CN104995189B - Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes - Google Patents
Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes Download PDFInfo
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- CN104995189B CN104995189B CN201480007231.3A CN201480007231A CN104995189B CN 104995189 B CN104995189 B CN 104995189B CN 201480007231 A CN201480007231 A CN 201480007231A CN 104995189 B CN104995189 B CN 104995189B
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- C07—ORGANIC CHEMISTRY
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
The present invention relates 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, ten tetrahydrochysene 2 [[7 methoxyl group, 8 methyl 2 [4 (1 Methylethyl) 2 thiazolyls] 4 quinolyls] epoxide] 5 methyl 4 of 14a, 14 dioxo cyclopentano [c] rings third simultaneously [g] [1, 6] crystal formation of diazacyclo tetradecene 12a (1H) Methanamide (TMC435) sodium salt, the crystal formation is compared with known crystal formation with good degree of crystallinity and stability.The invention further relates to the preparation method of the crystal formation, its pharmaceutical composition and its for prepare treatment and/or prevention of hepatitis C infection or the hepatic disease related to infection with hepatitis C virus medicine in purposes.
Description
Technical field
The application belongs to pharmaceutical chemistry crystallization technique field.In particular to hepatitis C medicine (2R, 3aR, 10Z,
11aS, 12aR, 14aR)-N- (Cyclopropylsulfonyl) -2,3,3a, 4,5,6,7,8,9,11a, 12,13,14,14a- ten tetrahydrochysenes -
2- [[7- methoxyl group -8- methyl -2- [4- (1- Methylethyls) -2- thiazolyls] -4- quinolyls] epoxide] -5- methyl -4,14- bis-
The crystal formation of simultaneously [g] [1,6] diazacyclo tetradecene -12a (1H)-Methanamide (TMC435) sodium salt of oxo cyclopentano [c] ring third, also
It is related to preparation method, its pharmaceutical composition and the purposes of the crystal formation.
Background technology
TMC435 is hepatitis C viruss of new generation (HCV) NS3/4A protease inhibitor, by Medivir companies and Yang Sen
(Janssen) company's exploitation.TMC435 and glycol interferon and ribavirin (ribavirin) drug combination, are used for
Treatment chronic hepatitis C adult patients, and can be with compensatory hepatopathy (including the hepatic fibrosis in each stage).Its effect is former
Reason is, by the NS3/4A protease for suppressing HCV, to suppress duplications of the HCV in liver cell.In September, 2013, TMC435 (
The trade name Sovriad of Japan) Japanese work hygiene Department of Welfare (MHLW) approval is obtained, for -1 chronic hepatitis C of genotype
The treatment of viral the infected, this is the global first supervision approval that TMC435 is obtained.In November, 2013 obtains FDA approvals, trade name
For OLYSIO.OLYSIO is oral capsule (active component containing 150mg) once a day, and administering mode is：OLYSIO joints are poly-
PEGylation interferon and ribavirin combination therapy 12 weeks, subsequently carry out Peg-IFN alpha-2b and combining for ribavirin are controlled
Treat 12 weeks or 36 weeks.
The chemical name of TMC435 is：(2R, 3aR, 10Z, 11aS, 12aR, 14aR)-N- (Cyclopropylsulfonyl) -2,3,
3a, 4,5,6,7,8,9,11a, 12,13,14,14a- ten tetrahydrochysene -2- [[7- methoxyl group -8- methyl -2- [4- (1- Methylethyls) -
2- thiazolyls] -4- quinolyls] epoxide] -5- methyl -4, simultaneously [g] [1, the 6] diazacyclo ten of 14- dioxo cyclopentano [c] rings third
Tetraene -12a (1H)-Methanamide, English entitled Simeprevir, molecular formula is C38H47N5O7S2, molecular weight is 749.94, chemistry
Structural formula is as follows：
Patent documentation WO2007014926A1 discloses TMC435 compounds and preparation method thereof.
Patent documentation WO2008092954A2 discloses six kinds of crystal formations (crystal formation I, crystal formation II, crystal formation III, the crystalline substance of TMC435
Type IV, crystal formation V and crystal formation VI) and preparation method thereof, its dissolubility, XRPD, FT-IR and DSC data are disclosed, and addresses crystal formation
I is anhydride and most stable crystal form.
Patent documentation WO2010097229A2 discloses TMC435 sodium salt amorphous articles and preparation method thereof, and provides which
XRPD, FTIR, TGA, DSC, MDSC, DVS and stability data.Additionally, the patent documentation also discloses TMC435 sodium salts without fixed
The formulation protocol of type thing.
The present inventor's research finds that known TMC435 and its six kinds of crystal formations have following defect：Poor solubility, under room temperature
Dissolubility in water is 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 40
DEG C/75%RH under the conditions of place 10 days, it is impossible to maintain its original form.
In view of the novel crystal forms that prior art remains deficiency, TMC435 of the exploitation with more advantage performances and its salt have ten
Divide important realistic meaning.
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 degree of crystallinity and stability, and provide
Its preparation method, its pharmaceutical composition and purposes.
Purpose of the invention, the present invention provide the crystal formation A (hereinafter referred to as " crystal formation A ") of TMC435 sodium salts and its prepare
Method.
Radiated using Cu-K α, the crystal formation A has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：
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 crystal formation A has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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 crystal formation A has following characteristics peak and its phase with the X-ray powder diffraction figure that 2 θ angles are represented
To 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 wave number be 3423,3331,2961,2932,2866,1633,1611,1451,
1232nd, 1187,1119,870 and 780cm-1Place is with characteristic peak；
Differential scanning amount thermal map (DSC) of the crystal formation A is as shown in Figure 2；
Thermogravimetric analysiss (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 has preferable degree of crystallinity；
(2) crystal formation A has more preferable stability of crystal form and chemical stability.
The above-mentioned property of crystal formation A shows：Compared with known TMC435 sodium salts amorphous article, the TMC435 sodium salts of the present invention
Crystal formation A has higher melt, stability of crystal form and chemical stability good, can preferably resist medicine manufacture and/or storage etc.
During the problems such as content by caused by the factors such as time, temperature, humidity is uneven and purity is reduced, be more beneficial for the system of unit
Accurate quantitative analysis and the transport and storage in later stage in agent preparation, and reduction is unstable by activity substance content and impurity content increases
The risk that the curative effect brought declines, is more suitable for solid preparation application.
The preparation method of TMC435 sodium salt crystal formation A, comprises the following steps：Suspensions of the TMC435 crystal formation I in alcohol is formed,
Add sodium hydroxide and stir, 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, propanol, 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 is 1: 1-1: 2, more preferably 1: 1-1:
1.2。
Preferably, in the suspension, the consumption of TMC435 crystal formation I is the 2- of its dissolubility in alcohol under recrystallization temperature
10 times, more preferably 2-5 times.
