CN104995189A - Crystalline form of hepatitis c drug and preparation method, pharmaceutical composition and use thereof - Google Patents

Crystalline form of hepatitis c drug and preparation method, pharmaceutical composition and use thereof Download PDF

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CN104995189A
CN104995189A CN201480007231.3A CN201480007231A CN104995189A CN 104995189 A CN104995189 A CN 104995189A CN 201480007231 A CN201480007231 A CN 201480007231A CN 104995189 A CN104995189 A CN 104995189A
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tmc435
crystal formation
sodium salt
tmc435 sodium
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CN104995189B (en
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劳海萍
盛晓霞
盛晓红
贾强
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Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd
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Hangzhou Pushai Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The present invention relates to a crystalline form of a hepatitis C drug (2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropyl sulphonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxyl-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl] oxyl]-5-methyl-4,14-dioxocyclopentano[c]cyclopropo[g][1,6] diazacyclotetradecene-12a(1H)-methanamine(TMC435) sodium salt, the crystalline form having good crystallinity and stability compared with known crystalline forms. The present invention further relates to a preparation method, pharmaceutical composition and use of the crystalline form, the use in preparing drugs for treating and/or preventing hepatitis C viral infection or liver disease related to hepatitis C viral infection.

Description

Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes Technical field
The application belongs to pharmaceutical chemistry crystallization technique field.Specifically, it is related to hepatitis C medicine (2R, 3aR, 10Z, 11aS, 12aR, 14aR)-N- (Cyclopropylsulfonyl) -2, 3, 3a, 4, 5, 6, 7, 8, 9, 11a, 12, 13, 14, tetrahydrochysene-the 2- of 14a- ten [[7- methoxyl group -8- methyl -2- [4- (1- Methylethyls) -2- thiazolyls] -4- quinolyls] epoxide] -5- methyl -4, simultaneously [g] [1 of 14- dioxos cyclopentano [c] ring third, 6] crystal formation of diazacyclo tetradecene -12a (1H)-formamide (TMC435) sodium salt, further relate to the preparation method of the crystal formation, its pharmaceutical composition and purposes.
Background technology
TMC435 is HCV of new generation (HCV) NS3/4A protease inhibitors, is developed by Medivir companies and Yang Sen (Janssen) company.TMC435 and glycol interferon and Ribavirin (ribavirin) drug combination, for treating chronic hepatitis C adult patients, and can be with compensatory hepatopathy (liver fibrosis for including each stage).Its action principle is the NS3/4A protease by suppressing HCV, to suppress duplications of the HCV in liver cell.In September, 2013, TMC435 (in the trade name Sovriad of Japan) obtains Japanese labour health Department of Welfare (MHLW) approval, for the treatment of the chronic hcv infection person of genotype -1, this is the global first supervision approval that TMC435 is obtained.Obtain FDA approvals, trade name OLYSIO in November, 2013.OLYSIO is oral capsule (active component containing 150mg) once a day, and administering mode is：OLYSIO combines glycol interferon and ribavirin combination therapy 12 weeks, then the therapeutic alliance of progress Peg-IFN alpha-2b and Ribavirin 12 weeks or 36 weeks.
TMC435 chemical name is：(2R, 3aR, 10Z; 11aS, 12aR, 14aR)-N- (Cyclopropylsulfonyl) -2; 3,3a, 4; 5; 6,7,8; 9; 11a, 12,13; 14; tetrahydrochysene-the 2- of 14a- ten [[7- methoxyl group -8- methyl -2- [4- (1- Methylethyls) -2- thiazolyls] -4- quinolyls] epoxide] -5- methyl -4,14- dioxo cyclopentano [c] ring third simultaneously [g] [1,6] diazacyclo tetradecene -12a (1H)-formamide; the entitled Simeprevir of English, molecular formula is C38H47N5O7S2, molecular weight is 749.94, and chemical structural formula is as follows：
Patent document WO2007014926A1 discloses TMC435 compounds and preparation method thereof.
Patent document WO2008092954A2 discloses TMC435 six kinds of crystal formations (crystal formation I, crystal formation II, crystal formation III, crystal formation IV, crystal formation V and crystal formation VI) and preparation method thereof, its solubility, XRPD, FT-IR and DSC data are disclosed, and addresses crystal formation I for anhydride and most stable crystal form.
Patent document WO2010097229A2 discloses TMC435 sodium salt amorphous articles and preparation method thereof, and provides its XRPD, FTIR, TGA, DSC, MDSC, DVS and stability data.In addition, the patent document also discloses the formulation protocol of TMC435 sodium salt amorphous articles.
The present inventor's research finds that known TMC435 and its six kinds of crystal formations have following defect：Poor solubility, at room temperature the solubility in water be respectively less than 1 μ g/mL.
The present inventor's research finds that known TMC435 sodium salt amorphous articles have following defect：The amorphous article is placed 10 days under the conditions of 40 DEG C/75%RH, it is impossible to maintain its original form.
In view of prior art remains deficiency, TMC435 and its salt of the exploitation with more advantage performances novel crystal forms are of great practical significance.
The content of the invention
It is an object of the invention to provide the novel crystal forms of the TMC435 sodium salts with good crystallinity and stability, and provide its preparation method, its pharmaceutical composition and purposes.
According to the purpose of the present invention, the present invention provides crystal formation A (hereinafter referred to as " crystal formation A ") of TMC435 sodium salts and preparation method thereof.
Radiated using Cu-K α, the X-ray powder diffraction figure that the crystal formation A is represented with 2 θ angles has following characteristics peak：4.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 11.0 ± 0.2 °, 12.3 ± 0.2 ° and 18.1 ± 0.2 °.
Preferably, the X-ray powder diffraction figure that the crystal formation A is represented with 2 θ angles has following characteristics peak：4.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 11.0 ± 0.2 °, 12.3 ± 0.2 °, 15.1 ± 0.2 °, 16.6 ± 0.2 °, 18.1 ± 0.2 ° and 22.6 ± 0.2 °.
Further, the X-ray powder diffraction figure that the crystal formation A is represented with 2 θ angles has following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal formation A has X-ray powder diffraction figure as shown in Figure 1.
The crystal formation A has at least one following characteristic：
The FT-IR figures of the crystal formation A are 3423,3331,2961,2932,2866,1633,1611,1451,1232,1187,1119,870 and 780cm in wave number-1Place has characteristic peak；
The differential scanning amount thermal map (DSC) of the crystal formation A is as shown in Figure 2；
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation A is as shown in Figure 3.
Compared with known TMC435 sodium salts amorphous article, the crystal formation A has the advantages that：
(1) crystal formation A is crystalline state, and with preferable crystallinity；
(2) crystal formation A has more preferable stability of crystal form and chemical stability.
Crystal formation A above-mentioned property shows：Compared with known TMC435 sodium salts amorphous article, the TMC435 sodium salt crystal formations A of the present invention has higher melt, stability of crystal form and chemical stability are good, can preferably it resist during medicine manufacture and/or storage etc. as the problems such as the content caused by the factors such as time, temperature, humidity is uneven and purity is reduced, the accurate quantitative analysis being more beneficial in prepared by unit formulation and the transport and storage in later stage, and the risk declined by the curative effect that activity substance content is unstable and impurity content increase is brought is reduced, it is more suitable for solid pharmaceutical preparation application.
