WO2011066735A1

WO2011066735A1 - An Amorolfine HCl Crystal and the Preparation thereof

Info

Publication number: WO2011066735A1
Application number: PCT/CN2010/072516
Authority: WO
Inventors: Guibin Wang; Jianyong Feng; Qunhui Zhang; Guoqing Zhang
Original assignee: Zhejiang Hisoar Pharmaceutical Co., Ltd
Priority date: 2009-12-01
Filing date: 2010-05-27
Publication date: 2011-06-09

Abstract

This invention relates to an Amorolfine HCl crystal, to its preparation, to its use in the preparation of antifungal drugs and to a pharmaceutical composition containing the Amorolfine HCl crystal.

Description

An Amorolfine HCl Crystal and the Preparation thereof

Field of the Invention

This invention relates to the crystal chemistry of Amorolfine HCl. More specifically, this invention relates to an Amorolfine HCl crystal, to its preparation, to its use in the production of antifungal drugs and to a pharmaceutical composition containing the Amorolfine HCl crystal.

Background of the Invention

Onychomycosis refers to a nail plate or nail bed infectious disease caused by pathogenies such as dermatophyte, mildew, microzyme, etc. At present, the morbidity of onychomycosis by means of microscopy or culture confirmation is between 2.6% -16% and has been increasing in recent years. Onychmycosis is the most popular nail disease, taking up 40% of all nail diseases and this chronic pathological entity does not tend to be self-healed. The emergence of new generation anti-fungal drugs, such as itraconazole, fluconazole, terbinafme, naftifine, amorolfine etc, solves problems in the treatment of onychomycosis. Among them, the main indication of Amorolfine HCl (5% Amorolfine nail paint) is slight or intermediate infections without affecting the nail root.

The action mechanisms of the new generation antifungal drugs are various; and their main difference lies in the difference of selective action points. The sterilization or bacteriostasis activity of Amorolfine mainly depends on the synthesis of ergosterol on a fungal cell membrane. In the process of ergosterol biosynthesis, Amorolfine interferes with activities of reductase and isomerase, resulting in a shortage of ergosterol, an accumulation of squalene, ignosterol, etc and a change of the content of membrane sterol and further resulting in a change of the permeability of cell membranes which affects the metabolism process of fungi; in addition, an accumulation of chitin appears, leading to the growth obstruction of fungi; some morpholine derivatives (such as SBR morpholine, etc) can restrict activities of squalene epoxidase, reducing coenzyme I oxidase and Succinate cytochrome C reductase. However, Amorolfrne at a concentration of causing bacteriostasis does not affect cell breath and synthesis of DNA, RNA, protein, carbohydrate, etc.

The active ingredient of Amorolfme is 5% Amorolfme HC1 (or amorolfme hydrochloride). Amorolfme HC1 is a derivative of phenyl morpholine, the chemical designation thereof is cis-2,6 - dimethyl -4 - [2 - methyl -3 - (tert-amyl-phenyl) propyl] morpholine hydrochloride and the structure thereof is as follows:

Amorolfine is discovered in 1981 as an antifungal drug to treat skin fungal diseases. The chemical structure of Amorolfme is different from those of existing antifungal drugs. Itraconazole is an antifungal drug of triazoles and has three N atoms in its structure; the existence of the triazole ring allows it to have features of high activity against fungi, low toxicity, etc; terbinafine is a synthetic acrylamide and its chemical designation is N-(6, 6-dimethyl-2-heptene-4-alkynyl)-N-methyl- 1 -naphthalene methylamine. Therefore, Amorolfme is different in structure from antifungal drugs of azoles, acrylamides, polyenes, etc and is a novel antifungal drug.

The molecular conformation and tropism in unit cells may affect the above physical characteristics. A specific crystal form of a substance can be confirmed by unit cell. A multi-crystal form may make the thermal behavior of a crystal different from that of an amorphous form thereof or that of other multi-crystal forms thereof. In laboratory, thermal behaviors can be measured by technologies such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and these thermal behaviors can distinguish some multi-crystal forms from other multi-crystal forms. A specific multi-crystal may also be tested by X-ray diffraction and inf ared spectroscopy as per its certain characteristics.

