HU227539B1 - Polymorphs of donepezil hydrochloride and process for production and pharmaceutical compositions containing them - Google Patents

Abstract

Donepezil hydrochloride, (1-benzyl-4-((5,6-dimethoxy-1-indanon)- 2-yl)methylpiperidine hydrochloride) in the form of polymorphs (I), (II), (III), (IV) and (V) is new. (I)-(V) each have specified peaks at diffraction degrees with specific intensity in terms of I/Io in the powder X-ray diffraction pattern and specific absorption peaks in the IR absorption spectra in potassium bromide in terms of reciprocal centimetres, all shown in the specification.

Description

Polymorphic modification of onepezil hydrochloride (HI), process for its preparation, butylamine? pharmaceutical preparations containing this variant

The present invention is a pharmaceutical composition which exhibits excellent potency (as disclosed in the patent) · Donepezis hydrochloride, i.e., benzene-4- (15, 6-dimethoxy-1-methanone> -2'-yl) -methyl-piperidine hydrochloride. (U.S. Pat. No. 4,995,841 or EP-A 296,560-4) relates to a stable polymorph (ΪΠ), a process for the preparation of a stable polymorph (e) and its scaling,

Donepezil Hydrochloride has an inhibitory effect on ethylene cholinesterase and is therefore useful for the treatment of all types of aggravated dementia, particularly useful for the prevention, treatment and recovery of Alzheimer's disease. Dooepezil hydrochloride is usually administered orally and may be stored and placed on the market for a limited period prior to administration. The patient can then be stored at home for up to 1 month due to the special nature of the product. During storage, the stability of this pharmaceutical composition to heat and moisture is very important. Therefore, there is a need for more stable pharmaceutical formulations of donepezil hydrochloride. However, it is not known from the literature that polymorphic modifications of don epothelial order exist. No sufficiently stable pharmaceutical formulation containing donepezil hydrochloride has been developed so far.

Example 4 of US-4,895,841 shows that donepezil can be obtained by recrystallization of the crude donepezil feodichloride from ethanol and isopropyl ether, the son having a more stable crystalline dosepezide, product marketing and storage.

BP 8 290 568 A, EP 8 673 927 A and US 4 895 84; s. These applications relate to a cyclic amine compound having the general formula deoepezFl hydrochloride and the like. Crystals of the? (1) polymorph of this v-one species have also been described.

The EP 296 SóG A. BP 673 927 A, selected from Patent Application Ser. the subject matter of the application is similar. The compounds described herein are useful in the treatment of elderly demeoti-a.

In view of the above-mentioned difficulties, we carried out extensive research work. As a result, it has been found that a polymorphic form of douepezil hydrochloride (111) can be produced which has very good stability. The invention is based on this discovery. Thus, the present invention provides a novel d-onepezilic tetragonal polymorph modification and an industrial process for its preparation. More particularly, the present invention provides a polymorphic form of the below-described donepezil hydrochloride (X-ray junction) characterized by X-ray powder diffraction and peaks in the infrared spectrum of potassium bromide.

411732-49 up / VO / Lks

1. .Measurement method

The method and conditions of log diffraction imaging are the following. described below. X-ray diffraction scans are always made on a sample of 109 mg, under the following conditions.

2. Measuring conditions

Target: copper filter: monochromatic voltage: 40 kV current: 20 mA slit: DS 1, RSO.15, SS 1 sample rotation speed: rpm rotation range: 5 to 30 ° incremental step: 0.02 °.

The infrared absorption spectrum is recorded in potassium bromide according to the general procedure described in the Japanese Pharmacopoeia.

(Π (I) Polymorphic media (not required)

Powered X-ray & akeosa curve tube:

diffraction angle (20, °) intensity () /) «) 9.94 24 10.60 10 2.66 69 13.12 55 13.66 44 13.86 40 14.92 49 15.26 1? 16.08 35 16, Salt 34 17.50 34 17, SS 42 18.42 20 19.28 27 19.80 45 19.94 45 21.22 100 22.00 32 22.54 31 22.98 49 23.60 56 23.78 75

«« Fr

diffraction angle (20, °) intensity (l /? «) 23.92 79 26.46 33 ...... 28.02 25 29.50 37

The IR spectrum of the infra-red spectrum recorded in chaite bromide was 463, 502, 563, 589, 604, 701, 756, 15, 799, 860, 922, 947, 972, 1012, 1038, H04, 1120, 5128, 1175, 1192. , 1218, 1250, 1267, 1316, 1368, 1410, 1933, 1440, 1455, 1472, 1502, 1.59),. 1606, 1644, 1684, 2412, 2530, 2559, 2595, 2620, 2717, 2840, 2858, 2924, 3004, 3074, 3259, 3373, 3547, 3589 erna (2) (ib Pfrliasorf variant {required)

The peaks of the sputtered curve of the dusts are:

diffraction angle (20, °) intensity (1¾} 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 '? ·? ώΛ- 24.92 25 25.72 27 26.40 18 27/22 14

Hailat numbers of the infra-red spectra (era'h;

099, 748, 762, 845, 947, 1009, 1035, 1007, 1103, 1118, 1129, 1174, 1193, 1206, 1222, 5247, 1267,

13) 7, 1365, 1422, 1436, 1456, 1465 1502, 1592, 1607, 1688, 2412, 2489, 2627, 2846, 2868, 2913, 2928,

3435 cin;

X * »X

X * ♦ Φ »♦ * * β * φ φφ« ♦ ♦ ** »φφφ φ * ♦ * * ΦΦΧ Χ« 99 * (3) (511> Poliamrf modifyahu

The ponmnfáH raises the x-ray function curve peak

diffraction angle (20, *) infeassyphilis (í / í _Ít ) 6.56 30 9.94 S 13.00 1? 35 00 ⁴⁷ 35.26 14 1, 5.74 6 16.48 35 37.42 4 18.10 23 18.50 56 59.50 3? 20:10 32 20.94 21 25.66 308 22.32 25 22.92 37 23.92 39 24.68 17 26.00 44 27.20 23 28.02 29 28.22 40 28.60 13

The infrared spectrum absorbed into the cali briside has a number of cm -1 (cm ' ¹ ):

SS9; 641, 64: 8, 7Ö2, 749, 765, 786, 807, 853, 372, 327, $ 49, $ 66, $ 75, $ 82, 19Ö7, 3034, 1-071, 1080, 11-11, 1119 »1131, 3177, . 5,390, 3205, 1217, 3230, 3250, 3265, 3292-, 33 33, 3367, 3389, 1-420, 1438, 1453, 3463. 3470, 3500, 158-9, 1605, 3697, 2407, 2439, 2463, 2624, 2641, 2653, 2667, 2837, 2848, 2873, 2924, 2954, 2961, 2993, 3007, 3377, 3433 cm ', (4) (IV) Polyphosphate modification (not claimed)

Λ the peaks of the t-öatgmdií & akeío curve obtained from the power:

diffraction angle (.20, °) intensity (1¾) 6:24 15 9.66 12 3, 3.84 22 12.12 24

oil angle (20, °) intensity (1¾) 12.54 67 12.76 61 13.98 27 14.42 15 14, SS 11 16.34 52 17.46 100 18:12 25 18.60 32 19.06 15 19.98 74 20.42 41 20.62 34 21.30 48 21.80 63 .22,58 78 23.04 46 24.00 32 24.54 49 25.14 90 25.28 99 26.06 34 28.10 41 28.58 39 29.30 31 29.44 28 the..........................

Infrared Spectrum of Potassium Bre-Kid (cm · ''}:

40I, 43 3, 459, 467, 49®, 5Ö6, 5 IS, 563, 586, 606, 631, 651, 799, 758, 766, 857, 944, 3009, 104 3, 1106, 5 119, 1132, 1213 , 1225, 1265, 1304, 1318, 1429, 1458, 3470, 3500, 1589, 1605, 3630, 1647, 1683, 2562, 2577, 2608, 2634, 2689, 2717, 2836, 2924, 2949, 2989, 3007, 3032 , 3061, 3322, 3376, 3422 cm

Further analytical data for (1), (Η), (IV), and (V) polymorphic matrix are as follows: (1) (1) Polymorphic matrix is required)

The peaks of the powder-diffraction curve recorded on the dust sample are:

diHrake angle (29, °) in intensity (1¾) 9.82 13 .10 / · h 38 3, 2.52 93

diffraction angle {28, ®) Intensity 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 2.1,04 100 21.16 82 22> 92 52 23.82 72 24.14 32

The infrared spectrum absorbed by potassium chloroform at h-ámMátzz ot (ot ′ ¹ ):

562.7, 603.2, 700.4, 749.6, 798.1. 854.2, 896.0, 921.3, 946.3, 971.8, 1038.0, 1119.3, 1216.8, 1266.0, 13) 5.4, 1367.7, 1454.1, 1501.5, 1537.8, 1555.9, 1590.7, 1643.7, 1681.9, 2350.9, 2534.0, 2922.1, 3381.8, 2585.2 cm ^-1 , (2) (It ) Frawrawrf (ueíu need <4jök)

The peaks of the X-ray TFT curve recorded on the ponumania are:

dsffra angle (20, ®) satiety «1/1») 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 A, 36 28 18.58 51 18.66 46 19.48 4-2 20.18 81 20.80 36 22.26 45

* »Φφ φ

X φφφ

diffraction angle (20, ”1 mtenxitils (1.¾} 23.38 g6 23.52 59 24.06 34 24.32 55 25.14 94 25.94 50 25.72 39 25.96 35 26.19 2.5 28.06 25 28.20 34 28.38 34

Potassium bromide is an infrared spectrum

5-60.1, 608.9, 749.3, 846.2, 947, -S, 1036.1, 1319: 3, 1222.7, 1266.4, 1338,7, 1364.1, 1438, 3, 1509.9, 1522.3, 1534.0, 1542.6, 1560.2, 1570.3, 3592.0, 1637.9, 1647.9, 1654.4,. 1689.5, 1718.3, 1734.7,

1751.7, 3773.9, 1703.8, 1830.7, 1846.0, 1870.1, 2345.3, 2489.9, 2927.9, 3448.1 cm ^! , (4) (IV) Polymorphic Noodosyl (sscm required)

A. The peaks of the x-ray diffraction curve then recorded by A. p «r.mi»:

diffraction angle (20, °) intensity (1¾} 9.69 13 10.02 11 12.46 63 12.72 17 13.86 27 14:42 12 17.36 390 18.34 39 19.99 37 21.18 35 21.74 39 22.48 60 22.96 36 24.19 17 25.28 70 28.09 27 28.50 2?

Φ ΦΦ X * φ φφ «*» ♦ * ♦ X «*« φ φφ φφφ

The fluorescence spectrum of the caffe scavenger &apos; infrared spectrum (cm &lt; 1 &gt;;

561.5, 709.0, 766.2, 7863. 804.9, 857..0., 944.3, 979.3, 1041.5, 1 HS., 7, {.644.6, 1318.7. {.3 «4,!, 1458.1,

1499.2, 1542.5, 1560.1, 1588.1, 1636.6, 3647.8, 1654.3, 1684.5, 1718.2, 1734.4, 1751.4, 1773.7,

1793.5, 1830.5, 1845.8, 1870, {., 2344,8,2369,3,2719.2, 2922.9, 3524.0 cm '^; , <$> (V) Poííeeirí brewery (not sgéayeí)

The peaks of the powder x-ray diffraction curve are:

angle of diffraction & s (20, °) Shrink (l / l _ö ) 6.58 7 6.86 27 10.12 52 12.54 33 12.90 43 13.64 64 15.58 27 17.22 69 18.44 72 18.96 19 19,30 25 19.64 19 19.74 25 20,30 19 20.46 17 21,10 15 21.96 100 22.24 32 24.22 63 24,66 96 25.36 60 26,14 15 26.82 44 27,5.2 24 27,96 28.2 (1 49 29.58 1.3 29.66 17 29.76 17

The wavelengths of the infrared spectrum of potassium ferrofluorobas (csf '>:

506.5, 559.7, 594.4, 690, 740.8, 805. L 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, 22998.9, 3422.1 cm: ⁴ .