TMC435 sodium salt crystal formations A preparation method, comprises the following steps：Suspensions of the TMC435 crystal formations I in alcohol is formed, sodium hydroxide is added and stirs, kept for 2-5 days under -10 DEG C -50 DEG C of recrystallization temperature, obtain the TMC435 sodium salts crystal formation A.
Preferably, the alcohol is C2-C4Alcohol, the C2-C4Alcohol can be ethanol, propyl alcohol, isopropanol, butanol, sec-butyl alcohol or its mixture；More preferably ethanol.
Preferably, the mole dosage ratio of the TMC435 crystal formations I and sodium hydroxide are 1:1-1:2, more preferably 1:1-1:1.2.
Preferably, in the suspension TMC435 crystal formations I consumption for its under recrystallization temperature 2-10 times, more preferably 2-5 times of solubility in alcohol.
The suspension that the sodium hydroxide can be added for solid or it is formed in the alcohol is added；When it forms suspension, the consumption of sodium hydroxide for its under recrystallization temperature 2-10 times, preferably 2-5 times of solubility in the alcohol.
Preferably, the recrystallization temperature is 10 DEG C -40 DEG C, more preferably room temperature.
According to the purpose of the present invention, the present invention also provides crystal formation B (hereinafter referred to as " crystal formation B ") of TMC435 sodium salts and preparation method thereof.
Radiated using Cu-K α, the X-ray powder diffraction figure that the crystal formation B is represented with 2 θ angles has following characteristics peak：5.0 ± 0.2 °, 6.0 ± 0.2 °, 6.5 ± 0.2 °, 13.0 ± 0.2 °, 18.5 ± 0.2 ° and 23.2 ± 0.2 °.
Preferably, the X-ray powder diffraction figure that the crystal formation B is represented with 2 θ angles has following characteristics peak：3.6 ± 0.2 °, 4.2 ± 0.2 °, 5.0 ± 0.2 °, 6.0 ± 0.2 °, 6.5 ± 0.2 °, 10.6 ± 0.2 °, 13.0 ± 0.2 °, 14.6 ± 0.2 °, 17.7 ± 0.2 °, 18.5 ± 0.2 °, 22.6 ± 0.2 ° and 23.2 ± 0.2 °.
Further, the X-ray powder diffraction figure that the crystal formation B is represented with 2 θ angles has following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal formation B has X-ray powder diffraction figure as shown in Figure 5.
The crystal formation B has at least one following characteristic：
The FT-IR figures of the crystal formation B are 3453,3327,2960,2931,2863,1635,1611,1548,1408,1352,1235,1118,1022,869 and 780cm in wave number-1Place has characteristic peak；
The differential scanning amount thermal map (DSC) of the crystal formation B is as shown in Figure 6；
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation B is as shown in Figure 7.
Compared with known TMC435 sodium salts amorphous article, the crystal formation B has the advantages that：
(1) crystal formation B is crystalline state, and with preferable crystallinity；
(2) crystal formation B has more preferable stability of crystal form and chemical stability.
Crystal formation B above-mentioned property shows：Compared with known TMC435 sodium salts amorphous article, the TMC435 sodium salt crystal formations B of the present invention has higher melt, stability of crystal form and chemical stability are good, can preferably it resist during medicine manufacture and/or storage etc. as the problems such as the content caused by the factors such as time, temperature, humidity is uneven and purity is reduced, the accurate quantitative analysis being more beneficial in prepared by unit formulation and the transport and storage in later stage, and the risk declined by the curative effect that activity substance content is unstable and impurity content increase is brought is reduced, it is more suitable for solid pharmaceutical preparation application.
TMC435 sodium salt crystal formations B preparation method, comprises the following steps：TMC435 sodium salt amorphous articles are formed into suspension in a solvent, the solvent is selected from acetonitrile, acetone, the water saturation solution of butanone or its mixture, stirring and crystallizing, obtains the TMC435 sodium salts crystal formation B.
Preferably, the temperature of the crystallization is 10-40 DEG C, more preferably room temperature.
Preferably, the time of the crystallization is 1-2 weeks, more preferably 7-9 days.
Preferably, the consumption of TMC435 sodium salt amorphous articles is 2-10 times, more preferably 2-5 times of its solubility under recrystallization temperature in the solvent in the suspension.
The preparation method of the water saturation solution of the butanone is：Take after isometric butanone and water mixing, be stirred vigorously 10 minutes, stratification, take the water saturation solution that organic layer is butanone.
According to the purpose of the present invention, the present invention also provides crystal formation C (hereinafter referred to as " crystal formation C ") of TMC435 sodium salts and preparation method thereof.
Radiated using Cu-K α, the X-ray powder diffraction figure that the crystal formation C is represented with 2 θ angles has following characteristics peak：3.4 ± 0.2 °, 5.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 12.4 ± 0.2 ° and 18.4 ± 0.2 °.
Preferably, the X-ray powder diffraction figure that the crystal formation C is represented with 2 θ angles has following characteristics peak：3.4 ± 0.2 °, 4.2 ± 0.2 °, 5.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 9.1 ± 0.2 °, 12.4 ± 0.2 °, 15.2 ± 0.2 °, 18.4 ± 0.2 °, 22.4 ± 0.2 °, 22.7 ± 0.2 ° and 23.6 ± 0.2 °.
Further, the X-ray powder diffraction figure that the crystal formation C is represented with 2 θ angles has following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal formation C has X-ray powder diffraction figure as shown in Figure 9.
The crystal formation C has at least one following characteristic：
The FT-IR figures of the crystal formation C are 3500,3323,2957,2932,2865,1632,1610,1552,1350,1234,1186,1119,1017,870 and 780cm in wave number-1Place has characteristic peak；
The differential scanning amount thermal map (DSC) of the crystal formation C is as shown in Figure 10；
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation C is as shown in figure 11.
Compared with known TMC435 sodium salts amorphous article, the crystal formation C has the advantages that：
(1) crystal formation C is crystalline state, and with preferable crystallinity；
(2) crystal formation C has more preferable stability of crystal form and chemical stability.
Crystal formation C above-mentioned property shows：Compared with known TMC435 sodium salts amorphous article, the TMC435 sodium salt crystal formations C of the present invention has higher melt, stability of crystal form and chemical stability are good, can preferably it resist during medicine manufacture and/or storage etc. as the problems such as the content caused by the factors such as time, temperature, humidity is uneven and purity is reduced, the accurate quantitative analysis being more beneficial in prepared by unit formulation and the transport and storage in later stage, and the risk declined by the curative effect that activity substance content is unstable and impurity content increase is brought is reduced, it is more suitable for solid pharmaceutical preparation application.
TMC435 sodium salt crystal formations C preparation method, comprises the following steps：TMC435 sodium salt amorphous articles are formed into suspension in a solvent, the solvent is selected from ethyl acetate, isopropyl acetate, chloroform or its mixture, stirring and crystallizing, obtains the TMC435 sodium salts crystal formation C.
Preferably, the temperature of the crystallization is 10-40 DEG C, more preferably room temperature.
Preferably, the time of the crystallization is 1-2 weeks, more preferably 7-9 days.