The sodium hydroxide can be that the suspension that solid is added or which is formed in the alcohol is added；When which forms suspension
When, the consumption of sodium hydroxide be its under recrystallization temperature 2-10 times, preferably 2-5 times of dissolubility in the alcohol.
Preferably, the recrystallization temperature is 10 DEG C -40 DEG C, more preferably room temperature.
Purpose of the invention, the present invention also provide the crystal formation B (hereinafter referred to as " crystal formation B ") and its system of TMC435 sodium salts
Preparation Method.
Radiated using Cu-K α, the crystal formation B has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：
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 crystal formation B has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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 crystal formation B has following characteristics peak and its phase with the X-ray powder diffraction figure that 2 θ angles are represented
To 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 wave number be 3453,3327,2960,2931,2863,1635,1611,1548,
1408th, 1352,1235,1118,1022,869 and 780cm-1Place is with characteristic peak；
Differential scanning amount thermal map (DSC) of the crystal formation B is as shown in Figure 6；
Thermogravimetric analysiss (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 has preferable degree of crystallinity；
(2) crystal formation B has more preferable stability of crystal form and chemical stability.
The above-mentioned property of crystal formation B shows：Compared with known TMC435 sodium salts amorphous article, the TMC435 sodium salts of the present invention are brilliant
Type B has higher melt, stability of crystal form and chemical stability good, can preferably resist medicine manufacture and/or storage was waited
The problems such as content inequality and purity in journey by caused by the factors such as time, temperature, humidity is reduced, is more beneficial for unit formulation
The transport and storage of accurate quantitative analysis and later stage in preparation, and reduction is unstable by activity substance content and impurity content increases institute
The risk that the curative effect brought declines, is more suitable for solid preparation application.
The preparation method of TMC435 sodium salt crystal formation B, comprises the following steps：By TMC435 sodium salts amorphous article shape in a solvent
Into suspension, the solvent obtains described selected from acetonitrile, acetone, the water saturation solution of butanone or its mixture, stirring and crystallizing
TMC435 sodium salt crystal formation B.
Preferably, the temperature of the crystallize is 10-40 DEG C, more preferably room temperature.
Preferably, the time of the crystallize is that 1-2 is all, more preferably 7-9 days.
Preferably, in the suspension TMC435 sodium salt amorphous articles consumption for its under recrystallization temperature in the solvent
In 2-10 times, more preferably 2-5 times of dissolubility.
The preparation method of the water saturation solution of the butanone is：After taking isopyknic butanone and water mixing, 10 are stirred vigorously
Minute, stratification takes the water saturation solution that organic layer is butanone.
Purpose of the invention, the present invention also provide the crystal formation C (hereinafter referred to as " crystal formation C ") and its system of TMC435 sodium salts
Preparation Method.
Radiated using Cu-K α, the crystal formation C has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：
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 crystal formation C has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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 crystal formation C has following characteristics peak and its phase with the X-ray powder diffraction figure that 2 θ angles are represented
To 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 wave number be 3500,3323,2957,2932,2865,1632,1610,1552,
1350th, 1234,1186,1119,1017,870 and 780cm-1Place is with characteristic peak；
Differential scanning amount thermal map (DSC) of the crystal formation C is as shown in Figure 10；
Thermogravimetric analysiss (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 has preferable degree of crystallinity；
(2) crystal formation C has more preferable stability of crystal form and chemical stability.
The above-mentioned property of crystal formation C shows：Compared with known TMC435 sodium salts amorphous article, the TMC435 sodium salts of the present invention
Crystal formation C has higher melt, stability of crystal form and chemical stability good, can preferably resist medicine manufacture and/or storage etc.
During the problems such as content by caused by the factors such as time, temperature, humidity is uneven and purity is reduced, be more beneficial for the system of unit
Accurate quantitative analysis and the transport and storage in later stage in agent preparation, and reduction is unstable by activity substance content and impurity content increases
The risk that the curative effect brought declines, is more suitable for solid preparation application.
The preparation method of TMC435 sodium salt crystal formation C, comprises the following steps：By TMC435 sodium salts amorphous article shape in a solvent
Into suspension, the solvent obtains described selected from ethyl acetate, isopropyl acetate, chloroform or its mixture, stirring and crystallizing
TMC435 sodium salt crystal formation C.
Preferably, the temperature of the crystallize is 10-40 DEG C, more preferably room temperature.
Preferably, the time of the crystallize is that 1-2 is all, more preferably 7-9 days.
Preferably, in the suspension TMC435 sodium salt amorphous articles consumption for its under recrystallization temperature in the solvent
In 2-10 times, more preferably 2-5 times of dissolubility.
Purpose of the invention, the present invention also provide the crystal formation D (hereinafter referred to as " crystal formation D ") and its system of TMC435 sodium salts
Preparation Method.
Radiated using Cu-K α, the crystal formation D has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：
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 crystal formation D has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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 crystal formation D has following characteristics peak and its phase with the X-ray powder diffraction figure that 2 θ angles are represented
To 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 wave number be 3474,2955,2930,2868,1658,1609,1510,1452,
1351st, 1232,1186,1120,1105 and 844cm-1Place is with characteristic peak；
Compared with known TMC435 sodium salts amorphous article, crystal formation D is crystalline state and has preferable degree of crystallinity.
The preparation method of TMC435 sodium salt crystal formation D, comprises the following steps：Formation TMC435 sodium salt amorphous articles are in butanone
Suspension, stirring and crystallizing obtains the TMC435 sodium salts crystal formation D.
Preferably, the temperature of the crystallize is 10-40 DEG C, more preferably room temperature.
Preferably, the time of the crystallize is that 1-2 is all, more preferably 7-9 days.
Preferably, in the suspension, the consumption of TMC435 sodium salt amorphous articles is molten in butanone under recrystallization temperature for which
2-10 times of Xie Du, preferably 2-5 times.
In the crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, the above-mentioned preparation method of crystal formation C and crystal formation D, the stirring can
Carried out with the conventional method using this area, for example magnetic agitation, mechanical agitation etc..Stir speed (S.S.) is 50～1800 revs/min, excellent
Select 300～900 revs/min.