The melting point of the novel 111: ss undesired polymorphs Cl, 11, IV and V differs from that of Example 4 of US 4,295,841 (€ 211-212; step up).

The melting point of the liver (111) and undesired (!), (11), (IV) and (V) polymorphs is given below:

melting point of undesired polymorph (1): melting point of undesired polymorph (áj): melting point of the Cili) polymorph according to the invention:

melting point of undesired polymorph (IV):

melting point of non-claimed polymorph (V): melting point of undesired amorphous form:

225-220 'C (decomposes}, 224-226 ° C (decomposes); 229-23 1' C (decomposes),

226-228 ^e C (dec),

218-220 ° C (decomposed), 220-222 ° C (decomposed).

In addition, the data obtained for their polymorphic form by thermogravimetric and differential thermoanalysis also differ from that of the known material.

The thermogravimetric and differential t-thermoanalysis (TG-DTA) method of measurement and measurement are as follows. A sample of 3 to 6 mg is taken from the substance to be examined and subjected to the thermal analysis under the following conditions.

Re-venting tube: empty temperature change. speed: 5 'C / min sampling interval: 0.7 s upper limit: 300' C, lower limit: room temperature.

Detailed procedures for the preparation of polymorphic modifications are as follows: In these procedures, the term "donepezil" is used to describe the tertiary base of donepezil hydrochloride, i.e. 2-yl] -methyl-pi: peridi: nt means.

(Ϊ) Processes for the production of non-claimed (i) polymorphs;

Recrystallization of C1-1) doneperyl hydrochloride from methanol, dissolution of (1-2) donepezil hydrochloride in methanol followed by addition of diethyl ether or isopropyl ether, dissolution of (1-3) donepezil in methanol followed by addition of hydrochloric acid or hydrochloric acid Solubilization of (1-4) donepezil in ethanol followed by addition of diisopropyl ether followed by hydrochloric acid or hydrochloric acid, or (1-5) solubilization of donepezil in ethanol followed by addition of hydrochloric acid or hydrogen chloride followed by diisopropyl ether; filtration of crystals immediately after their precipitation.

Of the above methods, process (1-5) is preferred. This procedure is illustrated in Example 7.

(2) Processes for the production of the undesired polymorph (11):.

Dissolution of (2-1) donepezil hydrochloride in ethanol. followed by addition of distillate or diisopropyl ether, (2-2) solubilization of donepezil FeHP in ethanol followed by addition of diisopropylether and filtration of the crystals after 19-30 min, (2-3) donepezil and hydrochloric acid or dissolution of hydrogen chloride in ethanol followed by addition of diethyl ether.

φφ * »* ΧΦ X Φ ΦΦ ♦ Φ * Φ 99 Λ

Φ ΦΦΦΦ φφφ *

Dissolution of (2-4) donepezll in ethanol, addition of hydrochloric acid or hydrochloric acid followed by heat, dissolution of (2-5) donepezll in ethanol, followed by hydrochloric acid or hydrogen chloride followed by diisopropylether or dissolving (2-6) donepezil in ethanol, hydrochloric acid or hydrochloric acid, followed by addition of diisopropyl ether, and after 10-60 rounds, preferably 10-39 rounds after precipitation, to give a crystalline scatter.

From the above, process (2-6), which is exemplified in Example 14, is preferred.

(3) Processes for the preparation of polymorph (Ili):

Dissolution of (3-1) dooepezyl hydrochloride in ethanol followed by addition of ethyl ether, (3-2) donepezil hydrochloride in dichloromethane. then adding n-hexane, dissolving (3-3) donepezll in acetone, then adding hydrochloric acid or hydrochloric acid, (3-4) dissolving donepezll in ethyl acetate, then adding hydrochloric acid or hydrogen chloride, (3-5) dissolving donepezll in ethanol . followed by the addition of hydrochloric acid or hydrochloric acid followed by addition of diethyl ether, diisopropyl ether and n-hexane to the solvent of choice, (3-6) the process of (3-5) wherein the selected solvent is diisopropyl ether and after 1 hour, preferably 2 hours, more preferably 6 hours, filtration of the crystals, or (3-7). Heating the (1) or (pol) polymorphic matrix.

Methods (3-5) and (3-6) are preferred above. These procedures are illustrated in Examples 23 and 18, respectively.

(4) Process for Preparation of Non-Required Polymorph Module (IV):

(4-1) wetting the polymorph (II).

Process (4-1) is illustrated in Example 24.

In the above-mentioned processes (1-5), (2-a) and (3-6), the solution is dissolved in donepezed ethanol, followed by the addition of hydrochloric acid or hydrogen chloride, followed by the addition of dlisoprep H ether. Any of these methods can produce the polymorphic form <1), (11) or (111) of the recrystallization lake; by regulating the time interval between the crystals being separated by filtration. This Duration may vary depending on the crystallization conditions, such as temperature, agitation rate and solvent volume. The following live price versions are available:

(1) by filtration, immediately after crystallization, to obtain the polymorph (?);

(2) by filtration after 10 minutes to 30 minutes, preferably 10 minutes to 30 minutes, after precipitation of the crystals, and (3) 1 hour, preferably 2 hours, more preferably 5 hours, after precipitation of the crystals. filtration to give polymorph (II1).

.Any further detailed procedures for the preparation of polymorphs are the following, (1) Processes for preparing the non-claimed (1) polymorphs:

solubilization of (i-h) donepezil in methanol followed by addition of hydrochloric acid or hydrochloric acid, (1-7) solubilization of donepezil in methanol successively with hydrochloric acid or hydrochloric acid and tert-butyl ether, dilisopropyl ether or ethyl acetate. add, * * * φφ φ φφ **** · ****** φ Φ Φ φ »X Λ

Φ «* ΦΦ Φ Φ φ * | | Dissolution of (1-8) donepezil in ethanol, teflacharofuran or acetonitrile, followed by addition of hydrochloric acid or phthydroge B-chloride, dissolution of (1-9) donepezyl b-dichloroate in methanol, followed by -acetate. or the addition of n-hesate, recrystallization of (1-19) dihydrochloride hydrochloride from ethanes, or dissolution of (1-11) docepezyl hydrochloride in ethanol followed by the addition of tert-butyl methyl ether.

Of the methods below, the {1-7} method is eBay. Est procedure is illustrated in & Examples 30-32.

Process (1-9) is also preferred; example.

(2) Processes for the production of the undesired polymorph (fi):

(2-7) solubilization of donepezil in ethanol. addition of hydrochloric acid or hydrochloric acid followed by terbotyl methyl ether, solubilization of (2-8) donepezil in rzepropyl alpha, in acetone or tetrabitrofurated, followed by addition of hydrochloric acid or hydrogen chloride, solubilization of (2-9) donepezil in meal diethyl chloride followed by the addition of hydrochloric acid or hydrochloric acid followed by diisopropylether, the dissolution of (2-10) danepezitic hydrochloride in ethanol, the addition of m-cis-titanium methyl ether or diisopropyl ether and blowing at a temperature of (2-11). a solution of donepezil hydrechieride in methylene chloride followed by addition of tert-butyl wetyl ether or dilopropyl ether, or heating (2-12) of the polymorphic form or amorphous form of donepezil hydrochloride (I).

Of the above processes, process (2-7), exemplified in Example 45, is preferred.

Process (2-10) is also preferred, which is prepared according to the method (52-54). example.

(3) Methods for preparing the polymorphic form (IU);

Dissolution of (3-8) dooepezil in methanol, hydrochloric acid or hydrochloric acid and. followed by the addition of acetone, the dissolution of (3-9) donepezil in ethanol, the addition of hydrochloric acid or hydrochloric acid and thereafter tert-butyl methyl ether, the dissolution of (3-10) donepezil in acetonitrile, acetone, acetone / water, M, N-dimsl) l-imbrmam, followed by addition of hydrochloric acid or hydrochloride, (3-11) solubilization of donepezil in ethyl acetate, hydrochloric acid or hydrochloric acid followed by addition of tert-butyl mephyl ether, (3) -12) solubilization of donepezil in dhrsethylsulfoxide, addition of hydrochloric acid or hydrochloride followed by terbenylmethyl ether, (3-13) solubilization of donepezil in toluene, addition of hydrochloric acid or hydrochloride, (3-14) donepezil- hydrochloride recrystallized from methanol at 19 ° C or higher, dissolving (5-IS) donepezil hydrochloride in methanol, then. addition of tert-butyl teryl ether or acetonitrile, dissolution of <3-16) donepezil hydrochloride in ethanol followed by addition of tert-butyl methyl ether or acetonitrile and stirring at a temperature of at least about <RTI ID = 0.0> C </RTI>.

(3-17) Dissolution of donepextl-hydroctoid in Ν, Ν-dimethylfomamidobaryl or dimethylsulfoxide, followed by «*

I ?.

φφ ♦

X «♦« * * <β-tert-butylmethyl ether, recrystallization of (3-18) donepezil hydrochloride from isopropyl alcohol (3-19) doaepsyl hydrochloride (ϊ), (Π), (IV) or ( V) conversion of the polymorphic n-dosing moiety or amorphous form in a solvent or (3-20) according to (3-19) wherein a solvent selected from methanol, ethanol, ethyl acetate and steel is used.

Of the painting methods, process (3-11) as exemplified in Example 59 is preferred. Process A (3-16) is preferred as exemplified in Example 72. Also preferred is process (3-19), illustrated in Examples 76-95.

(4) Processes for the production of the unneeded polymorph (IV):

(4-2) donepezi! dissolution in hydrochloric acid followed by filtration of the precipitated crystals, (4-3) donepez! dissolution in hydrochloric acid, followed by addition of tetrahydrofuran, (4-4) donepez! solubilization in a mixture of water and tetrahydrofuran followed by addition of hydrochloric acid or hydrochloric acid, dissolution of (4-5) donepeail in methanol, toluene or n-hexane followed by addition of hydrochloric acid (4-6). Dissolve in a mixture of methanol and hydrochloric acid, (4-7) donepez! water, followed by addition of hydrochloric acid or hydrochloride, (recrystallization of 4-8? donepezil hydrochloride from water, wetting of (4-9) douepezil hydrochloride polymorph, or (4-10) doaepezil hydrochloride dehydration of the amorphous form.

Preferred above is process (4-4), exemplified in Example 101. Further preferred is process (4-8) e, exemplified by Example 196 (5).

(5 -1) donepeztl-hydrochlorortd. (IV) heating the polymorph.

Process (5-1) is illustrated in Example 199.

The process for preparing the polymorphic form (() of formula (3-6), which consists of dissolving donspesdl in mannose, adding hydrochloric acid or hydrochloric acid and then adding diisoptylether. preferred crystallization times, depending on, among other things, the stirring rate and solvent volume, however, increasing the temperature will reduce the crystallization time. A variation of the procedure with such parameters is illustrated in Example 96-98,

The present invention further provides the use of the above polymorphic form of donepezil hydrochloride for the preparation of a medicament for the treatment of a disease of a human patient with acetylcholinesterase activity for which the donepezil 1 hydrochloride is a pharmaceutically active agent. an effective amount.

The present invention further provides a pharmaceutical composition which is a pharmaceutically acceptable form of the above polymorphic form of donepezil-hytoclone. an effective amount of a pharmaceutically acceptable carrier.

