drug substance against heat, humidity, and the like is extremely important and necessary, and a drug substance with higher stability has been demanded. However, the existence of polymorphic crystals in donepezil hydrochloride has not been known at all, and it cannot be said that a drug substance having sufficient stability has been obtained.

[0003]

2. Description of the Related Art In a method described in Example 4 of JP-A-64-79151, a purified donepezil hydrochloride is obtained by recrystallizing a crude donepezil hydrochloride from ethanol / isopropyl ether.

[0004]

[Problems to be solved by the present invention] However, it is needless to say that a crystal form having more excellent storage stability than the drug substance crystal obtained by the above-mentioned conventional method is more preferable for distribution and storage.

[0005]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
The following novel polymorphic crystals (I) to (IV) and (V) were found to be extremely excellent in stability and completed the present invention. That is, the present invention provides five kinds of novel polymorph crystals excellent in the stability of donepezil hydrochloride, and an industrial production method thereof.

More specifically, the present invention relates to the preparation of donepezil hydrochloride represented by the following chemical formula:

[0007]

Embedded image

A peak in the powder X-ray diffraction pattern;
The following novel polymorphs (I) to (IV), which are characterized by absorption in an infrared absorption spectrum in potassium bromide.

Powder X-ray Diffraction Pattern Measurement Method and Conditions (1) Measurement Method A powder X-ray diffraction pattern was measured for about 100 mg of a sample under the following measurement conditions. (2) Measurement conditions Target: Cu Filter: monochro Voltage: 40KV Current: 20mA Slit: DS1, RS 0.15, SS1 Scan speed: 2deg / min. Range: 5-30 ゜

Infrared absorption spectrum measuring method and conditions Measured according to the Japanese Pharmacopoeia, general test method, infrared absorption spectrum, potassium bromide tablet method.

[0011]

Absorption wave number (cm ^-1 ) in the infrared absorption spectrum in potassium bromide: 463, 502, 563, 589, 604, 701, 750,
759, 799, 860, 922, 947, 972, 1012, 1038, 1104, 1120, 1128, 1
175, 1192, 1218, 1250, 1267, 1316, 1368, 1410, 1433, 1440, 1
455, 1472, 1502, 1591, 1606, 1644, 1684, 2412, 2530, 2559, 2
595, 2620, 2717, 2840, 2858, 2924, 3004, 3074, 3259, 3373, 3
547, 3589cm ^-1

[0013]

Absorption wave number (cm ^-1 ) in infrared absorption spectrum in potassium bromide; 699, 748, 762, 845, 947, 1009, 103
5, 1067, 1103, 1118, 1129, 1174, 1193, 1206, 1222, 1247, 126
7, 1317, 1365, 1422, 1436, 1456, 1465, 1502, 1592, 1607, 168
8, 2412, 2489, 2627, 2846, 2868, 2913, 2928, 3435cm ^-1

[0015]

Absorption wave number (cm ^-1 ) in infrared absorption spectrum in potassium bromide: 559, 641, 648, 702, 749, 765, 786,
807, 851, 872, 927, 949, 966, 975, 982, 1007, 1034, 1071, 108
0, 1111, 1119, 1131, 1177, 1190, 1205, 1217, 1230, 1250, 126
5, 1292, 1313, 1367, 1389, 1420, 1438, 1453, 1461, 1470, 150
0, 1589, 1605, 1697, 2407, 2419, 2461, 2624, 2641, 2651, 266
7, 2837, 2848, 2873, 2924, 2954, 2961, 2993, 3007, 3377, 343
3cm ^-1

[0017]

Absorption wave number (cm ^-1 ) in infrared absorption spectrum in potassium bromide; 401, 431, 459, 467, 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, 3422cm ^-1

Further, as a result of re-measurement, the polymorph according to the present invention is a novel polymorph which is also characterized by the following peaks in the powder X-ray diffraction pattern and absorption in the infrared absorption spectrum in potassium bromide ( I) to (IV) and (V)
It is.

The infrared absorption spectrum of potassium bromide
Absorption wave number (cm^-1); 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, 15
01.5, 1537.8, 1555.9, 1590.7, 1643.7, 1681.9, 235
0.9, 2534.0, 2922.1, 3381.8, 3585.2 cm ^-1

[0021]

Absorption wave number (cm ^-1 ) in the infrared absorption spectrum of potassium bromide; 560.1, 698.9, 749.1, 846.2,
947.6, 1036.1, 1119.3, 1222.7, 1266.4, 1318.7, 136
4.1, 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, 1
846.0, 1870.1, 2345.1, 2489.9, 2927.9, 3448.1 cm ^-1

[0023]

Absorption wave number (cm ^-1 ) in the infrared absorption spectrum of potassium bromide; 558.3, 641.1, 702.4, 748.5,
765.0, 786.1, 807.3, 850.8, 872.0, 926.8, 974.9, 1
034.1, 1071.5, 1111.6, 1190.1, 1216.6, 1265.4, 129
1.9, 1312.9, 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, 1
773.7, 1793.5, 1845.8, 2345.3, 2461.6, 2924.2, 344
7.9 cm ^-1

[0025]

Absorption wave number (cm ^-1 ) in infrared absorption spectrum in potassium bromide; 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, 1
588.1, 1636.6,1647.8, 1654.3, 1684.3, 1718.2, 173
4.4, 1751.4, 1773.7, 1793.5, 1830.5, 1845.8, 1870.
1, 2344.8, 2369.3, 2719.2, 2922.9, 3324.0 cm ^-1

[0027]

Absorption wave number (cm ^-1 ) in the infrared absorption spectrum in potassium bromide: 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, 1
542.5, 1560.2, 1592.1, 1692.9, 2500.1, 2924.2, 299
8.9, 3422.1 cm ^-1

The donepezil hydrochloride crystal disclosed in Example 4 of JP-A-64-79151 and the novel donepezil hydrochloride polymorphic crystals (I) to (IV) and (V) according to the present invention are as follows: As described above, the melting point is different, and this is a new crystal which has not been known so far. Donepezil hydrochloride disclosed in JP-A-64-79151, melting point: 211-212 ° C (decomposition) Polymorph (I) of the present invention, melting point: 225-226 ° C (decomposition) Polymorph (II) of the present invention, melting point; 224-226 ° C (decomposition) Polymorph (III) of the present invention, melting point: 229-231 ° C (decomposition) Polymorph (IV) of the present invention, melting point: 226-228 ° C (decomposition) Polymorph of the present invention (V ), Melting point: 218-220 ℃ (decomposition) [Amorphous, melting point: 220-222 ℃ (decomposition)]

The novel polymorphs of donepezil hydrochloride (I) to (IV) and (V) according to the present invention are different from thermogravimetric-differential thermal analysis (TG-DTA) measured under the following conditions. It is a crystalline form. (See Figures 11-14)

Thermogravimetric-differential thermal analysis (TG-DTA) measurement method and conditions About 3 to 6 mg of a sample was weighed and subjected to thermal analysis under the following conditions. Reffernce: empty Scan speed: 5 ℃ / min. Sampling: 0.7sec Upper limit: 300 ℃ Lower limit: Room temperature

Next, a method for actually producing these novel polymorphic crystals will be specifically described. In addition, donepezil in the present invention means a free form of donepezil hydrochloride, that is, 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine. (1) Polymorph (I) 1-1) Donepezil hydrochloride is crystallized from methanol. 1-2) Dissolve donepezil hydrochloride in methanol and add diethyl ether or isopropyl ether. 1-3) Dissolve donepezil in methanol and add hydrochloric acid or hydrogen chloride. 1-4) Dissolve donepezil in ethanol, add isopropyl ether, and then add hydrochloric acid or hydrogen chloride. 1-5) Dissolve donepezil in ethanol, add hydrochloric acid or hydrogen chloride, and then add isopropyl ether.

Of these, 1-5) is more preferred. This production method is specifically described in Example 7.

(2) Polymorph (II) 2-1) Donepezil hydrochloride is dissolved in ethanol, and diethyl ether or isopropyl ether is added. 2-2) Donepezil hydrochloride is dissolved in ethanol, isopropyl ether is added, and the crystals are collected after 10 to 30 minutes of crystal precipitation. 2-3) Dissolve donepezil and hydrochloric acid or hydrogen chloride in ethanol, and add diethyl ether. 2-4) Dissolve donepezil in ethanol, add hydrochloric acid or hydrogen chloride and concentrate. 2-5) Dissolve donepezil in ethanol, add hydrochloric acid or hydrogen chloride, and then add isopropyl ether. 2-6) Donepezil is dissolved in ethanol, hydrochloric acid or hydrogen chloride is added, and then isopropyl ether is added. After 10 to 60 minutes, preferably 10 to 30 minutes after crystal precipitation, the crystals are collected by filtration.

Of these, 2-6) is more preferred. This production method is specifically described in Example 14.

(3) Polymorph (III) 3-1) Donepezil hydrochloride is dissolved in ethanol, and diethyl ether is added. 3-2) Dissolve donepezil hydrochloride in methylene chloride and add n-hexane. 3-3) Dissolve donepezil in acetone and add hydrochloric acid or hydrogen chloride. 3-4) Dissolve donepezil in ethyl acetate and add hydrochloric acid or hydrogen chloride. 3-5) Donepezil is dissolved in ethanol, hydrochloric acid or hydrogen chloride is added, and then one kind of solvent selected from diethyl ether, isopropyl ether or n-hexane is added. 3-6) When the solvent is isopropyl ether in the above 3-5), the crystals are collected after 1 hour or more, more preferably after 2 hours or more, further preferably after 6 hours or more. 3-7) Heat the donepezil hydrochloride polymorph (I) or (II).

Of these, 3-5) and 3-6) are more preferred. The present production method is specifically described in Examples 23 and 18.

(4) Polymorph (IV) 4-1) The polymorph (II) of donepezil hydrochloride is humidified.

The production method 4-1) is specifically described in Example 24.