Preferably, the consumption of TMC435 sodium salt amorphous articles is 2-10 times, more preferably 2-5 times of its solubility under recrystallization temperature in the solvent in the suspension.
According to the purpose of the present invention, the present invention also provides crystal formation D (hereinafter referred to as " crystal formation D ") of TMC435 sodium salts and preparation method thereof.
Radiated using Cu-K α, the X-ray powder diffraction figure that the crystal formation D is represented with 2 θ angles has following characteristics peak：5.4 ± 0.2 °, 6.3 ± 0.2 °, 8.5 ± 0.2 °, 8.8 ± 0.2 °, 12.8 ± 0.2 ° and 20.0 ± 0.2 °.
Preferably, the X-ray powder diffraction figure that the crystal formation D is represented with 2 θ angles has following characteristics peak：5.4 ± 0.2 °, 6.3 ± 0.2 °, 8.5 ± 0.2 °, 8.8 ± 0.2 °, 11.3 ± 0.2 °, 12.5 ± 0.2 °, 12.8 ± 0.2 °, 15.3 ± 0.2 °, 20.0 ± 0.2 °, 21.4 ± 0.2 °, 22.4 ± 0.2 ° and 22.8 ± 0.2 °.
Further, the X-ray powder diffraction figure that the crystal formation D is represented with 2 θ angles has following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal formation D has X-ray powder diffraction figure as shown in figure 13.
The crystal formation D has at least one following characteristic：
The FT-IR figures of the crystal formation D are 3474,2955,2930,2868,1658,1609,1510,1452,1351,1232,1186,1120,1105 and 844cm in wave number-1Place has characteristic peak；
Compared with known TMC435 sodium salts amorphous article, crystal formation D is crystalline state and has preferable crystallinity.
TMC435 sodium salt crystal formations D preparation method, comprises the following steps：Suspension of the TMC435 sodium salt amorphous articles in butanone is formed, stirring and crystallizing obtains the TMC435 sodium salts crystal formation D.
Preferably, the temperature of the crystallization is 10-40 DEG C, more preferably room temperature.
Preferably, the time of the crystallization is 1-2 weeks, more preferably 7-9 days.
Preferably, in the suspension TMC435 sodium salt amorphous articles consumption for its under recrystallization temperature 2-10 times, preferably 2-5 times of solubility in butanone.
In the crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, crystal formation C and crystal formation D above-mentioned preparation method, the stirring can be carried out using the conventional method of this area, such as magnetic agitation, mechanical agitation.Stir speed (S.S.) is 50~1800 revs/min, preferably 300~900 revs/min.
In the crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, crystal formation C and crystal formation D above-mentioned preparation method, the crystal of precipitation is separated, washed and dried using this area conventional method.The separation, using the conventional method of this area Such as filtering, centrifugation；The concrete operations of filtering are：The sample for being intended to separation is placed on filter paper, depressurizes suction filtration；The concrete operations of centrifugation are：The sample for being intended to separation is placed in centrifuge tube, and rotation is until solid is all sink to centrifugation bottom of the tube at a high speed afterwards, and centrifugation rate is, for example, 6000 revs/min.The solvent of the washing is preferably identical with solvent used in the crystal formation preparation method, and the consumption of cleaning solvent is 2-10 times of recrystallisation solvent.The drying, is for example spontaneously dried using this area conventional method, forced air drying or is dried under reduced pressure；Drying equipment is fume hood, convection oven or vacuum drying oven；Dry and carried out in the case where depressurizing or not depressurizing, preferably pressure is less than 0.09Mpa；Drying temperature about room temperature is to 60 DEG C；Drying time is 1~48 hour, preferably 1~16 hour.
In the present invention, " room temperature " refers to about 10~30 DEG C.
In the present invention, " crystal ", " crystal formation " or " amorphous article " refers to characterizing what is confirmed by shown X-ray diffractogram.It will be appreciated by those skilled in the art that experimental error therein depends on the purity of condition, the preparation of sample and the sample of instrument.Particularly, as well known to those skilled in the art, X-ray diffractogram would generally be changed with the condition of instrument.In particular, the relative intensity of X-ray diffractogram may also change with the change of experiment condition, so the order of peak intensity cannot function as unique or deciding factor.In addition, the experimental error of peak angle degree is generally 5% or less, the error of these angles should also be considered into, allow generally for ± 0.2 ° of error.Further, since the influence of the empirical factor such as height of specimen, can cause the overall offset of peak angle degree, certain skew is allowed generally for.Thus, it will be appreciated by persons skilled in the art that it is any have belonged to the same or analogous crystal formation in TuPu method peak of the present invention in scope." single crystal form " refers to that through X-ray powder diffraction detection be single crystal form.
Crystal formation A, crystal formation B, crystal formation C and the crystal formation D of TMC435 sodium salts of the present invention are pure, single, and any other crystal formation or amorphous article are not mixed substantially.In the present invention, " not having substantially " is when being used to refer to novel crystal forms, refer to other crystal formations contained in this novel crystal forms or amorphous article is less than 20% (weight), more refer to less than 10% (weight), 5% (weight) is especially less than, particularly relates to be less than 1% (weight).
The preparation method that the initiation material TMC435 of the present invention is referred to patent document WO2007014926A1 is made or commercially available, the preparation method that TMC435 crystal formations I is referred to patent document WO2008092954A2 is made, and the preparation method that TMC435 sodium salt amorphous articles are referred to patent document WO2010097229A2 is made.
Further, the present invention provides a kind of pharmaceutical composition, the novel crystal forms or the novel crystal forms of the TMC435 sodium salts prepared by the inventive method of one or more of the present invention TMC435 sodium salts of the described pharmaceutical composition comprising treatment and/or prevention effective dose, and at least one pharmaceutically acceptable carrier.Wherein, the novel crystal forms of the TMC435 sodium salts include crystal formation A, crystal formation B, crystal formation C or the crystal formation D of TMC435 sodium salts.In addition, described pharmaceutical composition can also include the pharmaceutically useful crystal formation or amorphous article of other other salt of pharmaceutically useful crystal formation or amorphous article or TMC435 and TMC435 of TMC435 sodium salts.Optionally, described pharmaceutical composition can also include one or more other active constituents of medicine, such as other antiviral compound, especially HCV-Ab IgG compounds.
Aforementioned pharmaceutical compositions can be made into certain formulation, it is preferred that the formulation of the form such as oral administration, parenteral (including subcutaneous, intramuscular and intravenous), rectally, cutaneous penetration, buccal administration, nose administration, including but not limited to solid dosage forms, liquid dosage form, semiliquid formulation, aerosol or suppository etc..For example, being adapted to the formulation of oral administration includes tablet, capsule, granule, powder, pill, pulvis, lozenge, syrup or supensoid agent；Being adapted to the formulation of parenteral includes aqueous or non-aqueous solution or emulsion；It is adapted to the formulation of rectally including the use of hydrophily or the suppository of hydrophobic carrier；Being adapted to the formulation of cutaneous penetration includes paste, creme；Being adapted to the formulation of nose administration includes aerosol, spray.As needed, above-mentioned formulation may be adapted to the quick release, sustained release or regulation release of active component.