The polymorphic form of the invention is effective against various types of senile dementia, particularly Alzheimer's type dementia: cerebrovascular diseases such as stroke, such as stroke or cerebral infarction, cerebral atherosclerosis, cranial injury; and ♦ Φ ♦ Φ Φ ·) «* Φ» Φ «Φ Φ Φ **«

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THE.

in the treatment of hallucinatory parsoid syndrome and behavioral changes. prevention and mitigation.

In addition, the polymorphic n-precipitate of the present invention exhibits a potent and highly selective acetylcholinesterase-inhibiting tea which makes this compound useful in pharmaceutical formulations based on lupus activity.

The polymorphic modification of the above compound of the present invention is particularly effective against, inter alia, Huntington's chorea, Psck's disease, and ischemic A type. late ataxia or retarded.

The polymorphic form of the compound of the invention may be administered orally or parenterally as a pharmaceutical composition for the treatment of these diseases. Such a pharmaceutical composition is generally administered by injection, including intravenous, subcutaneous or intramuscular injection, parenterally or in the form of lozenges or sufelmoic tablets. The dose depends to a large extent on symptoms, age, sex, weight and sensitivity of the patient; · »The method, time and intervals of administration, the type of medicinal product; there is no particular dose limitation. The compound is administered in a daily dose of 1.0-300 mg, preferably i -106 mg, per adult patient, usually in 1-4 divided doses.

Pharmaceutical compositions in dosage forms such as injection, suppositories, suppository tablets, tablets and capsules are prepared by conventional techniques in the art.

In preparing the injection, the active ingredient is optionally mixed with a pH-modifying agent, a buffer, a suspending agent, a solubilizing agent, a stylizing agent, a tonicity-adjusting agent and / or a preservative, and is then administered by conventional intravenous, intramuscular or subcutaneous route. In this case, if necessary, the compositions can also be lyophilized by conventional means.

Examples of suspending agents include methylcellulose, polysorbate SO, hydroxyethylcellulose, acacia, powdered tragacanth, sodium ^: 4-carboxymethylcellulose, and polyoxyethylene sorbitan monolaarate.

Examples of solubilizing agents are the polyoxyethylene derivative of hydrogenated castor oil, polysorbate 80, α-icotinic afn-id, polyoxyl ethyl and sorbitan monolaurate, the product Macrobol and the ethyl ester of castor oil z-butyric acid.

Examples of stabilizing agents include sodium sulfate, sodium disulfide and diethyl ether, while preserving agents include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorcresol. .

Of the drawings attached to the description, neither is I. Xa-Yslt (.1) shows powder X-ray diffraction pattern on bim.

Figure 2 shows an X-ray diffraction pattern of a powder sample of the undesired polymorphic form (11).

Figure 3 shows an X-ray diffraction pattern of the polymorphic form (ΙΠ).

Fig. 4 is an X-ray diffraction pattern of a.

'Ϊ *

«« »♦ * * ft« φ ♦ φ Λ »shows.

Figure 5 depicts an x-ray ditTracrograph image of the undesired amorphous modification in powder form.

Yeah. Fig. 4A shows the infrared absorption test result of the undesired polymorphic form (1).

Figure 7. the infrared absorption test for the polymorphic form 01) does not show the potassium bromide-idbaa.

Figure S shows the infrared absorption assay of polymorphic form (III) in potassium.

Figure 9 does not require the infrared absorption test for the (N) polymorph, shown by potassium bromide.

Figure 10 shows the infrared absorption test result of the non-claimed amorphous form in potassium bromide.

A. li. Fig. 4A shows the results of the assay of the polymorphic form (I) obtained by thermogravimetric measurement and differential thermal analysis (TG-DTA).

Figure 12 shows the results of the undesired polymorphic (H) polymorph modification obtained by thermogravimetric measurement and differential thermoanalysis (TG-DTA),

Á 1.3. Fig. 3A shows the results of the assay of the (HI) polymorphic form by thermogravimetric measurement and differentiation thermoanalysis (TG-DTA).

Figure 14 shows the results of the assay of the undesired polymorphic form (IV) by thermogravimetric measurement and differential temo-analysis (TG-DTA).

Figure 15 shows the results of the test for the non-amorphous form by thermogravimetric measurement and differential thermal analysis (TG-DTA).

Figure 16 shows the change in impurity content of each polymorph and the amorphous form during storage at -20 ° C.

Figure 17 shows the changes in the solubilization content of each of the polymorphs and of the amorphous form during storage at 40 ° C.

Figure 18 shows the change in impurity content of each polymorph and its amorphous form during storage at 60 ° C.

Figure 19 shows the changes in the solubility content of each polymorph and the amorphous form when stored at 8 ° C,

Figure 20 shows the water content of some polymorphs and the?, Amorphous form stored at 25 ° C at different relative humidity.

Figure 21 shows an X-ray diffraction pattern of the purified potato sample of the undesired polymorph (I).

Figure 22 is an X-ray diffraction pattern of the purified permeate of the unwanted polymorph (H).

Figure 23 shows an X-ray diffraction pattern of a purified powder sample of polymorph (HI).

Fig. 24 is an x-ray image of a purified po (sample of the undesired ßiV) polymorph.

- i.

shows diffraction pattern.

Figure 25 is a cleanser of the optional polyvinyl form (V); X-ray powder diffraction image of the powder.

Fig. 26 is an X-ray diffraction pattern of the purified-powdered unwanted amorphous form,

Figure 27 shows the infrared absorption test results for purified polymorph (I) in potassium bromide.

Figure 28 is refined for the needs of the sex; (11) shows the infrared absorption test for polymorph in potassium bromide.

Figure 29 shows the infrared absorption test result of purified (HI) polymorph in potassium broth.

Fig. 39 is the un-claimed purified. Infrared absorption test for polymorph (IV) shows potassium brom tdbaa.

Figure 31 shows the result of the infrared absorption test for undesired purified (V) polymorph in potassium bromide.

Figure 32 plots the infrared absorption assay of the undesired purified amorphous form in potassium bromide.

Figure 33 shows the non-claimed purified (5) · polymorphic form in a test result obtained by thermogravimetric measurement and differential yield analysis (TG-DTA).

Fig. 34 shows the results of the assay of the undesired purified polymorphic form (iii) by thermogravimetric measurement and differential thermoanalysis (TG-ÖTA).

Fig. 35 shows the results of the assay of the purified (HI) polymorph by thermogravimetric measurement and differential tennoaural (TG-DTA);

Fig. 36 shows the results of the non-claimed purified (IV) poliswrf form obtained by iermogravimetric measurement and differentials by $ 10 thermoanalysis (TG-DTA).

A. Figure 37 shows the results of the assay for the undesired purified (V) polymorphic form by thermogravimetric measurement and differential chemoanalysis (TG-DTA).

Figure 38 shows the results of the assay of the undesired purified amorphous form by thermogravimetric measurement and differential thermal analysis (TG-DTA).

1-15. ·, repeated tests on a purified version of the tax products confirm the results obtained previously.

The invention is illustrated by the following non-limiting Examples.

I-8. Example 1B illustrates methods for preparing the undesired polymorphic form (I).

9-15. EXAMPLE 1 illustrates methods for preparing the undesired polymorphic form (11).

16-27. Example III illustrates methods for preparing the (III) polymorph.

Example 28 illustrates methods for preparing the undesired polymorphic form (IV).

Reference Example 1 illustrates a process for preparing an amorphous form of donepezil hydrofluoride.

Preparation of Polymorphic Form of Oesepezil Hydrochloride (1) (Compound R-W) Dissolve g donepczil hydrochloride in 5 ml of methanol. To the solution was added diisopropylether, φ kap ·φ ♦ »φφ and the resulting mixture was cooled with ice-water, and the precipitated crystals were filtered off and dried to give 6.9 g of the title compound.

Example 2

Donepezil Hydreklnrld (1) Polymer? (Comparative example)

g-dooepezyl hydrochloride is dissolved in 5 ml of methanol with heating. After cooling to room temperature, isopropyl ether (1 ml) was added. After stirring at room temperature for 30 minutes, the precipitated crystals were filtered off and air-dried to give 9.9 g of the title compound.

Example 3

Preparation of polymorphic form of onepezil hydrochloride (I) (Comparative Example) g Onepezil hydrochloride (g) was dissolved in methanol (5 mL) with heating. The o-ldatof: h five! start, and as soon as the inside of the solution reaches 15 C, crystals begin to precipitate. After 10 min, isopropyl ether (10 mL) was added. Stirring was continued at room temperature for 1 hour and the precipitated crystals were dried in a horn and air to give 0.9 g of the compound of the formula.

Example 4 Preparation of polymorphic form of oouepezil hydrochloride (Comparative Example I) (Donepezil hydrochloride g) was dissolved in methanol (25 mL) with heating. The mixture was then cooled in an ice-water bath. The precipitated crystals were filtered and air-dried to give 4.6 g of the title compound.

Example 5 {Comparative Example)

Preparation of polymorphic form of Onepezyl Hlorochloride (1)

Dissolve 0.3 g of denepezil in 1.5 ml of methanol and then 0.9? we add 19% hydrochloric acid in methanol. The crystals were filtered and air dried to give 0.2 g of the title compound.

Example 6 (Comparative Example)

Preparation of Donepezil Hydrochloride (I) Polymorphic Late

9.3 g of don-epezil during heating. Dissolve in 3 ml of ethanol. Subsequently, 3 ml of diisopropyl ether and 0.79 ml of 5% methanol in hydrochloric acid were added to the solution. The crystals were filtered and air dried to give 0.2 g of the title compound.

Example 7

Preparation of Polymorphic Ozepezyl Hydrochloride (I) (Example Example) Dissolve donepezil in hot ethanol (199 mL). 3.1 g of concentrated hydrochloric acid and 28 ml of ethyl acetate are added to the solution, followed by 150 ml of diisopropyl ether. After filtration and air drying at 100 sec after crystalline precipitation, 9.36 g of the title compound are obtained in a yield of SS, 4%. Water content 5.17%, m.p. 225-226 ° C (dec.).

Preparation of the polymorphic form of Donepezil Hydrochloride (I) (Comparative Example) A large amount of donepezil hydrochloride is dissolved in 30 ml of methanol with heating. The solution was cooled with stirring in an ice-water bath, and then 9 ml of diethyl ether were added. Stirring of the mixture was continued under the same conditions for 1 hour, followed by filtration of the crystals and air drying to give the compound of the formula: gcins.

Example 9 (Comparative Example)

Synthesis of Dosepezyl Histachloride (II) Polystyrene

Dissepezil (13.7) and hydrochloric acid (4.4 mL) were dissolved in ethanol (mL) with heating, and 200 mL of distopropyl ether was added with stirring at room temperature. The crystalline solid was filtered and dried under vacuum to give 11.2 g of the eu.

Example 10 {Comparative Example)

Preparation of polymorph 'form of Oouepezyl Hydrochloride (II) While heating gmepezil, dissolve in 2.000 ml ethanol. Solution A is cooled to room temperature and 27.3 g of a 18% w / w solution of hydrogen chloride in ethanol are added. 1 hour of sedimentation «. The mixture was concentrated in vacuo and the resulting crystals were air-dried to give 55.0 g of the title compound.