In the crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, the above-mentioned preparation method of crystal formation C and crystal formation D, using this area
The crystal of precipitation is separated, washed and is dried by conventional method.The separation, using the conventional method such as mistake of this area
Filter, centrifugation etc.；The concrete operations of filtration are：It is intended to detached sample to be placed on filter paper, reduce pressure sucking filtration；The concrete operations of centrifugation
For：It is intended to detached sample to be placed in centrifuge tube, rotation is all sink to centrifugation bottom of the tube, centrifugation rate up to solid at a high speed afterwards
For example, 6000 revs/min.The solvent of the washing is preferably identical with solvent used in the crystal formation preparation method, cleaning solvent
2-10 times for recrystallisation solvent of consumption.The drying, is for example spontaneously dried using this area conventional method, forced air drying or decompression
It is dried；Drying equipment is fume hood, convection oven or vacuum drying oven；Being dried is carried out in decompression or under not reducing pressure, preferably pressure
Less than 0.09Mpa；Baking 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 " is referred to be characterized by shown X-ray diffractogram and is confirmed
's.It will be appreciated by those skilled in the art that experimental error therein depends on the pure of condition, the preparation of sample and the sample of instrument
Degree.Particularly, as well known to those skilled in the art, X-ray diffractogram would generally be changed with the condition of instrument.Especially need
It is noted that the relative intensity of X-ray diffractogram is likely to change with the change of experiment condition, so peak intensity is suitable
Sequence cannot function as unique or deciding factor.In addition, the experimental error of peak angle degree is generally 5% or less, the mistake of these angles
Difference should also be considered into, allow generally for ± 0.2 ° of error.Further, since the impact of the empirical factor such as height of specimen,
The overall offset of peak angle degree can be caused, certain skew is allowed generally for.Thus, it will be appreciated by persons skilled in the art that appointing
What is with belonging in scope with the same or analogous crystal formation in TuPu method peak of the present invention." single crystal form " is referred to
The detection of Jing X-ray powder diffractions is single crystal form.
The crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, crystal formation C and crystal formation D are pure, single, are not mixed substantially
Any other crystal formation or amorphous article.In the present invention, " not having substantially " is contained in referring to this novel crystal forms when novel crystal forms are used to refer to
Other crystal formations or amorphous article be less than 20% (weight), more refer to less than 10% (weight), especially less than 5% (weight), it is special
Do not refer to less than 1% (weight).
The present invention initiation material TMC435 be referred to patent documentation WO2007014926A1 preparation method be obtained or
It is commercially available, TMC435 crystal formation I be referred to patent documentation WO2008092954A2 preparation method be obtained, TMC435 sodium salts without
Sizing thing is referred to the preparation method of patent documentation WO2010097229A2 and is obtained.
Further, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition is comprising treatment and/or prevents effective
The novel crystal forms or the TMC435 sodium salts prepared by the inventive method of the TMC435 sodium salts of the present invention of one or more of amount
Novel crystal forms, and at least one pharmaceutically acceptable carrier.Wherein, the novel crystal forms of the TMC435 sodium salts include TMC435
The crystal formation A of sodium salt, crystal formation B, crystal formation C or crystal formation D.Additionally, described pharmaceutical composition can also include other of TMC435 sodium salts
The pharmaceutically useful crystal formation or amorphous article of pharmaceutically useful crystal formation or amorphous article or TMC435 and TMC435 other salt.Optionally
Ground, described pharmaceutical composition can also be comprising one or more other active constituents of medicine, such as other antiviral chemical combination
Thing, especially HCV-Ab IgG compound.
Aforementioned pharmaceutical compositions can be made into certain dosage form, and preferred oral administration, parenteral (include subcutaneous, flesh
In meat and intravenouss), rectally, transdermal administration, buccal administration, the dosage form of the form such as nose administration, it is including but not limited to solid
Body dosage form, liquid dosage form, semiliquid dosage form, aerosol or suppository etc..For example, being adapted to peroral administration dosage form includes tablet, glue
Wafer, granule, powder, pill, powder, lozenge, syrup or suspensoid；The dosage form of suitable parenteral include aqueouss or
Nonaqueous solution or emulsion；The dosage form of suitable rectally includes the suppository using hydrophilic or hydrophobic carrier；It is adapted to saturating
The dosage form of skin administration includes unguentum, cream；The dosage form of suitable nose administration includes aerosol, spray.As needed, above-mentioned dosage form
May be adapted to quick release, sustained release or the regulation release of active component.
Pharmaceutically acceptable carrier of the present invention includes solid-state carrier, is specifically including but not limited to：Diluent, for example
Starch, pregelatinized Starch, Lactose, Powderd cellulose, Microcrystalline Cellulose, calcium hydrogen phosphate, tricalcium phosphate, Mannitol, Sorbitol, sugar
Deng；Binding agent, such as arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl fiber
Element, Polyethylene Glycol etc.；Disintegrating agent, such as starch, sodium starch glycollate, pregelatinized Starch, polyvinylpolypyrrolidone, cross-linked carboxymethyl
Sodium cellulosate, silica sol etc.；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate
Deng；Fluidizer, such as silica sol etc.；Complex forming agents, such as cyclodextrin and resin of various ranks；Rate of release
Controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methylcellulose,
Methyl methacrylate, wax etc..Pharmaceutically acceptable carrier of the present invention also includes liquid carrier, specifically includes but does not limit
In：The solvent of aqueouss, oiliness or alcohol solution for example sterilized water, normal saline solution, glucose solution, mannitol solution,
Vegetable oil, cod-liver oil, ethanol, propanol, glycerol etc..Further, it is also possible to use the carriers such as Polyethylene Glycol, polypropylene glycol.According to agent
The difference of type is also may be selected using other pharmaceutically acceptable carriers, such as including but not limited to film former, plasticizer, coloring
Agent, flavoring agent, viscosity modifier, preservative, antioxidant, penetrating agent, buffer agent etc..Each carrier must be acceptable
, can be compatible with the other compositions in formula and harmless for sufferer.
Described pharmaceutical composition can be using well known to a person skilled in the art method be preparing.Prepare pharmaceutical composition
When, the crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, crystal formation C, crystal formation D or its combination are pharmaceutically acceptable with one or more
Carrier mix, optionally, mix with one or more other active constituents of medicine.Solid preparation can be by mixed
Close, the technique such as granulation preparing, liquid or semiliquid dosage form can be prepared by techniques such as mixing, dissolving, dispersion, emulsifyings.
Further, the present invention provides the novel crystal forms of TMC435 sodium salts of the present invention or is obtained by preparation method of the present invention
The novel crystal forms of TMC435 sodium salts are being prepared for treatment and/or prevention of hepatitis C (HCV) infection or and hepatitis C virus
Purposes in the medicine of the related hepatic disease of malicious (HCV) infection, wherein the novel crystal forms of the TMC435 sodium salts include TMC435
The crystal formation A of sodium salt, crystal formation B, crystal formation C, crystal formation D or its combination；The hepatic disease related to HCV infection includes being drawn by HCV
The disease for rising, including gradual hepatic fibrosis, the inflammation for causing liver cirrhosis or necrosis, end-stage liver disease and hepatocarcinoma tumor (HCC).