Pharmaceutically acceptable carrier of the present invention includes solid-state carrier, is specifically including but not limited to：Diluent, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate, mannitol, sorbierite, sugar；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol；Disintegrant, such as starch, sodium starch glycollate, pregelatinized starch, PVPP, Ac-Di-Sol, cataloid；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate；Glidant, such as cataloid；Complex forming agents, such as cyclodextrin and resin of various ranks；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl are fine Tie up element, ethyl cellulose, methylcellulose, methyl methacrylate, wax etc..Pharmaceutically acceptable carrier of the present invention also includes liquid carrier, is specifically including but not limited to：The solvent of aqueous, oiliness or alcohol solution is such as sterilized water, normal saline solution, glucose solution, mannitol solution, vegetable oil, cod-liver oil, ethanol, propyl alcohol, glycerine.Further, it is also possible to use the carriers such as polyethylene glycol, polypropylene glycol.Different according to formulation also may be selected to use other pharmaceutically acceptable carriers, such as including but not limited to film forming agent, plasticizer, colouring agent, flavor enhancement, viscosity modifier, preservative, antioxidant, bleeding agent, buffer.Each carrier must be it is acceptable, can be compatible with the other compositions in formula and harmless for sufferer.
Described pharmaceutical composition can be used to be prepared well known to a person skilled in the art method.When preparing pharmaceutical composition, crystal formation A, crystal formation B, crystal formation C, crystal formation D or its combination and the one or more pharmaceutically acceptable carriers of TMC435 sodium salts of the present invention are mixed, optionally, are mixed with one or more other active constituents of medicine.Solid pharmaceutical preparation can be prepared by techniques such as mixing, granulations, and liquid or semiliquid formulation can be prepared by the technique such as mixing, dissolving, scattered, emulsification.
Further, the present invention provides the purposes of the novel crystal forms of TMC435 sodium salts of the present invention or the novel crystal forms of the TMC435 sodium salts obtained by preparation method of the present invention in the medicine for treatment and/or prevention of hepatitis C (HCV) infection or the liver diseases related to HCV (HCV) infection is prepared, wherein the novel crystal forms of the TMC435 sodium salts include crystal formation A, crystal formation B, crystal formation C, crystal formation D or its combination of TMC435 sodium salts；The liver diseases related to HCV infection include the illness as caused by HCV, including gradual liver fibrosis, the inflammation or necrosis, end-stage liver disease and liver cell carcinoma (HCC) that cause hepatic sclerosis.
Further, a kind of method that the present invention provides treatment and/or prevention of hepatitis C (HCV) infection or the liver diseases related to HCV (HCV) infection, methods described includes giving the novel crystal forms or its combination or its pharmaceutical composition of the TMC435 sodium salts of the invention of patient's treatment of needs and/or prevention effective dose, wherein the novel crystal forms of the TMC435 sodium salts include crystal formation A, crystal formation B, crystal formation C, crystal formation D or its combination of TMC435 sodium salts.The liver diseases related to HCV infection include the illness as caused by HCV, including gradual liver fibrosis, the inflammation or necrosis, end-stage liver disease and liver cell carcinoma (HCC) that cause hepatic sclerosis.The patient includes but is not limited to mammal.The amount given refers to effectively suppress or reduce HCV infection or effectively suppresses or reduce the amount of HCV infection relevant disease.Generally effective daily dose is 0.01-500 mg kg of body weight, preferably 0.1-50 mg kg of body weight.Required daily dose single can be given or repeatedly be given with suitable interval in a unit, per unit dose form contains 1-1000 milligrams, especially 5-200 milligrams, e.g., from about 25 milligrams or about 50 milligrams or about 75 milligrams or about 100 milligrams or about 150 milligrams or about 200 milligrams of TMC435 active components.In addition, previously known HCV-Ab IgG compound, such as interferon-' alpha ' (IFN-α), glycol interferon-α and/or triazole nucleoside and other optional HCV-Ab IgG compounds, crystal formation A, crystal formation B, crystal formation C, crystal formation D or its combination of TMC435 sodium salts of the present invention can be combined, as the medicine in therapeutic alliance；Inhibitor, immunoregulation medicament, other antiviral drugs or their joint of other targets of other the described HCV-Ab IgG compounds selected from HCV polymer inhibitors, HCV protease inhibitor, in HCV life cycles.It is preferred that the therapeutic alliance includes glycol interferon-α, the crystal formation A of Ribavirin and TMC435 sodium salts of the present invention, crystal formation B, crystal formation C, crystal formation D or its combination.
Brief description of the drawings
Fig. 1 TMC435 sodium salts crystal formation A of the present invention XRPD collection of illustrative plates.
Fig. 2 TMC435 sodium salts crystal formation A of the present invention DSC collection of illustrative plates.
Fig. 3 TMC435 sodium salts crystal formation A of the present invention TGA collection of illustrative plates.
Fig. 4 TMC435 sodium salts crystal formation A of the present invention FT-IR collection of illustrative plates.
Fig. 5 TMC435 sodium salts crystal formation B of the present invention XRPD collection of illustrative plates.
Fig. 6 TMC435 sodium salts crystal formation B of the present invention DSC collection of illustrative plates.
Fig. 7 TMC435 sodium salts crystal formation B of the present invention TGA collection of illustrative plates.
Fig. 8 TMC435 sodium salts crystal formation B of the present invention FT-IR collection of illustrative plates.
Fig. 9 TMC435 sodium salts crystal formation C of the present invention XRPD collection of illustrative plates.
Figure 10 TMC435 sodium salts crystal formation C of the present invention DSC collection of illustrative plates.
Figure 11 TMC435 sodium salts crystal formation C of the present invention TGA collection of illustrative plates.
Figure 12 TMC435 sodium salts crystal formation C of the present invention FT-IR collection of illustrative plates.
Figure 13 TMC435 sodium salts crystal formation D of the present invention XRPD collection of illustrative plates.
Figure 14 TMC435 sodium salts crystal formation D of the present invention FT-IR collection of illustrative plates.
XRPD collection of illustrative plates of the Figure 15 with reference to the WO2008092954A2 TMC435 crystal formations I prepared.
XRPD collection of illustrative plates of the Figure 16 with reference to the WO2010097229A2 TMC435 sodium salt amorphous articles prepared.
FT-IR collection of illustrative plates of the Figure 17 with reference to the WO2010097229A2 TMC435 sodium salt amorphous articles prepared.
TMC435 sodium salts crystal formation A stability test result (sequentially consist of and place forward and backward sample) in Figure 18 comparative examples 1.
TMC435 sodium salts crystal formation B stability test result (sequentially consist of and place forward and backward sample) in Figure 19 comparative examples 1.
TMC435 sodium salt crystal formations C stability test result (sequentially consist of and place forward and backward sample) in Figure 20 contrasts 1.
The stability test result (sequentially consist of and place forward and backward sample) of TMC435 sodium salts amorphous article in Figure 21 comparative examples 1.
Embodiment
It will be helpful to further understand the present invention by following embodiments, but be not used in the limitation present invention.