The polymorphic crystal (I), (II) or (III)
Can be prepared by dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, and then adding isopropyl ether (the above, 1-5), 2-6), 3-6)
), And each type is obtained separately depending on the difference in the time required for filtering the crystals after crystallization. This time difference varies depending on crystallization conditions such as temperature, stirring speed, amount of solvent and the like, and is not determined unconditionally. However, usually, (1) a crystal is obtained immediately after crystal precipitation to obtain polymorphic crystal (I). (2) Filtration after 10 to 60 minutes, more preferably 10 to 30 minutes after crystal deposition yields polymorph (II). (3) Filtration after 1 hour or more, more preferably 2 hours or more, and still more preferably 6 hours or more after crystal precipitation gives polymorphic crystal (III).

Further, the method for producing a novel polymorphic crystal according to the present invention will be described in detail in addition to the following. (1) Polymorph (I) 1-6) Donepezil is dissolved in methanol, and hydrochloric acid or hydrogen chloride is added. 1-7) Dissolve donepezil in methanol, add hydrochloric acid or hydrogen chloride, and then add t-butyl methyl ether, diisopropyl ether or ethyl acetate. 1-8) Dissolve donepezil in ethanol, tetrahydrofuran or acetonitrile, and add hydrochloric acid or hydrogen chloride. 1-9) Dissolve donepezil hydrochloride in methanol, and add t-butyl methyl ether, ethyl acetate or n-hexane. 1-10) Donepezil hydrochloride is recrystallized from ethanol. 1-11) Dissolve donepezil hydrochloride in ethanol and add t-butyl methyl ether. Among these, 1-7) is more preferable. This manufacturing method is Example 3.
0, 31 and 32 are specifically described. 1-9) is also preferred. The process is specifically described in Examples 39, 40 and 41.

(2) Polymorph (II) 2-7) Donepezil is dissolved in ethanol, hydrochloric acid or hydrogen chloride is added, and then t-butyl methyl ether is added. 2-8) Dissolve donepezil in isopropyl alcohol, acetone or tetrahydrofuran, and add hydrochloric acid or hydrogen chloride. 2-9) Dissolve donepezil in methylene chloride, add hydrochloric acid or hydrogen chloride, and then add diisopropyl ether. 2-10) Dissolve donepezil hydrochloride in ethanol, add t-butyl methyl ether or diisopropyl ether,
Stir below 10 ° C. 2-11) Dissolve donepezil hydrochloride in methylene chloride and add t-butyl methyl ether or diisopropyl ether. 2-12) Heat the polymorph (I) or amorphous form of donepezil hydrochloride. Among these, 2-7) is preferable. This production method is specifically described in Example 45. 2-10) is also preferred. This process is specifically described in Examples 52, 53 and 54.

(3) Polymorph (III) 3-8) Donepezil is dissolved in methanol, hydrochloric acid or hydrogen chloride is added, and then acetone is added. 3-9) Dissolve donepezil in ethanol, add hydrochloric acid or hydrogen chloride, and then add t-butyl methyl ether. 3-10) Dissolve donepezil in acetonitrile, acetone, aqueous acetone, tetrahydrofuran or N, N-dimethylformamide, and add hydrochloric acid or hydrogen chloride. 3-11) Dissolve donepezil in ethyl acetate, add hydrochloric acid or hydrogen chloride, and then add t-butyl methyl ether. 3-12) Dissolve donepezil in dimethyl sulfoxide, add hydrochloric acid or hydrogen chloride, and then add t-butyl methyl ether. 3-13) Dissolve donepezil in toluene and add hydrochloric acid or hydrogen chloride. 3-14) Donepezil hydrochloride is recrystallized from methanol at 10 ° C or higher. 3-15) Dissolve donepezil hydrochloride in methanol, and add t-butyl methyl ether or acetonitrile. 3-16) Dissolve donepezil hydrochloride in ethanol, add t-butyl methyl ether or acetonitrile, and stir at 10 ° C or higher. 3-17) Dissolve donepezil hydrochloride in N, N-dimethylformamide or dimethylsulfoxide, and then add t-butyl methyl ether. 3-18) Donepezil hydrochloride is recrystallized from isopropyl alcohol. 3-19) The polymorphs (I), (II), (IV), (V) or the amorphous form of donepezil hydrochloride are converted by stirring in a solvent. 3-20) In Production method 3-19, methanol, ethanol, ethyl acetate or acetone is used as a solvent. Among these, 3-11) is preferable. This process is specifically described in Example 59. 3-16) are also preferred. This process is specifically described in Example 72. 3-19) is also preferred. This process is specifically described in Examples 76-95.

(4) Polymorph (IV) 4-2) Donepezil is dissolved in hydrochloric acid, and the precipitated crystals are collected by filtration. 4-3) Dissolve donepezil in hydrochloric acid and add tetrahydrofuran. 4-4) Donepezil is dissolved in hydrous tetrahydrofuran,
Add hydrochloric acid or hydrogen chloride. 4-5) Dissolve donepezil in methanol, toluene or n-hexane, and add hydrochloric acid. 4-6) Dissolve donepezil in a methanol / hydrochloric acid mixture. 4-7) Dissolve donepezil in water and add hydrochloric acid or hydrogen chloride. 4-8) Recrystallize donepezil hydrochloride from water. 4-9) Humidify the polymorph (II) of donepezil hydrochloride. 4-10) Humidify the donepezil hydrochloride amorphous. Among these, 4-4) is preferable. This process is specifically described in Example 101. 4-8) are also preferred. This process is specifically described in Example 106.

(5) Polymorph (V) 5-1) Heat the polymorph (IV) of donepezil hydrochloride. This process is specifically described in Example 109.

In order to obtain polymorphic crystal (III), the above production method
6) consists of dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, and then adding diisopropyl ether. Here, the preferable time for crystallization depends on the stirring speed, the amount of the solvent used, and the like. However, higher temperature conditions reduce the crystallization time. This change is described in Examples 96-98.

Accordingly, the present invention provides a method for inhibiting acetylcholinesterase activity by administering to a human a pharmacologically effective amount of the above-mentioned donepezil hydrochloride polymorph.
It is intended to provide a method for treating a disease associated with acetylcholinesterase activity. The present invention further provides a therapeutic composition comprising a pharmacologically effective amount of the above-mentioned donepezil hydrochloride polymorph and a pharmacologically acceptable excipient.

The polymorphic crystals of the compound according to the present invention include various senile dementias; in particular, senile dementia of the Alzheimer type, stroke (cerebral hemorrhage, cerebral infarction), cerebral arteriosclerosis, head trauma, etc .; Effective for the treatment, prevention, remission and improvement of seizures, impaired attention, dysmotility, attention deficit / hyperactivity disorder, emotional disorders, memory disorders, hallucinations, delusional states, behavioral abnormalities, etc. associated with cerebral palsy It is.

Furthermore, the polymorphic crystals according to the present invention have a potent and highly selective anticholinesterase action, and are therefore useful as pharmaceuticals based on these actions. In particular, the polymorphic crystal according to the present invention is useful for, for example, Alzheimer's type senile dementia, as well as, for example, Huntington's disease, Pick's disease, and late-onset abnormalities.

When the polymorphic crystals according to the present invention are used as these medicaments, they are administered orally or parenterally. Usually, injections such as intravenous, subcutaneous and intramuscular, transdermal, suppository, etc. Or parenteral administration such as sublingual tablets. The dosage varies depending on the degree of symptoms; age, sex, weight, and sensitivity difference of the patient; administration method; timing of administration, interval, properties of pharmaceutical preparation, preparation, type; type of active ingredient, and is not particularly limited. , Usually about one adult per day
The dose is 0.1 to 300 mg, preferably about 1 to 100 mg, which is usually administered in 1 to 4 times a day.

In order to formulate the polymorphic crystals according to the present invention, they are formed into injection forms, suppositories, sublingual tablets, tablets, capsules, transdermals and the like by a usual method in the technical field of preparation. . When preparing an injection, a pH adjusting agent, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, an isotonic agent, a preservative, and the like are added to the main drug as necessary, and intravenous, Subcutaneous or intramuscular injection. At that time, if necessary, a freeze-dried product can be obtained by a conventional method.

Examples of the suspending agent include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate, and the like.

Examples of solubilizers include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate,
Examples include tuna gross and castor oil fatty acid ethyl ester.

Examples of the stabilizer include sodium sulfite, sodium metasulfite, and ether. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. be able to.

Next, the present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.

【Example】

 Examples 1 to 8 Preparation of Donepezil Hydrochloride Polymorph (I) Examples 9 to 15 Preparation of Donepezil Hydrochloride Polymorph (II) Examples 16 to 27 Preparation of Donepezil Hydrochloride Polymorph (III) Examples 28 Preparation of Donepezil Hydrochloride Polymorph (IV) Reference Example 1 Preparation of Amorphous Donepezil Hydrochloride Examples 29-44 Preparation of Donepezil Hydrochloride Polymorph (I) Examples 45-57 Polymorph of Donepezil Hydrochloride (IV) Examples 58-98 Preparation of Donepezil Hydrochloride Polymorph (III) Examples 99-108 Preparation of Donepezil Hydrochloride Polymorph (IV) Example 109 Preparation of Donepezil Hydrochloride Polymorph (V)

Example 1 Polymorph of Donepezil Hydrochloride (I)
The manufacturing donepezil hydrochloride 1g was dissolved in methanol 5 ml. 10 ml of isopropyl ether was added thereto, and the precipitated crystals were separated by filtration and air-dried under ice-cooling and stirring to obtain 0.9 g of crystals of the title compound.

Example 2 Polymorph of Donepezil Hydrochloride (I)
The manufacturing donepezil hydrochloride 1g was heated dissolved in methanol 5 ml.
After returning to room temperature, 10 ml of isopropyl ether was added. After stirring at room temperature for 30 minutes, the precipitated crystals were separated by filtration and air-dried to obtain 0.9 g of the title compound.

Example 3 Polymorph of Donepezil Hydrochloride (I)
The manufacturing donepezil hydrochloride 1g was heated dissolved in methanol 5 ml.
When ice cooling was started, crystals began to precipitate at an internal temperature of 15 ° C. After 10 minutes, 10 ml of isopropyl ether was added, and the mixture was further stirred at room temperature for 1 hour. The crystals were separated by filtration and air-dried to obtain 0.9 g of the title compound as crystals.