Example 11 (Comparative Example)

Preparation of polymorphic form of Donepezil hydrochloride (11)

Dissolve 5 g of donepezil in 5 ml of ethanol while heating. After stirring at room temperature, 1.31 ml of a 50% w / w solution of hydrochloric acid was added, followed by 5 ml of diisopropyl ether. After 10 minutes of crystallization, the crystals were filtered off and dried to give 0.4 g of the title compound,

Example 12 {Comparative Example)

Preparation of polymorphic form of deaepezil hydrochloride (II)

Dissolve donepezil hydrochloride (3g) in ethanol (3S) and add diisopropyl ether (100ml). The mixture was cooled in an ice-water bath. The crystals were then filtered and dried at 50 ° C for 3 days to give 4.9 g of the cineth compound,

EXAMPLE 13 (Comparative Example) Preparation of Polymorphic Form of Phenyl-Pepyl Bipidium Chloride (Π)

23.3 g of donepezil hydrochloride are dissolved in 250 ml of ethanol with heating. To the solution, while stirring in an ice-water bath, was added diethyl ether (10 mL), after settling for 3 hours, the crystals were filtered and dried for 22 hours at 5 ° C to give 22.7 g of eimepilyl hydrochloride (III) polymorph. (Comparative Example) Dissolve 10 g of donepezift in 10 ml of tan with heating. While stirring, a mixture of 3.1 g of concentrated hydrochloric acid and 2S ml of ethanol was added, followed by 35 ml of diisopropyl ether. After 15 minutes after precipitation, the crystals were punctured and air-dried to give 9.0 g (82.1%) of the title compound. Mp 224-2.26 ^; 'C sbomlik).

Example 15

Preparation of Polymorph Modification of Onepezylhydroxyorsd (Π) (Comparative Example)

40 g of donepezil hydrochloride are dissolved in 700 ml of ethanol with heating. 500 ml of diisoprosil sphone were added to the solution while cooling in ice water, and the wall of the flask was rubbed with spMol to induce crystallization. The crystals were filtered and dried for 12 hours at 50 ° C.

♦ ♦ ♦ »κ« ♦> *

- A compound of 18 boobs? we get, shoot. example

Donepezil Hydrochloride (Polymorphic Form 2) is prepared by heating 1 g of donepezil hydrochloride in 2090 ml of ethanol under heating. dried to yield 12% male compound, yield 74.5%, water content 9.15%.

Preparation of the pelmorph modification of Donepezil hydroldoride (III)

35) Dissolve 8 g of donepezil in 790 ml of ethanol. While stirring, a solution of hydrogen chloride (239 ml, 10% w / w in ethanol) was added, and diethyl ether (5090 ml) was added. The crystals were filtered and heated at 59 ^° C for 1 hour, then at 69 ° C for 30 minutes, and then at 85 ° C for 12 hours. dried to give 269 g of the zinc compound.

Example 18

Preparation of polymorphic form of donepezil hydrochloride (111) g of donepezil is dissolved in 599 ml of ethanol. While cooling the solution in a bath of ice-water, 17.8 g of concentrated hydrochloric acid followed by 885 ml of diisopropyl ether. We are added. A mixture of water. After stirring overnight, the crystals were filtered and dried at 55 ° C for 22 hours to give 62 g of the title compound.

Preparation of polymorphic form of Donepezil Isydrocleride (III) g of donepezil hydrochloride is dissolved in 190 ml of ethanol with heating. The solution was stirred at room temperature and 190 ml of n-feexane were added with stirring, followed by stirring. cool in an ice-water bath. Stirring of the As mixture was continued for 1 hour. The crystals were filtered and dried at room temperature to give 4 g of the title compound.

Example 29

Preparation of the polymorphic form of donepezil hydrofeloride (Mi) Dissolve in 15 ml of dichloromethane with heating donepe2yl- hldr.okiori.dot. The solution is cooled to room temperature, 15 ml of st-hexane are added with stirring and then cooled in an ice-water bath. The mixing is continued for a while. The crystals were filtered and dried at room temperature to give 9.9 g of the cinnam compound.

Example 21

Preparation of the polymorphic form of Donepezyl Hydrochloride (III)

Dissolve 0.5 g of donepezil in 19 ml of acetone with heating. While stirring at room temperature, concentrated hydrochloric acid (0.3 mL) was added. Stirring was continued for 30 minutes. The crystals were dried and dried for 1 h at 5 ° C to give 9.5 g of the title compound.

Example 22

Preparation of polymorphic form of Donepezil hydrochloride (HI), 3. Dissolve donepezil (3 g) in ethyl acetate (3 ml). While stirring at room temperature, a solution of hydrogen chloride in ethanol (0.79 mL, w / w) was added. The Crystals «*

Φ * κ * φ φφ φφφ * «♦ ΦΦΦ

- 19 for 3 hours and filtered at 85 ° Co ', 16 May-d ERASE at 70 ^{- dried>} C. 9.3 g of the title compound kspvtak

Preparation of the Donepezil Hydrochloride (Ol) Polymorphic Method by Dissolution of Donepezyl G in 10 µl of Ethanol. While stirring, a mixture of? 3 g of concentrated hydrochloric acid and 28 ml of ethanol was added followed by 15 ml of diisopropyl ether. After stirring the crystals, stirring was continued for another hour. The crystals were dried and dried at room temperature to give 9.86 g (90%) of the title sserinri compound, with a water content of 0.26%. mp 229-231 ° C (dec.).

Example 24

Preparation of a polymorphic form of Dunepezil Bridge (ifi)

5.9 g of polymorphic form (1) of Donepezil hydrochloride (1) are spread in a laboratory beaker and left to stand at 85 ° C for 7 days in a forced-air atmosphere. 4.9 g of the title compound are obtained.

25, baker

Preparation of polymorphic form of Donepezil hydrochloride (111)

Donepezil feidrochloride 5.0 g (1) of the polymorph (Schale lpasil) was spread in a laboratory laboratory hood at 85 ° C for 2 days. For 3 days at 1G5 ° <. ' at room temperature. 4.8 g of the title compound are obtained.

Example 26

Preparation of polymorphic form of Disepezyl-Hydrochloride (1H)

Of Donepezil hydrochloride 5.0 g fi) polymorphs (Schale type) is spread and allowed to stand at laboratory bepáríócsőszében kényszerkeríngéső atmosphere at 85 C for 5 days ^e. 4.9 g of the title compound are obtained.

Example 27

Preparation of a polymorphic modification of Donepezfe feidochloride (fii)

Donepezil hydrochloride (5.0 g), polymorph (I) (Schale ttposö), was spread in a laboratory evaporator and allowed to stand at 105 ° C for 3 days in a forced atmosphere to give 4.9 g of the title compound.

Example 28

Preparation of polymorphic form of Donepezil Hydrochloride (Comparative Example)

15.0 g of polymorph (11) of Donepezsl hydrochloride (Schale's type) were spread in a laboratory evaporator for 2 weeks. Leave it at 100% relative humidity. During this process 14.8 g of the title! 226-228 ° C (dec.).

Reference Example I

Preparation of the amorphous form of donepezil hydrochloride 5.0 g of donepezil hydrochloride are dissolved in 3.000 ml of water. The solution was frozen in a bath of dry ice in a mixture of acetone and then frozen at -82 ° C for 9 days (lyophilisation).

The following examples further illustrate the invention. 29-44. Examples 45 to 57 illustrate methods for the pre-elution of polymorphic form (I). Examples 1 to 4 describe methods for preparing the polymorph (If). 58-98. Examples are the preparation of polymorphic form (D1). ♦ «cheese is described, pp. 99-108. Examples 1 to 4 describe methods for preparing polymorph (IV). Example 109 describes a process for preparing polymorph (V).

Preparation of Polymorph Modification of Doaepezylndroldoride (1) (Comparative Example)

1.0 g of donepezil was dissolved in 4 ml of methanol while heating to 40 ° C. The solution contains ice water bath:? hötjők ,. Concentrated hydrochloric acid (0.31 g) in methanol (1 ml) was added at 10 ° C inside the solution. The resulting mixture was stirred for 90 minutes in a bath of ice water. After filtration of the precipitated crystals, m.p. (The water content of the product is 5.33%,}

Example 30

Synthesis of Douepczil Hydrochloride (1) Polymorphic Salad (Comparative Example)

1 g of the product is dissolved in 4 ml of methanol with heating to 40 ° C. The solution is started in a bath containing ice water. To the solution was added 9.31 g of concentrated hydrochloric acid in 1 ml of methanol. After 5 minutes, 30 ml of tert-butyldimethyl ether (hereinafter: 'I'BME) are added at the measured temperature of 3 ° C. The resulting mixture is stirred for a further 39 minutes in ice water. Filtration of the precipitated crystals followed by drying afforded 1.1 g of the title compound. (The product has a water content of 5.60%,)

Example 31

Preparation of Polynsnrf Module of WnepezylhydrideSend (1) (Comparative Example)

Donepezil (1.0 g) was dissolved in methanol (4 mL) while heating to 4-0 ° C. The solution was bathed in ice water bath. To the solution was added concentrated hydrochloric acid (9.31 g) in methanol (1 ml). After 5 rounds, 30 ml of diisepropylether (1PE) was added at 3 ° C inside the mixture. The resulting mixture was stirred in an ice-water bath for 30 minutes. Filtration of the precipitated crystals followed by drying gave 1.13 g of the title compound. (The product has a water content of 5.50%.)

Example 32

Preparation of Donepezd Bihydrochloride ()) Polyisodium Salts (Comparative Example)

1.0 g. Donepezil was blended with 4 mL of methanol while heating to 40 ° C. The solution was sucked in a bath containing ice water. At an internal temperature of 12 ° C, 9.51 g of concentrated hydrochloric acid in 1 ml of methanol was added. After 7 rounds, 30 mL of ethyl uestate was added inside the mixture at 5 ° C for 3 minutes. Stir the resulting mixture in a bath of ice water »39 minutes? we continue. Filtration of the precipitated crystals followed by drying afforded 9.71 g of the title compound. (The water content of the product is 5.2299.)

Example 33

Preparation of polymorphic form of Donepezil Celar Chloride (1) (Comparative Example)

1.9 g of donepezil are dissolved in 4 ml of ethanol while heating to 49 ^° C. Cool the solution in an ice-water bath: After cooling for 5 minutes, add 1 ml of the

Concentrated hydrochloric acid (9.31 g) was added. Stirring in an ice-water-cooled bath was continued for 39 minutes. A small portion of the polymorphic form of donepezil gyl chloride is then added. Stirring is continued for a further 30 minutes while cooling with ice water. The precipitated crystals are filtered by filtration and then dried on a lead of 7 g. The title compound is obtained. (Water content of temples: 5.33%.}

Example 34

Preparation of polymorphic form of Dnepezil hydrochloride (Comparative Example)

1.9g. Donepezite is dissolved in 4 ml of tetrahydrofuran (hereinafter THF) at 24 'C. Cool the solution in a bath containing ice water. To the solution was added 0.31 g of concentrated hydrochloric acid in 1 ml of THF. The resulting mixture was stirred in an ice-water bath for 4 minutes. Filtration of the precipitated crystals followed by drying afforded 1.00 g of the title compound. (The product has a water content of 5.67% ·.}

Example 35

Preparation of Polymorphic Form of Dosepezd Hydrochloride (f) (Comparative Example) Dissolution of 8 g of Donepezitol in 9 ml of aetonitrile by heating to 40 ° C. I put the solution in a bath of ice water. After cooling for 2 minutes, 6.31 g of concentrated hydrochloric acid in 1 ml of acetonitrile are added. The resulting mixture was stirred in an ice-water bath for 59 minutes. Filtration of the precipitated crystals followed by drying afforded 0.63 g of the title compound. (The product v content today is 5.5 to 9%.)

EXAMPLE 36 Preparation of Polehnorph Module of Onepezil Chloride (Example III)

4.0 g of donepezes were dissolved in 20 ml of methanol while heating to 40 ° C. Cool in a bath of ice water. At a temperature of 3 ° C inside the page, gaseous hydrogen chloride is injected into the solution until the air above the solution becomes acidic. The resulting mixture was stirred in an ice-water bath for 20 minutes. Filtration of the precipitated crystals followed by drying afforded 3.40 g of the title compound. (The product has a water content of 5.19%.)