Detecting instrument and method：
Instrument used in X-ray powder diffraction (XPRD) is Bruker D8 Advance diffractometer, copper target wavelength is used for 1.54nm Ka X-rays, under 40kV and 40mA operating condition, θ -2 θ angular instruments, Mo monochromators, Lynxeye detectors.Instrument is calibrated using preceding with diamond dust.Acquisition software is Diffrac Plus XRD Commander.Sample is tested at ambient temperature, and the sample for needing to detect is placed on areflexia plate.Detailed testing conditions are as follows, angular range：3-40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.
Differential thermal analysis data (DSC) are picked up from TA Instruments Q200 MDSC, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.Generally take 1-10mg sample to be positioned in aluminium dish, N is dried in 40mL/min with 10 DEG C/min programming rate2Protection under sample from 0 DEG C is risen to 300 DEG C.
Thermogravimetric analysis data (TGA) is picked up from TA Instruments Q500 TGA, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.Generally take 1-15mg samples to be positioned in platinum crucible, using segmentation high resolution detection mode, N is dried in 40mL/min with 10 DEG C/min programming rate2Protection under sample from room temperature is risen to 350 DEG C.
Hydrogen nuclear magnetic resonance modal data (1HNMR) pick up from Bruker Avance II DMX 400MHZ nuclear magnetic resonance chemical analysers.1-5mg samples are weighed, with 0.5mL deuterochloroforms (CDCl3) dissolving, it is made into 2mg/mL -10mg/mL solution.
FTIR spectrum analysis (FT-IR) data are picked up from Bruker Tensor 27, and instrument control software and DAS are all OPUS.ATR equipment is generally used, in 600-4000cm-1In the range of, infrared absorption spectroscopy is gathered, the sweep time of sample and blank background is 16 seconds, instrumental resolution 4cm-1。
Raman spectrum analysis (Raman) data are picked up from Buddhist nun's high-tensile strength DXR 780, and instrument control software and DAS are all onmic 8.2.Generally under 10 times of mirrors, in wave number 50-3400cm-1In the range of, exposure frequency 8 times, Raman spectrum collection is carried out to sample at 1 second time for exposure.
Various reagents used are commercially available unless otherwise instructed in embodiment.
Ultrasound procedure in embodiment can promote sample to dissolve, and equipment is to carry out 15 minutes under ultrasonic cleaner, 40kHz power.
Preparation example 1
The preparation method that TMC435 can refer to patent document WO2007014926A1 embodiments 5 is made.Specially：By 17- [2- (4- isopropyl thiazole -2- bases) -7- methoxyl group -8- methylquinoline -4- bases epoxide] -13- methyl -2,14- dioxos -3,13- diaza tricyclics [13.3.0.04,6] 18 carbon -7- alkene -4- carboxylic acids (2.80g, 4.335mmol) with solution of the carbonyldiimidazole (1.54g, 9.5mmol) in anhydrous tetrahydro furan (50mL) return stirring 2 hours in nitrogen.Reactant mixture is cooled to room temperature, cyclopropylsulfonamide (2.00g, 16.505mmol) and DBU (1.43g, 9.405mmol) is added.Solution is heated 15 hours at 50 DEG C, and reactant mixture then is cooled into room temperature, is concentrated under reduced pressure.Residue is distributed between dichloromethane and 1 equivalent (1N) hydrochloric acid, organic layer salt water washing, with anhydrous sodium sulfate drying, evaporation.With flash chromatography (gradient：Ethyl acetate (0-25%) in dichloromethane) purifying obtain 1.60g (40%) pale powder, further washed with water and isopropyl ether, be dried in vacuo obtain 1.48g white solids.M/z=750 (M+H)+
1H-NMR(CDCl3):0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J=13Hz, 1H), 5.04 (t, J=11Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, J=10Hz, 1H), 7.45 (s, 1H), 7.99 (d, J=10Hz, 1H), 10.82 (bs, 1H).
Preparation example 2
The preparation method that TMC435 crystal formations I can refer to patent document WO2008092954A2 embodiments 3 is made.Specially：Take TMC4352.1g to be flowed back in 5mL n-butanols, 45mL n-butanols are added in the suspension boiled to obtaining settled solution.Stirred at reflux condition solution 48 hours, naturally cools to room temperature.Filtering, filter cake is washed with n-butanol, and 40 DEG C are dried in vacuum overnight, and obtain TMC435.
Its XRPD collection of illustrative plates as shown in figure 15, is shown consistent with TMC435 crystal formations I disclosed in WO2008092954A2.
Preparation example 3
The preparation method that TMC435 sodium salt amorphous articles can refer to patent document WO2010097229A2 embodiments 1 is made.Specially：Sodium hydroxide solution (24.10g sodium hydroxides are dissolved in 60.03g purified waters) is added in the dichloromethane that 5950.30g is stirred vigorously.Under stirring condition, TMC435 (450.09g) is added, continues gradual change with stirring until obtaining settled solution.Under a nitrogen atmosphere, the settled solution of gained is spray-dried, collects the product of spray drying in 50 DEG C of vacuum drying, obtain TMC435 sodium salts.
Its XRPD collection of illustrative plates as shown in figure 16, shows without characteristic peak, is amorphous article.
As shown in figure 17, FT-IR analyses are TMC435 sodium salt amorphous articles to FT-IR collection of illustrative plates.
Embodiment 1
At room temperature, in addition TMC435 crystal formation I (173.01mg in 5mL vials, 0.231mmol) with 2.0mL ethanol, ultrasound obtains white suspension for 15 minutes (TMC435 crystal formations I consumption is its 10 times of solubility in ethanol at such a temperature in the suspension), add sodium hydroxide (19.22mg, 0.480mmol) and the suspension prepared of 0.2mL ethanol, stirring obtains white suspension after mixing (consumption of sodium hydroxide is its 10 times of solubility in ethanol at such a temperature in the suspension)；Stirring obtains settled solution for 2 hours at room temperature, continues to stir 5 days precipitation white solids；Filter and washed with ethanol 3 times, room temperature in vacuo is dried 16 hours, obtains TMC435 sodium salt crystal formations A.Yield is 170.14mg, and yield is 95.4%.
Its XRPD collection of illustrative plates is as shown in figure 1, be TMC435 sodium salt crystal formations A.
DSC collection of illustrative plates is as shown in Figure 2.
TGA collection of illustrative plates is as shown in Figure 3.
FT-IR collection of illustrative plates is as shown in figure 4, crystal formation A is 3423,3331,2961,2932,2866,1633,1611,1451,1232,1187,1119,870 and 780cm in wave number-1Place has characteristic peak.
Embodiment 2
At -10 DEG C, in addition TMC435 crystal formation I (69.12mg in 20mL vials, 0.092mmol) with 6.2mL normal propyl alcohols, ultrasound obtains white suspension for 15 minutes (TMC435 crystal formations I consumption is it at such a temperature 2 times of solubility in normal propyl alcohol in the suspension), add sodium hydroxide (4.42mg, 0.1105mmol), stirring obtains white after mixing Color contamination suspension；Stirring obtains settled solution for 4 hours at -10 DEG C, continues to stir 2 days precipitation white solids；Filter and washed with normal propyl alcohol 2 times, 50 DEG C are dried in vacuo 10 hours, obtain TMC435 sodium salt crystal formations A.Yield is 40.28mg, and yield is 56.6%.