Further, the present invention provides a kind for the treatment of and/or prevention of hepatitis C (HCV) infection or and hepatitis C
The method of the related hepatic disease of viral (HCV) infection, methods described include the patient's treatment for giving needs and/or prevent effective
The novel crystal forms of the TMC435 sodium salts of the present invention of amount or its combination or its pharmaceutical composition, wherein the new crystalline substance of the TMC435 sodium salts
Type includes crystal formation A, crystal formation B, crystal formation C, crystal formation D or its combination of TMC435 sodium salts.The hepatic disease related to HCV infection
Including the disease caused by HCV, including gradual hepatic fibrosis, the inflammation for causing liver cirrhosis or necrosis, end-stage liver disease regulating liver-QI are thin
Born of the same parents' carcinoma (HCC).The patient includes but is not limited to mammal.The amount for giving refers to and can effectively suppress or reduce HCV infection
Or effectively suppress or reduce the amount of HCV infection relevant disease.Generally effectively 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 with suitable in a unit
Interval repeatedly gives, and per unit dose form contains 1-1000 milligrams, especially 5-200 milligrams, e.g., from about 25 milligrams, or about 50
Milligram, or about 75 milligrams, or about 100 milligrams, or about 150 milligrams, or about 200 milligrams of TMC435 active component.Additionally, previously
Known HCV-Ab IgG compound, such as interferon-' alpha ' (IFN-α), glycol interferon-α and/or ribavirin and optionally
Other HCV-Ab IgG compounds, the crystal formation A of TMC435 sodium salts of the present invention, crystal formation B, crystal formation C, crystal formation D or its combination can be combined,
As the medicine in therapeutic alliance；Described other HCV-Ab IgG compounds selected from HCV polymer inhibitors, HCV protease inhibitor,
The inhibitor of other targets in HCV life cycle, immunoregulation medicament, other antiviral drugs or their joint.It is excellent
Select the therapeutic alliance include 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.
Description of the drawings
The XRPD collection of illustrative plates of Fig. 1 TMC435 sodium salts crystal formation A of the present invention.
The DSC collection of illustrative plates of Fig. 2 TMC435 sodium salts crystal formation A of the present invention.
The TGA collection of illustrative plates of Fig. 3 TMC435 sodium salts crystal formation A of the present invention.
The FT-IR collection of illustrative plates of Fig. 4 TMC435 sodium salts crystal formation A of the present invention.
The XRPD collection of illustrative plates of Fig. 5 TMC435 sodium salts crystal formation B of the present invention.
The DSC collection of illustrative plates of Fig. 6 TMC435 sodium salts crystal formation B of the present invention.
The TGA collection of illustrative plates of Fig. 7 TMC435 sodium salts crystal formation B of the present invention.
The FT-IR collection of illustrative plates of Fig. 8 TMC435 sodium salts crystal formation B of the present invention.
The XRPD collection of illustrative plates of Fig. 9 TMC435 sodium salts crystal formation C of the present invention.
The DSC collection of illustrative plates of Figure 10 TMC435 sodium salts crystal formation C of the present invention.
The TGA collection of illustrative plates of Figure 11 TMC435 sodium salts crystal formation C of the present invention.
The FT-IR collection of illustrative plates of Figure 12 TMC435 sodium salts crystal formation C of the present invention.
The XRPD collection of illustrative plates of Figure 13 TMC435 sodium salts crystal formation D of the present invention.
The FT-IR collection of illustrative plates of Figure 14 TMC435 sodium salts crystal formation D of the present invention.
The XRPD collection of illustrative plates of the TMC435 crystal formation I that Figure 15 is prepared with reference to WO2008092954A2.
The XRPD collection of illustrative plates of the TMC435 sodium salt amorphous articles that Figure 16 is prepared with reference to WO2010097229A2.
The FT-IR collection of illustrative plates of the TMC435 sodium salt amorphous articles that Figure 17 is prepared with reference to WO2010097229A2.
In Figure 18 comparative examples 1, the stability test result of TMC435 sodium salts crystal formation A (sequentially consists of placement forward and backward
Sample).
In Figure 19 comparative examples 1, the stability test result of TMC435 sodium salts crystal formation B (sequentially consists of placement forward and backward
Sample).
In Figure 20 contrasts 1, the stability test result of TMC435 sodium salt crystal formation C (sequentially consists of placement forward and backward
Sample).
In Figure 21 comparative examples 1 TMC435 sodium salts amorphous article stability test result (sequentially consist of placement before,
Sample afterwards).
Specific embodiment
Will be helpful to further understand the present invention by following embodiments, but be not used in the restriction present invention.
Detecting instrument and method：
The instrument used by X-ray powder diffraction (XPRD) is Bruker D8Advance diffractometer, is adopted
With the Ka X-rays that copper target wavelength is 1.54nm, under the operating condition of 40kV and 40mA, θ -2 θ clinometers, Mo monochromators,
Lynxeye detectors.Instrument is being calibrated with corundum using front.Acquisition software is Diffrac Plus XRD Commander.
Sample is tested at ambient temperature, and the sample for needing detection is placed on areflexia plate.Testing conditions in detail are as follows, angle model
Enclose：3-40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.
Differential thermal analyses data (DSC) are picked up from TA Instruments Q200MDSC, and instrument control software is Thermal
Advantage, analysis software are Universal Analysis.The sample for generally taking 1-10mg is positioned in aluminium dish, with 10 DEG C/
The programming rate of min is dried N in 40mL/min2Protection under sample is risen to into 300 DEG C from 0 DEG C.
Thermogravimetric analysis data (TGA) is picked up from TA Instruments Q500TGA, and instrument control software is Thermal
Advantage, analysis software are Universal Analysis.Generally take 1-15mg samples to be positioned in platinum crucible, adopt
Segmentation high resolution detection mode, is dried N in 40mL/min with the programming rate of 10 DEG C/min2Protection under by sample from room temperature liter
To 350 DEG C.
Hydrogen nuclear magnetic resonance modal data (1HNMR) pick up from Bruker Avance II DMX 400MHZ NMR (Nuclear Magnetic Resonance) spectrum
Instrument.1-5mg samples are weighed, with 0.5mL deuterochloroform (CDCl3) dissolving, it is made into the solution of 2mg/mL-10mg/mL.