Example 4 Polymorph of Donepezil Hydrochloride (I)
The manufacturing donepezil hydrochloride 5g were dissolved by heating in methanol 25 ml.
The crystals precipitated on ice were separated by filtration and air-dried to obtain 4.6 g of crystals of the title compound.

Example 5 Polymorph of Donepezil Hydrochloride (I)
Of Donepezil 0.3g was dissolved in methanol 1.5 ml. 0.79 ml of a 10% -hydrochloric acid / methanol mixture was added thereto. The precipitated crystals were separated by filtration and air-dried to obtain 0.2 g of crystals of the title compound.

Example 6 Polymorph of Donepezil Hydrochloride (I)
Of Donepezil 0.3g were dissolved by heating in ethanol 3 ml. To this, 3 ml of isopropyl ether was added, and then 0.79 ml of a 10% hydrochloric acid / methanol mixture was added. The precipitated crystals were separated by filtration and air-dried to obtain 0.2 g of crystals of the title compound.

Example 7 Polymorph of Donepezil Hydrochloride (I)
Of Donepezil 10g it was heated and dissolved in ethanol 100 ml. Under stirring, a mixed solution of concentrated hydrochloric acid (3.1 g) / ethanol (28 ml) was added thereto, and then 150 ml of isopropyl ether was added. Ten seconds after the precipitation of the crystals, the crystals were collected by filtration and air-dried to obtain 9.36 g of the title compound. (Yield; 85.4%, moisture content;
5.17%)

Melting point: 225-226 ° C. (decomposition)

Example 8 Polymorph of Donepezil Hydrochloride (I)
The manufacturing donepezil hydrochloride 10.0g were dissolved by heating in methanol 50 ml, ice-cooling and stirring was added dropwise under in diethyl ether 600 ml. The stirring was continued for 1 hour, and the precipitated crystals were separated by filtration.
Air-drying gave 10.0 g of crystals of the title compound.

Example 9 Polymorph of Donepezil Hydrochloride (II)
Of Donepezil 13.7g hydrochloric acid 4.4ml was heated and dissolved in ethanol 100 ml. Under stirring at room temperature, diethyl ether
200 ml were added. The precipitated crystals were separated by filtration and dried in vacuo at 80 ° C. to obtain 11.2 g of crystals of the title compound.

Example 10 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Donepezil (50 g ) was dissolved by heating in ethanol (200 ml ), and the temperature was returned to room temperature. After standing for 1 hour, the mixture was concentrated under reduced pressure, and the obtained crystals were air-dried to obtain 55.0 g of crystals of the title compound.

Example 11 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Donepezil (0.5 g ) was dissolved by heating in ethanol (5 ml ) . Under stirring, 1.31 ml of a 10% hydrochloric acid / ethanol mixture was added thereto, and then 5 ml of isopropyl ether was added. After 10 minutes of crystal precipitation, the crystals were separated by filtration and air-dried to obtain 0.4 g of crystals of the title compound.

Example 12 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Donepezil hydrochloride (5.6 g ) was dissolved in ethanol (30 ml ) . 100 ml of isopropyl ether was added thereto, the mixture was cooled on ice, and the precipitated crystals were separated by filtration and dried at 50 ° C. for 3 days to obtain 4.9 g of crystals of the title compound.

Example 13 Polymorph of Donepezil Hydrochloride (I
Production of I) Donepezil hydrochloride (23.3 g ) was added to 250 ml of ethanol and dissolved by heating. With ice cooling and stirring, 600 ml of diethyl ether is added here.
Was added. After standing for 3 hours, the precipitated crystals were separated by filtration and 8
Drying at 5 ° C. for 22 hours gave 22.7 g of the title compound as crystals.

Example 14 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Donepezil (10 g ) was dissolved by heating in ethanol (100 ml ) . Under stirring, a mixed solution of concentrated hydrochloric acid (3.1 g) / ethanol (28 ml) was added thereto, and then 150 ml of isopropyl ether was added. Fifteen minutes after the precipitation of the crystals, the crystals were collected by filtration and air-dried to obtain 9.0 g of crystals of the title compound. (Yield; 82.1%)

Melting point: 224-226 ° C. (decomposition)

Example 15 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Donepezil hydrochloride (40.0 g ) was heated and dissolved in ethanol (700 ml ) . Under ice cooling, 500 ml of isopropyl ether was added dropwise, and the inner wall of the container was rubbed to precipitate crystals. After allowing to stand for 1 hour as it was, the precipitated crystals were separated by filtration and dried at 50 ° C. for 12 hours to obtain 31.4 g of crystals of the title compound.

Example 16 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil hydrochloride (161 g ) was dissolved in ethanol (2000 ml) by heating. Return to room temperature and add diethyl ether 500 under stirring.
0 ml was added. The precipitated crystals were separated by filtration and dried at 35 ° C. for 12 hours to obtain 120 g of the title compound as crystals. (Yield: 74.5%,
Moisture: 0.15%)

Example 17 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil (308 g ) was dissolved in ethanol (700 ml ) . Under stirring, 230 ml of 10% hydrogen chloride / ethanol was added thereto, followed by 5000 ml of diethyl ether. Precipitated crystals were filtered off, 50 ° C for 1 hour, 60 ° C for 30 minutes, and then 85 ° C for 1 hour.
After drying for 2 hours, 269 g of crystals of the title compound were obtained.

Example 18 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil (59 g ) was dissolved in ethanol (590 ml ) . Under cooling, 17.8 g of concentrated hydrochloric acid was added thereto, followed by 885 ml of isopropyl ether. After stirring overnight at room temperature,
The precipitated crystals were collected by filtration and dried at 50 ° C for 22 hours to obtain 62 g of the title compound as crystals.

Example 19 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil hydrochloride 5 g is dissolved by heating in ethanol 100 ml,
Return to room temperature. Under stirring, 100 ml of n-hexane was added thereto. After cooling on ice and stirring for 1 hour, the precipitated crystals were collected by filtration and air-dried to obtain 4 g of crystals of the title compound.

Example 20 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil hydrochloride (1 g ) was dissolved in 15 ml of methylene chloride by heating.
Return to room temperature. Under stirring, 15 ml of n-hexane was added thereto. Thereafter, the mixture was cooled on ice and stirred for 1 hour, and the precipitated crystals were collected by filtration and air-dried to obtain 0.9 g of crystals of the title compound.

Example 21 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil (0.5 g ) was dissolved by heating in acetone (10 ml ) , and concentrated hydrochloric acid (0.13 ml ) was added with stirring at room temperature. The stirring was continued as it was, and after 30 minutes, the precipitated crystals were collected by filtration and dried at 85 ° C. for 16 hours to obtain 0.5 g of crystals of the title compound.

Example 22 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil (0.3 g ) was dissolved by heating in ethyl acetate (3 ml ) . Under stirring at room temperature, 0.79 ml of 10% -hydrogen chloride / ethanol was added. The precipitated crystals were collected by filtration, kept at 85 ° C for 3 hours,
Drying at 16 ° C. for 16 hours gave 0.3 g of crystals of the title compound.

Example 23 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil (10 g ) was dissolved by heating in ethanol (100 ml ) . Under stirring, a mixed solution of concentrated hydrochloric acid (3.1 g) / ethanol (28 ml) was added thereto, and then 150 ml of isopropyl ether was added. After stirring for 1 hour after the crystals were precipitated, the precipitated crystals were collected by filtration and air-dried to obtain 9.86 g of crystals of the title compound. (Yield: 90.0%, moisture: 0.26%)

Melting point: 229-231 ° C. (decomposition)

Example 24 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil hydrochloride polymorph (I) 5.0 g spread in a Petri dish,
Let stand at 85 ° C for 7 days, and crystallize the title compound.
4.9 g were obtained.

Example 25 Polymorph of Donepezil Hydrochloride (I
Preparation of II) Donepezil hydrochloride polymorph (I) 5.0 g spread in a Petri dish,
The mixture was allowed to stand for 2 days at 85 ° C. and then for 3 days at 105 ° C. to obtain 4.8 g of crystals of the title compound.

Example 26 Polymorph of Donepezil Hydrochloride (I
Spread Polymorph producing donepezil hydrochloride II) and (II) 5.0 g in a petri dish, allowed to stand for 5 days under 85 ° C. blower to obtain crystals 4.9g of the title compound.

Example 27 Polymorph of Donepezil Hydrochloride (I
Spread Polymorph producing donepezil hydrochloride II) and (II) 5.0 g in a petri dish, and allowed to stand for 3 days under 105 ° C. blower to obtain crystals 4.9g of the title compound.

Example 28 Polymorph of Donepezil Hydrochloride (I
Preparation of V) 15.0 g of donepezil hydrochloride polymorphic crystal (II) was spread on a petri dish and allowed to stand at room temperature and 100% relative humidity for 2 weeks to obtain 14.8 g of crystals of the title compound.

Melting point: 226-228 ° C. (decomposition)

Reference Example 1 Production of amorphous donepezil hydrochloride 15.0 g of donepezil hydrochloride was dissolved in 300 ml of water, frozen in a dry ice / acetone bath, and lyophilized for 4 days (−
(82 ° C) to give 14.8 g of the title compound.