Example 37

Preparation of polymorphic form of Oouepezif hydrochloride (I) (comparative example)

10.9 g of donepezil tetrachloride are dissolved in 69 ml of methanol under reflux. The solution is then quenched. 1.29 ml of l'FE were added to the solution at 69 ° C inside the solution. Stirring of the ice-water cooled mixture was continued for 20 minutes. The precipitated crystals were filtered off and dried to give 0 .mu.g. (The water content of the product is 5.37%.)

Example 38

Preparation of the polymorphic form of Denepezil hydrochloride (Comparative Example)

3.9 g of donepezil hydrochloride are dissolved in IS ml of methanol under reflux. Subsequently, the solution is no longer heated. To the interior of the solution was added 36 ml of IPE at 54 ° C. Stirring of the ice-water cooled mixture was continued for 29 minutes. The precipitated crystals were filtered off and dried, yielding 2.95 g of the title compound. (The product has a water content of 5.55%.)

Values measured during elemental analysis are as follows:

C%; i% N% Cl%

65.55 7.53 3.05 8, Lake

Example 59

Preparation of polymorphic form of dooepezyl hydrochloride ff) (autopsy example)

Donepezil hydrochloride (1.0 g) was dissolved in methanol (5 mL) under reflux. Subsequently, the solution is no longer heated. The solution was bound in a bath of ice water. At a temperature of 3 X inside the solution, 30 ml of TBME is added at a temperature of 3 X. Φ * * *> »» The iced water coolers are stirred for 30 minutes. The precipitated crystals were filtered off and dried, yielding 3.0 g of the zinc compound (Water content: 3.40%.)

Example 40

Dissolve donepezil hydrochloride in 5 ml of methanol under reflux. The solution is then quenched. The solution is cooled in a bath of ice water. After cooling for 2 minutes, the solution begins to cool. Ethyl acetate (30 mL) was added to the mixture over 1 min from the onset of precipitation, and the mixture was cooled with ice-water for 30 minutes, the precipitated crystals were filtered and dried to give 1.00 g of the title compound; 5.00%.}

Example 41 Preparation of Polymorph Modification of Epesyl Hydride (1) (Comparative Example)

1.0 g of donepezil hydrochloride is dissolved in 5 ml of methanol under reflux. After the evening, the solution is no longer heated. The solution was bound in a bath of ice water. 30 ml of s-hexane were added at 3 ^° C inside the solution. Stirring of the ice-water cooled mixture was continued for 70 minutes. The precipitated crystals were collected by filtration and then dried to give 0.9 g of the title compound. (The product has a water content of 5.6633.)

EXAMPLE 42 Preparation of Polymer 1 'of Onepezyl Hydrochloride (1) (Comparative Example)

Dottepezil hydrochloride (1.0 g) was dissolved in ethanol (20 mL) under reflux. Subsequently, the solution is no longer heated. The solution was bound in an ice water flirt. .THE. stirring of the ice-water cooled mixture was continued for 70 minutes. The precipitated crystals were filtered off and dried, yielding 0.48 g of the title compound. (The water content of the rooms :: 5,7254.)

Example 43 Preparation of polymorphic form of onepezylhydrophoride (1) (Comparative Example)

I g of Donepedil hydrochloride was dissolved in ethanol (25 ml) under reflux. The solution is then quenched. The aqueous solution is bound in a bath of ice water. 3 ° C inside the solution · 50 ml of IPE are added. Stirring of the ice-water cooled mixture was continued for 5 minutes. The precipitated crystals were filtered off and dried, yielding 0.86 g of the title butter. (Water content of product; 5,325 (.)

Example 44 Preparation of polymorphic form of flonepezil hydrochloride (1) (comparative example)

1.0 g of donepezil hydrochloride in 20 ml. into ethanol under reflux. The solution is then quenched. The solution is ice water; bath containing, cool. TBME (30 ml) was added at 3 ^° C inside the solution. Stirring of the ice-water-cooled mixture was continued for 30 minutes. The precipitated crystals were filtered and dried to give 100 g of the title compound. (The product has a water content of 5.33%.}

Example 45

Preparation of polymorphic form of denepezil hydrochloride (Π) (comparative example)

Dissolve 1 g of donepezi.lt in 4 ml of ethanol with heating at 40 ° C. Then »write * ♦ # * *

X XX CO * * X «* *** '♦ · ♦' ***

- Cool the solution in a bath of ice water. After 4 rpm cooling, 0.31 g of concentrated hydrochloric acid was added to 1 mL of ethanol. After 3 minutes, 3 ml of TBM.E are added. The ice-water-cooled mixture was stirred for 50 minutes. The precipitated crystals were collected by filtration and dried to give 1.98 g of dm. (The water content of the product is 1.7S%.)

Example 46

Preparation of polymorphic form of onepezilic hydrocarbide (: ΪΙ> (comparative examples

1.0 g of doaepezil is dissolved in 9 ml of isopropyl alcohol (hereinafter IPA) while heating at 40 ° C. The solution is then quenched. In IAP, 9.31 g of concentrated hydrochloric acid was added. Stirring of the ice-water cooled mixture was continued for 30 minutes. The precipitated crystals were filtered and dried to give 0.87 g of the compound of the formula. (The water content of the products :: 1,1956.)

Example 47

Preparation of Polymorph Modification of Donepezil Hydrochloride (II) (Comparative Example)

Dissolve 1.0 g of denepezH in 9 ml of acetone at 9 ° C. Concentrated hydrochloric acid (0.31 g) in 1 ml of acetone was added. Stirring was continued at room temperature for 5 minutes. The precipitated crystals were filtered off and dried, yielding 0.87 g of dm. (Thermal water content: 0.83%,)

Example 48

Preparation of Polymorph Modification of Doaepezil Hydrochloride (II) (Comparative Example)

Doaepezil (1.0 g) was dissolved in acetone (9 ml) at 24 ° C and treated with concentrated hydrochloric acid (0.31 g) in acetone (1 ml). Stirring was continued in an ice-water-cooled bath for 30 minutes. The precipitated crystalline solid was filtered off and dried, yielding 0.92 g of the title compound. (The water content of the product is: 0.61%,)

Preparation of polymorphic form of Donepezif hydrochloride (Comparative Example)

1.0 g of donepez is dissolved in 9 ml of THF at 19 ° C. Concentrated hydrochloric acid (0.31 g) in THF (1 mL) was added. Stirring was continued in a ice-water bath for 39 minutes. The precipitated crystals were filtered off and dried, yielding 1.9 g of the title compound. we get. (The knees, water content: 0.7856.)

Example 59

Preparation of Polymorph Modifier List of Alum Pezyl Hydrochloride (1.1) (Comparative Example)

Dissolve 3.0 g of dooepezil in 30 ml of acetone.baa.2L. Gaseous hydrogen chloride was added to the solution at room temperature until the air above the solution became acidic, after stirring for 3 minutes, the precipitated crystals were filtered off and dried, yielding 2.89 g of the title compound. (The water content of the product is 2.78%.)

Example 51

Preparation of Dunepezil Liquid Chloride (III) Polymorphs (Comparative Example)

4.0 g are decapitated. Dissolve in 20 ml of m-ethylene chloride at 18 ° C. The solution was pooled in an ice water bath. At a temperature of 4 ° C inside the solution, gaseous hydrogen chloride is added to the solution until the air above the solution becomes acidic. Argon gas was then blown into the solution. After stirring for 2 hours in an ice-water bath, the precipitated crystals were dried by filtration to give 4.99 g of the title compound. (The water content of the product is 9.81%.)

Example 52

Preparation of polymorphic mode of Doaepezsl hydrochloride (Π) (Comparative example) φφ φφ

Φ X- Φ *

X ΧΦΦΦ *

ΦΦ -V «ΦΦ

1.9 g of mesepezyl hydrochloride are dissolved in 20 ml of ethanol under reflux. The aqueous solution is cooled in an ice-water bath. 30 ml of TBME are added at a temperature of 20 ° C inside the solution. The cooled mixture in ice-water bath was stirred for an additional 3 hours. The precipitated crystals were filtered and dried to give 0.92 g of the title compound. (The water content of the product is 0.7936 ..)

Example 53 (Comparative Example) Oneepezil hydrochloride (Preparation of Polymorphic Method 511 (Comparative Example)) Dissolve 0 g of donepezil hydrochloride in 20 ml of ethanol under reflux and cool in a bath of ice-water. 30 ml of T'BME were added to the solution at 28 A2 inside the solution, and the mixture cooled in an ice-water bath was stirred for an additional 20 minutes, and the precipitated crystals were filtered and dried to give 8.88 g of the title compound. water content 0.52%,)

Example 54 (Comparative Example)

Preparation of Polymorph Modification of Donepezlíláráröklortd (11) (Comparative Example)

18.0 g of benepezyl hydrochloride are dissolved in 180 ml of ethanol reflex. The solution was added with stirring to 200 ml of IPE cooled in an ice-water bath. Stirring was continued for 5 minutes. The precipitated crystals were filtered off and dried, yielding 9.40 g of the title compound. (. Water content of product; 0.1936.)

The values measured during elemental analysis are as follows;

C% H% N% CM

Ó 9.12 7.20 3.32 8.61

Example 55 (Comparative Example)

Preparation of polymorphic form of doysepezilyl hydrochloride (II)

1.0 g of donepezd hydrochloride was dissolved in 20 m-1 methylene chloride at 18 ° C. The solution was cooled in an ice-water bath. To the solution was added 38 mL of TBME, a mixture of ice-water bath. After stirring for 3 minutes, the precipitated crystals were filtered off and dried, yielding 0.88 g of the title compound. (Water content of the product: 2.33%,)

Example 56

Preparation of polymorphic form of Bonepezil hydrochloride (comparative example)

Donepezil bidrokiond 2.0 g (1) polymorphs (Schale type) laboratóriumibepárlócsészében and spread at 80 ° C for ⁵ lowering! allow to stand under pressure for 16 hours. 1.89 g of the title compound are obtained. we get. (The product has a water content of 9.22%.)

Example 57

Preparation of the Diphyreepezyl Felchlorocl (II) Polymorphic Molecule (Related Example)

The amorphous form of Donepezil hydrochloride (2.6 g) (Schale lips) was spread in a laboratory evaporator and allowed to stand at 80 ° C under reduced pressure for 16 hours. This gives 1.98 g of the title. to give your carbon compound. (The water content of the product is ·; 1.1% by weight.)

Example 58

Preparation of the peiltuorph form of Donepezil hydrochloride (115)

1.0 g of don-epesil was dissolved in 4 ml of methanol while heating to 40 ^° C. The solution was cooled in an ice-water bath. Measured inside the page. At 7 ° C, 0.31 g of concentrated hydrochloric acid in 1 ml of methanol is added, and after stirring for 5 minutes, 38 ml of acetone are added to the solution. Stirring of the resulting mixture was continued on a ice-water filter bowl for 69 minutes. Filtration of the precipitated crystals followed by drying gave 5 (44 g) of the title compound. {The water content of this product is 6.11%.)

Example 59

Preparation of polymorph of Soaepezil hydrochloride (111)

1.0 g of donepezitol was dissolved in 4 ml of ethno while heating to 49 ° C. The solution was cooled to room temperature in an ice-water bath. To the solution was added 0.31 g of concentrated hydrochloric acid in 1 ml of ethanol. Within 5 minutes, 39 ml of TB'ME were added at 22 ° C. The resulting mixture was stirred overnight. The precipitated crystals were collected by filtration and dried to give 1.09 g of the title compound. (The water content of the product is 6.9%.)

