CN1330639C

CN1330639C - Crystalline pharmaceutical

Info

Publication number: CN1330639C
Application number: CNB018076882A
Authority: CN
Inventors: D·A·迪克曼; S·切姆伯卡; J·J·福尔特; R·F·亨赖; D·勒楚加－巴勒斯特罗斯; Y·牛; W·波特
Original assignee: Abbott Laboratories
Current assignee: AbbVie Inc
Priority date: 2000-03-30
Filing date: 2001-03-21
Publication date: 2007-08-08
Anticipated expiration: 2021-03-21
Also published as: AR033360A1; CA2403635A1; EP1268442A2; WO2001074787A2; PE20011232A1; SA01220270B1; KR100773258B1; WO2001074787A3; CN101066952A; SK14832002A3; AU5092001A; AU2001250920B2; NO20024679D0; AU2006222711A1; HUP0302675A2; NO20024679L; NZ521183A; MXPA02009559A; IL151551A0; TWI284640B

Abstract

New crystalline forms of lopinavir are disclosed.

Description

Crystalline pharmaceutical

Technical field

The present invention relates to (2S; 3S; 5S)-and 2-(2,6-dimethyl benzene oxygen ethanoyl)-amino-3-hydroxyl-5-(2-(1-tetrahydrochysene-pyrimid-2-one base)-3-methylbutyryl base) amino-1, new crystalline form of 6-phenylbenzene hexane (being also referred to as lopinavir (that Wei of Luo Pin)) and preparation method thereof.New crystalline form of the present invention can be used for purifying or separation that Wei of Luo Pin or be used to prepare the pharmaceutical composition of that Wei of administration Luo Pin.

Background of invention

Several years, be used for the treatment of HIV and infect Approved by immunodeficiency virus (HIV) proteinase inhibitor.A kind of is (2S with the hiv protease inhibitor of ratifying recently especially effectively; 3S; 5S)-and 2-(2,6-dimethyl benzene oxygen ethanoyl)-amino-3-hydroxyl-5-(2-(1-tetrahydropyrimidine-2-ketone group)-3-methylbutyryl base) amino-1,6-phenylbenzene hexane (being also referred to as that Wei of Luo Pin).

That Wei of Luo Pin

That Wei of known Luo Pin can be used in and suppresses hiv protease and suppress the HIV infection.When with ritonavir (ritonavir) co-administered, that Wei of Luo Pin can suppress hiv protease especially effectively and suppress HIV and infect.When making up with ritonavir, that Wei of Luo Pin can also be combined with one or more reverse transcriptase inhibitors and/or one or more other hiv protease inhibitor and be used to suppress the HIV infection especially effectively.

Disclose that Wei of Luo Pin and preparation method thereof in the US 5,914,332 that authorized on June 22nd, 1999, the document is hereby incorporated by.This patent also discloses the method for preparing that Wei of amorphous Luo Pin.

The pharmaceutical composition that comprises that Wei of Luo Pin or its pharmacologically acceptable salt also is disclosed in the following document: the US 5,914,332 that on June 22nd, 1999 authorized; The 08/966th, No. 495 U.S. Patent application that on November 7th, 1997 submitted to; The 09/487th, No. 739 U.S. Patent application that the 60/177th, No. 020 U.S. Provisional Patent Application that on January 19th, 2000 submitted to and on January 19th, 2000 submit to, all these documents are hereby incorporated by.

Find surprisingly now: can prepare that Wei of Luo Pin and be separated into each in the multiple crystalline form.

Brief description of drawings

Fig. 1 is the powder x-ray diffraction figure of the I type hydration crystalline form of that Wei of Luo Pin, and wherein that Wei of per molecule Luo Pin comprises about 0.5 molecular water.

Fig. 2 is that the 100MHz of I type hydration crystalline form of that Wei of Luo Pin is solid-state ¹³The C NMR (Nuclear Magnetic Resonance) spectrum, wherein that Wei of per molecule Luo Pin comprises about 0.5 molecular water.

Fig. 3 is the solid-state FT near infrared spectrum of the I type hydration crystalline form of that Wei of Luo Pin, and wherein that Wei of per molecule Luo Pin comprises about 0.5 molecular water.

Fig. 4 is the solid-state FT middle infrared spectrum of the I type hydration crystalline form of that Wei of Luo Pin, and wherein that Wei of per molecule Luo Pin comprises about 0.5 molecular water.

Fig. 5 is the powder x-ray diffraction figure of the I type high degree of hydration crystalline form of that Wei of Luo Pin.

Fig. 6 is that the 100MHz of I type high degree of hydration crystalline form of that Wei of Luo Pin is solid-state ¹³The C NMR (Nuclear Magnetic Resonance) spectrum.

Fig. 7 is the solid-state FT near infrared spectrum of the I type high degree of hydration crystalline form of that Wei of Luo Pin.

Fig. 8 is the solid-state FT middle infrared spectrum of the I type high degree of hydration crystalline form of that Wei of Luo Pin.

Fig. 9 is the solid-state FT middle infrared spectrum of the II type Virahol half solvate crystalline form of that Wei of Luo Pin.

Figure 10 is the solid-state FT middle infrared spectrum of the II type isopropanol solvate crystalline form of that Wei of Luo Pin, and described crystalline form is measured through thermogravimetry and comprised about 2% solvent.

Figure 11 is the solid-state FT middle infrared spectrum of the II type ethyl acetate half solvate crystalline form of that Wei of Luo Pin.

Figure 12 is the solid-state FT middle infrared spectrum of the II type ethyl acetate solvent thing crystalline form of that Wei of Luo Pin, wherein measures per 2 moles of those Weis of Luo Pin through thermogravimetric analysis and comprises and be lower than 0.5 mole ethyl acetate.

Figure 13 is the solid-state FT middle infrared spectrum of the II type chloroform half solvate crystalline form of that Wei of Luo Pin.

Figure 14 is the solid-state FT near infrared spectrum of the II type Virahol half solvate crystalline form of that Wei of Luo Pin.

Figure 15 is the solid-state FT near infrared spectrum of the II type isopropanol solvate crystalline form of that Wei of Luo Pin, wherein measures through thermogravimetric analysis to comprise about 2% solvent.

Figure 16 is the solid-state FT near infrared spectrum of the II type ethyl acetate half solvate crystalline form of that Wei of Luo Pin.

Figure 17 is the solid-state FT near infrared spectrum of the II type ethyl acetate solvent thing crystalline form of that Wei of Luo Pin, wherein finds that through gravimetric analysis per 2 moles of those Weis of Luo Pin comprise 0.5 mole of acetic acid ethyl ester.

Figure 18 is the solid-state FT near infrared spectrum of the II type chloroform half solvate crystalline form of that Wei of Luo Pin.

Figure 19 is the solid-state FT middle infrared spectrum of the III type ethyl acetate solvent crystalline form of that Wei of Luo Pin.

Figure 20 is the solid-state FT near infrared spectrum of the III type ethyl acetate solvent crystalline form of that Wei of Luo Pin.

Figure 21 is the solid-state FT middle infrared spectrum of the III type desolvation crystalline form of that Wei of Luo Pin.

Figure 22 is the solid-state FT near infrared spectrum of the III type desolvation crystalline form of that Wei of Luo Pin.

Figure 23 is the powder x-ray diffraction figure of the III type desolvation crystalline form of that Wei of Luo Pin.

Figure 24 is that the 100MHz of III type desolvation crystalline form of that Wei of Luo Pin is solid-state ¹³The C NMR (Nuclear Magnetic Resonance) spectrum.

Figure 25 is the differential thermogram of dsc (DSC) of the III type desolvation crystalline form of that Wei of Luo Pin.

Figure 26 is the solid-state FT middle infrared spectrum of the IV type non-solvent crystalline form of that Wei of Luo Pin.

The solid-state FT near infrared spectrum of the IV type non-solvent crystalline form of that Wei of Figure 27 Luo Pin.

Figure 28 is the powder x-ray diffraction figure of the IV type non-solvent crystalline form of that Wei of Luo Pin.

Figure 29 is that the 100MHz of IV type non-solvent crystalline form of that Wei of Luo Pin is solid-state ¹³The C NMR (Nuclear Magnetic Resonance) spectrum.

Figure 30 is the differential thermogram of dsc (DSC) of the IV type non-solvent crystalline form of that Wei of Luo Pin.

Figure 31 is the powder x-ray diffraction figure that the III type solvent (ethyl acetate) of that Wei of Luo Pin is changed crystalline form.

Disclosure of an invention

The present invention's discovery (2S, 3S, 5S)-and 2-(2,6-dimethyl benzene oxygen ethanoyl) amino-3-hydroxyl-5-(2-(1-tetrahydropyrimidine-2-ketone group)-3-methylbutyryl base) amino-1,6-phenylbenzene hexane (that Wei of Luo Pin) has new crystalline form.

One embodiment of the invention comprise the hydration crystalline form of that Wei of Luo Pin.For the ease of identification, the hydration crystalline form is called the I type.In the I of that Wei of Luo Pin type hydration crystalline form, that Wei of per molecule Luo Pin comprises about 0.5 molecular water-Yue 2 molecular waters.

Be used for the pharmaceutical composition process of that Wei of administration Luo Pin during the final step of preparation Luo Pin that Wei Fangfa and in preparation, the I type hydration crystalline form of that Wei of Luo Pin can be used for purifying or separate that Wei of Luo Pin.

The I type hydration crystalline form that Wei of per molecule Luo Pin comprises that Wei of Luo Pin of about 0.5 molecular water is a hygroscopic matter.Therefore, unless maintain under the condition of about 0% relative humidity, in the I of that Wei of Luo Pin type hydration crystalline form, the water content of that Wei of per molecule Luo Pin is greater than 0.5 molecule., then obtain that Wei of amorphous Luo Pin if thereby dehydrated that Wei of per molecule Luo Pin that makes of the I type hydration crystalline form of that Wei of Luo Pin comprises the water that is lower than about 0.5 molecule.