The discovery of new crystal forms of pharmaceutical compounds offers a new opportunity to improve the performance and features of drugs and extends the selection scope of materials for pharmaceutical scientists. PCT application WO2007/012984 discloses the synthesis and refinement of Amorolfine HCl; PCT application WO2007/113218 discloses the synthesis of Amorolfine HCl; PCT application WO2007/000628 discloses the synthesis of Amorolfine HCl. However, none of them indicates or discloses the existence of multi-crystal of Amorolfine HCl.

Summary of the Invention

The first objective of this invention is to provide an Amorolfine HCl crystal.

The second objective of this invention is to provide a method for the preparation of the Amorolfine HCl crystal.

The third objective of this invention is to provide an application of the Amorolfine HCl crystal in the preparation of antifungal drugs.

The fourth objective of this invention is to provide a pharmaceutical composition containing the Amorolfine HCl crystal.

This invention provides an Amorolfine HCl crystal characterized by that the powder X-ray diffraction (PXRD) spectrum of said crystal has characteristic peaks at diffraction angles 2Θ±0.2° of 5.9, 10.7, 11.9, 13.6, 20.1, 22.1, 23.2, 25.0, 25.6, 32.4, 39.3 and 42.8 degree.

The Amorolfine HCl crystal of the invention is further characterized by that the powder X-ray diffraction (PXRD) spectrum of said crystal has characteristic peaks at diff action angles 2Θ±0.2° of 6.0, 10.7, 11.9, 13.7, 14.5,

15.1. 15.8, 15.9, 16.3, 16.5, 6.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2,

20.7. 20.9, 22.1, 22.6, 23.2, 23.6, 23.9, 24.9, 25.1, 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8 degree.

The Amorolfine HCl crystal of the invention is further characterized by that the powder X-ray diffraction (PXRD) spectrum of said crystal has substantially characteristic peaks as shown in Figure 1.

The Amorolfine HCl crystal of the invention has a characteristic peak at about 211±0.5^°C in its differential scanning calorimeter (DSC) spectrum; and the Amorolfine HCl crystal of the invention has substantially a DSC spectrum as shown in Figure 3 or Figure 5.

The Amorolfine HCl crystal of the invention has peaks at 1460.1, 1637.5, 2486.1, 2565.8, 2876.5, 2941.1 and 3424.8cm^"1 in its fourier transform infrared (FTIR) spectrum.

The Amorolfine HCl crystal of the invention belongs to a monoclinic system; its space group is P 121(3), Z=4 and its lattice parameters are a=29.9356A, b=8.565A, c=10.3839A; α=90.Ό°, β=93.5811° and y=90.0°; unit cell volume (UCV)=2657.22(A³); density=1.495 g/cm³; wherein, all parameters with an error within ±0.002 are the same as those of said Amorolfine HCl crystal in essence.

The invention provides a method used to prepare the Amorolfine HCl crystal, comprising the following steps:

dissolving Amorolfine HCl into isopropanol, methanol, acetonitrile, acetone, ethyl acetate or any of mixtures thereof;

crystallizing Amorolfine HCl and

separating Amorolfine HCl crystals.

Preferably, said method comprises the following steps:

adding Amorolfine HCl into isopropanol, acetone, acetonitrile, methanol, ethyl acetate or any of mixtures thereof;

raising the temperature of the mixture to dissolve Amorolfme HCl; and cooling down the solution of Amorolfme HCl and let Amorolfme HCl crystals precipitate out.

In a preferred embodiment, the method comprises the following steps: adding Amorolfme HCl into isopropanol, acetone, acetonitrile, methanol or any of mixtures thereof;

raising the temperature of the mixture to 50-90^°C and refluxing until Amorolfme HCl dissolves; and

cooling down the Amorolfme HCl solution to 0-30^°C, stirring to let Amorolfme HCl crystals precipitate out. The raised temperature is preferably 60-80 ^°C, more preferably 70-80 ^°C ; and the temperature after the cooling is preferably 5 -25 ^°C , more preferably 10-20^°C .