FTIR spectrum analysis (FT-IR) data are picked up from Bruker Tensor 27, instrument control software sum
All it is OPUS according to analysis software.ATR equipment is adopted generally, in 600-4000cm-1In the range of, gather infrared absorption spectroscopy, sample
16 seconds are with the sweep time of blank background, instrumental resolution 4cm-1。
Raman spectrum analyses (Raman) data are picked up from Buddhist nun's high-tensile strength DXR 780, instrument control software and data analysis software
All it is onmic 8.2.Generally under 10 times of mirrors, in wave number 50-3400cm-1In the range of, exposure frequency 8 times, time of exposure 1 second,
Raman spectrum collection is carried out to sample.
In embodiment, various reagents used are commercially available if no special instructions.
Ultrasound procedure in embodiment can promote sample to dissolve, and equipment is ultrasonic cleaner, is carried out under 40kHz power
15 minutes.
Preparation example 1
TMC435 can refer to the preparation method of patent documentation WO2007014926A1 embodiments 5 and be obtained.Specially：By 17-
[2- (4- isopropyl thiazol-2-yls) -7- methoxyl group -8- methylquinoline -4- base epoxides] -13- methyl -2,14- dioxo -3,
18 carbon -7- alkene -4- carboxylic acids (2.80g, 4.335mmol) of 13- diaza tricyclics [13.3.0.04,6] and carbonyldiimidazole
The solution of (1.54g, 9.5mmol) in anhydrous tetrahydro furan (50mL) is refluxed 2 hours in nitrogen.By reactant mixture
Room temperature is cooled to, cyclopropylsulfonamide (2.00g, 16.505mmol) and DBU (1.43g, 9.405mmol) is added.Solution is 50
DEG C heating 15 hours, reactant mixture is cooled to into room temperature, concentrating under reduced pressure subsequently.Residue is in dichloromethane and 1 equivalent (1N)
Distribute between hydrochloric acid, organic layer salt water washing, with anhydrous sodium sulfate drying, evaporate.With flash chromatography (gradient：In dichloromethane
Ethyl acetate (0-25%) in alkane) purification obtains 1.60g (40%) pale powder, further washed with water and isopropyl ether
Wash, vacuum drying obtains 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
TMC435 crystal formation I can refer to the preparation method of patent documentation WO2008092954A2 embodiments 3 and be obtained.Specially：
Take TMC4352.1g to flow back in 5mL n-butyl alcohol, 45mL n-butyl alcohol is added in the suspension for boiling to obtaining settled solution.Return
Under the conditions of stream, agitating solution 48 hours, naturally cool to room temperature.Filter, filter cake is washed with n-butyl alcohol, 40 DEG C of dried in vacuum overnight,
Obtain TMC435.
Its XRPD collection of illustrative plates as shown in figure 15, shows consistent with TMC435 crystal formations I disclosed in WO2008092954A2.
Preparation example 3
TMC435 sodium salt amorphous articles can refer to the preparation method of patent documentation WO2010097229A2 embodiments 1 and be obtained.
Specially：Sodium hydroxide solution (24.10g sodium hydroxide is dissolved in 60.03g purified water) is added to 5950.30g to be stirred vigorously
Dichloromethane in.Under stirring condition, TMC435 (450.09g) is added, continue gradual change with stirring until obtaining settled solution.
Under condition of nitrogen gas, the settled solution of gained is spray-dried, collects the product being spray-dried and be vacuum dried in 50 DEG C, 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
Under room temperature, TMC435 crystal formation I (173.01mg, 0.231mmol) and 2.0mL ethanol are added in 5mL vials,
Ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 crystal formations I is molten in ethanol at such a temperature for which
10 times of Xie Du), add the suspension that sodium hydroxide (19.22mg, 0.480mmol) and 0.2mL ethanol are prepared, stir after mixing
Obtain white suspension (in the suspension, the consumption of sodium hydroxide is its 10 times of dissolubility in ethanol at such a temperature)；Room
The lower stirring of temperature obtains settled solution for 2 hours, continues stirring and separates out white solid in 5 days；Washing with alcohol 3 times is filtered and uses, room temperature is true
It is empty to be dried 16 hours, obtain TMC435 sodium salt crystal formation 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 formation 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 as shown in figure 4, crystal formation A wave number be 3423,3331,2961,2932,2866,1633,1611,
1451st, 1232,1187,1119,870 and 780cm-1Place is with characteristic peak.
Embodiment 2
At -10 DEG C, TMC435 crystal formation I (69.12mg, 0.092mmol) and 6.2mL positive third is added in 20mL vials
Alcohol, ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 crystal formations I is which at such a temperature in normal propyl alcohol
2 times of middle dissolubility), addition sodium hydroxide (4.42mg, 0.1105mmol), stirring after mixing obtain white suspension；-10℃
Lower stirring obtains settled solution for 4 hours, continues stirring and separates out white solid in 2 days；Filter and washed with normal propyl alcohol 2 times, 50 DEG C true
It is empty to be dried 10 hours, obtain TMC435 sodium salt crystal formation A.Yield is 40.28mg, and yield is 56.6%.
Embodiment 3
At 50 DEG C, TMC435 crystal formation I (120.01mg, 0.160mmol) and 3.0mL Zhong Ding is added in 5mL vials
Alcohol, ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 crystal formations I is which at such a temperature in sec-butyl alcohol
5 times of middle dissolubility), add the suspension that sodium hydroxide (6.40mg, 0.160mmol) and 0.2mL sec-butyl alcohols are prepared, after mixing
Stirring obtain white suspension (in the suspension consumption of sodium hydroxide be its at such a temperature in sec-butyl alcohol dissolubility 5
Times)；Stirring at 50 DEG C obtains settled solution for 1 hour, continues stirring and separates out white solid in 3 days；Filter and 3 are washed with sec-butyl alcohol
Secondary, 60 DEG C are vacuum dried 48 hours, obtain TMC435 sodium salt crystal formation A.Yield is 100.17mg, and yield is 81.8%.
Embodiment 4
At 10 DEG C, TMC435 crystal formation I (46.08mg, 0.061mmol) and 3.8mL propanol are added in 5mL vials,
Ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 crystal formations I is which at such a temperature in normal propyl alcohol
2 times of dissolubility), addition sodium hydroxide (2.44mg, 0.061mmol), stirring after mixing obtain white suspension；Stir at 10 DEG C
Mix and obtain within 1 hour settled solution, continue stirring and separate out white solid in 5 days；Filter and use propanol rinse 3 times, 60 DEG C of vacuum drying 1
Hour, obtain TMC435 sodium salt crystal formation A.Yield is 21.85mg, and yield is 46.0%.