In the I of that Wei of Luo Pin type crystalline form, the water content upper and lower bound of that Wei of per molecule Luo Pin is respectively 0.5 molecule and about 2 molecules, temperature according to this crystalline form environment of living in is different with water content, and the solvation water yield of the I type hydration crystalline form of viewed that Wei of Luo Pin can change in above-mentioned scope.Term " I type high degree of hydration crystalline form " is used to refer to such I type hydration crystalline form at this: wherein the water content of that Wei of per molecule Luo Pin comprises about 2 molecular waters greater than 0.5 molecule up to that Wei of per molecule Luo Pin.Preferably, in the I of that Wei of Luo Pin type high degree of hydration crystalline form, that Wei of per molecule Luo Pin comprises about 0.75 molecular water to about 1.9 molecular waters.More preferably, in the I of that Wei of Luo Pin type high degree of hydration crystalline form, that Wei of per molecule Luo Pin comprises about 1.0 molecular waters to about 1.8 molecular waters.

In preferred embodiments, the I type hydration crystalline form of that Wei of Luo Pin is pure material with respect to that Wei of Luo Pin of other form basically, and that Wei of the Luo Pin of wherein said other form comprises amorphous, solvation form, non-solvent form and the form of desolvating.

Have found that: solid-state FT middle infrared spectrum is that the I type hydration crystalline form that characterizes that Wei of Luo Pin is levied, and a kind of means that other crystalline form of this hydration crystalline form and that Wei of Luo Pin is distinguished.

The I type hydration crystalline form of that Wei of Luo Pin (the I type hydration crystalline form that comprises pure basically that Wei of Luo Pin) has among the solid-state FT of characteristic as shown in table 1-infrared spectral band.Table 1 shown in 17 characteristics of I type hydration crystalline form of that Wei of Luo Pin-in the infrared spectral band each in solid-state FT-peak position scope in the IR spectrum.The I type hydration crystalline form that this means any that Wei of Luo Pin will (be minimal to maximum) and have the peak in the position range at each peak shown in the table 1.

For the I type hydration crystalline form (the I type hydration crystalline form that comprises pure basically that Wei of Luo Pin) of that Wei of Luo Pin, the most outstanding feature be amido linkage carbonyl tensile solid-state in infrared band position.For the I type hydration crystalline form of that Wei of Luo Pin, these bands of a spectrum are positioned at 1652-1666cm ^-1And 1606-1615cm ^-1Scope in, the I type hydration crystalline form of all those Weis of Luo Pin (the I type hydration crystalline form that comprises pure basically that Wei of Luo Pin) is all at 1652-1666cm ^-1A peak is arranged and at 1606-1615cm in the scope ^-1A peak is arranged in the scope.

The I type hydration crystalline form of that Wei of Luo Pin (the I type hydration crystalline form that comprises pure basically that Wei of Luo Pin) also has a feature to be exactly: be positioned at 778-783cm ^-1, 765-769cm ^-1, 755-759cm ^-1And 738-742cm ^-1Each scope in solid-state infrared peak is all arranged.

Table 1

The peak position scope of the solid-state FT mid-infrared light of the I type hydration crystalline form bands of a spectrum of that Wei of Luo Pin

Minimum maximum strength ^*

cm ^-1 cm ^-1

3,495 3505 W/ do not exist

3371 3386 S/MS

3281 3299 MS

3058 3064 W

3024 3031 W

2958 2967 M

2926 2938 W

2868 2875 W

1652 1666 VS

1606 1615 S/MS

1524 1532 S

1450 1456 MS

1404 1410 WNW

1304 1311 MS

1187 1197 MS

1089 1094 M

1048 1056 W

* a little less than the W=; The M=moderate; MS=is stronger; S=is strong; VS=is very strong

That Wei of per molecule Luo Pin comprise about 0.5 molecular water that Wei of Luo Pin I type crystalline form powder x-ray diffraction figure as shown in Figure 1.That Wei of per molecule Luo Pin comprises I type crystalline form solid-state of that Wei of Luo Pin of about 0.5 molecular water ¹³C NMR (Nuclear Magnetic Resonance) spectrum, FT near infrared spectrum and FT middle infrared spectrum are respectively shown in Fig. 2,3 and 4.Because the water absorbability of crystalline form, when that Wei of per molecule Luo Pin comprises about 0.5 molecular water, measures infrared and sample NMR (Nuclear Magnetic Resonance) spectrum and may in that Wei of per molecule Luo Pin, comprise water greater than 0.5 molecule.

That Wei of per molecule Luo Pin comprise that Wei of Luo Pin of about 0.5 molecular water I type hydration crystalline form (comprising that pure basically that Wei of per molecule Luo Pin comprises the I type hydration crystalline form of that Wei of Luo Pin of about 0.5 molecular water) powder X-ray-ray diffraction diagram characteristic peak position, 2 θ angle as shown in Figure 1, they are:

7.25 ° ± 0.1 °, 8.53 ° ± 0.1 °, 10.46 ° ± 0.1 °, 11.05 ° ± 0.1 °, 11.71 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.30 ° ± 0.1 °, 16.67 ° ± 0.1 °, 17.32 ° ± 0.1 °, 19.10 ° ± 0.1 °, 19.57 ° ± 0.1 °, 21.24 ° ± 0.1 °, 21.84 ° ± 0.1 ° and 22.46 ° ± 0.1 °.

By under the condition of 0% relative humidity, dewatering, can prepare the I type hydration crystalline form that Wei of per molecule Luo Pin comprises that Wei of Luo Pin of about 0.5 molecular water from the I type hydration crystalline form that Wei of per molecule Luo Pin comprises greater than that Wei of Luo Pin of 0.5 molecular water.Surpass the semihydrate stage if continue dehydration, then obtain that Wei of amorphous Luo Pin.

Can or obtain the I type hydration crystalline form of that Wei of Luo Pin from the formulations prepared from solutions of the mixture of water and water miscibility organic solvent from the aqueous solution or aqeous suspension.The water miscibility representative examples of organic comprises: the C1-C4 alcohols is methyl alcohol and ethanol etc. for example; And acetonitrile etc.In the mixture of water and water miscibility organic solvent, water content can be from about 10 volume % to about 90 volume % (preferably from about 40 volume % to about 60 volume %).In a preferred method, the I type high degree of hydration crystalline form of that Wei of Luo Pin can prepare through the following steps: that Wei of crystalline hydrate Luo Pin from the warm solution of water and alcoholic acid mixture, the environment of the higher relative humidity of continuation contact then.

In addition, can under the higher relative humidity (for example about 20% or higher relative humidity under), by the I type half hydration crystalline form of that Wei of Luo Pin is carried out the I type high degree of hydration crystalline form that aquation prepares that Wei of Luo Pin.

The powder x-ray diffraction figure of the I type high degree of hydration crystalline form of that Wei of Luo Pin, solid-state ¹³C NMR (Nuclear Magnetic Resonance) spectrum, solid-state FT near infrared spectrum and solid-state FT middle infrared spectrum are respectively shown in Fig. 5,6,7 and 8.

The position, 2 θ angle of the characteristic peak of the I type high degree of hydration crystalline form of that Wei of Luo Pin (the I type high degree of hydration crystalline form that comprises pure basically that Wei of Luo Pin) in powder x-ray diffraction figure as shown in Figure 5, they are:

3.89 ° ± 0.1 °, 6.55 ° ± 0.1 °, 7.76 ° ± 0.1 °, 8.55 ° ± 0.1 °, 9.70 ° ± 0.1 °, 10.56 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.57 ° ± 0.1 °, 18.30 ° ± 0.1 °, 18.95 ° ± 0.1 ° and 22.74 ° ± 0.1 °.

More preferably, the I type high degree of hydration crystalline form of that Wei of Luo Pin (the I type high degree of hydration crystalline form that comprises pure basically that Wei of Luo Pin) is characterised in that: the position, 2 θ angle that the peak in powder X-ray-ray diffraction diagram has as shown in Figure 5, they are:

3.89 ° ± 0.1 °, 6.55 ° ± 0.1 °, 7.76 ° ± 0.1 °, 8.55 ° ± 0.1 °, 9.70 ° ± 0.1 °, 10.56 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.06 ° ± 0.1 °, 15.57 ° ± 0.1 °, 16.49 ° ± 0.1 °, 17.51 ° ± 0.1 °, 18.30 ° ± 0.1 °, 18.95 ° ± 0.1 °, 21.73 ° ± 0.1 ° and 22.74 ° ± 0.1 °.

Details are as follows for the monocrystalline X-ray parameter of the I type high degree of hydration crystalline form of that Wei of Luo Pin and experiment:

The monocrystalline X-ray parameter of the I type high degree of hydration crystalline form of that Wei of Luo Pin and experiment are described in detail

Experiment is described in detail

Crystal data

The crystallographic system oblique system

Unit cell parameters a=46.922 (2) _

b＝13.9945(4)_

c＝11.7231(4)_

β＝105.605(1)°

V＝7414.2(4)_ ³

Spacer C2 (#5)

Z value 8

D _Calculate1.19g/cm ³

Strength detection

Diffractometer Bruker SMART

Radiation Mo K α (λ=0.7107_)

The temperature room temperature

2 θ _Maximum46.6 °

Proofread and correct the Lorentz-polarization

The reflection number of measuring is altogether: 27795

Structure elucidation and refining

The number of times (1＞3.0 σ (I)) 5368 of observation

Variable number: 932

Reflection/parameter is than 5.76

Residual errors: R; Rw 0.107; 0.128

Two other embodiment of the present invention comprises the solvation crystalline form of that Wei of Luo Pin.Based single crystal X-ray structure is measured, and first embodiment of the solvation crystalline form of that Wei of Luo Pin relates to a kind of crystalline structure, and in this structure, that Wei molecule of Luo Pin is deposited in together by hydrogen bond action, is arranged in a straight line along short crystallographic axis.Solvent molecule does not act on hydrogen bond, but only is filled in the gap of that Wei packing of molecules of Luo Pin.In order to be easy to identification, the solvation crystalline form of this embodiment is called the II type.