In another preferred embodiment, the method comprises the following steps:

adding Amorolfine HCl into isopropanol;

raising the temperature of the mixture to 70^°Cand refluxing until Amorolfine HCl dissolves; then

cooling down the solution to 5°C ; and stirring the solution to let Amorolfine HCl crystals precipitate out.

In another preferred embodiment, the method comprises the following steps:

adding Amorolfine HCl into acetone;

raising the temperature of the mixture to 60^°C and refluxing until Amorolfine HCl dissolves; and

cooling down the solution to room temperature (about 20 ^°C), and stirring the solution to let Amorolfme HCl crystals precipitate out.

In another preferred embodiment, the method comprises the following steps: adding Amorolfine HCl into acetonitrile;

raising the temperature of the mixture to 80°Cand refluxing until Amorolfine HCl dissolves; and

cooling down the solution to room temperature (around 20 °C), and stirring the solution to let Amorolfine HCl crystals precipitate out.

In another preferred embodiment, the method comprises the following steps:

adding Amorolfine HCl into methanol;

raising the temperature of the mixture to 50-90 ^°C, refluxing and adding purified water by drops to dissolve Amorolfine HCl, wherein the volume of purified water is 50 times than that of methanol;

cooling down the Amorolfine HCl solution to 0-30°C, and stirring the solution to let Amorolfine HCl crystals precipitate out. The raised temperature is preferably 60-80 V, more preferably 70-80 °C; and the temperature after the cooling is preferably 5-25 ^°C, more preferably 10-20^°C .

In another preferred embodiment, the method includes the following steps:

adding Amorolfine HCl into methanol;

raising the temperature of the mixture to 70 °C, refluxing and adding purified water by drops to dissolve Amorolfine HCl, wherein the volume of purified water is 10 times than that of methanol;

cooling down the Amorolfine HCl solution to room temperature (about 20 ^*C), and stirring the solution to let Amorolfine HCl crystals precipitate out.

In another preferred embodiment, the method comprises the following steps:

adding Amorolfine HCl into a mixture of ethyl acetate and purified water wherein the volume ratio of ethyl acetate and purified water is 40:1 ;

raising the temperature of the mixture to 50-90 ^°C, and refluxing until Amorolfine HCl dissolves; and cooling down the Amorolfine HC1 solution to 0-30^°C , and stirring the solution to let Amorolfine HC1 crystals precipitate out.

In another aspect of the invention, the invention provides an application of the Amorolfine HC1 crystal in the preparation of antifungal drugs.

In another aspect of the invention, the invention provides an antifungal pharmaceutical composition comprising the Amorolfine HC1 crystal and at least one regular pharmaceutical carrier or excipient.

The dosage forms of the antifungal pharmaceutical composition of the invention comprise troche containing excipients that are beneficial to conglutinating the active ingredients and other excipients.

Due to the multi-crystal phenomenon of drugs, a drug in an amorphous form and the drug in a crystal form are different from each other in terms of solubility, melting point, density, stability, bioavailability, etc.

Amorolfine HC1 in a crystal form is beneficial to the improvement of stability of drugs and the consistency of product quality, the increase of bioavailability, the decrease of untoward effects and the improvement of clinic treatment effects. The Amorolfine HC1 crystal may increase the bulk density of the antifungal pharmaceutical composition. The Amorolfine HC1 crystal according to the refinement method of the invention has a yield increasing from 80% to 90%, purity increasing from 99% to 99.6% and individual impurity content of below 0.1% in respect to the one obtained from conventional refinement methods. The solubility and clarity in ethanol of the Amorolfine HC1 crystal are significantly improved.

Description of Drawings

Figure 1 shows the PXRD spectrum of the Amorolfine HC1 crystal obtained in Example 1 ;

Figure 2 shows the FTIR spectrum of the Amorolfine HC1 crystal obtained in Example 1 ; Figure 3 shows the DSC spectrum of the Amorolfme HC1 crystal obtained in Example 1 ;

Figure 4 shows the FTIR spectrum of the Amorolfme HC1 crystal obtained in Example 5;

Figure 5 shows the DSC spectrum of the Amorolfme HC1 crystal obtained in Example 5.