The values measured during the elecmanal analysis are as follows:

C% H% N% € 1%

69.27 ?, 23 3.34 8.58

Preparation of the polymorphic form of Donepeztl celium chloride (113)

Dissolve 1.0 g of donepe2L in 49 ° C by hand and dissolve in 9 ml of ethyl acetate. Immerse the solution in a bath containing ice water. To the page: Concentrated hydrochloric acid (9.31 g) in ethyl acetate (1 ml) was added. The resulting mixture was stirred at room temperature for 30 minutes. Filtration of the precipitated crystals followed by drying afforded 1. 08 g of the title compound. (The product has a water content of 9.21%.)

Example 61

Preparation of polymorphic form of Donepezd hydrochloride (1.11)

9 ml of acetonitrile at almost completely dissolved in 1.6 g denepezíft ^21e C. The solution was placed in a bath containing ice water. To the solution is added 6.31 g of concentrated hydrochloric acid in 1 ml of acetonitrile. The solution becomes homogeneous. The resulting mixture was stirred at room temperature overnight. Filtration of the precipitated crystals followed by drying. 1.95 g of the title compound are obtained. (The water content of the product is 0.65%,)

Example 62

Preparation of polymorphic form of donepezil hydrochloride (iii)

1.9 g of donepezil were dissolved in 9 ml of acetone while heating to 40 ° C. The solution was cooled to room temperature in an ice-water bath. To the solution is added 6.3 ml of concentrated hydrochloric acid in 1 ml of acetone. The resulting mixture was stirred at room temperature overnight. Filtration of the precipitated crystals followed by drying gave the title compound (08 g). (The product has a water content of 0.93%.)

Example 63

Preparation of polymorphic form of Dooepezsl-bidrekiond (fi 1)

With stirring, 1.9 g of donepezil are dissolved in 26 ml of acetone and 1 ml of deionized water at 26 ^° C. The solution was cooled in an ice-water bath. To the solution is added 0.31 g of concentrated hydrochloric acid in 1 ml of acetone. The resulting mixture was stirred in an ice-water bath for 36 minutes. Filtration of the precipitated crystals followed by drying afforded 6.83 g of the title compound. (The product has a water content of 0.58%.)

Φ *

Preparation of the ρ o ski morphine form of Donepezil Hydrochloride (UI)

Dissolve 1.0 g of donepezite in 1 ml of THF at 24 ° C. For solution As, 0.31 g in 1 r of THF. Concentrated hydrochloric acid was added. The mixture was stirred for 30 minutes in a water bath. Filtration of the precipitated crystals followed by drying afforded I.09 g of the title compound. (The water content of the product is Ö, 5-4%). example

Preparation of polymorphic mode of Oonepezd-hhlroklerla (UI)

Donepezil (1.0 g) was heated to 40 ° C with 4 ml of DMF. The solution was cooled in an ice-water bath. 31 g of concentrated hydrochloric acid in 1 ml of DMF are added. The resulting mixture was stirred in an ice-water bath for 30 minutes. The precipitated crystals are filtered and then dried! 1.08 g of the title compound are obtained. (The water content of the product is 0.72%).

uh. example

Preparation of Donepezil Hydrochloride (H1) Pimorphic Nucleotide

1.0 g -donepezil was dissolved in 9 ml of DMSO almost at 20 ° C. To the solution. Concentrated hydrochloric acid (0.31 g) in DMSO (1 mL) was added. After stirring at room temperature for 1 hour, 30 mL of TBME was added. The resulting mixture was stirred at room temperature overnight. The precipitated crystals were filtered and then dried (0.97 g). yielding the title compound. (The water content of the product is 0.2595.)

Example 67 Synthesis of polymorphic form of boron-bis-dihydrochloride (111)

2.0 g of donepezil are dissolved in 20 ml of ethanol by heating to 40 ° C. The solution was cooled to room temperature in an ice-water bath. Gaseous hydrogen chloride gas was bubbled through the solution at a temperature of 24 ° C. «Ticket while it is. air above the mixture becomes acidic. After stirring for 10 minutes, 50 mL of TSMB is added to the mixture. The resulting mixture was stirred at room temperature overnight. Filtration of the precipitated crystals followed by drying gave 2.11 g of the title compound (water content 0.7%).

Example 68

Polymorphic mode of donepezil hydrochloride (ifi) preparation of lat

Donepezil (2.0 g) was dissolved in toluene (3: 0) at 26 ° C. At room temperature, gaseous bridging chloride gas was added to the solution until the air above solution became acidic. Then. we blown gas into the mixture. After stirring for 30 minutes, the precipitated crystals were filtered and dried to give 2.21 g of the title compound. (Water content of product: she, 6S%,>

Example 69

Preparation of polymorphic form of docosepilyl hydrochloride (115)

1.0 g of doocpezilyl chloride is dissolved in 5 ml of methanol at reflux temperature. After heating, the heating is stopped. After stirring overnight at room temperature, stirring was continued for a further 2 hours in an ice-water bath. The precipitated crystals were filtered off and dried, yielding 0.90 g of the title compound. (Water content of the product: 0.05%,) «*« ♦♦ * ♦ · «·» * ♦ ♦ «* + ♦ *« * * * -x * * ♦ ♦♦ «*« ♦ «« ·· « ♦

Polymorphic mode of onepezyl hydrochloride (II?)

Dissolve 5.8 g of doneperitol hydroxide in 5 ml of methanol at reflux. The solution was cooled and 30 ml of T'BME was added at 40 ° C inside the solution. Stirring is continued at 40 ° C for 3 hours. The mixture was cooled in an ice-water bath and stirred for an additional 45 minutes. The precipitated crystals were filtered off and dried, yielding 8.94 g of the title compound (water content: 0.13%).

Example 71 Preparation of polymorphic form of llosepczsMridföklörid (III)

1.0 g. Donepezil hydrochloride is dissolved in 5 mL of methanol at reflux temperature. The solution was cooled in an ice-water bath, and after 4 minutes crystals precipitated. To the mixture was added 30 ml of ether. so that the crystals dissolve immediately. After stirring overnight at room temperature, the precipitated crystals were filtered off and dried, yielding 8.10 g of the title compound. (Product water content: 0.0975.)

Example 72

Preparation of Polymorphic Media of Donepezil Feidrochloride (Ili)

Dissolve 1.8 g of donepezitol hydrochloride in 20 ml of ethanol at reflux. The solution was cooled and 30 ml of TBME was added at 48 ° C inside the solution. Stirring was continued at 40 ° C for 3 hours. The mixture was cooled in an ice water bath and stirring was continued for a further 20 minutes. The precipitated crystals were filtered off and dried, yielding 8.97 g of the title compound. (The water content of the products ;: 8.14%.)

Example 73

Preparation of polymorphic form of Doaepez H-hydrochloride (III)

1.8 g of donepezil todochlorochlorofol 128 are dissolved in IFA at reflux temperature. After tasting, the cooling is stopped. The solution was stirred overnight at room temperature. Stirring was continued for 1 hour in an ice-water bath. The precipitated crystals were filtered off and dried, yielding 8.92 g of the title compound. (The product has a water content of 0.21%.)

Example 74

Preparation of polymorphic form of Doepepezil Hydrochloride (III)

1.0 g of donepezil hydrochloride was dissolved in 15 ml of Ν-, Ν-d'imethylformamide at a temperature of 1-8 ° C. The heating was stopped and the solution was stirred overnight. At 20 ° C inside the solution, 38 mL of TBME was added. The mixture was cooled in a bath of ice water and stirring was continued for a further 3 hours. The precipitated crystals were filtered off and dried, yielding 8.90 g of the title compound. (Water content of product: 0.58%,)

Example 75

Preparation of the polymorphic form of Bonepezil hydrochloride (115) Dissolve 1.5 g of donepezil hydrochloride in 15 ml of dimethylmethyl (ovid (hereinafter: DMSO)) by heating to 80 ° C. TBME (30 ml) was added at room temperature at 20 ° C. Stirring was continued at room temperature overnight, and the precipitated crystals were filtered and dried at 0.1 g of c-im.

Φ Φ χ Φ «♦

Φ «* ΦΦ Φ * *»

Φ Φ Α φ ΦΦ * φ «φ * ν Φ» Φ «

ΧΦΦ szerinti ΦΦΦ ΦΦ ***. (The product has a water content of 0.88%.)

76-95. example

Dnesesesil hydrochloride (preparation of a polymorph of a shoot)

A sample of 1.9 g of the substances listed in the table below is suspended on a sled in a solvent of the weight of ml ml listed in the table at room temperature. Thereafter, stirring was continued at room temperature overnight. The precipitated crystals were filtered and dried to give the title compound.

example material solvent product 76th (1) polymorph methanol 8.91 g 77th (Ί) polymorph ethanol 8.94 g 78th (1) polymorph ethyl acetate providing 8.93 g 79th (I) polymorph acetone 0.93 g Salt. (11) polymorph methanol 8.93 g 81st (bow polymorph ethanol 0.95 g §2. (11) polymorph ethyl acetate 0.95 g 83rd (li) polymorph acetone 8.94 g 84th (IV) polymorph methanol 9.92 g 85th (IV) polymorph ethanol 0.80 g 86th (IV) polymorph ethyl acetate 8.92 g 87 (IV) polymorph acetone 8.94 g 88th (V) polymorph methanol 0.96 g 89th (V) polymorph ethanol 0.93 g 90th (V) polymorph ethyl acetate. 0.97 g 91st (V) polymorph steel 0.92 g: 92nd amorphous methanol 0.94 g 93rd amorphous ethanol 0.94 g 94th amorphous ethyl acetate 0.92 g 95th amorphous acetone 0.96 g

Example 96

Preparation of the polymorphic form of Denepezil-feidreklorjd (shoot)

10.0 g of donepezil are dissolved in 180 ml of ethanol with heating to 48 ° C. The solution was cooled to room temperature. Concentrated hydrochloric acid (3.01 g) was added at 20 ° C inside the solution. The solution was then placed in a bath containing ice water. After stirring for 9 inside edge of ^this solution at 3 C, 550 mL of Isopropyl ethene added. The resulting mixture was stirred for 30 minutes in an ice-water bath. The precipitated crystals are filtered and dried to give the title. . is obtained.

Preparation of polymorphic form of onepezylbihydrochloride (ΪΙ1)

9 9 99 »- ** * * φ φφφ« φ »* ·»

19.9 g of donepezil are dissolved in 1 ml of ethanol with heating to 40 * €. The solution was cooled to room temperature. Concentrated hydrochloric acid (3.01 g) was added at 20 ° C inside the solution. After 9 minutes of mixing, the. ISO solution of isopropyl ether (20 ml) was added to the solution at 20 ° C. The resulting mixture was stirred for 120 minutes at room temperature. The precipitated crystals were filtered and dried to give the title compound.

Example 98

Preparation of a polymorphic form of Dooepezyl-bridged chloride (III)

19.0 g of donepezil are dissolved in 109 ml of ethanol while heating to 40 ° C. The solution is cooled to room temperature. At a temperature of 2 ° C inside the solution add 3 Ό 1 g of concentrated hydrochloric acid. The solution is then placed in an oil swirl and heated to 40 ° C, measured inside the solution. 15. At 49 ° C inside the solution. ml of isopropyl ether are added to the solution. The resulting mixture was stirred for 2 minutes at an internal temperature of 60 ° C. The precipitated crystals were filtered and dried to give the title compound.

Example 99

Preparation of the polymorphic form of Donepezil Feherchloride (IV) (Comparative Example)

2.0 g of donepezil is mixed with stirring. he O5 g of concentrated hydrochloric acid were dissolved in 22 ml 1Θ and a mixture of deionized ^{water, 'C} to room temperature resulting solution was stirred at room temperature for I h, then the precipitated crystals were sprayed and dried to obtain 1.80 g of the title compound. (The product has a water content of 11.0%.)