Based single crystal X-ray structure is measured, and second embodiment of the solvation crystalline form of that Wei of Luo Pin relates to a kind of crystalline structure, and in this structure, that Wei molecule of Luo Pin is lined up sheet by hydrogen bond action.That Wei molecule sheet of hydrogen-bonded Luo Pin is that fold is arranged, thereby forms the passage that is occupied by various content solvent molecules.Solvent molecule is to the not effect of hydrogen bond of second embodiment of that Wei solvation crystalline form of Luo Pin.In order to be easy to identification, the solvation crystalline form of this embodiment is called the III type.

The II type

In the final step process of that Wei Fangfa of preparation Luo Pin, the II type solvation crystalline form of that Wei of Luo Pin can be used for purifying or separate that Wei of Luo Pin.

Can produce many impurity in the preparation process of that Wei of Luo Pin, the II type solvation crystalline form of that Wei of Luo Pin can be used in especially and obtains free from foreign meter or reduce that Wei of crystal Luo Pin of impurity level far away.

The II type solvation crystalline form of that Wei of Luo Pin is generally half solvate.In other words, for each asymmetric crystal unit, two that Wei of molecule Luo Pin and a part solvents are arranged.More the solvation of low levels also is possible.The II type solvation crystalline form of that Wei of Luo Pin can be partly by the dry desolventizing of heating, vacuum.Yet, if after being removed greater than about 75% exempt quantities solvent (exempt quantities is half solvation amount), obtain that Wei of amorphous Luo Pin.Therefore, in the II of that Wei of Luo Pin type solvation crystalline form, that Wei of per molecule Luo Pin comprises about 0.125 molecule to about 0.5 molecular solvent.

The II type solvation crystalline form of that Wei of Luo Pin comprises few relatively polar organic solvent.These few relatively polar organic solvents comprise: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, tertiary amyl alcohol, ethyl acetate, acetone, tetrahydrofuran (THF), chloroform, methylene dichloride, propylene glycol, methyl ethyl ketone and methyl-sulphoxide etc.

In particularly preferred embodiments, the II type solvation crystalline form of that Wei of Luo Pin is purified basically with respect to that Wei of other form Luo Pin (comprising amorphous, hydrated form, other solvation form, non-solvent form and the form of desolvating).

Have found that: solid-state FT middle infrared spectrum is to characterize the II type solvation crystalline form of that Wei of Luo Pin and make the II type solvation crystalline form of that Wei of Luo Pin and the means that other crystalline form distinguishes.

The II type solvation crystalline form of that Wei of Luo Pin (the II type solvation crystalline form that comprises pure basically that Wei of Luo Pin) has among the solid-state FT of characteristic as shown in table 2-infrared spectral band.Table 2 shown in 18 characteristics of II type solvation crystalline form of that Wei of Luo Pin-in the infrared spectral band each in solid-state FT-peak position scope in the IR spectrum.The II type solvation crystalline form that this means any that Wei of Luo Pin will (be minimal to maximum) and have the peak in the position range at each peak shown in the table 2.

For the II type solvation crystalline form (the II type solvation crystalline form that comprises pure basically that Wei of Luo Pin) of that Wei of Luo Pin, the most outstanding feature is the solid-state mid-infrared light bands of a spectrum of amido linkage carbonyl tensile positions.For the II type solvation crystalline form of that Wei of Luo Pin, these bands of a spectrum are positioned at 1661-1673cm ^-1, 1645-1653cm ^-1And 1619-1629cm ^-1Scope in, the II type solvation crystalline form of all those Weis of Luo Pin (the II type solvation crystalline form that comprises pure basically that Wei of Luo Pin) is all at 1661-1673cm ^-1A peak is arranged in the scope, at 1645-1653cm ^-1A peak is arranged and at 1619-1629cm in the scope ^-1A peak is arranged in the scope.

The II type solvation crystalline form of that Wei of Luo Pin (the II type solvation crystalline form that comprises pure basically that Wei of Luo Pin) also has a feature to be exactly: be positioned at 776-781cm ^-1, 767-771cm ^-1, 747-758cm ^-1And 742-746cm ^-1Each scope in solid-state infrared peak is all arranged.

Table 2

The peak position scope of the solid-state FT mid-infrared light of the II type solvation crystalline form bands of a spectrum of that Wei of Luo Pin

Minimum maximum strength ^*

cm ^-1 cm ^-1

3391 3415 M

3324 3340 MS

3057 3063 W

3023 3029 W

2961 2970 M

2913 2938 W

2866 2879 W

1661 1673 S

1645 1653 S

1619 1629 VS

1540 1548 MS

1514 1522 S

1450 1456 MS

1418 1426 M

1302 1309 M

1181 1193 MS

1089 1095 M

1045 1056 W

The solid-state FT middle infrared spectrum of the II type solvation crystalline form (Virahol type, ethyl acetate type and chloroform type) of that Wei of Luo Pin is shown in Fig. 9,10,11,12 and 13.The solid-state FT near infrared spectrum of the II type solvation crystalline form (Virahol type, ethyl acetate type and chloroform type) of that Wei of Luo Pin is shown in Figure 14,15,16,17 and 18.

The II type solvation crystalline form of that Wei of Luo Pin can be prepared as follows: excessive that Wei of solid Luo Pin is suspended in the solvent, makes this suspension balance for some time, separate the II type solvation crystalline form of that Wei of Luo Pin then after filtration.

The II type solvation crystalline form of that Wei of Luo Pin can also prepare like this: adding or do not adding under the condition of kind of crystalline substance, making the supersaturated solution cooling of that Wei of Luo Pin in solvent, the II type solvation crystalline form of separating that Wei of Luo Pin then after filtration.

The II type solvation crystalline form of that Wei of Luo Pin can also prepare like this: the solvent in that Wei solution of Luo Pin is slowly evaporated, then the II type solvation crystalline form of that Wei of filtering separation Luo Pin.

The II type solvation crystalline form of that Wei of Luo Pin can also prepare like this: in the solvent thermal solution of that Wei of Luo Pin, slowly add anti-solvent (antisolvent), thus induced crystallization, the II type solvation crystalline form of that Wei of filtering separation Luo Pin then.

Details are as follows for the monocrystalline X-ray parameter of the II type ethyl acetate half solvation crystalline form of that Wei of Luo Pin and the II type chloroform half solvation crystalline form of that Wei of Luo Pin and experiment:

The monocrystalline X-ray parameter of the II type ethyl acetate half solvation crystalline form of that Wei of Luo Pin and experiment are described in detail

Experiment is described in detail

Crystal data

The crystallographic system oblique system

Unit cell parameters a=11.3455 (1) _

b＝33.9490(2)_

c＝9.8641(2)_

β＝89.930(1)°

V＝3799.37(7)_ ³

Spacer P2 ₁(#4)

Z value 4

D _Calculate1.18g/cm ³

Strength detection

Diffractometer Bruker SMART

Radiation Mo K α (λ=0.7107_)

The temperature room temperature

2 θ _Maximum46.7 °

Proofread and correct the Lorentz-polarization

The reflection number of measuring is altogether: 14824

Single: 5211

Structure elucidation and refining

The number of times (1＞3.0 σ (I)) 4411 of observation

Variable number: 882

Reflection/parameter is than 5.0

Residual errors: R; Rw 0.104; 0.099

The monocrystalline X-ray parameter of the II type chloroform half solvation crystalline form of that Wei of Luo Pin and experiment are described in detail

Experiment is described in detail

Crystal data

The crystallographic system rhombic system

Unit cell parameters a=9.7703 (51) _

b＝33.410(2)_

c＝11.4874(6)_

V＝3749.8(3)_ ³

Spacer P2

₁2 ₁2 ₁(#18)

Z value 4

D _Calculate1.22g/cm ³

Strength detection

Diffractometer Bruker SMART

Radiation Mo K α (λ=0.7107_)

The temperature room temperature

2 θ _Maximum46.6 °

Proofread and correct the Lorentz-polarization

The reflection number of measuring is altogether: 14920

Single: 4359

Structure elucidation and refining

The number of times (1＞3.0 σ (I)) 4234 of observation

Variable number: 438

Reflection/parameter is than 9.67

Residual errors: R; Rw 0.094; 0.104

The III type

In the final step process of that Wei Fangfa of preparation Luo Pin, the III type solvation crystalline form of that Wei of Luo Pin can be used for purifying or separate that Wei of Luo Pin.

Can produce many impurity in the preparation process of that Wei of Luo Pin, the III type solvation crystalline form of that Wei of Luo Pin is used in particular for obtaining free from foreign meter or contains that Wei of crystal Luo Pin that reduces impurity level far away.

The III type solvation crystalline form of that Wei of Luo Pin is an isolating Thermodynamically stable crystalline form from solvent, and wherein said solvent comprises hydrophobic organic solvent usually or can not be filled to solvent in the II type lattice of that Wei of Luo Pin because molecule is too big.The solvent that the III type solvation crystalline form of that Wei of Luo Pin comprises comprises: n-hexyl alcohol, n-Octanol, 3-ethyl-3-amylalcohol, propylene glycol, ethyl acetate, isopropyl acetate, n-butyl acetate, triacetin, acetone, methyl iso-butyl ketone (MIBK), 2,4-dimethyl pentanone, α-Tetralone an intermediate of Sertraline, methyl tertiary butyl ether, 2,2,4,4-tetramethyl-tetrahydrofuran (THF), Isosorbide dimethyl ether, toluene, naphthane, oil of mirbane, p-Xylol, tetramethylene sulfone, hexane, heptane, perhydronaphthalene and oleic acid etc.