Detailed Description of the Invention

The present invention is described in further detail in connection with the following examples which illustrate or simulate various aspects involved in the practice of the invention. Based on the foregoing detailed description and certain preferred embodiments, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention. It is to be understood that all changes that come within the spirit of the invention are desired to be protected and thus the invention is not to be construed as limited by these examples.

Instruments

PXRD

The method is well known in the art. A Scintag X'TRA X-ray diffraction spectrometer adjustable goniometer, an X-ray tube with Cu target anode and a solid-state detector are used to obtain PXRD spectra, and a round standard aluminum sample holder with a round zero background quartz disc is also used. A continuous scanning is conducted within 2Θ angle of 2-50° at a speed of 3 degree/min.

PXRD test method:

For powder diffraction, a Panalytical X'Pert PRO X-ray diffractometer is used and for X-ray transmission, a Cu target Kal is used. Tube pressure: 50mA @ 50KV max tube flow;

Test samples, after being milled, have a granularity of below 200 mesh.

DSC

A DSC Mettler 821 is used to obtain DSC spectra. Scanning temperature is 30-350^°C , and scanning speed is 10^°C/min. Samples are 3-5mg respectively and washed with nitrogen at a flow rate of 40ml/min. A standard 40 μΐ aluminum crucible with a cover having three small holes is used.

FTIR

In order to obtain FTIR results, among the existing technologies, a Perkin- Elmer Spectrum One FTIR spectrometer with diffuse reflection may be used. The sample is fine grounded with potassium bromide and a potassium bromide background in the diffuse reflection annex is used to record diffuse reflection spectrum. The spectrum recording scope is 4000-400cm^"1; and 16 scans are conducted with a resolution of 4.0 cm^"1.

Jade processing software is used to index and extract the test data so as to calculate unit cell parameters and define space group; the Dash software is used to analyze and correct the structure and then calculate structure data.

In this invention, the term "purified water" refers to water used to produce drugs, containing no additives and produced from raw water with a distillation method, an icon exchange method, a reverse osmosis method or other proper methods. Purified water can be used as solvent or as test water for common drug preparations rather than the preparation of injections.

Examples

Example 1 : Preparation of the Amorolfine HC1 crystal

5g raw Almorolfine HC1 is added into 15ml isopropanol, temperature is raised to 70 °C , and the mixture is refluxed for 30min until the sample dissolves. Then obtained solution is cooled down to 5^°C and stirred for 3h to let the sample cool down and crystals precipitate out. Solids are collected by filtration. The solids are washed with 2*2ml isopropanol and then dried in a vacuum oven at 60^°Cfor 24h. 4.5g (90%) Amorolfme HC1 crystal is obtained.

The PXRD spectrum of obtained Amorolfme HC1 crystal is as shown in Figure 1 and its diffraction angles of 2Θ±0.2° have characteristic peaks in the following positions: 6.0, 10.7, 11.9, 13.7, 14.5, 15.1, 15.8, 15.9, 16.3, 16.5, 16.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2, 20.7, 20.9, 22.1, 22.6, 23.2, 23.6, 23.9, 24.9, 25.1, 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8°. Detailed PXRD spectrum data is shown in Table 1 below:

Table 1 PXRD Spectrum Data of Amorolfme HC1 Crystal

2-Theta d(l or 2) BG Height H% Area A% FWHM

5.973 14.7836 45 23998 100.0 134610 100.0 0.095

10.739 8.2315 36 666 2.8 4755 3.5 0.121

11.919 7.4189 37 1875 7.8 11936 8.9 0.108

13.659 - 6.4776 40 45 0.2 285 0.2 0.108

13.937 6.3489 41 72 0.3 742 0.6 0.175

14.457 6.1218 52 304 1.3 1815 1.3 0.102

15.079 5.8706 77 60 0.2 425 0.3 0.121

15.779 5.6118 82 2107 8.8 27653 20.5 0.223

15.937 5.5566 64 1287 5.4 20962 15.6 0.277

16.255 5.4487 66 102 0.4 1112 0.8 0.185

16.519 5.3621 83 80 0.3 733 0.5 0.156

16.720 5.2979 81 145 0.6 1080 0.8 0.127

17.280 5.1276 57 267 1.1 1796 1.3 0.114

17.918 4.9465 79 648 2.7 3965 2.9 0.104

18.143 4.8856 93 286 1.2 1804 1.3 0.107

18.559 4.7771 71 749 3.1 6721 5.0 0.153

18.756 4.7272 92 291 1.2 3117 2.3 0.182

19.003 4.6664 86 202 0.8 1401 1.0 0.118

19.320 4.5905 77 1037 4.3 6895 5.1 0.113

20.180 4.3968 80 1315 5.5 11222 8.3 0.145

20.719 4.2837 70 844 3.5 10936 8.1 0.220

20.940 4.2388 81 1158 4.8 14260 10.6 0.209 22.100 4.0189 65 324 1.3 2975 2.2 0.156

22.580 3.9345 66 337 1.4 2719 2.0 0.137

23.220 3.8276 81 247 1.0 3276 2.4 0.226

23.598 3.7671 65 419 1.7 4927 3.7 0.200

23.943 3.7136 70 813 3.4 7547 5.6 0.158

24.864 3.5782 65 123 0.5 2006 1.5 0.278

25.060 3.5505 65 253 1.1 2891 2.1 0.194

25.679 3.4663 69 159 0.7 1665 1.2 0.178

25.976 3.4274 72 53 0.2 525 0.4 0.167

26.580 3.3508 70 365 1.5 5610 4.2 0.261

26.779 3.3263 68 270 1.1 3379 2.5 0.213

28.101 3.1729 65 316 1.3 3450 2.6 0.186

29.057 3.0706 91 127 0.5 1709 1.3 0.229

29.276 3.0482 101 71 0.3 1383 1.0 0.332

29.599 3.0156 80 123 0.5 3384 2.5 0.466

30.058 2.9706 99 2240 9.3 19652 14.6 0.149

30.919 2.8898 88 105 0.4 1495 1.1 0.243

31.256 2.8594 85 41 0.2 1702 1.3 0.707

31.561 2.8324 81 41 0.2 649 0.5 0.267

32.443 2.7575 71 131 0.5 1076 0.8 0.140

33.439 2.6776 63 47 0.2 584 0.4 0.210

34.079 2.6287 64 81 0.3 2225 1.7 0.470

34.339 2.6094 64 95 0.4 2366 1.8 0.425

35.205 2.5472 57 43 0.2 646 0.5 0.258

36.436 2.4639 66 61 0.3 780 0.6 0.217

39.302 2.2906 63 138 0.6 1593 1.2 0.196

39.919 2.2566 67 35 0.1 439 0.3 0.213

40.942 2.2025 66 35 0.1 633 0.5 0.306

42.840 2.1092 65 137 0.6 3368 2.5 0.417

45.081 2.0095 66 48 0.2 1349 1.0 0.476

45.818 1.9788 66 82 0.3 1818 1.4 0.375

The indexing and full-spectrum fitting of obtained Amorolfine HCl crystal are as follows: crystal system: monoclinic; space group: P121(3), Z=4; unit cell parameters: a=29.9356A, b=8.565A, c=10.3839A; a=90.0°, β=93.581 , γ=90.0°; UCV=2657.22(A³); density=1.495(g/cm³). Detailed data is shown in Tables 2-4 below.