Embodiment 3
At 50 DEG C, in addition TMC435 crystal formation I (120.01mg in 5mL vials, 0.160mmol) with 3.0mL sec-butyl alcohols, ultrasound obtains white suspension for 15 minutes (TMC435 crystal formations I consumption is it at such a temperature 5 times of solubility in sec-butyl alcohol in the suspension), add sodium hydroxide (6.40mg, 0.160mmol) and the suspension prepared of 0.2mL sec-butyl alcohols, stirring obtains white suspension after mixing (consumption of sodium hydroxide is it at such a temperature 5 times of solubility in sec-butyl alcohol in the suspension)；Stirring obtains settled solution for 1 hour at 50 DEG C, continues to stir 3 days precipitation white solids；Filter and washed with sec-butyl alcohol 3 times, 60 DEG C are dried in vacuo 48 hours, obtain TMC435 sodium salt crystal formations A.Yield is 100.17mg, and yield is 81.8%.
Embodiment 4
At 10 DEG C, in addition TMC435 crystal formation I (46.08mg in 5mL vials, 0.061mmol) with 3.8mL propyl alcohol, ultrasound obtains white suspension for 15 minutes (TMC435 crystal formations I consumption is it at such a temperature 2 times of solubility in normal propyl alcohol in the suspension), add sodium hydroxide (2.44mg, 0.061mmol), stirring obtains white suspension after mixing；Stirring obtains settled solution for 1 hour at 10 DEG C, continues to stir 5 days precipitation white solids；Filter and use propanol rinse 3 times, 60 DEG C are dried in vacuo 1 hour, obtain TMC435 sodium salt crystal formations A.Yield is 21.85mg, and yield is 46.0%.
Embodiment 5
At 40 DEG C, in addition TMC435 crystal formation I (60.00mg in 5mL vials, 0.080mmol) with 1.5mL butanol, ultrasound obtains white suspension for 15 minutes (TMC435 crystal formations I consumption is it at such a temperature 5 times of solubility in butanol in the suspension), add sodium hydroxide (3.84mg, 0.096mmol) and the suspension prepared of 0.12mL butanol, stirring obtains white suspension after mixing (consumption of sodium hydroxide is it at such a temperature 5 times of solubility in butanol in the suspension)；Stirring obtains settled solution for 5 hours at 40 DEG C, continues to stir 2 days precipitation white solids；Filter and washed with butanol 3 times, 60 DEG C are dried in vacuo 16 hours, obtain TMC435 sodium salt crystal formations A.Yield is 50.27mg, and yield is 82.1%.
Sample prepared by embodiment 2~5 has and the same or analogous XRPD collection of illustrative plates of the sample of embodiment 1, DSC collection of illustrative plates, TGA collection of illustrative plates, FT-IR collection of illustrative plates and Raman collection of illustrative plates (not shown).Illustrate that the sample of embodiment 2~5 and the sample of embodiment 1 are identical materials.
Embodiment 6
At room temperature, in addition TMC435 sodium salts amorphous article (50.47mg) and 2.0mL acetonitriles in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 10 times of solubility in acetonitrile in the suspension), it is stirred at room temperature one week, filter and washed with acetonitrile 2 times, 40 DEG C are dried in vacuo 16 hours, obtain TMC435 sodium salt crystal formations B.Yield is 45.75mg；Yield is 90.6%.
Its XRPD collection of illustrative plates is as shown in figure 5, be TMC435 sodium salt crystal formations B.
DSC collection of illustrative plates is as shown in Figure 6.
TGA collection of illustrative plates is as shown in Figure 7.
FT-IR collection of illustrative plates is as shown in figure 8, crystal formation B is 3453,3327,2960,2931,2863,1635,1611,1548,1408,1352,1235,1118,1022,869 and 780cm in wave number-1Place has characteristic peak.
Embodiment 7
At 40 DEG C, in addition TMC435 sodium salts amorphous article (11.15mg) and 2.0mL acetone in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is its 2 times of solubility in acetone at such a temperature in the suspension), 40 DEG C are stirred 9 days, filter and washed with acetone 2 times, room temperature in vacuo is dried 48 hours, obtains TMC435 sodium salt crystal formations B.Yield is 4.73mg；Yield is 42.4%.
Embodiment 8
At 10 DEG C, in the water saturation solution that TMC435 sodium salts amorphous article (30.47mg) and 3.0mL butanone are added in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 5 times of solubility in the water saturation solution of butanone in the suspension), stirred 2 weeks at 10 DEG C, filtering, and washed with the water saturation solution of butanone 3 times, 60 DEG C are dried in vacuo 1 hour, obtain TMC435 sodium salt crystal formations B.Yield is 27.89mg；Yield is 91.5%.
Sample prepared by embodiment 7,8 has and the same or analogous XRPD collection of illustrative plates of the sample of embodiment 6, DSC collection of illustrative plates, TGA collection of illustrative plates, FT-IR collection of illustrative plates and Raman collection of illustrative plates (not shown).Illustrate that embodiment 7,8 samples and the sample of embodiment 6 are identical materials.
Embodiment 9
At room temperature, in addition TMC435 sodium salts amorphous article (71.85mg) and 1.5mL ethyl acetate in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 10 times of solubility in ethyl acetate in the suspension), it is stirred at room temperature one week, filter and washed with ethyl acetate 3 times, 40 DEG C are dried in vacuo 16 hours, obtain TMC435 sodium salt crystal formations C.Yield is 62.57mg；Yield is 87.1%.
XRPD collection of illustrative plates is as shown in figure 9, be TMC435 sodium salt crystal formations C.
DSC collection of illustrative plates is as shown in Figure 10.
TGA collection of illustrative plates is as shown in figure 11.
As shown in figure 12, crystal formation C is 3500,3323,2957,2932,2865,1632,1610,1552,1350,1234,1186,1119,1017,870 and 780cm in wave number to FT-IR collection of illustrative plates-1Place has characteristic peak；
Embodiment 10
At 40 DEG C, in addition TMC435 sodium salts amorphous article (11.93mg) and 1.0mL isopropyl acetates in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 2 times of solubility in isopropyl acetate in the suspension), 40 DEG C are stirred 9 days, filter and washed with isopropyl acetate 3 times, room temperature in vacuo is dried 48 hours, obtains TMC435 sodium salt crystal formations C.Yield is 5.47mg, and yield is 45.9%.
Embodiment 11
At 10 DEG C, in addition TMC435 sodium salts amorphous article (10.55mg) and 1.0mL chloroforms in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 5 times of solubility in chloroform in the suspension), stirred 2 weeks at 10 DEG C, filter and use chloroform 3 times, 60 DEG C are dried in vacuo 1 hour, obtain TMC435 sodium salt crystal formations C.Yield is 7.20mg, and yield is 68.2%.
Sample prepared by embodiment 10,11 has and the same or analogous XRPD collection of illustrative plates of the sample of embodiment 9, DSC collection of illustrative plates, TGA collection of illustrative plates, FT-IR collection of illustrative plates and Raman collection of illustrative plates (not shown).Illustrate that embodiment 10,11 samples and the sample of embodiment 9 are identical materials.