In preferred embodiments, the III type solvation crystalline form of that Wei of Luo Pin is purified basically with respect to that Wei of Luo Pin (comprising amorphous, hydrated form, other solvation form, non-solvent form and the form of desolvating) of other form.

Have found that: solid-state FT middle infrared spectrum is the III type solvation crystalline form that characterizes that Wei of Luo Pin, and a kind of means that other crystalline form of this solvation crystalline form and that Wei of Luo Pin is distinguished.

The III type solvation crystalline form of that Wei of Luo Pin (the III type solvation crystalline form that comprises pure basically that Wei of Luo Pin) has in the table 3 of being shown among the solid-state FT of characteristic-infrared spectral band.16 mid-infrared light bands of a spectrum of III type solvation crystalline form that table 3 has shown that Wei of Luo Pin in solid-state FT-peak position scope in the IR spectrum.The III type solvation crystalline form (being minimal to maximum) in the peak scope shown in the table 3 that this means all those Weis of Luo Pin has the peak.

For the III type solvation crystalline form (the III type solvation crystalline form that comprises pure basically that Wei of Luo Pin) of that Wei of Luo Pin, the most outstanding feature is the solid-state FT mid-infrared light of amido linkage carbonyl tensile bands of a spectrum positions.For the III type solvation crystalline form of that Wei of Luo Pin, bands of a spectrum are positioned at 1655-1662cm ^-1Scope in.As a rule, for the III type solvation crystalline form of that Wei of Luo Pin, also have second bands of a spectrum to be positioned at 1636-1647cm usually ^-1Scope in.Yet, in some cases, second bands of a spectrum (1636-1647cm ^-1) be shown as the acromion of first bands of a spectrum, be not enough to open, thereby can not be shown as second bands of a spectrum from first bands of a spectrum explanation.The III type solvation crystalline form of all those Weis of Luo Pin (the III type solvation crystalline form that comprises pure basically that Wei of Luo Pin) is all at 1655-1662cm ^-1A peak is arranged in each scope, may be also at 1636-1647cm ^-1A peak is arranged in the scope.

The III type solvation crystalline form of that Wei of Luo Pin (the III type solvation crystalline form that comprises pure basically that Wei of Luo Pin) also has a feature to be exactly: at 772-776cm ^-1, 766-770cm ^-1And 743-747cm ^-1All there is solid-state infrared peak position in each scope.

The position, 2 θ angle of the characteristic peak of III type solvation (ethyl acetate) crystalline form of that Wei of Luo Pin (III type (ethyl acetate) the solvation crystalline form that comprises pure basically that Wei of Luo Pin) in powder x-ray diffraction figure as shown in figure 31, they are:

4.85 ° ± 0.1 °, 6.52 ° ± 0.1 °, 7.32 ° ± 0.1 °, 12.82 ° ± 0.1 °, 12.96 ° ± 0.1 °, 16.49 ° ± 0.1 ° and 19.31 ° ± 0.1 °.

Table 3

The peak position scope of the solid-state FT mid-infrared light bands of a spectrum of the III type solvation of that Wei of Luo Pin and desolvation crystalline form

Minimum maximum strength ^*

cm ^-1 cm ^-1

3394 3405 S

3278 3302 MS

3061 3071 W

3024 3033 W

2954 2965 M

2924 2939 W

2853 2872 W

1655 1662 VS

1636 1647 S

1517 1525 S

1501 1513 MS

1450 1455 MS

1300 1309 MS

1193 1200 MS

1090 1098 W

1051 1057 M

The solid-state FT middle infrared spectrum of the III type ethyl acetate solvent crystalline form of that Wei of Luo Pin as shown in figure 19.The solid-state FT near infrared spectrum of the III type ethyl acetate solvent crystalline form of that Wei of Luo Pin as shown in figure 20.

The III type solvation crystalline form of that Wei of Luo Pin can be prepared as follows: excessive that Wei of solid Luo Pin is suspended in the solvent, makes this suspension balance for some time, separate the III type solvation crystalline form that obtains that Wei of Luo Pin then after filtration.

The III type solvation crystalline form of that Wei of Luo Pin can also prepare like this: adding or do not adding under the condition of kind of crystalline substance, making the supersaturated solution cooling of that Wei of Luo Pin in solvent, the III type solvation crystalline form of separating that Wei of Luo Pin then after filtration.

The III type solvation crystalline form of that Wei of Luo Pin can also prepare like this: the solvent in that Wei solution of Luo Pin is slowly evaporated, then the III type solvation crystalline form of that Wei of filtering separation Luo Pin.

The III type solvation crystalline form of that Wei of Luo Pin can also prepare like this: in the solvent thermal solution of that Wei of Luo Pin, slowly add anti-solvent (antisolvent), thus induced crystallization, the III type solvation crystalline form of that Wei of filtering separation Luo Pin then.

The monocrystalline X-ray parameter of the III type ethyl acetate solvent crystalline form of that Wei of Luo Pin and experiment are described in detail

Experiment is described in detail

Crystal data

The crystallographic system rhombic system

Unit cell parameters a=23.961 (9) _

b＝27.58(1)_

c＝11.967(4)_

V＝7907(5)_ ³

Spacer C222 ₁(#20)

Z value 8

Strength detection

Diffractometer Rigaku AFC5R

Radiation Cu K α (λ=1.54178_)

The temperature room temperature

2 θ _Maximum120.2 °

Proofread and correct the Lorentz-polarization

Absorb (trans.Factor:0.87-1.00)

The reflection number of measuring is altogether: 6520

Single: 6520

Structure elucidation and refining

The number of times (1＞3.0 σ (I)) 2154 of observation

Variable number: 443

Reflection/parameter is than 4.86

Residual errors: R; Rw 0.096; 0.093

An example of the III type desolvation crystalline form of that Wei of Luo Pin prepares from acetonitrile.The III type crystalline form of complete desolvated that Wei of Luo Pin still can not prepare from all other solvents.

The III type desolvation crystalline form of that Wei of Luo Pin can be used in purifying or separates that Wei of Luo Pin, and can be used in the pharmaceutical composition of that Wei of preparation administration Luo Pin.

Have found that: solid-state FT middle infrared spectrum is the III type desolvation crystalline form that characterizes that Wei of Luo Pin, and makes this desolvation crystalline form and other crystalline form but do not comprise the means that III type solvation crystalline form distinguishes.

The III type solvation crystalline form of that Wei of Luo Pin (the III type solvation crystalline form that comprises pure basically that Wei of Luo Pin) has among the solid-state FT of characteristic as shown in table 3-infrared spectral band.Table 3 shown in 16 characteristics of III type solvation crystalline form of that Wei of Luo Pin-in the infrared spectral band each in solid-state FT-position in the IR spectrum.The III type solvation crystalline form that this means any that Wei of Luo Pin will (be minimal to maximum) and have the peak in the position range at each peak shown in the table 3.

For the III type desolvation crystalline form (the III type desolvation crystalline form that comprises pure basically that Wei of Luo Pin) of that Wei of Luo Pin, the most outstanding feature is the position of the solid-state FT mid-infrared light of amido linkage carbonyl tensile bands of a spectrum.For the III type desolvation crystalline form of that Wei of Luo Pin, bands of a spectrum are positioned at 1655-1662cm ^-1In the scope.As a rule, for the III type solvation crystalline form of that Wei of Luo Pin, second bands of a spectrum (1636-1647cm ^-1) be shown as the acromion of first bands of a spectrum, be not enough to separately, thereby can not be distinguished as second bands of a spectrum from first bands of a spectrum.The III type desolvation crystalline form of any that Wei of Luo Pin (the III type desolvation crystalline form that comprises pure basically that Wei of Luo Pin) is all at 1655-1662cm ^-1A peak is arranged in the scope, may be also at 1636-1647cm ^-1A peak is arranged in the scope, and this peak is as 1655-1662cm ^-1An acromion at peak, position.

The solid-state FT middle infrared spectrum of the III type desolvation crystalline form of that Wei of Luo Pin as shown in figure 21.The solid-state FT near infrared spectrum of the III type desolvation crystalline form of that Wei of Luo Pin as shown in figure 22.The powder x-ray diffraction figure of the III type desolvation crystalline form of that Wei of Luo Pin as shown in figure 23.The 100MHz of the III type desolvation crystalline form of that Wei of Luo Pin is solid-state ¹³The C NMR (Nuclear Magnetic Resonance) spectrum as shown in figure 24.The DSC differential thermogram of the III type desolvation crystalline form of that Wei of Luo Pin as shown in figure 25.

Lose 0.0% sample for being heated to 150 ℃ of starting weights with 1 ℃/minute speed, when with 1 ℃/minute when the scanning speed that arrives 150 ℃ is carried out the differential scanning calorimetric, the DSC thermogram of the III type desolvation crystalline form of that Wei of Luo Pin express 95 ℃ initial, at 98 ℃ of fusing endotherms (Δ H=18J/g) that reach peak value.

The position, 2 θ angle of the III type desolvation crystalline form of that Wei of Luo Pin (the III type desolvation crystalline form that comprises pure basically that Wei of Luo Pin) characteristic peak in powder x-ray diffraction figure as shown in figure 23, they are:

4.85 ° ± 0.1 °, 6.39 ° ± 0.1 °, 7.32 ° ± 0.1 °, 8.81 ° ± 0.1 °, 12.20 ° ± 0.1 °, 12.81 ° ± 0.1 °, 14.77 ° ± 0.1 °, 16.45 ° ± 0.1 ° and 17.70 ° ± 0.1 °.