Table 2 Coordinates of Atoms in Unit Cell

Atom X Y Z

1 CI 0.02365 0.38359 -0.28676

2 N2 0.06663 0.3417 -0.22409

3 C3 0.08004 0.18751 -0.27903

4 C4 0.03762 0.0855 -0.31595

5 05 0.00673 0.10646 -0.2213

6 C6 -0.0112 0.26563 -0.23256

7 C7 0.10194 0.4613 -0.2403

8 C8 0.14271 0.41609 -0.14781

9 C9 0.09695 0.76672 0.19829

10 CIO 0.08102 0.87112 0.11182

11 Cl l 0.0743 0.82558 -0.02637

12 C12 0.08493 0.68086 -0.06345

13 C13 0.10195 0.56962 0.03356

14 C14 0.10742 0.60973 0.15689

15 C15 0.08081 0.62165 -0.20377

16 C16 -0.05486 0.2727 -0.31914

17 C17 0.05143 -0.08634 -0.33111

18 C18 0.10562 0.80472 0.3397

19 C19 0.08411 0.69075 0.4319

20 C20 0.11459 0.69164 0.55785

21 C21 0.16285 0.73707 0.53264

22 C22 0.1761 0.88157 0.61527

23 CL23 0.05914 0.32319 -0.06375

24 H38 0.01498 0.50331 -0.263

25 H39 0.02445 0.37167 -0.39104

26 H40 0.09829 0.20807 -0.365

27 H41 0.10148 0.12558 -0.20734

28 H42 0.02257 0.12665 -0.40797

29 H43 -0.01868 0.30479 -0.13637

30 H44 0.11144 0.46339 -0.33993

31 H45 0.15609 0.30418 -0.17736

32 H46 0.13216 0.40698 -0.04961

33 H47 0.16854 0.50537 -0.15172

34 H48 0.07291 0.98907 0.14214 35 H49 0.06081 0.90969 -0.09733

36 H50 0.11033 0.4515 0.00432

37 H51 0.11989 0.52393 0.22792

38 H52 0.04514 0.61386 -0.23123

39 H53 0.09605 0.71027 -0.26224

40 H54 -0.07917 0.19176 -0.28286

41 H55 -0.04795 0.24037 -0.41753

42 H56 -0.06833 0.39097 -0.31858

43 H57 0.02186 -0.15664 -0.35675

44 H58 0.06735 -0.12844 -0.24043

45 H59 0.07491 -0.09566 -0.40686

46 H60 0.1417 0.80386 0.36189

47 H61 0.0925 0.92118 0.3566

48 H62 0.05047 0.72949 0.45097

49 H63 0.08254 0.57382 0.39052

50 H64 0.1014 0.77535 0.62476

51 H65 0.11463 0.57526 0.60045

52 H66 0.18529 0.64043 0.55911

53 H67 0.16512 0.76455 0.43078

54 H68 0.21036 0.91526 0.59829

55 H69 0.17375 0.85384 0.71706

56 H70 0.15356 0.97791 0.58885

Table 3 Bond lengths between atoms

Number Atoml Atom2 Length

1 CI N2 1.45

2 CI C6 1.581

3 CI H38 1.09

4 CI H39 1.089

5 N2 C3 1.503

6 N2 C7 1.489

7 N2 CL23 1.701

8 C3 C4 1.569

9 C3 H40 1.09

10 C3 H41 1.09

11 C4 05 1.402

12 C4 C17 1.539 13 C4 H42 1.089

14 05 C6 1.467

15 C6 C16 1.541

16 C6 H43 1.09

17 C7 C8 1.554

18 C7 C15 1.568

19 C7 H44 1.09

20 C8 H45 1.09

21 C8 H46 1.089

22 C8 H47 1.09

23 C9 CIO 1.334

24 C9 C14 1.452

25 C9 C18 1.511

26 CIO Cl l 1.488

27 CIO H48 1.09

28 Cl l C12 1.342

29 Cl l H49 1.09

30 C12 C13 1.455

31 C12 C15 1.54

32 C13 C14 1.326

33 C13 H50 1.09

34 C14 H51 1.09

35 C15 H52 1.09

36 C15 H53 1.09

37 C16 H54 .1.089

38 C16 H55 1.091

39 C16 H56 1.09

40 C17 H57 1.09

41 C17 H58 1.09

42 C17 H59 1.09

43 C18 C19 1.537

44 C18 H60 1.09

45 C18 H61 1.09

46 C19 C20 1.547

47 C19 H62 1.09

48 C19 H63 1.09

49 C20 C21 1.534 50 C20 H64 1.089

51 C20 H65 1.091

52 - C21 C22 1.544

53 C21 H66 1.09

54 C21 H67 1.09

55 C22 H68 1.09

56 C22 H69 1.09

57 C22 H70 1.09 i angles among atoms

Atoms Bond angles (degree)