Embodiment 5
At 40 DEG C, TMC435 crystal formation I (60.00mg, 0.080mmol) and 1.5mL butanol are added in 5mL vials,
Ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 crystal formations I is molten in butanol at such a temperature for which
5 times of Xie Du), add the suspension that sodium hydroxide (3.84mg, 0.096mmol) and 0.12mL butanol are prepared, stir after mixing
Obtain white suspension (in the suspension, the consumption of sodium hydroxide is which at such a temperature 5 times of dissolubility in butanol)；40
Stirring at DEG C obtains settled solution for 5 hours, continues stirring and separates out white solid in 2 days；Filter and washed with butanol 3 times, 60 DEG C true
It is empty to be dried 16 hours, obtain TMC435 sodium salt crystal formation A.Yield is 50.27mg, and yield is 82.1%.
Embodiment 2～5 prepare sample with the same or analogous XRPD collection of illustrative plates of 1 sample of embodiment, 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 2～5 sample of embodiment and 1 sample of embodiment are identical things
Matter.
Embodiment 6
Under room temperature, TMC435 sodium salt amorphous articles (50.47mg) and 2.0mL acetonitriles, ultrasound are added in 5mL vials
(in the suspension, the consumption of TMC435 sodium salts amorphous article is which at such a temperature in acetonitrile to obtain within 15 minutes white suspension
10 times of dissolubility), it is stirred at room temperature one week, filters and washed with acetonitrile 2 times, 40 DEG C are vacuum dried 16 hours, obtain TMC435
Sodium salt crystal formation 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 formation 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 as shown in figure 8, crystal formation B wave number be 3453,3327,2960,2931,2863,1635,1611,
1548th, 1408,1352,1235,1118,1022,869 and 780cm-1Place is with characteristic peak.
Embodiment 7
At 40 DEG C, TMC435 sodium salt amorphous articles (11.15mg) and 2.0mL acetone, ultrasound are added in 5mL vials
Obtain within 15 minutes white suspension (in the suspension consumption of TMC435 sodium salts amorphous article for its at such a temperature in acetone
2 times of dissolubility), 40 DEG C are stirred 9 days, are filtered and with washing with acetone 2 times, room temperature in vacuo drying 48 hours, are obtained TMC435 sodium
Salt crystal formation B.Yield is 4.73mg；Yield is 42.4%.
Embodiment 8
At 10 DEG C, the water of TMC435 sodium salt amorphous article (30.47mg) and 3.0mL butanone is added in 5mL vials
Saturated solution, ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 sodium salts amorphous article is which at this
At a temperature of 5 times of dissolubility in the water saturation solution of butanone), stir 2 weeks at 10 DEG C, filter, and molten with the water saturation of butanone
Liquid is washed 3 times, and 60 DEG C are vacuum dried 1 hour, obtain TMC435 sodium salt crystal formation B.Yield is 27.89mg；Yield is 91.5%.
Embodiment 7,8 prepare sample with the same or analogous XRPD collection of illustrative plates of 6 sample of embodiment, 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 6 sample of embodiment are identical materials.
Embodiment 9
Under room temperature, TMC435 sodium salt amorphous articles (71.85mg) and 1.5mL ethyl acetate are added in 5mL vials,
Ultrasound obtains white suspension for 15 minutes, and (in the suspension, the consumption of TMC435 sodium salts amorphous article is which at such a temperature in second
10 times of dissolubility in acetoacetic ester), it is stirred at room temperature one week, filters and washed with ethyl acetate 3 times, 40 DEG C of vacuum drying 16 are little
When, obtain TMC435 sodium salt crystal formation 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 formation C.
DSC collection of illustrative plates is as shown in Figure 10.
TGA collection of illustrative plates is as shown in figure 11.
FT-IR collection of illustrative plates as shown in figure 12, crystal formation C wave number be 3500,3323,2957,2932,2865,1632,1610,
1552nd, 1350,1234,1186,1119,1017,870 and 780cm-1Place is with characteristic peak；
Embodiment 10
At 40 DEG C, TMC435 sodium salt amorphous articles (11.93mg) and 1.0mL isopropyl acetates are added in 5mL vials
Ester, ultrasound obtain within 15 minutes white suspension (in the suspension consumption of TMC435 sodium salts amorphous article for its at such a temperature
2 times of dissolubility in isopropyl acetate), 40 DEG C are stirred 9 days, are filtered and are washed with isopropyl acetate 3 times, and room temperature in vacuo is dried
48 hours, obtain TMC435 sodium salt crystal formation C.Yield is 5.47mg, and yield is 45.9%.
Embodiment 11
At 10 DEG C, TMC435 sodium salt amorphous articles (10.55mg) and 1.0mL chloroforms, ultrasound are added in 5mL vials
(in the suspension, the consumption of TMC435 sodium salts amorphous article is which at such a temperature in chloroform to obtain within 15 minutes white suspension
5 times of dissolubility), to stir 2 weeks at 10 DEG C, filter and with chloroform 3 times, 60 DEG C of vacuum drying 1 hour obtain TMC435 sodium
Salt crystal formation C.Yield is 7.20mg, and yield is 68.2%.
Embodiment 10,11 prepare sample with the same or analogous XRPD collection of illustrative plates of 9 sample of embodiment, 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 9 sample of embodiment are identicals
Material.
Embodiment 12
Under room temperature, TMC435 sodium salt amorphous articles (20.55mg) and 0.5mL butanone, ultrasound are added in 5mL vials
(in the suspension, the consumption of TMC435 sodium salts amorphous article is which at such a temperature in butanone to obtain within 15 minutes white suspension
5 times of dissolubility), it is stirred at room temperature 1 week, filters and washed with butanone 2 times, 40 DEG C are vacuum dried 16 hours, obtain TMC435 sodium
Salt crystal formation D.Yield is 8.12mg, and yield is 39.5%.
Its XRPD collection of illustrative plates as shown in figure 13, is TMC435 sodium salt crystal formation D.
FT-IR collection of illustrative plates as shown in figure 14, crystal formation D wave number be 3474,2955,2930,2868,1658,1609,1510,
1452nd, 1351,1232,1186,1120,1105 and 844cm-1Place is with characteristic peak；
Embodiment 13
At 40 DEG C, TMC435 sodium salt amorphous articles (50.93mg) and 0.4mL butanone, ultrasound are added in 5mL vials
(in the suspension, the consumption of TMC435 sodium salts amorphous article is which at such a temperature in butanone to obtain within 15 minutes white suspension
10 times of dissolubility), 40 DEG C are stirred 9 days, are filtered and are washed with butanone 3 times, and room temperature in vacuo is dried 48 hours, obtains TMC435 sodium
Salt crystal formation D.Yield is 10.11mg, and yield is 19.8%.