Example 29 Polymorph of Donepezil Hydrochloride
Preparation of (I) To 1.0 g of donepezil was added 4 ml of methanol, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. Here, at an internal temperature of 10 ° C, concentrated hydrochloric acid (0.31 g) /
A methanol (1 ml) solution was added, and the mixture was stirred under ice cooling for 90 minutes.
The precipitated crystals were collected by filtration and dried to give 0.43 g of the title compound. (Moisture content: 5.33%)

Example 30 Polymorph of Donepezil Hydrochloride
Preparation of (I) To 1.0 g of donepezil was added 4 ml of methanol, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. Here concentrated hydrochloric acid (0.31g) / methanol
(1 ml) solution, and further 5 minutes later, 30 ml of t-butyl methyl ether (hereinafter, TBME) was added at an internal temperature of 3 ° C. After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration and dried to give 1.10 g of the title compound. (Moisture content: 5.60%)

Example 31 Polymorph of Donepezil Hydrochloride
Preparation of (I) To 1.0 g of donepezil was added 4 ml of methanol, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. Here concentrated hydrochloric acid (0.31g) / methanol
(1 ml) solution, and 5 minutes later, 30 ml of diisopropyl ether (hereinafter IPE) was added at an internal temperature of 3 ° C. After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration and dried to give the title compound.
1.13 g was obtained. (Moisture content; 5.50%)

Example 32 Polymorph of Donepezil Hydrochloride
Preparation of (I) To 1.0 g of donepezil was added 4 ml of methanol, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. Here, at an internal temperature of 12 ° C, concentrated hydrochloric acid (0.31 g) /
A methanol (1 ml) solution was added, and after an additional 7 minutes, 30 ml of ethyl acetate was added at an internal temperature of 3 ° C. After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration and dried to obtain 0.71 g of the title compound. (Moisture content; 5.22%)

Example 33 Polymorph of Donepezil Hydrochloride
Preparation of (I) To 4 g of donepezil was added 4 ml of ethanol, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. Here concentrated hydrochloric acid (0.31g) / ethanol
(1 ml) solution was added. After stirring for 30 minutes under ice-cooling, a small amount of polymorph (I) was added. After stirring at the same temperature for 30 minutes, the precipitated crystals were collected by filtration and dried to obtain 0.70 g of the title compound.
(Moisture content: 5.33%)

Example 34 Polymorph of donepezil hydrochloride
Preparation of (I) donepezil 1.0 g tetrahydrofuran (hereinafter, THF) 4 ml
Was added and dissolved at 24 ° C., followed by ice cooling. Here concentrated hydrochloric acid (0.3
1 g) / THF (1 ml) solution was added. After stirring for 40 minutes under ice-cooling, the precipitated crystals were collected by filtration and dried to give the title compound (1.00 g).
I got (Moisture content; 5.67%)

Example 35 Polymorph of Donepezil Hydrochloride
Preparation of (I) Acetonitrile (9 ml) was added to donepezil ( 1.0 g ), and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. To this was added a concentrated hydrochloric acid (0.31 g) / acetonitrile (1 ml) solution. After stirring under ice-cooling for 50 minutes, the precipitated crystals were collected by filtration and dried to give 0.63 g of the title compound.
I got (Moisture content: 5.59%)

Example 36 Polymorph of Donepezil Hydrochloride
Preparation of (I) 20 g of methanol was added to 4.0 g of donepezil, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. Hydrochloric acid gas was blown therein at an internal temperature of 3 ° C. until the space in the reaction vessel became acidic. After stirring under ice cooling for 20 minutes, the precipitated crystals were collected by filtration and dried to give the title compound.
3.40 g was obtained. (Moisture content: 5.19%)

Example 37 Polymorph of Donepezil Hydrochloride
Preparation of (I) 60 g of methanol was added to 10.0 g of donepezil hydrochloride, and the mixture was dissolved by heating under reflux, allowed to cool, and 120 ml of IPE was added thereto at an internal temperature of 60 ° C. The mixture was stirred for 20 minutes under ice cooling, and the precipitated crystals were collected by filtration and dried to obtain 9.80 g of the title compound. (Moisture content: 5.87%)

Example 38 Polymorph of Donepezil Hydrochloride
Production of (I) 18 ml of methanol was added to 3.0 g of donepezil hydrochloride, and the mixture was dissolved by heating under reflux, allowed to cool, and 36 ml of IPE was added thereto at an internal temperature of 54 ° C. The mixture was stirred under ice cooling for 20 minutes, and the precipitated crystals were collected by filtration and dried to give 2.95 g of the title compound. (Moisture content; 5.55%) Elemental analysis value (%) C; 65.55 H; 7.53 N; 3.05 Cl; 8.1
6

Example 39 Polymorph of Donepezil Hydrochloride
Production of (I) To 1.0 g of donepezil hydrochloride was added 5 ml of methanol, and the mixture was dissolved under reflux with heating and then cooled with ice. Here, 30 ml of TBME was added at an internal temperature of 3 ° C. The mixture was stirred for 30 minutes under ice-cooling, and the precipitated crystals were collected by filtration and dried to obtain 1.00 g of the title compound. (Moisture content: 5.40%)

Example 40 Polymorph of Donepezil Hydrochloride
Production of (I) To 1.0 g of donepezil hydrochloride was added 5 ml of methanol, and the mixture was dissolved under reflux with heating and then cooled with ice. One minute after the start of crystal precipitation, 30 ml of ethyl acetate was added, and the mixture was stirred under ice cooling for 30 minutes, and the precipitated crystals were collected by filtration and dried to obtain 1.00 g of the title compound. (Moisture content: 5.60%)

Example 41 Polymorph of donepezil hydrochloride
Production of (I) To 1.0 g of donepezil hydrochloride was added 5 ml of methanol, and the mixture was dissolved under reflux with heating and then cooled with ice. N-Hexane 30m at 3 ℃
After stirring for 70 minutes under ice cooling, the precipitated crystals were collected by filtration.
Drying yielded 0.89 g of the title compound. (Moisture content: 5.66
%)

Example 42 Polymorph of Donepezil Hydrochloride
Production of (I) 20 g of ethanol was added to 1.0 g of donepezil hydrochloride, and the mixture was dissolved by heating under reflux and cooled with ice. After stirring for 70 minutes under ice-cooling, the precipitated crystals were collected by filtration and dried to obtain 0.48 g of the title compound.

[0103] (Moisture content: 5.72%)

Example 43 Polymorph of Donepezil Hydrochloride
Production of (I) To 1.0 g of donepezil hydrochloride was added 25 ml of ethanol, and the mixture was dissolved under reflux with heating and cooled with ice. 50 ml of IPE was added at an internal temperature of 3 ° C., and the mixture was stirred for 5 minutes under ice cooling, and the precipitated crystals were collected by filtration and dried to obtain 0.86 g of the title compound. (Moisture content: 5.32%)

Example 44 Polymorph of Donepezil Hydrochloride
Production of (I) 20 g of ethanol was added to 1.0 g of donepezil hydrochloride, and the mixture was dissolved by heating under reflux and cooled with ice. Here, 30 ml of TBME was added at an internal temperature of 3 ° C. After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration.
Drying afforded 1.00 g of the title compound. (Moisture content: 5.33
%)

Example 45 Polymorph of Donepezil Hydrochloride (I
Preparation of I) To 1.0 g of donepezil was added 4 ml of ethanol, and the mixture was dissolved by heating at 40 ° C. and then cooled with ice. Here concentrated hydrochloric acid (0.31g) / ethanol (1m
l) The solution was added and 3 minutes later 30 ml of TBME was added. After stirring for 50 minutes under ice-cooling, the precipitated crystals were collected by filtration and dried to obtain 1.08 g of the title compound. (Moisture content; 1.78%)

Example 46 Polymorph of Donepezil Hydrochloride (I
I) Production Donepezil 1.0 g in isopropyl alcohol (hereinafter IPA)
9 ml was added, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. To this was added a concentrated hydrochloric acid (0.31 g) / IPA (1 ml) solution. After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration and dried to give the title compound.
0.87 g was obtained. (Moisture content: 1.10%)

Example 47 Polymorph of Donepezil Hydrochloride (I
Acetone 9ml added to Donepezil 1.0g of I), optionally in dissolved at 19 ° C.. A concentrated hydrochloric acid (0.31 g) / acetone (1 ml) solution was added thereto. After stirring at room temperature for 5 minutes, the precipitated crystals were collected by filtration and dried to obtain 0.87 g of the title compound. (Water content; 0.83%)

Example 48 Polymorph of Donepezil Hydrochloride (I
9 ) Acetone (9 ml) was added to donepezil (1.0 g ) , dissolved at 24 ° C., and cooled with ice. To this was added a concentrated hydrochloric acid (0.31 g) / acetone (1 ml) solution. After stirring for 30 minutes under ice-cooling, the precipitated crystals were collected by filtration and dried to obtain 0.92 g of the title compound. (Water content; 0.61%)

Example 49 Polymorph of Donepezil Hydrochloride (I
Preparation of I) To 1.0 g of donepezil was added 9 ml of THF, the mixture was dissolved at 24 ° C., and cooled with ice. To this was added a concentrated hydrochloric acid (0.31 g) / THF (1 ml) solution.
After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration and dried to obtain 1.09 g of the title compound. (Moisture content; 0.78%)

Example 50 Polymorph of Donepezil Hydrochloride (I
Preparation of I) 30 ml of acetone was added to 3.0 g of donepezil and dissolved at 21 ° C. At the same temperature, hydrochloric acid gas was blown in until the space in the reaction vessel became acidic. After stirring for 3 minutes, the precipitated crystals were collected by filtration and dried to give 2.80 g of the title compound. (Moisture content; 2.78%)

Example 51 Polymorph of Donepezil Hydrochloride (I
Preparation of I) To 4.0 g of donepezil, 20 ml of methylene chloride was added, dissolved at 18 ° C., and cooled with ice. Hydrochloric acid gas was blown therein at an internal temperature of 4 ° C. until the space in the reaction vessel became acidic. After bubbling argon gas, 30 ml of IPE was added. After stirring for 2 hours under ice-cooling, the precipitated crystals were collected by filtration and dried to give the title compound (4.09 g).
I got (Moisture content; 0.81%)

Example 52 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Ethanol (20 ml) was added to donepezil hydrochloride (1.0 g ), and the mixture was dissolved by heating under reflux and then cooled with ice. Here, 30ml of TBME at 20 ℃
Was added. After stirring for 3 hours under ice cooling, the precipitated crystals were collected by filtration and dried to obtain 0.92 g of the title compound. (Moisture content;
(0.79%)