C12 -C13 -C3 119.01810

C15 -C12 -C7 124.68382

CIO -Cl l -C2 119.89914

C14 -C13 -C9 121.03648

C7 -C15 -C12 120.48910

C9 -CIO -Cl l 119.61900

N2 -C7 -C15 105.97687

C8 -C7 -C15 112.43886

C18 -C9 -CIO 122.84212

CI -N2 -C7 113.27532

C3 -N2 -C7 110.68577

C123 -N2 -C7 108.21365

C19 -C18 -C9 114.55585

C6 -CI -N2 105.59016

C4 -C3 -N2 110.53050

C20 -C19 -C3 106.00150

05 -C6 -CI 112.08189

C16 -C6 -CI 108.76785

C17 -C4 -C3 109.81165

C21 -C20 -C4 111.63718

C22 -C21 -C6 108.68787

The FTIR spectrum of obtained Amorolfine HCl crystal is shown Figure 2.

The DSC spectrum of obtained Amorolfine HCl crystal is shown Figure 3. Example 2: Preparation of the Amorolfine HC1 crystal

5g raw Almorolfuie HC1 is added into 40ml acetone, temperature is raised to 60^°C and the mixture is refluxed for 30min until the sample dissolves. Then obtained solution is cooled down to room temperature (20 °C) and stirred for 3h. Solids are collected by filtration. The solids are washed with 2x2ml acetone; and then dried in a vacuum oven at 60°Cfor 24h. 3 g (60%) Amorolfine HC1 crystal is obtained.

The PXRD spectrum of the obtained Amorolfine HC1 crystal is as shown in Figure 1 and its diffraction angles of 2Θ±0.2° have characteristic peaks in the following positions: 6.0, 10.7, 11.9, 13.7, 14.5, 15.1, 15.8, 15.9, 16.3, 16.5, 16.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2, 20.7, 20.9, 22.1, 22.6, 23.2, 23.6, 23.9, 24.9, 25.1, 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8°.

The FTIR spectrum and the DSC spectrum of obtained Amorolfine HC1 crystal are the same as those of the crystal obtained in Example 1.

Example 3: Preparation of the Amorolfine HC1 crystal

5g raw Almorolfme HC1 is added into 6ml acetonitrile, temperature is raised to 80^°C , the mixture is refluxed for 30min until the sample dissolves. Then obtained solution is cooled down to room temperature and stirred for 3h to let the sample cool down and crystals precipitate out. Solids are collected by filtration. The solids are washed with 1 =<2ml acetonitrile; and then dried in a vacuum oven at 60 ^°C for 24h. 3.5 g (70%) Amorolfine HQ crystal is obtained.

The PXRD spectrum of obtained Amorolfine HC1 crystal is shown in Figure 1 and its diffraction angles of 2Θ±0.2° have characteristic peaks in the following positions: 6.0, 10.7, 11.9, 13.7, 14.5, 15.1, 15.8, 15.9, 16.3, 16.5, 16.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2, 20.7, 20.9, 22.1, 22.6, 23.2,

23.6, 23.9, 24.9, 25.1, 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8°.

Example 4: Preparation of the Amorolfine HC1 crystal

5g raw Almorolfine HC1 is added into 7ml methanol, temperature is raised up to 70 ^°C , the mixture is refluxed for 30min and 70ml purified water is added by drops. Then obtained solution is cooled down to room temperature and stirred for 3h. Solids are collected by filtration. The solids are washed with 2> 2ml purified water; and then dried in a vacuum oven at 60^°C for 24h. 3.8 g (76%) Amorolfine HC1 crystal is obtained.

The PXRD spectrum of the obtained Amorolfine HC1 crystal is as shown in Figure 1 and its diffraction angles of 2Θ±0.2° have characteristic peaks in the following positions: 6.0, 10.7, 11.9, 13.7, 14.5, 15.1, 15.8, 15.9, 16.3, 16.5,

16.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2, 20.7, 20.9, 22.1, 22.6, 23.2, 23.6, 23.9, 24.9, 25.1 , 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8°.

The FTIR spectrum and the DSC spectrum of obtained Amorolfine HC1 crystal are the same as those of the crystals obtained in Example 1.