More preferably, the III type desolvation crystalline form of that Wei of Luo Pin (the III type desolvation crystalline form that comprises pure basically that Wei of Luo Pin) is characterised in that: the position, 2 θ angle that the peak in powder x-ray diffraction figure has as shown in figure 23:

4.85 ° ± 0.1 °, 6.39 ° ± 0.1 °, 7.32 ° ± 0.1 °, 8.81 ° ± 0.1 °, 12.20 ° ± 0.1 °, 12.81 ° ± 0.1 °, 14.77 ° ± 0.1 °, 16.45 ° ± 0.1 °, 17.70 ° ± 0.1 °, 18.70 ° ± 0.1 °, 20.68 ° ± 0.1 °, 20.92 ° ± 0.1 °, 22.06 ° ± 0.1 ° and 22.76 ° ± 0.1 °.

The monocrystalline X-ray parameter of the III type desolvation crystalline form of that Wei of Luo Pin and experiment are described in detail

Experiment is described in detail

Crystal data

The crystallographic system rhombic system

Lattice parameter a=24.0465 (10) _

b＝27.5018(11)_

c＝11.9744(3)_

V＝7918.9(8)_

Spacer C222 ₁(#20)

Z value 8

D _Calculate1.055g/cm ³

Strength detection

Diffractometer Nonius KappaCCD

Radiation Mo K α (λ=0.71073_)

The temperature room temperature

2 θ _Maximum61 °

The reflection number of measuring is altogether: 28494

Single: 5148

Structure elucidation and refining

Observation frequency (1＞2.0 σ (I)) 4069

Variable number 442

Reflection/parameter is than 9.21

Residual errors: R; R _w0.056; 0.116

Another embodiment of the present invention is the non-solvent crystalline form of that Wei of Luo Pin.In order to distinguish, the non-solvent crystalline form of that Wei of Luo Pin of this embodiment is called the IV type.

The IV type non-solvent crystalline form of that Wei of Luo Pin can be used for the pharmaceutical composition that purifying or separation that Wei of Luo Pin and preparation are used that Wei of Luo Pin.

In preferred embodiments, the IV type non-solvent crystalline form of that Wei of Luo Pin is pure basically with respect to other form of that Wei of Luo Pin, and described other form comprises amorphous, hydrated form, solvation form, other non-solvent form and desolvation form.

Have been found that solid-state FT middle infrared spectrum is to characterize the IV type non-solvent crystalline form of that Wei of Luo Pin and the means of distinguishing other crystalline form of this IV type non-solvent crystalline form and that Wei of Luo Pin.

The IV type non-solvent crystalline form of that Wei of Luo Pin (the IV type non-solvent crystalline form that comprises pure basically that Wei of Luo Pin) has infrared band among the solid-state FT-of characteristic as shown in table 4.Table 4 shown in 19 characteristics of IV type non-solvent crystalline form of that Wei of Luo Pin-in the infrared band each in solid-state-peak position scope in the IR spectrum.The IV type non-solvent crystalline form (minimum to maximum) in the position range at each peak shown in the table 4 that this means any that Wei of Luo Pin has the peak.When with 4cm ^-1Resolving power obtain solid-state in during IR spectrum, can also observe the peak of position in one or more following additional features bands of a spectrum: 1668-1674cm ^-1(by force), 1656-1662cm ^-1(by force), 1642-1648cm ^-1(by force).In higher resolving power, perhaps after Fuli's leaf deconvoluted, these other peaks can be distinguished and draw.

The principal character of the IV type non-solvent crystalline form of that Wei of Luo Pin (the IV type non-solvent crystalline form that comprises pure basically that Wei of Luo Pin) is the position about infrared band among the solid-state FT-of amido linkage carbonyl tensile.For the IV type non-solvent crystalline form of that Wei of Luo Pin, these bands of a spectrum are positioned at 1680-1685cm ^-1And 1625-1630cm ^-1In the scope.In addition, especially in high-resolution, bands of a spectrum are positioned at 1668-1674cm ^-1, 1656-1662cm ^-1And 1642-1648cm ^-1In the scope.The IV type non-solvent crystalline form of any that Wei of Luo Pin (the IV type non-solvent crystalline form that comprises pure basically that Wei of Luo Pin) all will have the 1680-1685cm of being positioned at ^-1Peak in the scope and be positioned at 1625-1630cm ^-1Peak in the scope, and can have the 1668-1674cm of being positioned at ^-1Peak, 1656-1662cm in the scope ^-1Peak and 1642-1648cm in the scope ^-1Peak in the scope.

The feature of the IV type non-solvent crystalline form of that Wei of Luo Pin (the IV type non-solvent crystalline form that comprises pure basically that Wei of Luo Pin) also has respectively at 780-784cm ^-1, 764-768cm ^-1And 745-749cm ^-1Solid-state infrared peak in the scope.

Table 4

The peak position scope of infrared band among the solid-state FT-of the IV type non-solvent crystalline form of that Wei of Luo Pin

Minimum maximum strength ^*

cm ^-1 cm ^-1

3433 3439 M

3415 3421 M

3406 3412 M

3338 3345 MS

3309 3315 M

3272 3278 M

3082 3089 W

3025 3030 W

2959 2965 M

2926 2932 W

2870 2875 W

1680 1685 S

1625 1630 VS

1514 1526 S

1451 1456 MS

1306 1312 M

1189 1194 M

1089 1094 W

1044 1050 W

* a little less than the W=; M=is medium; MS=is stronger; S=is strong; VS=is very strong

The IV type non-solvent crystalline form of that Wei of Luo Pin has solid-state FF middle infrared spectrum, solid-state FT near infrared spectrum, powder x-ray diffraction figure, solid-state 13C NMR (Nuclear Magnetic Resonance) spectrum and dsc (DSC) differential thermogram that shows respectively in accompanying drawing 26,27,28,29 and 30.

The position, 2 θ angle of the characteristic peak in the powder x-ray diffraction figure of the IV type non-solvent crystalline form (the IV type non-solvent crystalline form that comprises pure basically that Wei of Luo Pin) of as shown in Figure 28 that Wei of Luo Pin is: 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 ° and 18.53 ° ± 0.1 °.

More preferably, the feature of the IV type non-solvent crystalline form of that Wei of Luo Pin (the IV type non-solvent crystalline form that comprises pure basically that Wei of Luo Pin) is, in x-ray diffraction pattern as shown in Figure 28, has following peak, position, 2 θ angle: 6.85 ° ± 0.1 °, 9.14 ° ± 0.1 °, 10.80 ° ± 0.1 °, 12.04 ° ± 0.1 °, 12.88 ° ± 0.1 °, 15.09 ° ± 0.1 °, 17.74 ° ± 0.1 °, 18.01 ° ± 0.1 °, 18.26 ° ± 0.1 °, 18.53 ° ± 0.1 °, 20.47 ° ± 0.1 ° and 2 5.3 5 ° ± 0.1 °.

When carrying out dsc (to 150 ℃) with 1 ℃/minute sweep velocity, the DSC differential thermogram of the IV type non-solvent crystalline form of that Wei of Luo Pin show 117 ℃ initial, at 122 ℃ of fusing endotherms (Δ H=47J/g) that reach peak value.

That details are as follows is described for the monocrystalline X ray parameter of the IV type non-solvent crystalline form of that Wei of Luo Pin and experiment.

The monocrystalline X ray parameter of the IV type non-solvent crystalline form of that Wei of Luo Pin and experiment are described in detail

Experiment is described in detail

The crystallization data

The crystallographic system rhombic system

Lattice parameter a=15.065 (8) _

b＝25.27(1)_

c＝9.732(3)_

V＝3704(3)_ ³

Spacer P2

₁2 ₁2 ₁(#20)

Z value 4

D _Calculate1.13g/cm ³

Strength detection

Diffractometer Rigaku AFC5R

Radiation Cu K α (λ=1.54178_)

The temperature room temperature

2 _Maximum120.2 °

Proofread and correct the Lorentz-polarization

Absorb (trans.Factors:0.8362-0.9496)

The reflection number of measuring is altogether: 3145

Structure elucidation and refining

The number of times (1＞2.0 σ (I)) 1434 of observation

Variable number 415

Reflection/parameter is than 3.46

Residual errors: R; R _w0.081; 0.085

The IV type non-solvent crystalline form of that Wei of Luo Pin can slowly be evaporated by slow cooling and with saturated solution and be prepared from acetonitrile, perhaps prepares by that Wei of amorphous Luo Pin is exposed in the acetonitrile atmosphere.In addition, the acetonitrile solution of that Wei of Luo Pin can be inoculated the IV type non-solvent crystalline form that produces more that Wei of Luo Pin with the IV type non-solvent crystal of that Wei of Luo Pin.

Further specify the preparation of new that Wei crystalline form of Luo Pin of the present invention with following embodiment.

Embodiment 1

The preparation of the crystalline form of the I type high degree of hydration of that Wei of Luo Pin

In the saturated solution that in the mixture of 20mL alcohol 40mL water, prepares that Wei of Luo Pin under the room temperature.Add entry (54mL) with saturated solution stirring at room and with syringe pump lentamente with 0.15mL/ minute speed.After stirring is spent the night, the precipitation (crystal) that suction filtration goes out to form.

Embodiment 2

In the NMR pipe, add 1.75mL water.Place the ethanolic soln (that Wei of 99.482mg Luo Pin/mL ethanol) of that Wei of 0.5mL Luo Pin then very carefully at the top of water.The test tube cover lid to avoid evaporating, is left standstill it then.Obtain the crystallization of the I type hydration crystalline form of that Wei of Luo Pin after about 30 days, that Wei Hanyou of per molecule Luo Pin is greater than the water of 0.5 molecule.