Embodiment 12
At room temperature, in addition TMC435 sodium salts amorphous article (20.55mg) and 0.5mL butanone in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 5 times of solubility in butanone in the suspension), it is stirred at room temperature 1 week, filter and washed with butanone 2 times, 40 DEG C are dried in vacuo 16 hours, obtain TMC435 sodium salt crystal formations D.Yield is 8.12mg, and yield is 39.5%.
Its XRPD collection of illustrative plates is TMC435 sodium salt crystal formations D as shown in figure 13.
As shown in figure 14, crystal formation D is 3474,2955,2930,2868,1658,1609,1510,1452,1351,1232,1186,1120,1105 and 844cm in wave number to FT-IR collection of illustrative plates-1Place has characteristic peak；
Embodiment 13
At 40 DEG C, in addition TMC435 sodium salts amorphous article (50.93mg) and 0.4mL butanone in 5mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 10 times of solubility in butanone in the suspension), 40 DEG C are stirred 9 days, filter and washed with butanone 3 times, room temperature in vacuo is dried 48 hours, obtains TMC435 sodium salt crystal formations D.Yield is 10.11mg, and yield is 19.8%.
Embodiment 14
At 10 DEG C, in addition TMC435 sodium salts amorphous article (18.17mg) and 10mL butanone in 20mL vials, ultrasound obtains white suspension for 15 minutes (consumption of TMC435 sodium salts amorphous article is it at such a temperature 2 times of solubility in butanone in the suspension), stirred 2 weeks at 10 DEG C, filter and washed with butanone 3 times, 60 DEG C are dried in vacuo 1 hour, obtain TMC435 sodium salt crystal formations D.Yield is 5.45mg, and yield is 30.0%.
Sample prepared by embodiment 13,14 has and the same or analogous XRPD collection of illustrative plates of the sample of embodiment 12, FT-IR collection of illustrative plates and Raman collection of illustrative plates (not shown).Illustrate that embodiment 13,14 samples and the sample of embodiment 12 are identical materials.
Embodiment 15
Prepare the capsule containing TMC435 sodium salts crystal formation A of the present invention.Single dose unit formulation is as follows.
Preparation method：Mixed TMC435 sodium salt crystal formation A, 1.2g NaLS of the 72.0g present invention, 1.2g colloidal silica anhydrous and the sieving of 159.0g lactose monohydrates 10 minute and by three-dimensional mixer.The 1.2g magnesium stearates sieved are added in the mixture and mixed 5 minutes.Gained mixture is filled into hard gelatine capsule, 700 capsules containing TMC435 sodium salts crystal formation A of the present invention are prepared.
Embodiment 16
Prepare the capsule containing TMC435 sodium salts crystal formation A of the present invention.Single dose unit formulation is as follows.
Preparation method：Mixed TMC435 sodium salt crystal formation A, 1.8g NaLS of the 108.0g present invention, 1.8g colloidal silica anhydrous and the sieving of 238.5g lactose monohydrates 10 minute and by three-dimensional mixer.The 1.8g magnesium stearates sieved are added in the mixture and mixed 5 minutes.Gained mixture is filled into hard gelatine capsule, 700 capsules containing TMC435 sodium salts crystal formation A of the present invention are prepared.
Embodiment 17
Prepare the capsule containing TMC435 sodium salts crystal formation B of the present invention.
By in embodiment 15 and embodiment 16 " TMC435 sodium salt crystal formations A " replaces that " TMC435 sodium salt crystal formation B ", other operation be the same as Examples 15 and embodiment 16, prepare the capsule containing TMC435 sodium salts crystal formation B of the present invention.
Embodiment 18
Prepare the capsule containing TMC435 sodium salts crystal formation C of the present invention.
By in embodiment 15 and embodiment 16 " TMC435 sodium salt crystal formations A " replaces that " TMC435 sodium salt crystal formation C ", other operation be the same as Examples 15 and embodiment 16, prepare the capsule containing TMC435 sodium salts crystal formation C of the present invention.
Embodiment 19
Prepare the capsule containing TMC435 sodium salts crystal formation D of the present invention.
By in embodiment 15 and embodiment 16 " TMC435 sodium salt crystal formations A " replaces that " TMC435 sodium salt crystal formation D ", other operation be the same as Examples 15 and embodiment 16, prepare the capsule containing TMC435 sodium salts crystal formation D of the present invention.
Comparative example 1
Crystal formation A, crystal formation B and the crystal formation C of the TMC435 sodium salts of the present invention, and known TMC435 sodium salts amorphous article prepared by preparation example 3 are taken, stability of crystal form contrast test is carried out.
Concrete operations are as follows：20mg samples are respectively taken to be placed in 20ml vials, opening is positioned over 40 DEG C, and lower 10 days of 75%RH environment carries out XRPD signs before and after placing.Crystal formation A, the crystal formation B of TMC435 sodium salts of the present invention are shown in Figure 18 to Figure 21 respectively to crystal formation C and known TMC435 sodium salts amorphous article related collection of illustrative plates.
Figure 18 to Figure 21 stability of crystal form comparative test result is shown：Known TMC435 sodium salts amorphous article is after placing 10 days, it is impossible to keep its original form；And crystal formation keeps constant to the crystal formation A or crystal formation B or crystal formation C of the TMC435 sodium salts of the present invention after placement, with certain stability.
Comparative example 2
Crystal formation A, crystal formation B and the crystal formation C of the TMC435 sodium salts of the present invention, and known TMC435 sodium salts amorphous article prepared by preparation example 3 are taken, chemical stability contrast test is carried out.
Concrete operations are as follows：20mg samples are respectively taken to be placed in 20ml vials, opening is positioned over 25 DEG C of driers or 60 DEG C of convection ovens or 40 DEG C/75%RH environment or 40 DEG C/carbamide peroxide environment or lower 10 days of 25 DEG C/illumination (4500 ± 500Lux) environment respectively, and HPLC purity signs are carried out before and after placing.
As a result show：The crystal formation A or crystal formation B or crystal formation C of TMC435 sodium salts of the present invention were placed after 10 days under these conditions, and its HPLC purity is held essentially constant or is slightly decreased；And known TMC435 sodium salts amorphous article was placed after 10 days under these conditions, its HPLC chemical purity has under decline, particularly 40 DEG C/carbamide peroxide environment, placed 10 days under 25 DEG C/illumination (4500 ± 500Lux) environment after HPLC purity be decreased obviously；Illustrating the crystal formation A or crystal formation B or the more known TMC435 sodium salts amorphous articles of crystal formation C of TMC435 sodium salts of the present invention has more preferable chemical stability.
Cited all patent documents and non-patent publications, are incorporated by herein by quoting with it in this specification.
It is described above; only embodiment of the invention; but protection scope of the present invention is not limited thereto; any those skilled in the art disclosed herein technical scope in; the change or replacement that can be expected without creative work, should all be included within the scope of the present invention.

Claims (15)

  1. Structural formula TMC435 as follows sodium salt crystal formation A,
    Characterized in that, the X-ray powder diffraction figure that the crystal formation A is represented with 2 θ angles has following characteristics peak：4.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 11.0 ± 0.2 °, 12.3 ± 0.2 ° and 18.1 ± 0.2 °.