Example 53 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Ethanol (20 ml) was added to donepezil hydrochloride (1.0 g ), and the mixture was dissolved by heating under reflux and then cooled with ice. At an internal temperature of 20 ° C., 30 ml of TBME was added. After stirring at the same temperature for 20 minutes, the precipitated crystals were collected by filtration and dried to obtain 0.80 g of the title compound. (Moisture content; 0.52%)

Example 54 Polymorph of Donepezil Hydrochloride (I
Production of I) 100 g of ethanol was added to 10.0 g of donepezil hydrochloride, and the mixture was dissolved under reflux with heating. This solution was added with stirring to 200 ml of IPE which had been cooled on ice beforehand. After stirring at the same temperature for 5 minutes, the precipitated crystals were collected by filtration and dried, and the title compound was 9.40 g.
I got (Moisture content; 0.19%) Elemental analysis value (%) C; 69.12 H; 7.20 N; 3.32 Cl; 8.6
1

Example 55 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Add 1.0 ml of donepezil hydrochloride to 20 ml of methylene chloride, and add
Then, the mixture was cooled with ice. Here, 30 ml of TBME was added. After stirring for 3 minutes under ice cooling, the precipitated crystals were collected by filtration and dried,
0.88 g of the title compound was obtained. (Water content: 2.33%)

Example 56 Polymorph of Donepezil Hydrochloride (I
Spread I) of producing donepezil hydrochloride polymorph crystals (I) 2.0 g on a petri dish,
Dry in a vacuum oven at 80 ° C. overnight to give the title compound 1.8
9 g were obtained. (Moisture content; 0.22%)

Example 57 Polymorph of Donepezil Hydrochloride (I
Preparation of I) Donepezil hydrochloride (amorphous) 2.0 g spread on a Petri dish, in a vacuum dryer, dried at 80 ° C. overnight, 1.98 g of the title compound
I got (Moisture content; 1.15%)

Example 58 Polymorph of Donepezil Hydrochloride (I
Preparation of II) To 1.0 g of donepezil was added 4 ml of methanol, and the mixture was dissolved by heating at 40 ° C. and then cooled with ice. A concentrated hydrochloric acid (0.31 g) / methanol (1 ml) solution was added thereto at an internal temperature of 7 ° C., and after 5 minutes, 30 ml of acetone was added at an internal temperature of 3 ° C. After stirring at the same temperature for 1 hour, the precipitated crystals were collected by filtration and dried to obtain 0.44 g of the title compound. (Moisture content; 0.11%)

Example 59 Polymorph of Donepezil Hydrochloride (I
Preparation of II) To 1.0 g of donepezil was added 4 ml of ethanol, and the mixture was dissolved by heating at 40 ° C., cooled with ice, and returned to room temperature. At 22 ° C, a solution obtained by adding 0.31 g of concentrated hydrochloric acid to 1 ml of ethanol was added, and after an additional 5 minutes, the internal temperature was 22 ° C.
Then, 30 ml of TBME was charged. Crystal deposition during charging. After stirring at room temperature overnight, the crystals were collected by filtration and dried to give 1.09 g of the title compound.
(Moisture content; 0.19%) Elemental analysis value (%) C; 69.27 H; 7.23 N; 3.34 Cl; 8.5
8

Example 60 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 9 g of ethyl acetate was added to 1.0 g of donepezil, and the mixture was heated and dissolved at 40 ° C., and then cooled with ice. A concentrated hydrochloric acid (0.31 g) / ethyl acetate (1 ml) solution was added thereto at 5 ° C., and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and dried to obtain 1.08 g of the title compound.
(Moisture content; 0.21%)

Example 61 Polymorph of Donepezil Hydrochloride (I
9 ) Acetonitrile (9 ml) was added to donepezil (1.0 g ), and the mixture was almost dissolved at 21 ° C. with stirring. When a concentrated hydrochloric acid (0.31 g) / acetonitrile (1 ml) solution was added thereto, the mixture became homogeneous. After stirring at room temperature overnight, the precipitated crystals were collected by filtration and dried to give 1.05 g of the title compound. (Moisture content; 0.05%)

Example 62 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 9 g of acetone was added to 1.0 g of donepezil, and the mixture was dissolved by heating at 40 ° C. and then cooled with ice. Concentrated hydrochloric acid (0.31 g) / acetone at an internal temperature of 22 ° C
(1 ml) solution was added. After stirring at room temperature overnight, the precipitated crystals were collected by filtration and dried to give 1.08 g of the title compound. (Moisture content; 0.03%)

Example 63 Polymorph of Donepezil hydrochloride (I
Preparation of II) 29 g of acetone and 1 ml of ion-exchanged water were added to 1.0 g of donepezil, dissolved at 20 ° C., and cooled with ice. Here concentrated hydrochloric acid (0.31 g)
/ Acetone (1 ml) solution was added. After stirring for 30 minutes under ice-cooling, the precipitated crystals were collected by filtration and dried to give the title compound (0.83 g).
I got (Moisture content; 0.56%)

Example 64 Polymorph of Donepezil hydrochloride (I
Preparation of II) 9 g of THF was added to 1.0 g of donepezil, dissolved at 24 ° C., and cooled with ice. To this was added a concentrated hydrochloric acid (0.31 g) / THF (1 ml) solution.
After stirring for 30 minutes under ice cooling, the precipitated crystals were collected by filtration and dried to obtain 1.09 g of the title compound. (Moisture content; 0.54%)

Example 65 Polymorph of Donepezil Hydrochloride (I
II) Preparation of donepezil 1.0 g was added to DMF 4 ml, and dissolved by heating at 40 ° C.
Ice cooled. At 5 ° C., a concentrated hydrochloric acid (0.31 g) / DMF (1 ml) solution was added thereto. After stirring for 30 minutes under ice-cooling, the precipitated crystals were collected by filtration and dried to obtain 1.08 g of the title compound. (Moisture content; 0.7
2%)

Example 66 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 9 g of DMSO was added to 1.0 g of donepezil, and the mixture was almost dissolved at 20 ° C. with stirring. To this was added a concentrated hydrochloric acid (0.31 g) / DMSO (1 ml) solution. After stirring at the same temperature for 1 hour, 30 ml of TBME was added. The mixture was stirred overnight at room temperature, and the precipitated crystals were collected by filtration and dried to obtain 0.97 g of the title compound. (Moisture content; 0.25%)

Example 67 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 20 g of ethanol was added to 2.0 g of donepezil, and the mixture was dissolved by heating at 40 ° C. and then cooled with ice. At an internal temperature of 24 ° C, hydrochloric acid gas was blown in until the space in the reaction vessel became acidic. Five minutes later, 50 ml of TBME was added, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration and dried to give 2.11 g of the title compound. (Moisture content; 0.07%)

Example 68 Polymorph of Donepezil Hydrochloride (I
Preparation of II) To 2.0 g of donepezil, 30 ml of toluene was added and dissolved at 20 ° C. Hydrochloric acid gas was blown at the same temperature until the space in the reaction vessel became acidic. After blowing argon gas, the mixture was stirred at the same temperature for 30 minutes. The precipitated crystals are collected by filtration and dried to give the title compound.
2.21 g was obtained. (Water content; 0.65%)

Example 69 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 5 g of methanol was added to 1.0 g of donepezil hydrochloride, and the mixture was dissolved under reflux with heating. After stirring at room temperature overnight, the mixture was stirred for 2 hours under ice cooling. The precipitated crystals were collected by filtration and dried to give 0.90 g of the title compound.
I got (Moisture content; 0.05%)

Example 70 Polymorph of Donepezil Hydrochloride (I
II) Preparation of Donepezil hydrochloride (1.0 g ), add methanol (5 ml ), dissolve under heat reflux, transfer to a 40 ° C oil bath,
30 ml of ME were added. After stirring at the same temperature for 3 hours, the mixture was stirred under ice cooling for 45 minutes. The precipitated crystals are collected by filtration and dried to give the title compound.
0.94 g was obtained. (Moisture content; 0.13%)

Example 71 Polymorph of Donepezil Hydrochloride (I
II) Preparation of Donepezil hydrochloride (1.0 g ) , methanol (5 ml) was added, and the mixture was dissolved under reflux with heating, followed by ice cooling. 30 ml of acetonitrile at 2 ° C internal temperature
After the addition, the mixture was returned to room temperature and stirred at the same temperature overnight. The precipitated crystals were collected by filtration and dried to give 0.10 g of the title compound.
(Moisture content; 0.09%)

Example 72 Polymorph of Donepezil Hydrochloride (I
II) Preparation of Donepezil hydrochloride (1.0 g ) , ethanol (20 ml) was added, and the mixture was dissolved by heating under reflux.
After adding 30 ml of ME and stirring at the same temperature for 3 hours, the mixture was stirred under ice cooling for 20 minutes. The precipitated crystals are collected by filtration and dried to give the title compound.
0.97 g was obtained. (Moisture content; 0.14%)

Example 73 Polymorph of Donepezil Hydrochloride (I
Preparation of II) IPA (120 ml) was added to donepezil hydrochloride (1.0 g ) , and the mixture was dissolved by heating under reflux and allowed to cool. After stirring at room temperature overnight, cool on ice and add
Stirred for hours. The precipitated crystals were collected by filtration and dried to give 0.92 g of the title compound. (Moisture content; 0.21%)

Example 74 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 15 g of DMF was added to 1.0 g of donepezil hydrochloride, and the mixture was heated and dissolved at 100 ° C., and then allowed to cool. The mixture was stirred at room temperature overnight. Inner temperature 20
At 30 ° C., 30 ml of TBME was added, and the mixture was stirred for 3 hours under ice cooling. The precipitated crystals were collected by filtration and dried to give 0.90 g of the title compound.
(Moisture content; 0.10%)

Example 75 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 15 g of DMSO was added to 1.0 g of donepezil hydrochloride, and the mixture was heated and dissolved at 80 ° C., and then cooled with ice. Here, add 30ml of TBME at an internal temperature of 20 ° C,
The mixture was stirred overnight at the same temperature. The precipitated crystals are collected by filtration and dried,
1.01 g of the title compound was obtained. (Moisture content; 0.08%)