Embodiment 3

By about 60 ℃ warm and leniently stir the alcoholic acid mixture that Wei of Luo Pin (30g) is dissolved in 360mL deionized-distilled water and 418mL 190 checkings.The solution gravity of heat is removed by filter insolubles.Filtrate is slowly cooled to room temperature under soft stirring, inoculate with the product of about 50mg embodiment 1 then.With mixture middling speed stirring at room temperature 3 days.With the mixture vacuum filtration that forms.The solid transfer that leaches is gently broken into pieces bulk to filter paper and with spatula.Then with solid transfer in the glass crystallizing dish and place and be placed on moisture eliminator on the saturated nacl aqueous solution, keep constant 75% relative humidity.After under room temperature (24 ± 1 ℃) and 75% relative humidity dry 12 days, obtain the hydration crystalline form of required that Wei of Luo Pin of about 20.5g.X-ray diffractogram of powder (Fig. 5).100MHz is solid-state ¹³C NMR (Nuclear Magnetic Resonance) spectrum (accompanying drawing 6).The nearly IR of solid-state FT (accompanying drawing 7).IR among the solid-state FT (accompanying drawing 8).Thermogravimetric analysis confirms that product contains 4.3% volatile matter.

Embodiment 4

The preparation of the I type hydration crystalline form of that Wei of Luo Pin of about 0.5 molecular water of that Wei Hanyou of per molecule Luo Pin

The product (about 100mg) of embodiment 3 is loaded on the sample rack of the powder x-ray diffraction instrument that is equipped with controlled atmosphere sample chamber and hot Stage microscope.Under the exsiccant nitrogen atmosphere, sample is warmed to 30 ℃ with 1 ℃/minute speed, and keeps in this temperature.Change into semihydrate after 60-90 minute fully.Powder x-ray diffraction figure (Fig. 1).

Embodiment 5

The product (1g) of embodiment 3 is layered in the polypropylene weighing boat as thin layer, and in vacuum drying oven, spends the night in pact-65kPa and drying at room temperature.Gained water absorbability product (semihydrate of that Wei of Luo Pin) is transferred in the vial, and at pact-65kPa in dry again 6 hours of room temperature.With the polypropylene lid vial is covered rapidly then, and in moisture eliminator, store with anhydrous calciumsulphate.100MHz is solid-state ¹³C NMR (Nuclear Magnetic Resonance) spectrum (accompanying drawing 2).The nearly IR of solid-state FT (accompanying drawing 3).IR among the solid-state FT (accompanying drawing 4).Thermogravimetric analysis confirms that product contains 2% volatile matter.

Embodiment 6

The II type Virahol half solvate crystalline form of that Wei of preparation Luo Pin

Under stirring, on hot-plate, mixture heating up to boiling point is dissolved in that Wei of Luo Pin (16g) in the 50mL Virahol at magnetic.Then this solution is cooled to room temperature, has formed precipitation.The gained mixture stirring at room 24 hours, is carried out agitation as appropriate simultaneously so that precipitation just suspends.By the suction filtration collecting precipitation, air-dry, obtained the II type Virahol half solvate crystalline form of that Wei of 9.9g Luo Pin.The thermogravimetric analysis of product shows and has volatile matter, is equivalent to that Wei of per 2 moles of Luo Pin and has 1 mole of Virahol.The powder x-ray diffraction analysis has confirmed that product is a crystal, and infrared spectra has confirmed that product is the II type solvation crystalline form of that Wei of Luo Pin. IR among the solid-state FT (accompanying drawing 9).The nearly IR of solid-state FT (accompanying drawing 14).

Embodiment 7

The II type isopropanol solvate crystalline form (thermogravimetric analysis has confirmed to contain the Virahol of 1.6% weight) of that Wei of preparation Luo Pin

In the blended vial that Wei of Luo Pin (1g) is suspended in the 2.5mL Virahol promoting at granulated glass sphere that to contain four diameters be 4mm.Cover vial, in room temperature with this suspension in room temperature scroll-up/down 4 months.Then suspension is transferred on the Petri ware, and allowed solvent evaporate lentamente.Then the Petri ware is placed vacuum drying oven, this vacuum drying oven is warmed to 50 ℃, and with sample at-65kPa in 50 ℃ of dryings 25 days to obtain this title compound.Thermogravimetric analysis has confirmed that product contains 1.6% volatile matter.

Embodiment 8

The II type isopropanol solvate crystalline form (thermogravimetric analysis has confirmed to contain the Virahol of 2% weight) of that Wei of preparation Luo Pin

With the sample heptane wash of embodiment 6 products, in Rotary Evaporators dry 2 days then.Resistates is transferred on the Petri ware, and dry in vacuum drying oven, this vacuum drying oven is warmed to 50 ℃, and with sample at-65kPa in 50 ℃ of dryings 3 days to obtain this title compound.Thermogravimetric analysis has confirmed that product contains 2% volatile matter.IR among the solid-state FT (accompanying drawing 10).The nearly IR of solid-state FT (Figure 15).

Embodiment 9

The II type ethyl acetate half solvate crystalline form of that Wei of preparation Luo Pin

Embodiment 9A

That Wei crude product of preparation Luo Pin

Will be according to U.S. patent 5; 914; 332 (embodiment 38) are by (2S; 3S; 5S)-and 2-amino-3-hydroxyl-5-[2S-(1-tetrahydropyrimidine-2-ketone group)-3-methylbutyryl base] amino-1; that Wei crude product of the Luo Pin that 6-phenylbenzene hexane (S)-pyroglutamate makes (about 85g has done correction according to solvent) be dissolved in 318.5 the gram ethyl acetate in, and with this solution for vacuum concentration to oily matter.Resistates is dissolved in the 225 gram ethyl acetate, and vacuum concentration is to twice of oily matter then.At 65 ℃ resistates is dissolved in the ethyl acetate (about 300mL), filter removing the undissolved solid of any trace, and vacuum concentration is to foam.This foam is dissolved in the 338 gram ethyl acetate, and this solution is divided into 4 equal portions.

Embodiment 9B

That Wei solution for vacuum concentration of Luo Pin that portion is made in embodiment 9A is dissolved in the 50mL dehydrated alcohol then to oily matter.Solvent removed in vacuo.At heating condition (about 55-60 ℃) resistates was kept 30 minutes under vacuum.The gained foam is dissolved in the ethyl acetate (87mL) in room temperature.In mixing less than 5 minutes time, tangible solid has appearred.The gained slurries were mixed 16 hours, then with the dilution of 87mL heptane.After 3 hours, by solid collected by filtration, with 36mL EtOAc/ heptane (1: 1v/v) wash, and, obtained II type ethyl acetate half solvate of 19.4 Crow those Weis of product 60 ℃ of vacuum-dryings 72 hours.IR among the solid-state FT (accompanying drawing 11).The nearly IR of solid-state FT (accompanying drawing 16).Record product by thermogravimetric analysis and contain 4.4% volatile matter.

Embodiment 9C

Another kind method prepares the II type ethyl acetate half solvate crystalline form of that Wei of Luo Pin

Will be according to U.S. patent 5; 914; 332 (embodiment 38) are by (2S; 3S; 5S)-and 2-amino-3-hydroxyl-5-[2S-(1-tetrahydropyrimidine-2-ketone group)-3-methylbutyryl base] amino-1; that Wei crude product of the Luo Pin that 6-phenylbenzene hexane (S)-pyroglutamate makes (about 20g has done correction according to solvent) is dissolved in the 118 gram ethyl acetate, then and with this solution for vacuum concentration to oily matter.At 46 ℃ resistates is dissolved in the 95.7 gram ethyl acetate, vacuum concentration is to oily matter then.At 64 ℃ resistates is dissolved in the 95.8 gram ethyl acetate.Measure moisture by KF and show that moisture content is less than 0.05%.Product solution is cooled to 41 ℃, and inoculates with the product of 0.20 gram embodiment 9B.This solution is cooled to 35 ℃, and mixed 1.25 hours in this temperature.With 10 minutes the gained slurries are cooled to 15 ℃ then, and mixed 1.5 hours at 15-18 ℃.By solid collected by filtration,,, obtained II type ethyl acetate half solvate of 12.3 Crow those Weis of product 56-58 ℃ of vacuum-drying 16 hours with 13.3 gram ethyl acetate washings.

Embodiment 10A

The II type ethyl acetate solvent thing crystalline form of preparation Luo Pin that Wei (thermogravimetric analysis has confirmed that per 2 moles of those Wei Hanyou of Luo Pin are less than 0.5 mole ethyl acetate)

That Wei solution for vacuum concentration of Luo Pin that portion is made in embodiment 9A is dissolved in the 50mL dehydrated alcohol then to oily matter.Solvent removed in vacuo.Under heating (about 55-60 ℃) condition, resistates was kept 30 minutes under vacuum.The crystal seed of embodiment 9B product is added in the gained foam.In room temperature this spumescence resistates is dissolved in the ethyl acetate (87mL) then.In mixing less than 5 minutes time, tangible solid has appearred.The gained slurries were mixed 16 hours, then with the dilution of 87mL heptane.After 3 hours, by solid collected by filtration, usefulness 36mL EtOAc/ heptane (1: 1v/v) washing, and, obtained the II type ethyl acetate solvent thing of 19.37 Crow those Weis of product 60 ℃ of vacuum-dryings 72 hours. IR among the solid-state FT (accompanying drawing 12).The nearly IR of solid-state FT (accompanying drawing 17).Record product by thermogravimetric analysis and contain 1.7% volatile matter.

Embodiment 10B

Another kind method prepares the II type ethyl acetate solvent thing crystalline form (thermogravimetric analysis has confirmed that per 2 moles of those Wei Hanyou of Luo Pin are less than 0.5 mole ethyl acetate) of that Wei of Luo Pin

Will (embodiment 2 according to U.S. patent 5,914,332; Via the EDAC/HOBT coupling with 17.0g (2S; 3S; 5S)-2-(2; 6-dimethyl phenoxy ethanoyl) amino-3-hydroxyl-5-amino-1,6-phenylbenzene hexane and 8.0g 2S-(1-tetrahydropyrimidine-2-ketone group)-3 Methylbutanoic acid coupling) solution (about 250mL) vacuum concentration of that Wei crude product of Luo Pin in isopropyl acetate that makes is to oily matter.Resistates is dissolved in the 250mL ethyl acetate, and vacuum concentration, foam obtained.This foam is dissolved in the warm ethyl acetate of 120mL.This solution is divided into 3 parts, every part heavy 44.9 gram.This solution is cooled to room temperature, crystallization has promptly taken place afterwards.With a copy of it in stirred overnight at room temperature.By solid collected by filtration,,,, obtained the II type ethyl acetate solvent thing of 6.23 Crow those Weis of product afterwards 70 ℃ of vacuum-dryings 44 hours then 22 ℃ of vacuum-dryings 40 hours with the washing of 8ml ethyl acetate.