Embodiment 14
At 10 DEG C, TMC435 sodium salt amorphous articles (18.17mg) and 10mL butanone, ultrasound are added in 20mL vials
(in the suspension, the consumption of TMC435 sodium salts amorphous article is which at such a temperature in butanone to obtain within 15 minutes white suspension
2 times of dissolubility), stir 2 weeks at 10 DEG C, filter and washed with butanone 3 times, 60 DEG C are vacuum dried 1 hour, obtain TMC435 sodium
Salt crystal formation D.Yield is 5.45mg, and yield is 30.0%.
Embodiment 13,14 prepare sample with the same or analogous XRPD collection of illustrative plates of 12 sample of embodiment, FT-IR collection of illustrative plates
With Raman collection of illustrative plates (not shown).Illustrate that embodiment 13,14 samples and 12 sample of embodiment 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：By TMC435 sodium salt crystal formation A, 1.2g sodium lauryl sulfates of the 72.0g present invention, 1.2g anhydrous colloidals
Silicon dioxide and 159.0g lactose monohydrates are sieved and are mixed 10 minutes by three-dimensional mixer.The stearic acid that 1.2g is sieved
During magnesium adds the mixture and mix 5 minutes.Gained mixture is filled in hard gelatine capsule, 700 is prepared and is contained
The capsule of TMC435 sodium salts crystal formation A of the present invention.
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：By TMC435 sodium salt crystal formation A, 1.8g sodium lauryl sulfates of the 108.0g present invention, 1.8g without glue
Body silicon dioxide and 238.5g lactose monohydrates are sieved and are mixed 10 minutes by three-dimensional mixer.The Hard Fat that 1.8g is sieved
During sour magnesium adds the mixture and mix 5 minutes.Gained mixture is filled in hard gelatine capsule, 700 are prepared
Capsule containing TMC435 sodium salts crystal formation A of the present invention.
Embodiment 17
Prepare the capsule containing TMC435 sodium salts crystal formation B of the present invention.
By " the TMC435 sodium salt crystal formation A " replacement " TMC435 sodium salt crystal formation B " in embodiment 15 and embodiment 16, other behaviour
Make with embodiment 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 " the TMC435 sodium salt crystal formation A " replacement " TMC435 sodium salt crystal formation C " in embodiment 15 and embodiment 16, other behaviour
Make with embodiment 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 " the TMC435 sodium salt crystal formation A " replacement " TMC435 sodium salt crystal formation D " in embodiment 15 and embodiment 16, other behaviour
Make with embodiment 15 and embodiment 16, prepare the capsule containing TMC435 sodium salts crystal formation D of the present invention.
Comparative example 1
Take the present invention TMC435 sodium salts crystal formation A, crystal formation B and crystal formation C, and preparation example 3 prepare it is known
TMC435 sodium salt amorphous articles, carry out stability of crystal form contrast test.
Concrete operations are as follows：Respectively take 20mg samples to be placed in 20ml vials, it is open to be positioned over 40 DEG C, under 75%RH environment
10 days, XRPD signs are carried out before and after placement.Crystal formation A, the crystal formation B of TMC435 sodium salts of the present invention and crystal formation C and known
The related collection of illustrative plates of TMC435 sodium salt amorphous articles is shown in Figure 18 to Figure 21 respectively.
The stability of crystal form comparative test result of Figure 18 to Figure 21 shows：Known TMC435 sodium salts amorphous article is being placed
After 10 days, it is impossible to keep its original form；And the crystal formation A or crystal formation B or crystal formation C of the TMC435 sodium salts of the present invention is after placement
Crystal formation keeps constant, with certain stability.
Comparative example 2
Take the present invention TMC435 sodium salts crystal formation A, crystal formation B and crystal formation C, and preparation example 3 prepare it is known
TMC435 sodium salt amorphous articles, carry out chemical stability contrast test.
Concrete operations are as follows：Respectively take 20mg samples to be placed in 20ml vials, respectively it is open be positioned over 25 DEG C of exsiccators or
60 DEG C of convection ovens or 40 DEG C/75%RH environment or 40 DEG C/carbamide peroxide environment or 25 DEG C/illumination (4500 ±
500Lux) environment is lower 10 days, and HPLC purity signs are carried out before and after placement.
As a result show：After the crystal formation A or crystal formation B of TMC435 sodium salts of the present invention or crystal formation C place 10 days under these conditions,
Its HPLC purity is held essentially constant or is slightly decreased；And known TMC435 sodium salts amorphous article places 10 under these conditions
After it, its HPLC chemical purity has under decline, particularly 40 DEG C/carbamide peroxide environment, 25 DEG C/illumination (4500 ±
HPLC purity after 500Lux) placing 10 days under environment is decreased obviously；Illustrate the crystal formation A or crystal formation of TMC435 sodium salts of the present invention
The more known TMC435 sodium salts amorphous articles of B or crystal formation C have more preferable chemical stability.
Cited all patent documentations and non-patent publications in this specification, are incorporated by this with which by quoting
Wen Zhong.
The above, the only specific embodiment of the present invention, but protection scope of the present invention is not limited thereto, any
Those of ordinary skill in the art disclosed herein technical scope in, the change that can expect without creative work or
Replace, should all be included within the scope of the present invention.
Claims (36)
1. the sodium salt crystal formation A of structural formula TMC435 as follows,
Characterized in that, the crystal formation A has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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- that the crystal formation A is represented with 2 θ angles
Ray powder diffraction pattern 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- that the crystal formation A is represented with 2 θ angles
Ray powder diffraction pattern has following characteristics peak and its relative intensity：
4. the preparation method of the TMC435 sodium salt crystal formation A any one of claim 1-3, comprises the following steps：Formed
Suspensions of the TMC435 crystal formation I in alcohol, adds sodium hydroxide and stirs, keep 2-5 under -10 DEG C -50 DEG C of recrystallization temperature
My god, obtain the TMC435 sodium salts crystal formation A；The TMC435 crystal formations I has X-ray powder diffraction figure as shown in figure 15.
5. the preparation method of TMC435 sodium salts crystal formation A according to claim 4, it is characterised in that the alcohol is C2-C4Alcohol.
6. the preparation method of TMC435 sodium salts crystal formation A according to claim 5, it is characterised in that the alcohol is ethanol.
7. the preparation method of TMC435 sodium salts crystal formation A according to claim 4, it is characterised in that the TMC435 crystal formations I
Mole dosage ratio with sodium hydroxide is 1:1-1:2.
8. the preparation method of TMC435 sodium salts crystal formation A according to claim 7, it is characterised in that the TMC435 crystal formations I
Mole dosage ratio with sodium hydroxide is 1:1-1:1.2.