Examples 76-95 Polymorphs of Donepezil Hydrochloride
According to the table below, 1.0 g of donepezil hydrochloride was added to the solvent 10
The mixture was suspended in ml, and stirring was continued overnight. The precipitated crystals were collected by filtration and dried to give the title compound. The results are shown in the table below. ────────────────────── Example Starting material Solvent yield ────────────────────── 76 Polymorph (I) methanol 0.91 g 77 Polymorph (I) ethanol 0.94 g 78 Polymorph (I) ethyl acetate 0.93 g 79 Polymorph (I) acetone 0.93 g 80 Polymorph (II) methanol 0.93 g 81 polymorph (II) ethanol 0.95 g 82 polymorph (II) ethyl acetate 0.95 g 83 polymorph (II) acetone 0.94 g 84 polymorph (IV) methanol 0.92 g 85 polymorph (IV) ethanol 0.90g 86 Polymorph (IV) Ethyl acetate 0.92g 87 Polymorph (IV) Acetone 0.94g 88 Polymorph (V) Methanol 0.96g 89 Polymorph (V) Ethanol 0.93g 90 Polymorph (V) Ethyl acetate 0.97g 91 Polymorph (V) Acetone 0.92g 92 Amorphous methanol 0.94g 93 Amorphous ethanol 0.94g 94 Amorphous ethyl acetate 0.92g 95 Amorphous acetone 0.96g ─────── ─ ──────────────

Example 96 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 100 g of ethanol was added to 10.0 g of donepezil, and the mixture was heated and dissolved at 40 ° C. After cooling to room temperature, 3.01 g of concentrated hydrochloric acid at an internal temperature of 20 ° C
Was added. After cooling in ice water and stirring for 9 minutes, the internal temperature is 3 ° C
Then, 150 ml of IPE was added, and stirring was continued for 300 minutes under ice cooling. The precipitated crystals were collected by filtration and dried to give the title compound.

Example 97 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 100 g of ethanol was added to 10.0 g of donepezil, and the mixture was heated and dissolved at 40 ° C. After cooling to room temperature, 3.01 g of concentrated hydrochloric acid at an internal temperature of 20 ° C
Was added. After stirring for 9 minutes, 150 ml of IPE was added at an internal temperature of 20 ° C., and stirring was continued at room temperature for 120 minutes. The precipitated crystals were collected by filtration and dried to give the title compound.

Example 98 Polymorph of Donepezil Hydrochloride (I
Preparation of II) 100 g of ethanol was added to 10.0 g of donepezil, and the mixture was heated and dissolved at 40 ° C. After cooling to room temperature, 3.01 g of concentrated hydrochloric acid at an internal temperature of 20 ° C
Was added. After transferring to an oil bath and heating to an internal temperature of 40 ° C. with stirring, 150 ml of IPE was added, followed by stirring at 60 ° C. for 20 minutes. The precipitated crystals were collected by filtration and dried to give the title compound.

Example 99 Polymorph of Donepezil Hydrochloride (I
Preparation of V) 0.65 g of concentrated hydrochloric acid was added to 10 ml of ion-exchanged water, and 2.0 g of donepezil was added with stirring at 22 ° C. The mixture was stirred for 1 hour. The precipitated crystals were collected by filtration and dried to give 1.80 g of the title compound.
I got (Moisture content; 11.00%)

Example 100 Polymorph of donepezil hydrochloride
Production of (IV) 0.31 g of concentrated hydrochloric acid was added to 4 ml of ion-exchanged water, and 1.0 g of donepezil was added and dissolved at 22 ° C. with stirring, followed by cooling with ice. Here T
100 ml of HF was added and stirred for 30 minutes. The precipitated crystals were collected by filtration and dried to give 1.06 g of the title compound. (Moisture content; 11.
14%)

Example 101 Polymorph of donepezil hydrochloride
Preparation of (IV) To 3.0 g of donepezil, 88 ml of THF and 3 ml of ion-exchanged water were added, dissolved at 20 ° C., and cooled with ice. Here concentrated hydrochloric acid (0.93g) / T
An HF (2 ml) solution was added, and the mixture was stirred under ice cooling for 30 minutes. The precipitated crystals were collected by filtration and dried to give 3.21 g of the title compound. (Moisture content; 11.34%) Elemental analysis value (%) C; 61.30 H; 7.76 N; 2.86 Cl; 7.6
8

Example 102 Polymorph of donepezil hydrochloride
Preparation of (IV) To 1.0 g of donepezil, 9 ml of toluene was added and dissolved at 22 ° C. A concentrated hydrochloric acid (0.31 g) / toluene (1 ml) solution was added thereto,
Stirred overnight at room temperature. The precipitated crystals are collected by filtration and dried,
1.23 g of the title compound were obtained. (Moisture content; 11.40%)

Example 103 Polymorph of donepezil hydrochloride
Preparation of (IV) 9 g of n-hexane was added to 1.0 g of donepezil and dissolved at 21 ° C. A concentrated hydrochloric acid (0.31 g) / n-hexane (1 ml) solution was added thereto, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration and dried to give 1.23 g of the title compound. (Moisture content; 11.24%)

Example 104 Polymorph of donepezil hydrochloride
Production of (IV) 1 ml of methanol, 3 ml of ion-exchanged water and 0.93 g of concentrated hydrochloric acid
To this mixture, 1.0 g of donepezil was added and dissolved at 20 ° C.
Stirring was continued for 3 days. The precipitated crystals were collected by filtration and dried to give the title compound (0.83 g). (Moisture content; 11.04%)

Example 105 Polymorph of donepezil hydrochloride
Preparation of (IV) 10 g of ion-exchanged water was added to 2.0 g of donepezil, and suspended at 23 ° C., and hydrochloric acid gas was blown into the suspension until all crystals were dissolved. The mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration and dried to give 1.77 g of the title compound.
(Moisture content; 11.10%)

Example 106 Polymorph of Donepezil Hydrochloride
(IV) Preparation of donepezil hydrochloride 1.0 g, ion-exchanged water 5 ml was added, 60 ℃
After heating and dissolving in, the mixture was allowed to cool. Stirred overnight at room temperature. The precipitated crystals were collected by filtration and dried to give 0.92 g of the title compound.
(Moisture content; 11.12%)

Example 107 Polymorph of donepezil hydrochloride
Production of (IV) 1.0 g of donepezil hydrochloride polymorphic crystal (II) was placed in a 50 mmφ petri dish and allowed to stand at 90% or more of relative humidity for 24 hours to obtain 1.15 g of the title compound. (Moisture content; 12.33%)

Example 108 Polymorph of donepezil hydrochloride
Production of (IV) 10 g of donepezil hydrochloride polymorphic crystal (III) was placed in a 250 mm Petri dish, and 300 ml of ion-exchanged water was added to dissolve at 21 ° C.
This was transferred to a lyophilizer and dried for 3 days to obtain an amorphous. This was allowed to stand at a relative humidity of 90% or higher for 24 hours to obtain 11.20 g of the title compound. (Moisture content; 11.21%)

Example 109 Polymorph of Donepezil Hydrochloride
Preparation of (V) 2.0 g of the polymorph (IV) of donepezil hydrochloride was placed in a Petri dish and dried in a vacuum dryer at 80 ° C. under reduced pressure overnight to obtain 1.75 g of the title compound. (Moisture content; 0.28%)

Finally, in order to demonstrate the effects of the present invention, the results of comparing the stability and hygroscopicity of the novel polymorphic crystal of donepezil hydrochloride according to the present invention with those of an amorphous polymorph are listed below.

【The invention's effect】

(1) Stability (Experimental method) Polymorphic crystals (I) to (IV) of donepezil hydrochloride and amorphous donepezil hydrochloride were weighed twice in 10 ml spitzrolls, and the following conditions were used. And the impurity concentration (%) was measured over time.

(HPLC Purity Measuring Method and Conditions) 10 ml of the following mobile phase was added to each spitz roll and dissolved,
Measure the impurity concentration (%) under the conditions, and
The average value of the books was determined. ───────────────────────── Column; Inertsil ODS-II (4.6 mm I.D. × 150 mm) Mobile phase: CH ₃ CN / water / 70 % HClO ₄ (V / V / V = 300: 700: 1) detection; UV271nm flow rate; 1.0ml / min injection volume; 5μl column temperature; room temperature ───────────────── ────────

[0155]

[0156]

[0157]

[0158] From the above experimental results, polymorphic crystals of donepezil hydrochloride (I) to (I
It is clear that V) is superior in thermal stability to amorphous donepezil hydrochloride.

(2) Hygroscopicity (Experimental method) Polymorphs (I) to (IV) of donepezil hydrochloride and amorphous donepezil hydrochloride were stored at 25 ° C. in the relative humidity shown in the following table for 2 weeks. The water content was measured according to the pharmacopoeia, general test method, and moisture measurement method (Karl Fischer method).

[0160]

In the above experimental results, donepezil hydrochloride polymorph (I) had a relative humidity of up to 96.6%, polymorph (II) had a relative humidity of up to 75.0%, and polymorph (III) had a relative humidity of up to 96.6%.
Furthermore, polymorph (IV) did not show hygroscopicity up to a relative humidity of 100%, whereas amorphous donepezil hydrochloride showed hygroscopicity from a relative humidity of 10.6% when the experiment was started. Therefore, it is clear that the polymorphs (I) to (IV) of donepezil hydrochloride have superior moisture absorption stability to amorphous donepezil hydrochloride.

From the above experimental results, it is clear that the novel polymorphic crystals (I) to (IV) of donepezil hydrochloride according to the present invention have excellent heat stability and low hygroscopicity.

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction pattern of donepezil hydrochloride polymorph (I).

FIG. 2 is a powder X-ray diffraction pattern of donepezil hydrochloride polymorph (II).

FIG. 3 is a powder X-ray diffraction pattern of donepezil hydrochloride polymorph (III).

FIG. 4 is a powder X-ray diffraction pattern of donepezil hydrochloride polymorph (IV).

FIG. 5 is a powder X-ray diffraction pattern of amorphous donepezil hydrochloride.