Embodiment 11

The II type chloroform half solvate crystalline form of that Wei of preparation Luo Pin

That Wei of Luo Pin (10g) is dissolved in the 30mL chloroform.Under magnetic stirs, in hot-plate, this solution is heated to then and boils.The volume of solution reduce to original volume about 1/2 after, drip about 10mL normal heptane and begin to become muddy until solution.Add about 30mL chloroform then, and continue to boil and reduce to about 1/2 of original volume again until volume.Add about 20mL chloroform, continue to boil and reduce to about 1/2 of original volume again until volume.Then this mixture is cooled to room temperature lentamente, allows its part evaporate.After the evaporation, remain glassy resistates lentamente with molasses denseness.This resistates is mixed with about 20mL chloroform, and warm on hot-plate.Drip normal heptane until beginning to form precipitation.By coming dissolution precipitation with this mixture is warm again.The solution that this is warm is transferred to beaker, is placed in the wide-necked bottle that contains the 20mL heptane of having an appointment, and allows its cooling.After about 1 hour, formed dense solid precipitation.By in the content of beaker, adding about 20mL chloroform with the dissolving again of major part precipitation.After this mixture left standstill about 1 hour, formed a little needle-like crystal.In the wide-necked bottle that comprises beaker, add heptane (about 40mL) again, with on the lid for jar and leave standstill.After one day, beaker contains a large amount of crystal.Collect crystal by vacuum filtration.Use spatula that crystal block is gently broken into pieces, and with the chloroform/heptane mixture washing crystal outside the beaker of growing crystal in the wide-necked bottle.The thermogravimetric analysis of product shows and has volatile matter, is equivalent to per 2 moles of those Weis of Luo Pin and comprises 1 mole of chloroform.The powder x-ray diffraction analysis has confirmed that product is a crystal, and infrared spectra has confirmed that product is the II type solvation crystalline form of that Wei of Luo Pin.IR among the solid-state FT (accompanying drawing 13).The nearly IR of solid-state FT (accompanying drawing 18).

Embodiment 12

The III type ethyl acetate solvent thing crystalline form of that Wei of preparation Luo Pin

At 71 ℃ that Wei of Luo Pin (7.03g) is dissolved in the ethyl acetate (33.11g).With 45 minutes this solution is cooled to 42 ℃, tangible solid is arranged this moment.With 30 minutes these slurries are cooled to 35 ℃, mixed then 1 hour.With 13 minutes these slurries are cooled to 15 ℃, mixed then 1 hour.With 13 minutes dropping blended heptane (25.1g).The gained slurries were mixed 30 minutes.Collect the gained solid by filtering, and usefulness ethyl acetate/blended heptane (1: 1v/v, 20mL) washing, and, obtained this title compound of 6.4g 62 ℃ of vacuum-dryings 20 hours.The powder x-ray diffraction analysis has confirmed that this product is a crystal, and infrared spectra has confirmed that this product is the III type solvation crystalline form of that Wei of Luo Pin.IR among the solid-state FT (accompanying drawing 19).The nearly IR of solid-state FT (accompanying drawing 20).Thermogravimetric analysis has confirmed that product contains 2.3% volatile matter.

Embodiment 13

The III type ethyl acetate solvent crystalline form of that Wei of preparation Luo Pin

About that Wei of 100mg Luo Pin is dissolved in about 3mL ethyl acetate.In this solution, slowly and carefully add about 3mL heptane.After leaving standstill, by the grow III type solvation crystalline form of that Wei of Luo Pin of liquid diffusion crystallization.

Embodiment 14

That Wei solution of Luo Pin that portion is made in embodiment 9A dilutes with 14.8 gram ethyl acetate, is heated to 70-75 ℃, with 75 gram heptane dilutions, keeps the interior temperature greater than 70 ℃ simultaneously then.Gained solution 75 ℃ of heating 15 minutes, is cooled to room temperature then gradually.After mixed at room temperature is spent the night, by solid collected by filtration, with 36mL ethyl acetate/heptane (1: 1v/v) wash, and, obtained 21.5 these title compounds of gram 60 ℃ of vacuum-dryings 72 hours.

Embodiment 15

The desolvated crystalline form of III type of that Wei of preparation Luo Pin

That Wei of Luo Pin (5g) is placed the 100mL beaker.The acetonitrile that adds appropriate amount is just to dissolve about that Wei of 95% Luo Pin.There are some needle-like crystals to keep not dissolving.Beaker is placed in the wide-necked bottle of the anhydrous calciumsulphate (DRIERITE) that comprises the about 1cm of a bed thickness.On lid for jar, make material wherein keep leaving standstill in room temperature.After the standing over night, be settled out a large amount of white crystalline material.From beaker, incline and supernatant liquor (about 6mL).In precipitation, add fresh acetonitrile (3-4mL), gently break into pieces with spatula then.Collect solid by suction filtration, with about 1mL acetonitrile washing.Solid transfer is arrived the Petri ware, and, obtained the III type desolvation crystalline form of that Wei of Luo Pin in room temperature vacuum-drying.The powder x-ray diffraction analysis has confirmed that this product is a crystal, and infrared spectra has confirmed that product is the III type crystalline form of that Wei of Luo Pin.Thermogravimetric analysis is measured and have been confirmed that product contains and be lower than 0.05% volatile matter.IR among the solid-state FT (accompanying drawing 21).The nearly IR of solid-state FT (accompanying drawing 22).Powder x-ray diffraction figure (accompanying drawing 23).100MHz is solid-state ¹³C NMR (Nuclear Magnetic Resonance) spectrum (accompanying drawing 24).DSC thermogram (accompanying drawing 25).

Embodiment 16

The IV type non-solvent crystalline form of that Wei of preparation Luo Pin

(amorphous 1g) places crystallizing dish (A) with that Wei of Luo Pin.This crystallizing dish placed to contain have an appointment the 10mL acetonitrile and be placed on bigger crystallizing dish (B) on the hot-plate.Undersized crystallizing dish broad in the middle (C) is reversed and be placed on the crystallizing dish A, but still in crystallizing dish B.Big crystallizing dish (D) is reversed and be placed on crystallizing dish A, B and the C.Hot-plate is warmed to about 35 ℃, turns off hot-plate then.Whole assomble was placed 10 days in room temperature.After 10 days, all acetonitriles all evaporate.

A part of gained crystallized product (0.1g) is mixed with acetonitrile (0.6mL), and stirred 1 hour.This mixture is filtered, and make this solid air-dry, obtained the IV type non-solvent crystalline form of that Wei of Luo Pin.

Embodiment 17

The IV type non-solvent crystalline form of that Wei of preparation Luo Pin

At 40-42 ℃ that Wei of Luo Pin (259g) is dissolved in the 500g acetonitrile.This turbid solution is filled in the 2L round-bottomed flask via 0.45 μ nylon membrane, and the inoculation of the crystalline product of a small amount of embodiment 16.Use the rotary evaporation instrument apparatus with flask do not heat or the condition of vacuum under spend the night with the 10-20rpm rotation.The slurries of dense needle-like crystal have been formed.These slurries were cooled off in ice bath 1 hour, in the desk-top Neutsche filter that covers with nitrogen and cover, filter then with plastic film.Filter cake is washed with acetonitrile, and under nitrogen atmosphere, blotted about 30 minutes.Filter cake is transferred in the crystallizing dish, and " Hg pressure is dry weekend under nitrogen gas stream, has obtained the IV type non-solvent crystalline form of that Wei of 194.3g Luo Pin at 60-65 ℃, 20-21.Confirmed that by powder x-ray diffraction product is a crystal, and it has been classified as the IV type non-solvent crystalline form of that Wei of Luo Pin by IR among the solid-state FT.IR among the solid-state FT (accompanying drawing 26).The nearly IR of solid-state FT (accompanying drawing 27).Powder x-ray diffraction pattern (accompanying drawing 28).100MHz is solid-state ¹³C NMR (Nuclear Magnetic Resonance) spectrum (accompanying drawing 29).DSC thermogram (accompanying drawing 30).Confirmed by thermogravimetric analysis that product contains and be lower than 0.1% volatile matter.

When administration was infected with treatment HIV, (that Wei of Luo Pin: ratio ritonavir) was co-administered with 4: 1 for that Wei Youxuan of Luo Pin and ritonavir.That Wei of Luo Pin that comprises 4: 1 ratios: the preferred pharmaceutical compositions of using that Wei of Luo Pin of ritonavir has the following composition that is encapsulated in the soft elastic gelatin capsule.

That Wei of Luo Pin 133.3mg

Ritonavir 33.3mg

Oleic acid, NF 598.6mg

Propylene glycol, USP 64.1mg

Poly--oxyl 35 Viscotrol C, NF 21.4mg

(Cremephor?EL_)

Purified water, USP (distillatory) 4.3mg

If in composition, use the hydration or the solvation crystalline form of that Wei of Luo Pin, then regulate the hydration of that Wei of Luo Pin or the amount of solvation crystalline form according to the amount of the water that exists in the crystalline form or other solvent.

Preferred compositions can make according to following method.

Adopt following scheme to prepare 1000 soft gelatin capsules:

Specification (mg/ capsule) denominate quantity (g)

Q.S. nitrogen, N.F. Q.S.