  2. TMC435 sodium salts crystal formation A according to claim 1, it is characterised in that the X-ray powder diffraction figure that the crystal formation A is represented with 2 θ angles has following characteristics peak：4.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 11.0 ± 0.2 °, 12.3 ± 0.2 °, 15.1 ± 0.2 °, 16.6 ± 0.2 °, 18.1 ± 0.2 ° and 22.6 ± 0.2 °.
  3. TMC435 sodium salts crystal formation A according to claim 2, it is characterised in that the X-ray powder diffraction figure that the crystal formation A is represented with 2 θ angles has following characteristics peak and its relative intensity：
  4. The preparation method of TMC435 sodium salt crystal formations A any one of claim 1-3, comprises the following steps：Suspensions of the TMC435 crystal formations I in alcohol is formed, sodium hydroxide is added and stirs, kept for 2-5 days under -10 DEG C -50 DEG C of recrystallization temperature, obtain the TMC435 sodium salts crystal formation A；
    Preferably, the alcohol is C2-C4Alcohol, more preferably ethanol；
    Preferably, the mole dosage ratio of the TMC435 crystal formations I and sodium hydroxide are 1:1-1:2, more preferably 1:1-1:1.2；
    Preferably, TMC435 crystal formations I consumption is 2-10 times, more preferably 2-5 times of its solubility under recrystallization temperature in alcohol in the suspension；
    Preferably, suspension of the sodium hydroxide formation in the alcohol is added, and wherein the consumption of sodium hydroxide is it 2-10 times, more preferably 2-5 times of solubility under recrystallization temperature in the alcohol；
    Preferably, the recrystallization temperature is 10-40 DEG C, more preferably room temperature.
  5. Structural formula TMC435 as follows sodium salt crystal formation B,
    Characterized in that, the X-ray powder diffraction figure that the crystal formation B is represented with 2 θ angles has following characteristics peak：5.0 ± 0.2 °, 6.0 ± 0.2 °, 6.5 ± 0.2 °, 13.0 ± 0.2 °, 18.5 ± 0.2 ° and 23.2 ± 0.2 °.
  6. TMC435 sodium salts crystal formation B according to claim 5, it is characterised in that the X-ray powder diffraction figure that the crystal formation B is represented with 2 θ angles has following characteristics peak：3.6 ± 0.2 °, 4.2 ± 0.2 °, 5.0 ± 0.2 °, 6.0 ± 0.2 °, 6.5 ± 0.2 °, 10.6 ± 0.2 °, 13.0 ± 0.2 °, 14.6 ± 0.2 °, 17.7 ± 0.2 °, 18.5 ± 0.2 °, 22.6 ± 0.2 ° and 23.2 ± 0.2 °.
  7. TMC435 sodium salts crystal formation B according to claim 6, it is characterised in that the X-ray powder diffraction figure that the crystal formation B is represented with 2 θ angles has following characteristics peak and its relative intensity：
  8. The preparation method of TMC435 sodium salt crystal formations B any one of claim 5-7, comprises the following steps：TMC435 sodium salt amorphous articles are formed into suspension in a solvent, the solvent is selected from acetonitrile, acetone, the water saturation solution of butanone or its mixture, stirring and crystallizing, obtains the TMC435 sodium salts crystal formation B；
    Preferably, the temperature of the crystallization is 10-40 DEG C, more preferably room temperature；
    Preferably, the time of the crystallization is 1-2 weeks, more preferably 7-9 days；
    Preferably, in the suspension TMC435 sodium salt amorphous articles consumption for its under recrystallization temperature described molten 2-10 times, more preferably 2-5 times of solubility in agent.
  9. Structural formula TMC435 as follows sodium salt crystal formation C,
    Characterized in that, the X-ray powder diffraction figure that the crystal formation C is represented with 2 θ angles has following characteristics peak：3.4 ± 0.2 °, 5.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 12.4 ± 0.2 ° and 18.4 ± 0.2 °.
  10. TMC435 sodium salts crystal formation C according to claim 9, it is characterised in that the X-ray powder diffraction figure that the crystal formation C is represented with 2 θ angles has following characteristics peak：3.4 ± 0.2 °, 4.2 ± 0.2 °, 5.3 ± 0.2 °, 6.3 ± 0.2 °, 8.6 ± 0.2 °, 9.1 ± 0.2 °, 12.4 ± 0.2 °, 15.2 ± 0.2 °, 18.4 ± 0.2 °, 22.4 ± 0.2 °, 22.7 ± 0.2 ° and 23.6 ± 0.2 °.
  11. TMC435 sodium salts crystal formation C according to claim 10, it is characterised in that the X-ray powder diffraction figure that the crystal formation C is represented with 2 θ angles has following characteristics peak and its relative intensity：
  12. The preparation method of TMC435 sodium salt crystal formations C any one of claim 9-11, comprises the following steps：TMC435 sodium salt amorphous articles are formed into suspension in a solvent, the solvent is selected from ethyl acetate, isopropyl acetate, chloroform or its mixture, stirring and crystallizing, obtains the TMC435 sodium salts crystal formation C；
    Preferably, the temperature of the crystallization is 10-40 DEG C, more preferably room temperature；
    Preferably, the time of the crystallization is 1-2 weeks, more preferably 7-9 days；
    Preferably, the consumption of TMC435 sodium salt amorphous articles is 2-10 times, more preferably 2-5 times of its solubility under recrystallization temperature in the solvent in the suspension.
  13. A kind of pharmaceutical composition, its one or more TMC435 sodium salt crystal formations A being selected from any one of claim 1-3 comprising treatment and/or prevention effective dose, TMC435 sodium salt crystal formations B any one of claim 5-7, TMC435 sodium salt crystal formations C any one of claim 9-11, the TMC435 sodium salt crystal formations A that according to claim 4, preparation method is obtained, the TMC435 sodium salt crystal formations C that the TMC435 sodium salt crystal formation B or the preparation method according to claim 12 that according to claim 8, preparation method is obtained are obtained, and at least one pharmaceutically acceptable carrier.
  14. TMC435 sodium salt crystal formations A any one of claim 1-3, TMC435 sodium salt crystal formations B any one of claim 5-7, TMC435 sodium salt crystal formations C any one of claim 9-11, the TMC435 sodium salt crystal formations A that according to claim 4, preparation method is obtained, purposes of the TMC435 sodium salt crystal formation C that the TMC435 sodium salt crystal formation B or the preparation method according to claim 12 that according to claim 8, preparation method is obtained are obtained in the medicine for the treatment of and/or prevention of hepatitis C infection or the liver diseases related to infection with hepatitis C virus is prepared.
  15. A kind for the treatment of and/or the method for prevention of hepatitis C infection or the liver diseases related to infection with hepatitis C virus, methods described includes giving one or more TMC435 sodium salt crystal formations A being selected from any one of claim 1-3 of patient's treatment of needs and/or prevention effective dose, TMC435 sodium salt crystal formations B any one of claim 5-7, TMC435 sodium salt crystal formations C any one of claim 9-11, the TMC435 sodium salt crystal formations A that according to claim 4, preparation method is obtained, the TMC435 sodium salt crystal formations B that according to claim 8, preparation method is obtained, the pharmaceutical composition described in TMC435 sodium salt crystal formation C or claim 13 that the preparation method according to claim 12 is obtained.
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