FIG. 6 is an infrared absorption spectrum of donepezil hydrochloride polymorph (I) in potassium bromide.

FIG. 7 is an infrared absorption spectrum of donepezil hydrochloride polymorph (II) in potassium bromide.

FIG. 8 is an infrared absorption spectrum of donepezil hydrochloride polymorph (III) in potassium bromide.

FIG. 9 is an infrared absorption spectrum of donepezil hydrochloride polymorph (IV) in potassium bromide.

FIG. 10 is an infrared absorption spectrum of amorphous donepezil hydrochloride in potassium bromide.

FIG. 11 is a thermogravimetric-differential thermal analysis (TG-DTA) of donepezil hydrochloride polymorph (I).

FIG. 12 is a thermogravimetric-differential thermal analysis (TG-DTA) of donepezil hydrochloride polymorph (II).

FIG. 13 is a thermogravimetric plot of donepezil hydrochloride polymorph (III).
It is a differential thermal analysis (TG-DTA).

FIG. 14—Thermogravity of donepezil hydrochloride polymorph salt crystals (IV) —
It is a differential thermal analysis (TG-DTA).

FIG. 15 is a thermogravimetric-differential thermal analysis (TG-DTA) of amorphous donepezil hydrochloride.

FIG. 16 is a graph showing the change over time of impurities in each polymorphic crystal and amorphous when stored at −20 ° C.

FIG. 17 is a graph showing the change over time of impurities in each polymorphic crystal and amorphous when stored at 40 ° C.

FIG. 18 is a graph showing changes over time of impurities in each polymorphic crystal and amorphous when stored at 60 ° C.

FIG. 19 is a graph showing the change over time of impurities in each polymorphic crystal and amorphous when stored at 80 ° C.

FIG. 20 is a graph showing the water content in each polymorph and amorphous when stored at 25 ° C. and each relative humidity.

FIG. 21 is a re-measured powder X-ray diffraction pattern of donepezil hydrochloride polymorph (I).

FIG. 22 is a remeasured powder X-ray diffraction pattern of donepezil hydrochloride polymorph (II).

FIG. 23 is a remeasured powder X-ray diffraction pattern of donepezil hydrochloride polymorph (III).

FIG. 24 is a re-measured powder X-ray diffraction pattern of donepezil hydrochloride polymorph (IV).

FIG. 25 is a powder X-ray diffraction pattern of donepezil hydrochloride polymorph (V).

FIG. 26 is a remeasured powder X-ray diffraction pattern of amorphous donepezil hydrochloride.

FIG. 27 is a re-measurement infrared absorption spectrum of donepezil hydrochloride polymorph (I) in potassium bromide.

FIG. 28 is a re-measurement infrared absorption spectrum of donepezil hydrochloride polymorph (II) in potassium bromide.

FIG. 29 is a re-measurement infrared absorption spectrum of donepezil hydrochloride polymorph (III) in potassium bromide

FIG. 30 is a re-measured infrared absorption spectrum of donepezil hydrochloride polymorph (IV) in potassium bromide.

FIG. 31 is an infrared absorption spectrum of donepezil hydrochloride polymorph (V) in potassium bromide.

FIG. 32 is a remeasured infrared absorption spectrum of amorphous donepezil hydrochloride in potassium bromide.

FIG. 33 is a remeasured differential thermal analysis (DSC) of donepezil hydrochloride polymorph (I).

FIG. 34 is a remeasured differential thermal analysis (DSC) of donepezil hydrochloride polymorph (II).

FIG. 35 is a re-measured differential thermal analysis (DSC) of donepezil hydrochloride polymorph (III).

FIG. 36 is a re-measurement differential thermal analysis (DSC) of donepezil hydrochloride polymorph salt crystals (IV).

FIG. 37 shows a differential thermal analysis (DSC) of donepezil hydrochloride polymorph salt crystals (V).

FIG. 38: Re-measurement differential thermal analysis of amorphous donepezil hydrochloride
(DSC).

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yasushi Ishihama 3-5-1-101, Kasuga, Tsukuba, Ibaraki (72) Inventor Akiyo Otsuka 668-56, Shimohirooka, Tsukuba, Ibaraki Prefecture (72) Inventor Tomohide Tanaka 9-13-5-A202 9-1-2-5-A202, Chisu-Chuo, Kamisu-cho, Kashima-gun, Ibaraki Prefecture 5-9809-229 5-8909-229 Inventor Yukio Narabe Ibaraki Pref.

Claims (77)