Yeah, example

Preparation of Polymorph Modification of Onepezil-13 Ischloride (IV) (Comparative Example)

A solution of 1.9 g of donepezil in 0.31 g of concentrated hydrochloric acid and 4 ml of deionized water was stirred at 22 ° C. To the resulting solution was added 199 mL of TUF. The resulting solution was stirred at room temperature for 30 minutes and then the precipitated crystals were filtered and dried to give the title compound. (The product has a water content of 11.14%). example

Preparation of polymorphic form of onepezyl hydrochloride (IV) (Comparative Example) 0 g of donepezil was dissolved in a mixture of 88 ml of FHF and 3 ml of exchanged water at 20 ° C with stirring. To the resulting solution was added 0.93 g of concentrated hydrochloric acid in 2 ml of THF. The resulting mixture was stirred in an ice-water bath for 30 minutes, and the precipitated crystals were filtered and dried to give 3.2 g of the title compound. (The product has a water content of 1L, 34%.)

The values measured during the eiemalysis are as follows:

C% 11% N% Ci% δ 7.76 2.86 7.68

Preparation of Polymeric Form of Donepczil Hydrochloride (IV) (Autosamplicloro Example)

1.0 g of donepezil is dissolved in 9 ml of toluene at 22 ° C. To the solution was added 9.3 g of concentrated hydrochloric acid in 1 ml of toluene. The mixture was stirred at room temperature overnight. The precipitated crystals were filtered and dried to give 1.23 g of the title compound. (The water content of the product is 11.40%.) · «* Φ φ φ

Φ »* ΦΦ Φ X XX ♦ * * * * * φ« «φφφ * * φ Φ *** Φ Φφφ φφ ΛΦφ

Example 103

Preparation of polymorphic form of onepezyl hydrolyld (IV) (comparative example)

1.8 g of donepezil are dissolved in 9 ml of o-hexa at 21 ° C. To the solution was added 0.31 g of concentrated hydrochloric acid in 1 ml of n-hexane. The mixtures are stirred at room temperature overnight. The precipitated crystals were filtered and dried to give 1.23 g of the title compound (water content: 11.24%).

Example 104

Preparation of Douepezil Hydrociosdd (IV) Polymorph Modifiers (Comparative Example)

Donepezil (1.0 g) in a mixture of 1 ml of methanol, 3 ml of deionized water and 0.03 g of concentrated hydrochloric acid is aged at 20 ° C. The resulting solution was stirred for 3 days at room temperature. The precipitated crystals were filtered and dried to give 0.83 g of the title compound. (The product has a water content of 11.04%.)

Example 185

Preparation of Polymorph Modification of Donepezhydroclend (IR) (Comparative Example)

2.0 g of donepezil are suspended in 10 ml of deionized water. The resulting slurry was blown into gaseous hydrogen chloride at 23 ^° C inside the slurry until homogeneous. After stirring at room temperature for 2.5 hours, the precipitated crystals were filtered off and dried, yielding 1.77 g of the title compound (water content: 11.10%).

Example 106

Preparation of Polymorph Modification of Donepezil Hydrochloride (IV) (Comparative Example)

Dissolve 1.0 g of donepezil hydrochloride in 5 ml of deionized water at 68 ° C. The solution was cooled to room temperature. After stirring overnight at room temperature, the precipitated crystals were filtered and dried to give 0.92 g / cm 2 of compound. (Water content of product: 11.12%,)

Example 107

Preparation of Donepezil Chloride (IV) Polymorphic Module (Comparative Example) One gram of (U) polymorphic form of donepezilchloride (IV) is spread on a laboratory beaker and left to stand at 90% relative humidity for 24 hours. During this

I, 15 g of polymorph (IV) are obtained. (The water content of the product is 12.3374.)

EXAMPLE 108 Preparation of Amorphous and (IV) Polymorphic Form of Oesepezyl Hydrochloride (Comparative Example)

12onepezil.-hidmki.orid. 18.0 g _; Polymorphic form (HI) (250 mm in diameter) was spread in a laboratory evaporator dish and dissolved in 308 ml deionized water at 21 ° C. The resulting solution was placed in a freeze-drying apparatus and dried for 3 days.9.90 g of an amorphous form. This material is stored for 24 hours in an atmosphere having a relative humidity of 98%

II, 20 g of polymorph (IV) is obtained. (The water content of the product is 11.2174),

Example 109

Preparation of Polymorphic Media of Honepezilium Hydroxide (V) (Comparative Example)

Donepezil Hydrochloride 2.8 g of (IV) pol interf is modified (258 mm in diameter) in a laboratory evaporator and allowed to stand under reduced pressure at S0 for 1 h. 1.75 g of the title compound are obtained. we get. (The water content of the product is 8,285¾.)

Finally, the efficacy of the invention relative to .amorphic denepezicidal hydrocarbide is described in terms of stability or dilution. The invention provides the advantages described below.

(!) Stu & Jill water

The assay is performed as follows. Samples of donepezil hydrochloride polymorphs (1) to (IV) weighing 1 mg are filled into tubes. The samples are stored under the following conditions.

and determining the impurity content at regular intervals.

storage temperature storage duration 80 ° C 1 week 2 weeks 60 ° C 2 weeks 1 month 40 * e I month 3 months -20 ° C 1 week 2 weeks: I month 3 months

The impurity content is determined by HPLC as follows

To the aforementioned myotubes, 1 ml of the mobile phase specified below is charged. The soiling content of each sample is determined under the following test conditions. The results of two parallel measurements were revised.

Column (solid phase): mobile phase:

detector;

flow rate, ': injection. reach & gat: column temperature:

ferntsll OOS-1I (4.6mm inside diameter- ISOmm length), CH ₅ CN / water / 7% w / w HCl-Oa (300: 700: 1 by volume),

LV27I n:), um / ml, ml, room temperature.

1. Storage at -20 ° C (see Figure IJ).

material impurity (%) 0 1 beta 2 weeks 1 month 3 months (1) polymorph comparative 0.11 0.12 0.12 0.13 0.11 (.11) polymorph comparative 0:09 0.09 0.13 0.10 0.09 (HI): polymorph 0:15 0:14 0.13 0J3 0.15 (IV) polymorph comparative 0.08 0.08 0:08 0.08 0:08 amorphous comparative 0:12 .............................. 0.14 0.15 0.15 ÖJ4

2. Storage temperature 4 O ^e C (see Fig .. 17)

material dirt- <% ·) 0 hő heat day 3 months

* »*» * *

* · ♦ '*

«0

; t · polymorph Comparative 0.1! 0.12 0.13 (11) polymorph comparative Uh, O9 0.08 0.08 (1) 1) polymorph 0.15 0.14 0. 15 (IV) polymorph comparative 0.98 0.08 0.07 amorphous comparative L ................................................. . 0.12 © 0.2 0:45

3. Storage at 60 'C (see Figure 1S)

material dirt (%} 0 2 weeks 1 month (!) polymorph comparative 0.11 0.12 you (11) polymorph comparative 0:09 0.12. 0.09 (III) polymorph 0.15 0.14 0.14 (IV) polymorph Comparative 0:08 0.09 0.13 amorphous comparative 0.12 0.30 0.39

4. Storage at 89 ° C (see Figure 19)

material impurity (%) 0 1 week 2 weeks (1) polymorph comparative 0.11 0.12 0.39 (11) polymorph comparative O, 09 0.20 0.22 (III) polymorph 0. 1 5 0.14 0, I4 (IV) polymorph comparative 0.08 0.09 0.19 amorphous comparative 0.12 2.02 3.29

It is clear from the results below that the thermal stability of the (H1) polymorph is greater than that of the amorphous form.

* * * ♦ · '* ** «« »*« »« i2) Hggrescess Pessibility Test

The assay is carried out as follows. Polymorphs (I) to (IV) are stored in a relative humidity atmosphere as described below at 25 ° C.

relative humidity (%) water content (% by weight) (I) together similar (ID together like l'RTO (III) (ARC) together like Exterminator amorphous A comparison parative initially 4.34 0:26 0.11 12.87 2.03 10.6 4.54 0.28 0.15 10.76 4.09 77 7 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, 3 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 5 1.62 13.89 84.0 5.64 13.76 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 10:37 15.93 9.71 12.26 15.44

Polymorphs (1) to (IV) have been deduced from the above test results. no. show a togoscopicity below 96.6%, 75%, Ö%, 96.6% and 189% relative humidity, respectively. The polymorphic forms of donepezil hydrochloride (I) to (IV) show excellent thermal stability and low hygroscopic properties.

Claims (30)