Example 5: Preparation of the Amorolfine HC1 crystal

5g raw Almorolfine HC1 is added into a mixture of 40ml ethyl acetate and 1ml purified water, temperature is raised to 70 ^°C , and the mixture is refluxed for 30min until the sample dissolves. Then obtained solution is cooled down to room temperature and stirred for 3h. Solids are collected by filtration. The solids are washed with 2x2ml ethyl acetate; then dried in a vacuum oven at 60 ^°C for 24h. 4g (80%) Amorolfine HC1 crystal is obtained.

The PXRD spectrum of obtained Amorolfine HC1 crystal is as shown in Figure 1 and its diffraction angles of 2Θ±0.2° have characteristic peaks in the following positions: 6.0, 10.7, 11.9, 13.7, 14.5, 15.1, 15.8, 15.9, 16.3, 16.5, 16.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2, 20.7, 20.9, 22.1, 22.6, 23.2, 23.6, 23.9, 24.9, 25.1, 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8°.

The FTIR spectrum of obtained Amorolfine HC1 crystal is shown in Figure 4.

The DSC spectrum of obtained Amorolfine HC1 crystal is shown in Figure 5.

Claims

WE CLAIM:

1. An Amorolfine HC1 crystal, characterized by that the X-ray powder diffraction pattern of said crystal has characteristic peaks at diffraction angles of 2Θ±0.2° of 6.0, 10.7, 11.9, 13.7, 20.2, 22.1, 23.2, 25.1, 25.7, 32.4, 39.3 and 42.8 degree.

2. The Amorolfine HC1 crystal of claim 1, characterized by that the X-ray powder diffraction pattern of said crystal has characteristic peaks at diffraction angles of 2Θ±0.2° of 6.0, 10.7, 11.9, 13.7, 14.5, 15.1, 15.8, 15.9, 16.3, 16.5, 16.7, 17.3, 17.9, 18.1, 18.6, 18.8, 19.0, 19.3, 20.2, 20.7, 20.9, 22.1, 22.6, 23.2, 23.6, 23.9, 24.9, 25.1, 25.7, 26.0, 26.6, 26.8, 28.1, 29.1, 29.3, 29.6, 30.1, 30.9, 31.3, 31.6, 32.4, 33.4, 34.0, 34.3, 35.2, 36.4, 39.3, 39.9, 40.9, 42.8, 45.1 and 45.8 degree.

3. The Amorolfine HC1 crystal of claim 2, characterized by that said crystal substantially has an X-ray powder diffraction pattern as shown in Figure 1.

4. The Amorolfine HC1 crystal of any of claims 1-3, characterized by that said crystal is a monoclinic system; its space group is P121(3), Z=4 and its lattice parameters are a=29.9356A, b=8.565A, c=10.3839A; a=90.0°, P=93.5811^o and y=90.0°.

5. A method used to prepare the Amorolfine HC1 crystal of any of claims 1-4,. comprising the following steps:

adding Amorolfine HC1 into isopropanol, acetone, acetonitrile, methanol or any mixture thereof;

increasing the temperature until Amorolfine HC1 dissolves; and

cooling down the solution of Amorolfine HC1 and letting the Amorolfine

HC1 crystal precipitate out.

6. The method of claim 5, comprising the following steps:

adding Amorolfine HC1 into methanol; increasing the temperature to 50-90^°C , refluxing, and dropping purified water to dissolve Amorolfine HCl, wherein the volume of purified water is about 50 times than that of methanol; and

cooling down the Amorolfine HCl solution to 0-30^°C and stirring it until the Amorolfine HCl crystal precipitates out.

7. A method used to prepare the Amorolfine HCl crystal of any of claims 1-4, comprising the following steps:

adding Amorolfine HCl into a mixture of ethyl acetate and purified water, wherein the volume ratio of ethyl acetate and purified water is 40: 1 ;

increasing the temperature until Amorolfine HCl dissolves; and

cooling down the solution of Amorolfine HCl and let the Amorolfine HCl crystal precipitate out.

8. Use of the Amorolfine HCl crystal of any of claims 1-4 in the preparation of antifungal drugs.

9. An antifungal pharmaceutical composition, wherein said composition comprises the Amorolfine HCl crystal of any of claims 1-4 and at least one common drug carrier or excipient.