9. the preparation method of TMC435 sodium salts crystal formation A according to claim 4, it is characterised in that in the suspension
The consumption of TMC435 crystal formation I is 2-10 times of its dissolubility under recrystallization temperature in alcohol.
10. the preparation method of TMC435 sodium salts crystal formation A according to claim 9, it is characterised in that in the suspension
The consumption of TMC435 crystal formation I is 2-5 times of its dissolubility under recrystallization temperature in alcohol.
The preparation method of 11. TMC435 sodium salts crystal formation A according to claim 4, it is characterised in that the sodium hydroxide shape
Add into the suspension in the alcohol, the consumption of wherein sodium hydroxide is its dissolubility under recrystallization temperature in the alcohol
2-10 times.
The preparation method of 12. TMC435 sodium salts crystal formation A according to claim 11, it is characterised in that the sodium hydroxide
Consumption be 2-5 times of its dissolubility under recrystallization temperature in the alcohol.
The preparation method of 13. TMC435 sodium salts crystal formation A according to claim 4, it is characterised in that the recrystallization temperature is
10-40℃。
The preparation method of 14. TMC435 sodium salts crystal formation A according to claim 13, it is characterised in that the recrystallization temperature
For room temperature.
The sodium salt crystal formation B of 15. structural formulas TMC435 as follows,
Characterized in that, the crystal formation B has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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 °.
16. TMC435 sodium salts crystal formation B according to claim 15, it is characterised in that the crystal formation B is represented with 2 θ angles
X-ray powder diffraction figure 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°。
17. TMC435 sodium salts crystal formation B according to claim 16, it is characterised in that the crystal formation B is represented with 2 θ angles
X-ray powder diffraction figure has following characteristics peak and its relative intensity：
The preparation method of the TMC435 sodium salt crystal formation B any one of 18. claim 15-17, comprises the following steps：Will
TMC435 sodium salts amorphous article forms suspension in a solvent, the solvent selected from acetonitrile, acetone, the water saturation solution of butanone or
Its mixture, stirring and crystallizing obtain the TMC435 sodium salts crystal formation B.
The preparation method of 19. TMC435 sodium salts crystal formation B according to claim 18, it is characterised in that the temperature of the crystallize
Spend for 10-40 DEG C.
The preparation method of 20. TMC435 sodium salts crystal formation B according to claim 19, it is characterised in that the temperature of the crystallize
Spend for room temperature.
The preparation method of 21. TMC435 sodium salts crystal formation B according to claim 18, it is characterised in that the crystallize when
Between for 1-2 it is all.
The preparation method of 22. TMC435 sodium salts crystal formation B according to claim 21, it is characterised in that the crystallize when
Between be 7-9 days.
The preparation method of 23. TMC435 sodium salts crystal formation B according to claim 18, it is characterised in that in the suspension
The consumption of TMC435 sodium salt amorphous articles is 2-10 times of its dissolubility under recrystallization temperature in the solvent.
The preparation method of 24. TMC435 sodium salts crystal formation B according to claim 23, it is characterised in that in the suspension
The consumption of TMC435 sodium salt amorphous articles is 2-5 times of its dissolubility under recrystallization temperature in the solvent.
The sodium salt crystal formation C of 25. structural formulas TMC435 as follows,
Characterized in that, the crystal formation C has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles are represented：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 °.
26. TMC435 sodium salts crystal formation C according to claim 25, it is characterised in that the crystal formation C is represented with 2 θ angles
X-ray powder diffraction figure 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°。
27. TMC435 sodium salts crystal formation C according to claim 26, it is characterised in that the crystal formation C is represented with 2 θ angles
X-ray powder diffraction figure has following characteristics peak and its relative intensity：
The preparation method of the TMC435 sodium salt crystal formation C any one of 28. claim 25-27, comprises the following steps：Will
TMC435 sodium salts amorphous article forms suspension in a solvent, the solvent selected from ethyl acetate, isopropyl acetate, chloroform or its
Mixture, stirring and crystallizing obtain the TMC435 sodium salts crystal formation C.
29. TMC435 sodium salts crystal formation C according to claim 28, it is characterised in that the temperature of the crystallize is 10-40
℃。
30. TMC435 sodium salts crystal formation C according to claim 29, it is characterised in that the temperature of the crystallize is room temperature.
31. TMC435 sodium salts crystal formation C according to claim 28, it is characterised in that the time of the crystallize is that 1-2 is all.
32. TMC435 sodium salts crystal formation C according to claim 31, it is characterised in that the time of the crystallize is 7-9 days.
33. TMC435 sodium salts crystal formation C according to claim 28, it is characterised in that TMC435 sodium salts in the suspension
The consumption of amorphous article is 2-10 times of its dissolubility under recrystallization temperature in the solvent.
34. TMC435 sodium salts crystal formation C according to claim 33, it is characterised in that TMC435 sodium salts in the suspension
The consumption of amorphous article is 2-5 times of its dissolubility under recrystallization temperature in the solvent.
A kind of 35. pharmaceutical compositions, its include treatment and/or one or more of prevention effective dose selected from claim 1-3
Any one of TMC435 sodium salt crystal formation A, the TMC435 sodium salt crystal formation B any one of claim 15-17, right
It is required that the TMC435 sodium salt crystal formation C any one of 25-27, the preparation method according to any one of claim 4-14 are obtained
To TMC435 sodium salt crystal formation A, the TMC435 sodium salt crystal formations that obtain of the preparation method according to any one of claim 18-24
The TMC435 sodium salt crystal formation C that B or the preparation method according to any one of claim 28-34 are obtained, and at least one medicine
Acceptable carrier on.
Any one of TMC435 sodium salt crystal formation A, claim 15-17 any one of 36. claim 1-3
TMC435 sodium salt crystal formation C any one of TMC435 sodium salt crystal formation B, claim 25-27, according in claim 4-14
TMC435 sodium salt crystal formation A that preparation method described in any one is obtained, according to any one of claim 18-24 preparation method
The TMC435 sodium salts that the TMC435 sodium salt crystal formation B for obtaining or the preparation method according to any one of claim 28-34 are obtained
Crystal formation C is preparing treatment and/or prevention of hepatitis C infection or the hepatic disease related to infection with hepatitis C virus
Purposes in medicine.
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Effective date of registration: 20190821 Address after: 310018 Room 2B05, Building 452, No. 6 Street, Hangzhou Economic and Technological Development Zone, Zhejiang Province Patentee after: Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd Address before: 310018 room 2B12, building 452, No. 6, Hangzhou Economic & Technological Development Zone, Hangzhou, Zhejiang, China Patentee before: HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY CO., LTD. |