Free ski m i Claim Case i. Polymorphic modification of donepezilyl derectd, 1-benzyl-4 - {(5'-dimethoxymethyl) -2-yl ^: ] -tneti ^: 1-pipeddmdihydrochloride, which was powdered by X-ray diffraction · the following diffraction angles feltítntetett infrared absorption spectrum when determined following intensities and KALLUS bromide specified I / M ₈ below in the form of 1 / Exn. absorption peaks in units; (Formula III Polymer1 ' The peaks of the powder diffraction curve recorded on the powder sample; diffraction angle (20 °) j intensity (1¾} 6:56 30 9.94 § 13.00 17 15:00 47 15.26 14 15.74 6 16.48 25 f --—- - 1 18.10 j 21 18.58 56 __ __, 20,10 28.94 21 21.66 100 25 22.92 17 23.92 19 24.68 17 26.08 44 27.20 23 28.02 29 28.22 40 28.60 13 IR spectrum of the coat-brotnldban hullámszámal ^(cm): 559, 641, 648, 702, 749, 765, 786, 807, 851, 872, 927, 949, 966, 975, 982, 1007, 1834, 1071, 1080, 1111, 1119, 1131, Π77, 1190, 1205, 1217, 1230, 1250, 1265, 1292-, 1313, 1367, 1389, 1420, 1438, 1453, 1461, 1470, 150, 1589, 1605, 1697, 2407. 2419, 2461, 2624, 2641, 2651, 2667, 2837, 2848, 2873, 2924, 2954, 2961, 2993, 3007, 3377, 3433 a » ¹ ,« V A process for the preparation of the (H1) polymorphic salt of donepezil hydrochloride according to claim 1, wherein the denepezite hydrochloride is dissolved in ethanol and diethyl ether is added thereto. 3. Procedure for '1. (111) for the preparation of polymorphic donepezil hydrochloride according to claim 1, characterized in that the donepezil-bridged toofeloridol is dissolved in methylene chloride and to the resulting solution is added a-hexane. A process for the preparation of the polymorphic modifying donepezil hydrochloride of claim 1, wherein the donepezil is acetone and hydrochloric acid or hydrogen chloride is added to the resulting solution, A process for preparing donepezil hydrochloride of the polymorph of formula (III) according to claim 1, wherein the donepezil is dissolved in ethyl acetate and hydrochloric acid or hydrochloric acid is added to the resulting solution. A process for preparing the donepezil hydrochloride polymorph (III) according to claim 1, wherein the donepezil is dissolved in ethanol, to which is added hydrochloric acid or hydrochloric acid, and diethyl ether, isopropyl ether and n a solvent selected from hexane. 7. The process according to claim 6, wherein the solvent is isopropyl ether and the crystalline precipitate is dried for one or more hours after precipitation. A process for the polymorph modification (III) according to claim 1. for the preparation of donepezil hydrochloride, characterized in that the polymorphic form (I) or (11) defined below is heated: ()) · And (H) polymorphic jsódosolatok which infrared absorption spectrum when determined lZf provided in _this form following intensities and potassium bromide of the diffraction angles shown below for the following 1 / cm unit, as defined absorption peaks characterized pomínta rőntgéndiffrakeiós recording: (1) Polymorphic form The peaks of the X-ray diffraction curve recorded on the permeate; diffraction angle (20,) intensity (l / l _e ) 9.94 24 10.60 19 12.66 _k ........ ...................................... ....... 69 (3.12 55 13.66 44 13.86 40 4.92 49 15.26 17 I6, Os 35 16.36 34 17.50 34 17, SS 42 13.42 20 diffraction angle (20, ⁿ > intensity (1/1, () 19.28 27 19.86 45 19.94 45 21.22 100 22.00 32 22.54 31 22.98 49 23.60 56 23.78 75 23.92 79 26.46 33 28.02 25 29.50 37 The spectra of the infrared spectra recorded on the cali- brine "!" Bob are 463, 502, .563, 589, 604, 701 ,. 750, 759, 799, 860, 922, 947, 972, {012, 1038, 1104, 1120, 1128, 1175, 1192, 1218,. 1250, 1267, 1316, 1368, 1410, 1433, 1.440, 1455, 1472, 1502, 1591, 1606, 1644, 1684, 2412, 2530, 2559, 2595, 2620, 2717, 2040, 2858, 2924, 3004, 3074 , 3259, 3373, 3547, 3589 «β ¹ . i H) Poümörf vsódawlat The peaks of the powder X-ray diffraction pattern are: diffraction angle (20, °) intensity (.1 / 1 «) 7.40 8 9.88 100 12.36 13 15.34 46 16,10 38 {6,2.2 38 '6.48 35 17,30 17 18.04 20 18.44 17 18.84 19 19.34 19 19.84 47 21.16 24 22.46 19 23:18 33 24.02  ", ................................................ ............................. 22 Φ φ * * β Φ * XX * * XXΦ * * ♦ »*> angle of action (20, °) intensity (l / l ₀ ) 24.92 25 25.72 27 26.40 18 27.22 H . ...............................; The potassium brosridba? infrared spectrum.wave numbers (cm '): 699, 748, 762, 845, .947, 5869, 1035, 1967, 1103, I1} 8, 1129, 1574, 1193, 1266, 1222, 1247, 1267, 1317, 1365, 1422, 1436, 14S6, 1465 1592. 1592, 167, 1688, 2412, 2489; 2627, 2846, 2868, 2913, 2928, 3435 cm ^-1 , 9, The use of an effective amount of Donepezil Hydrochloride Coagulant is shown in Scheme I. The polymorph of claim 1 is associated with acetylcholinesterase activity. for the manufacture of a medicament for the treatment of a disease. Use according to claim 9, wherein the disease is senile dementia. The use of claim 9, wherein the disease is Alzheimer's? Type of Aged? dementia. A pharmaceutical composition comprising a therapeutically effective amount of the donepezil hydrochloride polymorph of Claim 1 in a pharmaceutically acceptable carrier. 13. A process for preparing donepezitic hydrochloride polymorph (111) according to claim 1, characterized in that the donepezinated methanol is dissolved in hydrochloric acid or hydrochloric acid. and acetone was added gradually to the resulting solution. 14. A process for the preparation of the (H1) polymorphic formaldehyde donepezil hydrochloride according to claim I, characterized by dissolving the donepezil in ethanol, adding hydrochloric acid or hydrogen chloride to the resulting solution, and adding to the resulting solution. b-util-milliliter is added .. Process for the preparation of the polymorphic form (111) according to claim 1, wherein the dostepezil is dissolved in ethenitrile, and hydrochloric acid or hydrochloric acid is added to the resulting solution. Shoot. A process for preparing donepezil hydrochloride of the polymorph of Formula (III) according to claim 1, wherein the volume of donepezil is 6 times dissolved in tetrahydrofuran, to which hydrochloric acid or hydrochloric acid is added, 17. A process for the preparation of the (E1) polymorph modifying donepezil hydrochloride of claim 1, wherein the donepezilized acetone is dissolved in water, and hydrochloric acid or hydrogen chloride is added to the resulting solution. 18. A process for the preparation of the (HI) polymorphic donspezil hydrochloride of claim 1, wherein the donepezilized is dissolved in N, hMemtOffromic amide, to which hydrochloric acid or HCl hydrochloride is added. 19. A process for the preparation of the polymorphic (H1) polymorphic denepezd hydrochloride according to claim 1, wherein the donepezed dimethyl sulfoxide is dissolved in hydrochloric acid or hydrochloric acid and added thereto. butylmethyl ether is added to the solution. 20. A process for the preparation of the donepezil hydrochloride polymorph according to claim I wherein the solubilized donepezil hydrochloride is solubilized in toluene, and hydrochloric acid or hydrochloric acid is added to the resulting solution. 21. A process for the preparation of the douepezil hydrochloride polymorph of claim 1, wherein the donepezil hydrochloride is crystallized from methanol at a temperature of at least 10 ° C. 22. Procedure i. A polymorphic modifying donepezil hydrochloride (10) according to claim 1, wherein the donspezil hydrochloride is dissolved in methanol and t-butyl methyl ether is added to the homogeneous solution. 23. A process for the preparation of donepezil hydrochloride polymorph (HI) according to claim 5, wherein the donepezil hydrochloride is dissolved in methanol, hydrochloric acid or hydrochloric acid is added to the resulting solution and acetonitrile is added to the resulting solution. 24. A process for the preparation of the (H1) polymorph of denepezil hydrochloride according to claim 1, wherein the donepezil hydrochloride is dissolved in ethanol, to which is added tert-butyl ether ethyl ether at a temperature greater than 30 ° C. 25th A process for preparing the donepezil hydrochloride polymorph of claim 1, wherein the donepezil hydrochloride is crystallized from the isopropanol. 2h. Process for the preparation of the (H1) polymorph of donepezil hydrochloride according to claim E, characterized in that the donepezil hydrochloride is dissolved in N, N-dimethylformamide and tertiary-hot methyl ether is added. 27. A process for the preparation of the (H1) polymorph modifying donepezil hydrochloride according to claim I, wherein dcuepezil hydrochloride is dissolved in dimethyl fiber and tert-butyl methyl ether is added. A process for preparing donepezil hydrochloride polymorph (1 H) according to claim 1, characterized in that (1) is transformed into a solvent for the donepezil hydrochloride polymorph and wherein polymorph modification (1) is defined as follows: the polymorphic form (I) is characterized by the following intensities as L-% at the diffraction angles of the ponsinium X-ray diffraction and the absorption peaks in the infrared absorption spectrum in potassium bromide below 1 / cm: (1) Polymorphic form Peak Diffraction · curve of dust sample: diffraction angle (20, °) intensity (l / ₈ ) 9.82 13 10:48 also 12.52 93 13.02. 69 13.52 34 13.74 3? 14.78 31st Δ 6.90 45 diffraction angle (20, ®) intensity Shoot. 76 37 17.46 34 19.18 26 19.66 32 25.04 500 25.56 82 •> • 7 Ö 7 52 23.82 72 ...................... 24.14 32 Infrared spectrum (cm * ¹ ) of potassium bromide: 5.62.7, 603.2,. 700.4, 749, he, 798.1, 359.2, 896.0, 921.3, 946.3, 971.8, 1033.0, 1519.3, 5216.8, 1266.0, 13 (5, 4, 1367.7, 1454.1, 1501.5, 1537.8, 1555.9, 1590.7, 1643.7, 1681.9, 2350.9, 2534.0, 2922.1, 3385.8, 3585.2 cm ' ^! A process for preparing donepezil hydrochloride polymorph (111) according to claim 5, characterized in that the tip polymorph modifying donspezil hydrochloride (51) is converted into a solvent and wherein the (U> polymorph modification) is defined as follows; The (55) polymorph is characterized by the following intensities at the diffraction angles shown in Figure 5.¾ at the powder X-ray diffraction pattern and by the absorption peaks in the infrared absorption spectrum in potassium bromide below: (Ski) Polymorphic form The vertices of the log-action curve recorded on the sample: diffraction angle (20, °) intensity (f / ₀ ) 10.10 76 52,64 14 15.74 85 55.82 86 16,20 500 5 to 6.46 87 17:40 50 17.50 48 57.88 31 18.36 23 58.58 51 18.66 46 59.48 42 20.18 81 20.80 36 diffraction angle (20,% intensity (I4 ₀ s 22.26 45 23.38 dependent 23.52 59 24.06 34 24.32. 55 25.14 44 25.44 50 25.72 39 25.96 35 26.19 25 28.06 25 28.20 34 28.38 34 The wavelengths of the infrared spectrum in potassium bromide (cm ' ⁵ ): 5604, 698.9, 7494, 846.2, 947, -S, 10364, 1119.3, 52224, 1266.4, 1318.7, 1364.1, 1458.3, 1560.9, 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, 23454, 2499.9, 2927.9, 3448.1 s @ ⁴ , 30. Procedure as. The polymorph of (Ili) according to claim I, for the preparation of donepezil hydrochloride, characterized in that the (IV) polymorphic cationic donepezil hydrocieride is converted in a solvent and wherein the polymorph is modified as follows; Following intensities and infrared absorption spectra in potassium bromide in (IV) polymorph form 3-porm snta röntgendlífrakciós recording the diffraction angles shown below 1.1 _δ specify the form as defined below is 1 / cm unit, absorption peaks are characterized by: <I.V> Polymorphic form The peaks of the fine-grained diffraction curve recorded on the powder sample are: diffraction angle (20, 4) intensity (1, ¾) 9.64 11 10.92 11 2.46 63 12.72 17 13.86 27 14.42 12 17.36 10o 18.54 39 19.90 .37 2148 35 2144 39 diffraction angle (20, °) intensity 0¾) 22.48 69 22.96 36 24.10 1? 25.28 70 2: 8.00 27 28.50 27 Infrared 'spectrum wavelength' in potassium bromide · (cm '*): 5613, 709.0, 766.2, 786.3, 804.9, 857.0, 944.3, 979.3, 1841.5, 1118.7, 1244.6, 1318.7, 1364.1, 1458.1, 1499.2, {542.5, 1560.1, 1588.1, 1836.6, 1647.8, 1654.3, 1684.3, 1718, 2, 1734.4, 1751.4, 1773.7, 17933, 1839.5, 1845.8, 1870.1, 2344.8, 23693, 2719.2, 2922.9, 3324.0 cntA A process for the preparation of the donepezil hydrochloride polymorph of the series (ill) polymorph of claim 1, wherein the polymorphic donepezil hydrochloride is converted into a solvent, and wherein the polymorph is defined as follows: The (¥) polymorph following intensities and potassium bramidbao permínta röntgendl'ffrakclós recording the diffraction angles given in the indicated below 1 / ϊ _<} form. in the infrared absorption spectrum, shown by the absorption peaks in units below 1 / cm: (V) Polymorphic form Λ poTtaintan raises the vertex of the log curve; diffraction angle (20, °) intensity (1/10 638 7 6.86 27 lo, 12 32 12.54 33 12.90 43 13.64 64 15.58 27 17.22 69 18.44 72 18.96 19 1930 25 19.64 19 19.74 25 20,30 19 29.46 17 21,10 15 21.96 100 22.24 32 diffraction angle (20, °) intensity (1¾} 24.22 63 24,66 96 25.36 60 26,14 15 26.82 44 27.52 24 27,96 15 28.20 49 29.58 13 29.66 17 29.76 17 Hlyan numbers of the infrared spectrum recorded in potassium broth (δ ⁵ ): 506.5, 559.7, 594.4, 698.0, 740.8, 805.1, 86i, 9, 940.5, 972.1, 1039.9, 1120.8, 1220.7, 5264, 8, 1314.6, 1364.1, 1458.0, 1499.5, f542.5, 1560.2, 1592.1, 1692.9, 2500.1, 2924.2, 2998.9, 3422.5 c ; n ' ^! . 32, A process for the preparation of the polymorphic form (111) of claim 1, which is a donepezil bridge. characterized in that the amorphous photosynthesis of donezepylbihydride is carried out in a solvent. 33, The process of claims 28-32, wherein the solvent is methanol, ethanol, ethyl acetate or acetone; used.