[Claims] 1. A powder X-ray diffraction pattern having a peak at the following diffraction angle represented by 2θ, In the infrared absorption spectrum in potassium bromide, the wave number 4
63, 502, 563, 589, 604, 701, 750, 759, 799, 860, 922, 947, 97
2, 1012, 1038, 1104, 1120, 1128, 1175, 1192, 1218, 1250, 126
7, 1316, 1368, 1410, 1433, 1440, 1455, 1472, 1502, 1591, 160
6, 1644, 1684, 2412, 2530, 2559, 2595, 2620, 2717, 2840, 285
A polymorphic crystal of donepezil hydrochloride (I) represented by the following chemical formula, having absorption at 8, 2924, 3004, 3074, 3259, 3373, 3547, and 3589 cm ^-1 . Embedded image 2. A powder X-ray diffraction pattern having a peak at the following diffraction angle represented by 2θ, In the infrared absorption spectrum in potassium bromide, the wave number 6
99, 748, 762, 845, 947, 1009, 1035, 1067, 1103, 1118, 1129, 1
174, 1193, 1206, 1222, 1247, 1267, 1317, 1365, 1422, 1436, 1
456, 1465, 1502, 1592, 1607, 1688, 2412, 2489, 2627, 2846, 2
Polymorph (II) of donepezil hydrochloride characterized by having absorption at 868, 2913, 2928, 3435 cm ^-1 . 3. A powder X-ray diffraction pattern having a peak at the following diffraction angle represented by 2θ, In the infrared absorption spectrum in potassium bromide, the wave number 5
59, 641, 648, 702, 749, 765, 786, 807, 851, 872, 927, 949, 96
6, 975, 982, 1007, 1034, 1071, 1080, 1111, 1119, 1131, 1177,
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,
Polymorph (III) of donepezil hydrochloride characterized by having absorption at 2954, 2961, 2993, 3007, 3377, 3433 cm ^-1 . 4. A powder X-ray diffraction pattern having a peak at the following diffraction angle represented by 2θ, In the infrared absorption spectrum in potassium bromide, the wave number 4
01,431,459,467,490,506,518,561,586,606,631,651,70
9,758,766,857,944,1009,1041,1106,1119,1132,1213,12
25, 1265, 1304, 1318, 1429, 1458, 1470, 1500, 1589, 1605, 16
30, 1647, 1683, 2562, 2577, 2608, 2634, 2689, 2717, 2836, 29
Polymorphs of donepezil hydrochloride characterized by having absorption at 24, 2949, 2989, 3007, 3032, 3061, 3322, 3376, 3422 cm ^-1
(IV). 5. A process for producing donepezil hydrochloride polymorphic crystal (I), characterized by crystallizing donepezil hydrochloride from methanol. 6. Dissolving donepezil hydrochloride in methanol,
A method for producing polymorphic crystal (I) of donepezil hydrochloride, which comprises adding diethyl ether or isopropyl ether. 7. Dissolving donepezil hydrochloride in methanol,
A method for producing polymorphic crystal (I) of donepezil hydrochloride, which is added to diethyl ether or isopropyl ether. 8. A method for producing a polymorphic crystal (I) of donepezil hydrochloride, comprising dissolving donepezil in methanol and adding hydrochloric acid or hydrogen chloride. 9. A polymorph crystal of donepezil hydrochloride (I), wherein donepezil is dissolved in ethanol, isopropyl ether is added, and then hydrochloric acid or hydrogen chloride is added.
Manufacturing method. 10. A method for producing a polymorphic crystal of donepezil hydrochloride (I), comprising dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, then adding isopropyl ether, and immediately filtering the crystal after precipitation. 11. A method for producing donepezil hydrochloride polymorph (II), comprising dissolving donepezil hydrochloride in ethanol and adding diethyl ether or isopropyl ether. 12. A process for producing donepezil hydrochloride polymorphic crystal (II), comprising dissolving donepezil hydrochloride in ethanol, adding isopropyl ether, stirring for 10 to 30 minutes after crystal precipitation, and collecting by filtration. 13. A method for producing a polymorphic crystal (II) of donepezil hydrochloride, comprising dissolving donepezil and hydrochloric acid or hydrogen chloride in ethanol, and adding diethyl ether. 14. A method for producing a polymorph (II) of donepezil hydrochloride, comprising dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride and concentrating the solution. 15. A polymorphic crystal of donepezil hydrochloride (I) comprising dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, and then adding isopropyl ether.
I) Manufacturing method. 16. The polymorph of donepezil hydrochloride according to claim 15, wherein the crystal is collected by filtration 10 to 60 minutes after the precipitation of the crystal.
Production method of (II). 17. A method for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in ethanol and adding diethyl ether. 18. A process for producing donepezil hydrochloride polymorph (III), comprising dissolving donepezil hydrochloride in methylene chloride and adding n-hexane. 19. A method for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil in acetone and adding hydrochloric acid or hydrogen chloride. 20. A process for producing donepezil hydrochloride polymorph (III), comprising dissolving donepezil in ethyl acetate and adding hydrochloric acid or hydrogen chloride. 21. A polymorphic crystal of donepezil hydrochloride, comprising dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, and then adding one kind of solvent selected from diethyl ether, isopropyl ether and n-hexane. III). 22. The solvent is isopropyl ether,
The method for producing polymorphic crystal (III) of donepezil hydrochloride according to claim 21, wherein the crystal is collected after one hour or more from the precipitation of the crystal. 23. Polymorphic crystal (I) of donepezil hydrochloride or
A method for producing polymorphic crystal (III) of donepezil hydrochloride, which comprises heating (II). 24. The method of humidifying polymorph (II) of donepezil hydrochloride. 25. In the powder X-ray diffraction pattern, 2θ
Having a peak at the following diffraction angle represented by In the infrared absorption spectrum in potassium bromide, the wave number 5
62.7, 603.2, 700.4, 749.6, 798.1, 859.2, 896.0, 92
1.3, 946.3, 971.8, 1038.0, 1119.3, 1216.8, 1266.0,
1315.4, 1367.7, 1454.1, 1501.5, 1537.8, 1555.9, 1
590.7, 1643.7, 1681.9, 2350.9, 2534.0, 2922.1, 338
1.8, Polymorphic crystal of donepezil hydrochloride (I) having absorption at 3585.2 cm ^-1 . 26. In the powder X-ray diffraction pattern, 2θ
Having a peak at the following diffraction angle represented by Wave number 560.1, 698.9, 749.1, 846.2, 947.6, 1036.1, 11
19.3, 1222.7, 1266.4, 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, 17
51.7, 1773.9, 1793.8, 1830.7, 1846.0, 1870.1, 2345.
Polymorph (II) of donepezil hydrochloride characterized by having absorption at 1, 2489.9, 2927.9, 3448.1 cm ^-1 . 27. In the powder X-ray diffraction pattern, 2θ
Having a peak at the following diffraction angle represented by Wave number 558.3, 641.1, 702.4, 748.5, 765.0, 786.1, 80
7.3, 850.8, 872.0, 926.8, 974.9, 1034.1, 1071.5, 1
111.6, 1190.1, 1216.6, 1265.4, 1291.9, 1312.9, 136
4.4, 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, 1
845.8, 2345.3, 2461.6, 2924.2, 3447.9 cm ^-1 absorption of donepezil hydrochloride polymorphic crystal (II
I). 28. In the powder X-ray diffraction pattern, 2θ
Having a peak at the following diffraction angle represented by Wave number 561.5, 709.0, 766.2, 786.3, 804.9, 857.0, 94
4.3, 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, 1
773.7, 1793.5, 1830.5, 1845.8, 1870.1, 2344.8, 236
Polymorph (IV) of donepezil hydrochloride characterized by having absorption at 9.3, 2719.2, 2922.9, 3324.0 cm ^-1 . 29. In the powder X-ray diffraction pattern, 2θ
Having a peak at the following diffraction angle represented by Wave number 506.5, 559.7, 594.4, 698.0, 740.8, 805.1, 86
1.9, 948.5, 972.1, 1039.9, 1120.8, 1220.7, 1264.8,
1314.6, 1364.1, 1458.0, 1499.5, 1542.5, 1560.2, 1
592.1, 1692.9, 2500.1, 2924.2, 2998.9, 3422.1 cm ^-1
Polymorph (V) of donepezil hydrochloride, characterized by having an absorption in water. 30. A process for producing donepezil hydrochloride polymorphic crystal (I), wherein the donepezil hydrochloride is crystallized from methanol at a temperature of less than 10 ° C. 31. A process for producing donepezil hydrochloride polymorphic crystal (I), comprising dissolving donepezil in methanol, adding hydrochloric acid or hydrogen chloride, and then adding t-butyl methyl ether, diisopropyl ether or ethyl acetate. . 32. A method for producing a polymorphic crystal (I) of donepezil hydrochloride, comprising dissolving donepezil in ethanol and adding hydrochloric acid or hydrogen chloride. 33. A method for producing a polymorphic crystal (I) of donepezil hydrochloride, comprising dissolving donepezil in less than 6 times the volume of tetrahydrofuran and adding hydrochloric acid or hydrogen chloride. 34. A method for producing a polymorphic crystal (I) of donepezil hydrochloride, comprising dissolving donepezil in acetonitrile and adding hydrochloric acid or hydrogen chloride. 35. A process for producing a polymorphic crystal of donepezil hydrochloride (I), comprising dissolving donepezil hydrochloride in methanol, and adding t-butyl methyl ether after starting the crystal precipitation. 36. A method for producing a polymorphic crystal (I) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in methanol and adding ethyl acetate. 37. A method for producing donepezil hydrochloride polymorphic crystal (I), comprising dissolving donepezil hydrochloride in methanol and adding n-hexane. 38. Polymorphic crystal of donepezil hydrochloride (I), wherein the donepezil hydrochloride is recrystallized from ethanol.
Manufacturing method. 39. A method for producing a polymorph (I) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in ethanol and adding t-butyl methyl ether at a temperature lower than 10 ° C. 40. A polymorphic crystal of donepezil hydrochloride (I) comprising dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, and then adding t-butyl methyl ether.
I) Manufacturing method. 41. A method for producing a polymorph (II) of donepezil hydrochloride, comprising dissolving donepezil in isopropyl alcohol or methylene chloride and adding hydrochloric acid or hydrogen chloride. 42. A method for producing a polymorphic crystal of donepezil hydrochloride (II), comprising dissolving donepezil in acetone, adding hydrochloric acid or hydrogen chloride and filtering the solution within 30 minutes after the start of crystal precipitation. 43. A method for producing donepezil hydrochloride polymorph (II), comprising dissolving donepezil hydrochloride in ethanol and adding t-butyl methyl ether at 10 to 30 ° C. 44. A method for producing a polymorph (II) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in ethanol and adding the solution to diisopropyl ether. 45. A process for producing a polymorph (II) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in methylene chloride and adding t-butyl methyl ether. 46. A method for producing donepezil hydrochloride polymorph (II), comprising drying the donepezil hydrochloride polymorph (I) or the amorphous. 47. A process for producing donepezil hydrochloride polymorph (III), comprising dissolving donepezil in methanol, adding hydrochloric acid or hydrogen chloride, and then adding acetone. 48. A polymorph of donepezil hydrochloride characterized by dissolving donepezil in ethanol, adding hydrochloric acid or hydrogen chloride, and then adding t-butyl methyl ether.
Production method of (III). 49. A method for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil in acetonitrile and adding hydrochloric acid or hydrogen chloride. 50. A method for producing donepezil hydrochloride polymorph (III), comprising dissolving donepezil in at least 6-fold volume of tetrahydrofuran and adding hydrochloric acid or hydrogen chloride. 51. Donepezil is dissolved in hydrated acetone,
A method for producing polymorphic crystal (III) of donepezil hydrochloride, which comprises adding hydrochloric acid or hydrogen chloride. 52. A method for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil in N, N-dimethylformamide and adding hydrochloric acid or hydrogen chloride. 53. A process for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil in dimethyl sulfoxide, adding hydrochloric acid or hydrogen chloride, and then adding t-butyl methyl ether. 54. A process for producing donepezil hydrochloride polymorph (III), comprising dissolving donepezil in toluene and adding hydrochloric acid or hydrogen chloride. 55. A method for producing a polymorph (III) of donepezil hydrochloride, wherein the donepezil hydrochloride is crystallized from methanol at a temperature lower than 10 ° C. 56. A method for producing donepezil hydrochloride polymorph (III), comprising dissolving donepezil hydrochloride in methanol and adding t-butyl methyl ether to a homogeneous solution. 57. A method for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in methanol and adding acetonitrile. 58. A process for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in ethanol and adding t-butyl methyl ether at 30 ° C. or higher. 59. A method for producing a polymorphic crystal (III) of donepezil hydrochloride, wherein the donepezil hydrochloride is crystallized from isopropyl alcohol. 60. A method for producing a polymorphic crystal (III) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in N, N-dimethylformamide and adding t-butyl methyl ether. 61. A method for producing a polymorph (III) of donepezil hydrochloride, comprising dissolving donepezil hydrochloride in dimethyl sulfoxide and adding t-butyl methyl ether. 62. Polymorphic crystals of donepezil hydrochloride (I), (II),
A method for producing donepezil hydrochloride polymorph (III), which comprises converting (IV), (V) or an amorphous substance by stirring in a solvent. 63. The method for producing polymorph (III) of donepezil hydrochloride according to claim 62, wherein the solvent is at least one selected from methanol, ethanol, ethyl acetate and acetone. 64. A process for producing donepezil hydrochloride polymorph (IV), which comprises humidifying donepezil hydrochloride polymorph (II). 65. A process for producing a polymorph (IV) of donepezil hydrochloride, comprising dissolving donepezil in water or hydrated tetrahydrofuran and adding hydrochloric acid or hydrogen chloride. 66. A method for producing donepezil hydrochloride polymorph (IV), comprising dissolving donepezil in hydrochloric acid and adding tetrahydrofuran. 67. A polymorphic crystal of donepezil hydrochloride (I) characterized by dissolving donepezil in toluene and adding hydrochloric acid.
V) Manufacturing method. 68. A polymorph of donepezil hydrochloride characterized by dissolving donepezil in n-hexane and adding hydrochloric acid
Production method of (IV). 69. A method for producing a polymorphic crystal (IV) of donepezil hydrochloride, wherein the donepezil is crystallized from a mixed solution of methanol / hydrochloric acid. 70. A method for producing donepezil hydrochloride polymorphic crystal (IV), comprising crystallizing donepezil hydrochloride from water. 71. A method for producing donepezil hydrochloride polymorph (II) or a polymorph (donepezil hydrochloride), which comprises humidifying an amorphous form of donepezil hydrochloride. 72. A process for producing a polymorph (V) of donepezil hydrochloride, comprising drying the polymorph (IV) of donepezil hydrochloride. 73. Polymorphic crystals of donepezil hydrochloride (I), (II),
A medicament comprising (III), (IV) or (V). 74. Polymorphic crystals of donepezil hydrochloride (I), (II),
An agent for preventing, treating or ameliorating a disease in which acetylcholinesterase inhibitory activity is effective, comprising (III), (IV) or (V) as an active ingredient. 75. Polymorphic crystals of donepezil hydrochloride (I), (II),
An agent for preventing, treating or improving senile dementia comprising (III), (IV) or (V) as an active ingredient. 76. Polymorphs of donepezil hydrochloride (I), (II),
An agent for preventing, treating or improving Alzheimer's disease comprising (III), (IV) or (V) as an active ingredient. 77. Polymorphic crystals of donepezil hydrochloride (I), (II),
A pharmaceutical composition containing (III), (IV) or (V).