578.6 oleic acid, NF 578.6

33.3 ritonavir 33.3

64.1 propylene glycol, USP 64.1

4.3 purified water, USP (distilled water) 4.3

133.3 that Wei 133.3 of Luo Pin

10.0 oleic acid, NF 10.0

21.4 poly--oxyl 35 Viscotrol C, 21.4

NF

10.0 oleic acid, NF 10.0

With mixing tank and suitable containers nitrogen purging.Then 578.6g oleic acid is added in the mixing tank.Mixing tank is heated to 28 ℃ (being no more than 31 ℃), and begins to mix.Under mixing condition, the 33.3g ritonavir is added in the oleic acid then.Propylene glycol and water are added in the mixing tank, and continue to mix and clarify until solution becomes.Then that Wei of 133.3g Luo Pin is added in the mixing tank, and continues to mix.10g oleic acid is added in the jar, and mixes and clarify until solution.With poly--oxyl 35 Viscotrol C of 21.4g, NF is added in this mixing tank and continues and mixes, and adds 10g oleic acid then.With this solution 2-8 ℃ of storage until encapsulated.This solution of 0.855g is filled in every soft gelatin capsule, then with the soft gelatin capsule drying, and 2-8 ℃ of storage.

When describing the crystalline form of that Wei of Luo Pin, term used herein " pure basically " is meant that the purity of crystalline form of this that Wei of Luo Pin is greater than about 90%.The crystalline form that this means this that Wei of Luo Pin does not contain any other compound of having an appointment more than 10%, that Wei of Luo Pin that does not particularly contain any other form more than 10% of having an appointment, for example amorphous, solvate forms, non-solvent compound form and desolvation thing form.More preferably, term " pure basically " is meant the crystalline form of purity greater than that Wei of Luo Pin of about 95%.The crystalline form that this means this that Wei of Luo Pin does not contain any other compound of having an appointment more than 5%, that Wei of Luo Pin that does not particularly contain any other form more than 5% of having an appointment, for example amorphous, solvate forms, non-solvent compound form and desolvation thing form.Even more preferably, term " pure basically " is meant the crystalline form of purity greater than that Wei of Luo Pin of about 97%.The crystalline form that this means this that Wei of Luo Pin does not contain any other compound of having an appointment more than 3%, that Wei of Luo Pin that does not particularly contain any other form more than 3% of having an appointment, for example amorphous, solvate forms, non-solvent compound form and desolvation thing form.

Also even more preferably, term " pure basically " is meant the crystalline form of purity greater than that Wei of Luo Pin of about 98%.The crystalline form that this means this that Wei of Luo Pin does not contain any other compound of having an appointment more than 2%, that Wei of Luo Pin that does not particularly contain any other form more than 2% of having an appointment, for example amorphous, solvate forms, non-solvent compound form and desolvation thing form.

Most preferably, term " pure basically " is meant the crystalline form of purity greater than that Wei of Luo Pin of about 99%.The crystalline form that this means this that Wei of Luo Pin does not contain any other compound of having an appointment more than 1%, that Wei of Luo Pin that does not particularly contain any other form more than 1% of having an appointment, for example amorphous, solvate forms, non-solvent compound form and desolvation thing form.

The powder x-ray diffraction analysis of sample is carried out in the following manner.The sample that carries out the X-ray diffraction analysis is by the form of sample powder (sample of limited amount being ground to form fine powder with mortar and pestle or with glass microscope slide) with thin layer is coated on the sample rack, and flattens lightly with microslide.Turn round in the preparation of sample in the middle of following 3 configurations: in bulk of ring-type, quartzy zero this base plate or hot Stage microscope fixer (similarly fixing) with zero this base plate.The X-ray powder diffraction is with XDS 2000 θ/θ diffractometer (Scintag; 2kW standard with liquid nitrogen or Peltier refrigerative germanium solid-state detector focuses on the X-x ray tube; 45kV and 30-40ma; X-ray source: Cu-K α 1; Scope; 2.00-40.00 ° 2 θ; Sweep velocity: 0.5 or 2 °/minute), XRD-6000 diffractometer (Shimadzu; Fine focus X-x ray tube with NaI scintillation detector; 45kV and 30-40ma; X-ray source: Cu-K α 1; Scope: 2.00-40.00 ° of 2 θ; Sweep velocity: 2 °/minute) or I-2X-x ray diffractometer x (Nicolet; Scintillation detector; 50kV and 30ma; X-ray source: Cu-K α 1; Scope: 2.00-40.00 ° of 2 θ; Sweep velocity: 2 °/minute).The relative humidity of the sample in hot Stage microscope fixer can be used relative humidity producer (model RH200, VTI Corp.) control.

The position at the characteristic powder X-ray diffraction figure peak of polymorphic form is according to position, angle (2 θ) report, and the fluctuation of permission is ± 0.1 °.The fluctuation of this permission is stipulated by American Pharmacopeia 1843-1844 page or leaf (1995).± 0.1 ° fluctuation is being used when comparing two powder x-ray diffraction figure.In fact, if it is position, angle (2 θ) scope of peak position ± 0.1 measured ° that the peak of the diffractogram of a pattern is given, it is position, angle (2 θ) scope of peak position ± 0.1 measured ° that the peak of the diffractogram of another pattern is given, if and the scope of these peak positions thinks that then two peaks have identical position, angle (2 θ) when overlapping.For example, if the peak of the diffractogram of a pattern of measuring has 5.20 ° peak position, then in order to compare, the fluctuation of permission allows that this peak is endowed 5.10 °-5.30 ° position.If the comparison peak of another diffractogram of measuring has 5.35 ° peak position, then in order to compare, the fluctuation of permission allows that this peak is endowed 5.25 °-5.45 ° peak position.Because overlapping (promptly 5.10 °-5.30 ° and 5.25 °-5.45 °) are arranged between the scope of these two peak positions, think that then these two peaks that compare have identical position, angle (2 θ).

The solid state nuclear magnetic resonance analysis of sample carries out in the following manner.Use has the Bruker AMX-400 instrument of following parameter: CP-MAS (cross polarization magic angle spinning); ¹³The spectrometer frequency of C is 100.6MHz; Pulse sequence is VA-CP2LEV; Be 2.5 milliseconds duration of contact; Roll rate is 7000Hz; Recirculation time of lag is 5.0 seconds; 3000 scanning).

The FT near-infrared analysis of sample carries out in the following manner.Sample is analyzed as the pure undiluted powder that is included in the 1 clean drachm bottle.Use has the NicoletMagna System 750 FT-IR spectrometers with Nicolet SabIR near-infrared diffuse reflectance fiber optic probe annex of following parameter: detector is PbS; The light beam splitter is CaF2; The number of times of scan sample is 16; Resolving power is 8cm ^-1

Infrared analysis carries out in the following manner among the FT of sample.Sample is as pure undiluted powdery analysis.Use has the Nicolet Magna System 750 FT-IR spectrometers of the detector of Nicolet NIC-PLAN microscope and MCT-A cooled with liquid nitrogen.Sample is placed on 13mm * 1mm BaF2 disk sample rack.4cm ^-1Resolving power is collected 64 scanning.

The dsc of sample is carried out in the following manner.Have TAInstruments DSC chamber and T.A.Instruments Model 2920 Differential Scanning Calorimeters that are used for the Thermal Solutions version 2 .3 software of data analysis.Analytical parameters is: sample size: 4-10mg, be placed in the aluminium dish, and a pin hole is stabbed in sealing then in lid; Rate of heating: (40-50mL/ minute) 1 ℃/minute under the exsiccant nitrogen purging.

Thermogravimetric analysis is by the speed with 1 ℃ or 5 ℃/minute sample to be heated to 200 ℃ from room temperature to carry out.

Above only being in order to demonstrate the invention, is not to limit the invention to disclosed embodiment.It will be apparent to those skilled in the art that modification and change are in by the scope of the invention and character that claims limited.

Claims

1. that Wei of Luo Pin is (2S; 3S; 5S)-2-(2; 6-dimethyl benzene oxygen ethanoyl)-amino-3-hydroxyl-5-(2-(1-tetrahydrochysene-pyrimid-2-one base)-3-methylbutyryl base) amino-1; the hydration crystalline form of 6-phenylbenzene hexane; wherein that Wei of per molecule Luo Pin comprises about 0.5 molecular water-Yue 2 molecular waters, and wherein said crystalline form has that its position is positioned at 1652-1666cm in solid-state infrared spectra ^-1Peak in the scope and in solid-state infrared spectra its position be positioned at 1606-1615cm ^-1A peak in the scope.

2. that Wei crystalline form of the Luo Pin of claim 1, wherein said crystalline form have that its position is positioned at 1652-1666cm in solid-state infrared spectra ^-1Peak in the scope and in solid-state infrared spectra its position be positioned at 1606-1615cm ^-1A peak in the scope, wherein that Wei of per molecule Luo Pin comprises the position, 2 θ angle of powder X-ray-ray diffraction diagram characteristic peak of I type hydration crystalline form of that Wei of Luo Pin of about 0.5 molecular water and is:

7.25 ° ± 0.1 °, 8.53 ° ± 0.1 °, 10.46 ° ± 0.1 °, 11.05 ° ± 0.1 °, 11.71 ° ± 0.1 °, 14.76 ° ± 0.1 °, 15.30 ° ± 0.1 °, 16.67 ° ± 0.1 °, 17.32 ° ± 0.1 °, 19.10 ° ± 0.1 °, 19.57 ° ± 0.1 °, 21.24 ° ± 0.1 °, 21.84 ° ± 0.1 ° and 22.46 ° ± 0.1 °

Wherein the water content of that Wei of per molecule Luo Pin is greater than 0.5 molecule, and the position, 2 θ angle of powder X-ray-ray diffraction diagram characteristic peak that comprises the I type hydration crystalline form of about 2 molecules up to that Wei of per molecule Luo Pin is: