CN105693624B - Macitentan crystal and preparation method thereof, its pharmaceutical composition and purposes - Google Patents
Macitentan crystal and preparation method thereof, its pharmaceutical composition and purposes Download PDFInfo
- Publication number
- CN105693624B CN105693624B CN201610072641.7A CN201610072641A CN105693624B CN 105693624 B CN105693624 B CN 105693624B CN 201610072641 A CN201610072641 A CN 201610072641A CN 105693624 B CN105693624 B CN 105693624B
- Authority
- CN
- China
- Prior art keywords
- macitentan
- crystal
- methylate
- preparation
- crystal form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- 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
Abstract
The present invention relates to the novel crystal forms of macitentan, the novel crystal forms have dominance in terms of solubility.Preparation method, its pharmaceutical composition and its purposes in the drug for treating hypertension, pulmonary hypertension is prepared the invention further relates to the novel crystal forms.
Description
The application is Application No. 201480001614.X (PCT/CN2014/ of on the December 31st, 2014 into China
078137, international filing date on May 22nd, 2014) patent application " macitentan crystal and preparation method thereof, its pharmaceutical composition
The divisional application of object and purposes ".
Technical field
This application involves pharmaceutical chemistry crystallization technique fields.More specifically, this application involves the novel crystal forms of macitentan, bags
Include macitentan crystal form II, macitentan methylate crystal, macitentan nitromethane compound crystal and macitentan methyl
Tertbutyl ether compound crystal, with and its preparation method and application.
Background technology
On October 18th, 2013, FDA (Food and Drug Adminstration) (FDA) approval U.S. love can ACE Semi (Actelion) pharmacy
The new drug macitentan (trade name Opsumit) of company is used to treat pulmonary hypertension (PAH) adult patient.PAH is a kind of
Certain types of pulmonary hypertension (PH) belongs to classification I grade of the World Health Organization (WHO) to PH, is a kind of serious, progressive
Property and threat to life pulmonary vasculature disease, it is characterised in that smooth muscle cell in the vessel retraction and pulmonary arterial wall of extreme
Paraplasm.Macitentan is a kind of two-way (ETA/ETB) endothelin-receptor antagonists, contraction and increasing to vascular smooth muscle
It grows reaction and plays inhibitory action, PAH progression of disease can be delayed, progression of disease includes dead, vein or prostacyclin is subcutaneously injected
Class drug or PAH symptoms, which deteriorate, (including walking distance decline in 6 minutes, the PAH symptoms deteriorated and needs other PAH drugs to control
The symptom for the treatment of).Opsumit is 10mg oral tablets, and approval dosage is 10mg/ days.
Macitentan, English name Macitentan, [[[(5- is bromo- by 2- by 5- (4- bromophenyls) -6- for N- for chemical name
2- pyrimidine radicals) oxygroup] ethyoxyl] -4- pyrimidine radicals]-N'- sulfonyl propyl amine, with following structural formula：
Patent document US7,094,781 describes the structural formula and its synthetic method of macitentan.Document
J.Med.Chem.2012 mentions macitentan in 55,7849 and crystallizes the product fusing point of acquisition in methyl alcohol as 135-136 DEG C,
For convenience, the crystal form in the document is known as " crystal form I " below.
The present inventor has found crystal form I to be hydrophobic under study for action, and solubility is very poor in water, and tablet dissolution rate is slow,
These properties may limit it is oral after active ingredient reach concentration and rate in blood stream of patients, influence drug effect.
Therefore, this field needs to develop the novel crystal forms of macitentan.
The content of the invention
The object of the present invention is to provide the novel crystal forms of macitentan, to solve the problems, such as that known crystal form exists, and provide institute
State the preparation method, its pharmaceutical composition and purposes of novel crystal forms.
The novel crystal forms of macitentan provided by the invention, including macitentan crystal form II, macitentan methylate crystal,
Macitentan nitromethane compound crystal and macitentan methyl tertbutyl etherate crystal.Compared to known crystal form, the new crystalline substance
The favorable property that type has at least one following：Higher crystallinity, the solubility of bigger, faster dissolution rate, granulated
State is good, is not susceptible to polymorphic inversion, calorifics and good mechanical stability, agent of low hygroscopicity, better mobility, suitable formulations application
Compressibility and good, the low-residual solvent of apparent density, storage stability etc..
Purpose according to the present invention, the present invention provide the crystal form II (hereinafter referred to as " crystal form II ") of macitentan and its prepare
Method.
Radiated using Cu-K α, the X-ray powder diffraction of the crystal form II 2 θ of the angle of diffraction be 8.9 ± 0.2 °, 11.5 ±
There is characteristic peak at 0.2 °, 14.1 ± 0.2 °, 18.7 ± 0.2 °, 19.6 ± 0.2 ° and 25.4 ± 0.2 °.
Typically, the X-ray powder diffraction of the crystal form II 2 θ of the angle of diffraction for 8.9 ± 0.2 °, 11.5 ± 0.2 °,
12.4±0.2°、14.1±0.2°、15.2±0.2°、17.8±0.2°、18.7±0.2°、19.6±0.2°、20.2±0.2°、
There is characteristic peak at 21.4 ± 0.2 °, 24.1 ± 0.2 ° and 25.4 ± 0.2 °.
Preferably, the X-ray powder diffraction of the crystal form II has characteristic peak and its relatively strong at following 2 θ of the angle of diffraction
Degree：
Without limitation, a representative instance of the crystal form II has X-ray powder diffraction figure as shown in Figure 3.
The crystal form II has at least one following characteristic：
Differential scanning amount thermal map (DSC) display of crystal form II：Fusing point is 106 DEG C；
Thermogravimetric analysis (TGA) collection of illustrative plates of crystal form II is shown：Substantially without weightlessness before 130 DEG C, for anhydride, decomposition temperature
For 150 DEG C；
The dynamic water absorption figure of crystal form II is shown：Weight change in 20%~80% RH range is
1.5%, it is not easy to moisture absorption.
The crystal form II has following beneficial property：
(1) compared with known macitentan crystal form I, in addition Surfactant SDS (SDS) or spit
In the case of -80 (Tween-80) of temperature, the solubility of crystal form II in water is much larger than the solubility of known crystal form I in water；
(2) under prescription unanimous circumstances, tablet dissolution rate of the tablet than known crystal form I of crystal form II of the invention
Soon；
(3) crystal form II is lower than the fusing point of crystal form I, is suitble to hot-melt extruded method；
(4) crystal form II is not easy to moisture absorption；
The above-mentioned property of crystal form II shows：Compared with known macitentan crystal form I, macitentan crystal form II of the invention
With better solubilizing effect, higher solubility and faster dissolution rate, such property causes formulation application more to have
Effect can improve the bioavilability of active ingredient and the pharmacokinetic property of positive influences active ingredient, can be more after taking orally
Reach maximum plasma concentration soon, work more quickly in the internal position for needing to play its effect；The fusing point of crystal form II is low, more
It is suitble to hot-melt extruded method；Crystal form II have is not easy hygroscopicity, can preferably resist drug manufacture and/or storage etc. during by
Ambient humidity causes the content of active ingredient uneven and the problems such as purity reduces, and reduces thus caused curative effect canyon wind
Danger and security risk, and be conducive to the accurate quantitative analysis in prepared by unit formulation and the transport and storage in later stage.
The preparation method of the crystal form II of macitentan, comprises the following steps：Macitentan is suspended in be formed in methanol and is hanged
Turbid is stirred crystallization, then by the separation of the solid of precipitation, more than 60 DEG C at it is dry, obtain the crystal form of the macitentan
II。
Preferably, the dosage of the macitentan is that 10-250mg macitentan is added in per ml methanol；More preferably per milli
It rises methanol and adds in 10-100mg macitentan.
Preferably, the recrystallization temperature is room temperature to 60 DEG C；More preferably room temperature.
Preferably, the crystallization time is 1-14 days；More preferably 1-7 days.
Preferably, the drying temperature is 70 DEG C -120 DEG C；More preferably 70 DEG C -100 DEG C.
Preferably, when the drying time is 1-72 small；When more preferably 1-24 is small.
Purpose according to the present invention, the present invention provide methylate crystal (hereinafter referred to as " the methylate crystalline substance of macitentan
Body ") and preparation method thereof.
In macitentan methylate crystal provided by the invention, per molecule macitentan carries about 1/2~1 methanol
Molecule, for example,：Per molecule macitentan carries about 2/3 methanol molecules.
Radiated using Cu-K α, the X-ray powder diffraction of the methylate crystal 2 θ of the angle of diffraction be 8.9 ± 0.2 °,
There is characteristic peak at 11.3 ± 0.2 °, 13.9 ± 0.2 °, 18.6 ± 0.2 °, 19.3 ± 0.2 ° and 25.3 ± 0.2 °.
Typically, the X-ray powder diffraction of the methylate crystal 2 θ of the angle of diffraction for 8.9 ± 0.2 °, 11.3 ±
0.2°、12.4±0.2°、13.9±0.2°、15.2±0.2°、18.6±0.2°、18.9±0.2°、19.3±0.2°、 20.1
There is characteristic peak at ± 0.2 °, 21.2 ± 0.2 °, 24.0 ± 0.2 ° and 25.3 ± 0.2 °.
Preferably, the X-ray powder diffraction of the methylate crystal at following 2 θ of the angle of diffraction have characteristic peak and its
Relative intensity：
Without limitation, there is a representative instance of the methylate crystal X-ray powder as shown in Figure 8 to spread out
Penetrate figure.
Compared with known macitentan crystal form I, the methylate crystal has following beneficial property：
(1) in the case of addition surfactant SDS or Tween-80, the solubility of methylate crystal in water is remote
More than the solubility of known crystal form I in water.
(2) methylate crystal has preferable granule-morphology and particle is larger.
The above-mentioned property of methylate crystal shows：Compared with known macitentan crystal form I, macitentan of the invention
Methylate crystal has better solubilizing effect, higher solubility, can improve the bioavilability of active ingredient so that
Formulation application is more effective；The operations such as preferable granule-morphology, the sieving convenient for being separated by filtration of bulk pharmaceutical chemicals, in preparation processing,
Production efficiency is improved, lot stability is good.Larger particle has better preparation machinability, is directly pressed available for powder
Piece avoids influence of the wet granulation solvent to bulk pharmaceutical chemicals, is conducive to the control of the quality of the pharmaceutical preparations, improves lot stability.
The preparation method of the methylate crystal of macitentan, comprises the following steps：Macitentan is suspended in methanol
Suspension is formed, is stirred crystallization, then separates the solid of precipitation, room temperature in vacuo drying obtains the macitentan
Methylate crystal.
Preferably, the dosage of the macitentan is that 10-250mg macitentan is added in per ml methanol；More preferably per milli
It rises methanol and adds in 10-100mg macitentan.
Preferably, the recrystallization temperature is room temperature to 60 DEG C；More preferably room temperature.
Preferably, the crystallization time is 1-14 days；More preferably 1-7 days.
Preferably, when the drying time is 1-72 small；When more preferably 1-24 is small.
Purpose according to the present invention, the present invention provide nitromethane compound crystal (hereinafter referred to as " the nitro first of macitentan
Alkide crystal ") and preparation method thereof.
In macitentan nitromethane compound crystal provided by the invention, per molecule macitentan carries about 1/2 nitro
Methane molecule.
Radiated using Cu-K α, the X-ray powder diffraction of the nitromethane compound crystal 2 θ of the angle of diffraction for 11.5 ±
There is characteristic peak at 0.2 °, 14.0 ± 0.2 °, 15.3 ± 0.2 °, 18.6 ± 0.2 °, 21.2 ± 0.2 ° and 25.5 ± 0.2 °.
Typically, the X-ray powder diffraction of the nitromethane compound crystal 2 θ of the angle of diffraction for 8.9 ± 0.2 °, 11.5
±0.2°、12.4±0.2°、14.0±0.2°、15.3±0.2°、18.6±0.2°、19.0±0.2°、 19.5±0.2°、
There is characteristic peak at 20.1 ± 0.2 °, 21.2 ± 0.2 °, 24.2 ± 0.2 ° and 25.5 ± 0.2 °.
Preferably, the X-ray powder diffraction of the nitromethane compound crystal has characteristic peak at following 2 θ of the angle of diffraction
And its relative intensity：
Without limitation, a representative instance of the nitromethane compound crystal has X-ray as shown in Figure 10
Powder diagram.
The nitromethane compound crystal has following beneficial property：
(1) compared with known macitentan crystal form I, in the case of addition surfactant SDS or Tween-80, nitre
The solubility of methylmethane compound crystal in water is much larger than the solubility of known crystal form I in water.
(2) it is suitable for crowd's use to ethyl alcohol allergy without ethyl alcohol in nitromethane compound crystal.
The above-mentioned property of nitromethane compound crystal shows：Compared with known macitentan crystal form I, Ma Xi of the invention
There is better solubilizing effect, higher solubility for smooth nitromethane compound crystal, the biology profit of active ingredient can be improved
Expenditure so that formulation application is more effective.And without ethyl alcohol in nitromethane compound crystal, the patient for ethyl alcohol allergy is
It is well-adapted.
The preparation method of the nitromethane compound crystal of macitentan, comprises the following steps：Macitentan is suspended in nitre
Suspension is formed in the water saturation solution of methylmethane, is stirred crystallization, then by solid separation, the drying of precipitation, obtains institute
State the nitromethane compound crystal of macitentan.
Preferably, the dosage of the macitentan is addition 1-100mg horses in the water saturation solution of every milliliter of nitromethane
West is for smooth；1-50mg macitentan is added in the water saturation solution of more preferable every milliliter of nitromethane.
Preferably, the recrystallization temperature is room temperature to 60 DEG C；More preferably room temperature.
Preferably, the crystallization time is 1-14 days；More preferably 1-7 days.
Preferably, the drying temperature is room temperature to 80 DEG C；More preferably 40 DEG C.
Preferably, when the time of the drying is 1-48 small；When more preferably 1-24 is small.
The water saturation solution of the nitromethane, specific preparation method are：10-20ml water is taken, adds 10-20ml nitro first
Alkane, stir at room temperature 10-24 it is small when, stand 0.5-2 it is small when after fetch water layer.
Purpose according to the present invention, the present invention provide the methyl tertbutyl etherate crystal (hereinafter referred to as " first of macitentan
Base tertbutyl ether compound crystal ") and preparation method thereof.
In macitentan methyl tertbutyl etherate crystal provided by the invention, per molecule macitentan with about 1/3~
1/2 methyl tertiary butyl ether(MTBE) molecule, such as per molecule macitentan carry 1/3 methyl tertiary butyl ether(MTBE) molecule.
It is radiated using Cu-K α, the X-ray powder diffraction of the methyl tertbutyl etherate crystal is 5.7 in 2 θ of the angle of diffraction
There is characteristic peak at ± 0.2 °, 6.9 ± 0.2 °, 9.7 ± 0.2 °, 16.7 ± 0.2 ° and 25.3 ± 0.2 °.
Typically, the X-ray powder diffraction of the methyl tertbutyl etherate crystal 2 θ of the angle of diffraction for 5.7 ±
0.2°、6.9±0.2°、9.7±0.2°、11.6±0.2°、14.0±0.2°、16.0±0.2°、16.7±0.2°、 19.3±
There is characteristic peak at 0.2 °, 19.8 ± 0.2 °, 20.6 ± 0.2 °, 23.3 ± 0.2 ° and 25.3 ± 0.2 °.
Preferably, the X-ray powder diffraction of the methyl tertbutyl etherate crystal has spy at following 2 θ of the angle of diffraction
Levy peak and its relative intensity：
Without limitation, there is a representative instance of the methyl tertbutyl etherate crystal X- as shown in figure 11 to penetrate
Line powder diagram.
Compared with known macitentan crystal form I, the methyl tertbutyl etherate crystal has following beneficial property：
(1) in the case of addition surfactant SDS or Tween-80, methyl tertbutyl etherate crystal is in water
Solubility is much larger than the solubility of known crystal form I in water.
(2) it is suitable for crowd's use to ethyl alcohol allergy without ethyl alcohol in methyl tertbutyl etherate crystal.
The above-mentioned property of methyl tertbutyl etherate shows：Compared with known macitentan crystal form I, Ma Xi of the invention
There is better solubilizing effect, higher solubility for smooth methyl tertbutyl etherate crystal, active ingredient can be improved
Bioavilability so that formulation application is more effective.And without ethyl alcohol in methyl tertbutyl etherate crystal, for ethyl alcohol mistake
Quick patient is well-adapted.
The preparation method of the methyl tertbutyl etherate crystal of macitentan, comprises the following steps：Macitentan is dissolved
Solution is formed in methyl tertiary butyl ether(MTBE), stands crystallization, then separates the crystal of precipitation, room temperature in vacuo drying obtains described
Macitentan methyl tertbutyl etherate crystal.
Preferably, the dosage of the macitentan dissolves 1-3mg macitentan for every milliliter of methyl tertiary butyl ether(MTBE)；More preferably
1-2mg macitentan is dissolved for every milliliter of methyl tertiary butyl ether(MTBE).
Preferably, the recrystallization temperature is room temperature to 40 DEG C；More preferably room temperature.
Preferably, the crystallization time is 1-14 days；More preferably 1-2 days.
Preferably, when the drying time is 1-72 small；When more preferably 1-24 is small.
The present invention macitentan crystal form II, macitentan methylate crystal, macitentan nitromethane compound crystal,
In the above-mentioned preparation method of macitentan methyl tertbutyl etherate crystal：
The conventional method that this field may be employed in " stirring " carries out, such as magnetic agitation, mechanical agitation etc..Stirring speed
Rate is 50~1800 revs/min, is preferably 300~900 revs/min；
The conventional method example that this field may be employed in " separation " carries out, such as filtering, centrifugation；The concrete operations of filtering
For：It is intended to separated sample to be placed on filter paper, decompression filters；The concrete operations of centrifugation are：It is intended to separated sample and is placed in centrifugation
Guan Zhong is rotated at a high speed afterwards until solid is all sink to centrifugation bottom of the tube, such as 6000 revs/min of centrifugation rate；
" room temperature " operation refers to that operation carries out under conditions of identical with the temperature in room or draught cupboard or close
's.This usual temperature is such as 17 DEG C or 22 DEG C from 15 to 25 DEG C.
It is brilliant that the present invention prepares macitentan crystal form II, macitentan methylate crystal, macitentan nitromethane compound
In the method for body and macitentan methyl tertbutyl etherate crystal, the initial substance used can be appointing for macitentan substance
What crystal or amorphous form, such as the macitentan obtained according to patent document US7,094,781 preparation method described,
Or the macitentan crystal form I that the preparation method described according to document J.Med.Chem.2012,55,7849 obtains.
The crystallization mode used in the present invention includes magma and volatilization.
Magma is that sample is formed to supersaturated solution (with the presence of undissolved solid, i.e. suspension) in dicyandiamide solution, then
Stirring and crystallizing is typically 1 day to 2 weeks.
Volatilization is that sample settled solution is placed in open-top receptacle, such as in 5mL vials, under specific temperature conditions
(being usually room temperature) volatilization.The method or directly volatilize at room temperature that nitrogen is blown can be used.
The macitentan crystal form of the present invention, including macitentan crystal form II, macitentan methylate crystal, macitentan
Nitromethane compound crystal and macitentan methyl tertbutyl etherate crystal, are pure, single, do not mix any other crystalline substance
Type.Particularly crystal form II does not mix any other crystal form substantially.In the present invention, " do not have substantially " when being used to refer to macitentan
During novel crystal forms, refer to the crystal form for other macitentan that this crystal form contains less than 20% (weight), especially less than 10% (weight
Amount), more refer to less than 5% (weight) or more refer to less than 1% (weight)." single crystal form " refers to through X-ray powder diffraction
Detection is the macitentan crystal form of single crystal form.
In the present invention, " crystal " or " crystal form " may be used interchangeably, and refer to by shown X-ray powder diffraction figure etc.
What characterization was confirmed.Experimental error therein depends on the purity of instrument condition, the preparation of sample and sample.In general, X-ray powder
Last diffraction pattern can be changed with the condition of instrument.In particular, it should be pointed out that the relative intensity of X-ray powder diffraction figure
It may also change with the variation of experiment condition, so the order of peak intensity should not be considered.In addition, the experiment of peak angle degree misses
Difference allows generally for ± 0.2 ° of error usually 5% or less.It is, therefore, to be understood that crystal form in the present invention
X ray powder diffraction patterns need not be completely the same with the X-ray powder diffraction figure in embodiment, any to have and these collection of illustrative plates bases
The crystal form of this same or similar collection of illustrative plates is within the scope of the present invention.
Unless stated otherwise, " anhydride " refers to macitentan crystal form through TGA measurements containing not more than in the present invention
The water of 1.5% (weight ratio) or not more than 1% (weight ratio).
Purpose according to the present invention, the present invention provide a kind of pharmaceutical composition, and it includes the present invention of therapeutically effective amount
Macitentan crystal form II, macitentan methylate crystal, macitentan nitromethane compound crystal, macitentan methyl- tert fourth
Base etherate crystal or its combination and at least one pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention can be solid-state or liquid.If the pharmaceutical composition is liquid, above-mentioned macitentan
Crystal form II, macitentan methylate crystal, macitentan nitromethane compound crystal and macitentan methyl tertbutyl etherificate
Object crystal remains solid in the fluid composition, such as suspension.
Pharmaceutically acceptable carrier of the present invention includes but not limited to：Diluent, for example, starch, pregelatinized starch,
Lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate, mannitol, sorbierite, sugar etc.；Adhesive, for example, Ah
Draw primary glue, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol etc.；It collapses
Solve agent, such as starch, sodium starch glycollate, pregelatinized starch, crospovidone, croscarmellose sodium, colloid two
Silica etc.；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate etc.；Glidant, such as glue
Body silica etc.；Complex forming agents, such as the cyclodextrin and resin of various ranks；Rate of release controlling agent, such as hydroxypropyl
Base cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methylcellulose, methyl methacrylate,
Wax etc..Other available pharmaceutically acceptable carriers include but not limited to film forming agent, plasticizer, colorant, flavoring agent, viscosity
Conditioning agent, preservative, antioxidant etc..
The present invention macitentan crystal form II, macitentan methylate crystal, macitentan nitromethane compound crystal,
Macitentan methyl tertbutyl etherate crystal or its combination are suitable for being prepared into various dosage forms.Such as it can be configured to：Oral formulations,
Can be conventional, dispersible, chewable including solid oral dosage form such as tablet, capsule, granule, pill, powder etc.
, Orally dissolving or rapid melting preparation, liquid oral dosage form such as syrup, suspension, dispersant, emulsion etc.；Injection
Preparation such as solution, dispersant and lyophilized composition.Formula may be adapted to the quick release, sustained release or adjusting of active ingredient
Release.The administration route of described pharmaceutical composition includes oral, intravenous injection, hypodermic injection, cutaneous penetration, rectally, drop
Nasal administration, eye drop administration etc..Preferably, described pharmaceutical composition is oral formulations or ejection preparation；It is highly preferred that the drug
Composition is solid orally ingestible, including tablet, capsule, granule, pill and powder.
Described pharmaceutical composition can be prepared using well known to a person skilled in the art methods in the prior art.It is preparing
When, macitentan crystal form II of the invention, macitentan methylate crystal, macitentan nitromethane compound crystal, Ma Xi
For smooth methyl tertbutyl etherate crystal or its combination and one or more pharmaceutically acceptable carriers, optional one kind or more
The other active components of kind mix.Solid pharmaceutical preparation can be prepared by the techniques such as mixing, pelletizing.
Purpose according to the present invention, the present invention provide the macitentan crystal form II, macitentan methylate crystal, horse
West is used for for smooth nitromethane compound crystal, macitentan methyl tertbutyl etherate crystal and described pharmaceutical composition in preparation
Treatment by Endothelin increase caused by with vessel retraction, cell Proliferation, the relevant disease of inflammation, such as hypertension, pulmonary hypertension,
Pulmonary hypertension, coronary heart disease, heart failure, kidney and myocardial atrophy, kidney failure, cerebral ischemia, cerebral angiospasm, dementia, inclined head
Bitterly, subarachnoid hemorrhage, thunder Na Shi syndromes, portal hypertension, arteriosclerosis, the restenosis of postangioplasty,
Purposes in the drug of the diseases such as cancer, asthma.
Purpose according to the present invention, the invention further relates to treatment hypertension, pulmonary hypertension, pulmonary hypertension, coronary heart disease,
Heart failure, kidney and myocardial atrophy, kidney failure, cerebral ischemia, cerebral angiospasm, dementia, antimigraine, subarachnoid hemorrhage, thunder
The side of the diseases such as Na Shi syndromes, portal hypertension, arteriosclerosis, the restenosis of postangioplasty, cancer, asthma
Method, including the patient is given therapeutically effective amount the present invention macitentan crystal form II, macitentan methylate crystal,
Macitentan nitromethane compound crystal, macitentan methyl tertbutyl etherate crystal or its combination or its pharmaceutical composition.
The patient refers to mammal, particularly the mankind.The dosage of drug depend on the type of active ingredient, patient age and
Demand and application method, the scope of usual dosage is that per kilogram human body weight uses 0.1~50 milligram daily.
Description of the drawings
The XRPD collection of illustrative plates of Fig. 1 macitentan crystal forms I.
The DSC collection of illustrative plates of Fig. 2 macitentan crystal forms I.
The XRPD collection of illustrative plates of Fig. 3 macitentan crystal forms II.
The PLM collection of illustrative plates of Fig. 4 macitentan crystal forms II.
The DSC collection of illustrative plates of Fig. 5 macitentan crystal forms II.
The TGA collection of illustrative plates of Fig. 6 macitentan crystal forms II.
The dynamic water absorption figure of Fig. 7 macitentan crystal forms II.
The XRPD collection of illustrative plates of Fig. 8 macitentan methylate crystal.
The PLM collection of illustrative plates of Fig. 9 macitentan methylate crystal.
The XRPD collection of illustrative plates of Figure 10 macitentan nitromethane compound crystal.
The XRPD collection of illustrative plates of Figure 11 macitentan methyl tertbutyl etherate crystal.
Figure 12 macitentan crystal forms II by embodiment 13 carry out stability place front and rear XRPD collection of illustrative plates (from top to bottom according to
It is secondary be sample when preparing and be placed at room temperature in cillin bottle 3 months after sample).
Figure 13 macitentan crystal forms I carries out the XRPD collection of illustrative plates of stability of crystal form tabletting experiment (from top to bottom by embodiment 24
Sample be crystal form I, the auxiliary material by 4 tablet formulation physical mixed of table, the crystal form I tablets that are prepared by embodiment 24 successively).
Figure 14 macitentan crystal forms II carries out the XRPD collection of illustrative plates of stability of crystal form tabletting experiment (from top to bottom by embodiment 24
Sample be crystal form II, the auxiliary material by 4 tablet formulation physical mixed of table, the crystal form II pieces that are prepared by embodiment 24 successively
Agent).
Specific embodiment
The application compound and its crystal or crystalline substance is described in detail with further reference to following embodiment, the embodiment in the application
Type, its preparation method and application.It will be apparent for a person skilled in the art that many changes for both material and method
It can implement in the case where not departing from the application scope.
Experiment instrument used
Instrument used in X-ray powder diffraction detection (XRPD) is Bruker D8 Advance
Diffractometer uses K α X-ray of the copper target wavelength for 1.54nm, under the operating condition of 40kV and 40mA, θ -2 θ surveys
Angle instrument, Mo monochromators, Lynxeye detectors.Instrument is detected before use with diamond dust.Acquisition software is Diffrac Plus
XRD Commander.Sample is tested at ambient temperature, and sample is placed on SiP on pieces.Testing conditions are as follows：Angular range：3-
40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：It walks within 0.2 second-1。
Polarization microscope (PLM) collection of illustrative plates is picked up from XP-500E polarization microscopes (the limited public affairs of the rectangular optical instrument in Shanghai
Department).A small amount of powder sample is taken to be placed on glass slide, a small amount of mineral oil is added dropwise to better disperse powder sample, covered,
Then sample is placed on objective table, selects the pattern of suitable amplification factor observing samples and taken pictures.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200 MDSC, and instrument control software is Thermal
Advantage, analysis software are Universal Analysis.1-10 milligrams of sample is usually taken to be positioned in aluminium crucible, with
The heating rate of 10 DEG C/min dries N in 40mL/min2Protection under sample risen to 250 DEG C from room temperature.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500 TGA, and instrument control software is Thermal
Advantage, analysis software are Universal Analysis.5-15mg samples is usually taken to be positioned in platinum crucible, are used
The mode of high resolution detection is segmented, N is dried in 40mL/min with the heating rate of 10 DEG C/min2Protection under by sample from room
Temperature rises to 300 DEG C, while weight change of the TA software records samples in temperature-rise period.
Isothermal adsorption analysis (DVS) data are picked up from TA Instruments Q5000 TGA, and instrument control software is
Thermal Advantage, analysis software are Universal Analysis.1-10mg samples is usually taken to be positioned over platinum crucible
It is interior, TA software records sample relative humidity from 0% to 90% to the weight change in 0% change procedure.According to the tool of sample
Body situation also can use different absorption and De contamination step to sample.
Nucleus magnetic hydrogen spectrum data (1H NMR) it picks up from Bruker Avance II DMX 400MHZ nuclear magnetic resonance chemical analysers.
1-5mg samples are weighed, with 0.5mL deuterochloroforms (CDCl3) dissolve, it is made into the solution of 2mg/mL-10mg/mL.
High performance liquid chromatography (HPLC) analysis data are picked up from Agilent 1260, B.04 chem workstation is.Corresponding ginseng
Number is as follows：Chromatographic column Eclipst XDB-C18,5 μm, 4.6 × 250mm, H-005#, 25 DEG C, flow velocity 0.3mL/min of column temperature flows
Dynamic 97% acetonitrile of phase and 3% water, wavelength 254nm, sample size 10ul and run time 20 minutes.
Preparation example 1
The method of reference literature J.Med.Chem.2012,55,7849 descriptions prepares N- [5- (4- bromophenyls) -6- [2-
[(the bromo- 2- pyrimidine radicals of 5-) oxygroup]-ethyoxyl] -4- pyrimidine radicals]-N '-sulfonyl propyl amine (macitentan) crystal form I.Specifically
For：
Sodium hydride (1.67g, 69.6mmol, 55% content are in mineral oil) is washed twice with 10mL n-hexanes, n-hexane
Solution abandons, and the sodium hydride after washing is dissolved in 200mL tetrahydrofurans, N- [5- (4- bromophenyls) -6- [2- [(hydroxyls are added portionwise
Ethyoxyl) -4- pyrimidine radicals]-N '-sulfonyl propyl amine (10.0g, 23.2mmol), mixture stirring 15 minutes, addition 400mL
DMF dilutes, and is eventually adding the bromo- 2- chlorine pyrimidines (5.38g, 27.8mmol) of 5-, and reaction solution is warming up to 60 DEG C, when heat preservation 2 is small, reaction
It completes.Reaction solution is poured into the aqueous citric acid solution of 250mL10%, is added in ethyl acetate and is extracted twice, each 300mL acetic acid second
Ester merges organic phase, is washed with water 2 times, each 200mL water, organic to be added to magnesium sulfate drying, filters, filtrate decompression concentration,
Crude product obtains target product white powder 11.9g, molar yield 88% with 100mL recrystallizing methanols.
XRPD collection of illustrative plates is as shown in Figure 1.
1HNMR(CDCl3):8.51(s,2H),8.49(s,1H),7.58-7.61(m,2H),7.16-7.19(m, 2H),
5.61 (t, J=6.2Hz, 1H), 4.73-4.76 (m, 2H), 4.62-4.65 (m, 2H), 2.98 (q, J=6.8Hz, 2H),
1.58-1.62 (m, 2H), 0.96 (t, J=7.4Hz, 3H)；It is shown as macitentan.
DSC collection of illustrative plates is as shown in Fig. 2, display：135 DEG C of fusing point and document Med.Chem.2012, the Ma Xi in 55,7849
It is consistent for the fusing point (135-136 DEG C) of smooth crystal form (crystal form I).
Embodiment 1
9.8mg macitentan is taken in 5mL vials, adds in 0.9mL methanol, suspension is formed, 1 is stirred at 60 DEG C
My god, white crystal is precipitated, is separated by filtration, is eluted 2 times with methanol, when room temperature in vacuo drying 1 is small, obtains macitentan methylate
Crystal.Yield 8.6mg, yield 85%.
XRPD collection of illustrative plates is as shown in Figure 8.
1HNMR(CDCl3):8.52(s,2H),8.50(s,1H),7.59-7.61(m,2H),7.17-7.19(m, 2H),
5.65 (t, J=6.2Hz, 1H), 4.73-4.76 (m, 2H), 4.63-4.65 (m, 2H), 3.52 (s, 2H), 2.98 (q, J=
6.8Hz, 2H), 1.58-1.63 (m, 2H), 1.30-1.52 (m, 7H), 0.97 (t, J=7.4Hz, 3H).Display：With preparation example 1
The macitentan crystal form I of preparation is compared, and methanol is contained in macitentan methylate crystal, and per molecule macitentan is containing about 2/
3 methanol molecules.
PLM collection of illustrative plates is as shown in figure 9, show that it has preferable pattern.
Embodiment 2
50.0mg macitentan is taken in 5mL vials, adds in 0.5mL methanol, suspension is formed, is stirred at room temperature 7 days,
White crystal is precipitated, is separated by filtration, is washed 3 times with methanol, when room temperature in vacuo drying 24 is small, obtains macitentan methylate crystalline substance
Body, yield 48.1mg, yield 93%.
Embodiment 3
124.9mg macitentan is taken in 5mL vials, adds in 0.5mL methanol, suspension is formed, is stirred at room temperature 14
My god, white crystal is precipitated, is separated by filtration, is washed 3 times with methanol, when room temperature in vacuo drying 72 is small, obtains macitentan methylate
Crystal, yield 118.6mg, yield 92%.
The sample of embodiment 2,3 has XRPD collection of illustrative plates the same or similar with 1 sample of embodiment, nucleus magnetic hydrogen spectrum and PLM figures
Compose (not shown).The sample and 1 sample of embodiment for illustrating embodiment 2,3 are identical crystal.
Embodiment 4
10.0mg macitentan is taken in 5mL vials, adds in 1mL methanol, suspension is formed, 1 is stirred at 60 DEG C
My god, white crystal is precipitated, is separated by filtration, is washed 2 times with methanol, when 70 DEG C of vacuum drying 72 are small, obtains macitentan crystal form II.
Yield 7.5mg, yield 75%.
XRPD collection of illustrative plates is as shown in Figure 3.
PLM collection of illustrative plates is as shown in Figure 4.Display：Sheet crystalline state.
DSC collection of illustrative plates is as shown in figure 5, display：106 DEG C of fusing point.
TGA collection of illustrative plates is as shown in Figure 6.Display：Substantially without weightlessness before 130 DEG C, decomposition temperature is 150 DEG C.
Dynamic water absorption figure is as shown in Figure 7.Display：20%RH~80%RH weight changes are 1.5%.
Above-mentioned testing result shows macitentan crystal form II as anhydride, sheet crystalline state, and with low (the suitable heat of fusing point
Molten extrusion molding) and the good physical property such as not easy to moisture absorption.
Embodiment 5
100.1mg macitentan is taken in 5mL vials, adds in 1mL methanol, suspension is formed, is stirred at room temperature 7 days,
White crystal is precipitated, is separated by filtration, is washed 3 times with methanol, when 100 DEG C of vacuum drying 24 are small, obtains macitentan crystal form II.
Yield 90.5mg, yield 90%.
Embodiment 6
125.0mg macitentan is taken in 5mL vials, adds in 0.5mL methanol, suspension is formed, is stirred at room temperature 14
My god, white crystal is precipitated, is separated by filtration, is washed 3 times with methanol, when 120 DEG C of vacuum drying 1 are small, obtains macitentan crystal form II.
Yield 120.1mg, yield 96%.
The sample of embodiment 5,6 has XRPD collection of illustrative plates the same or similar with 4 sample of embodiment, PLM collection of illustrative plates, DSC figures
Spectrum, TGA collection of illustrative plates and dynamic water absorption figure (not shown).The sample and 4 sample of embodiment for illustrating embodiment 5,6 are identical
Crystal form.
Embodiment 7
10mL nitromethanes and 10mL water is taken to mix, be stirred at room temperature 16 it is small when, stand 2 it is small when after fetch water layer, it is as following
Nitromethane water saturation solution.
15.1mg macitentan is taken to add in the water saturation solution of 0.3mL nitromethanes in 5mL vials, formed suspended
Liquid is stirred at room temperature 7 days, is separated by filtration, and washes 2 times, when 40 DEG C of vacuum drying 24 are small, obtains macitentan nitromethane
Object crystal.Yield 13.5mg, yield 85%.
XRPD collection of illustrative plates is as shown in Figure 10.
1HNMR(CDCl3):δ8.52(s,2H),8.50(s,1H),7.59-7.61(m,2H),7.18-7.19(m, 2H),
5.65 (t, J=6.2Hz, 1H), 4.74-4.75 (m, 2H), 4.64-4.65 (m, 2H), 4.35 (s, 1.5H), 2.99 (q, J=
6.8Hz, 2H), 1.59-1.65 (m, 4H), 0.97 (t, J=7.4Hz, 3H).Display：Compared with crystal form I prepared by preparation example 1,
Macitentan nitromethane compound crystal contains nitromethane, and per molecule macitentan carries about 1/2 nitromethane molecule.
Embodiment 8
50.0mg macitentan is taken to add in the water saturation solution of 0.2mL nitromethanes in 5mL vials, formed suspended
Liquid is stirred at room temperature 14 days, is separated by filtration, and is washed with water 3 times, when 80 DEG C of vacuum drying 1 are small, obtains macitentan nitromethane
Object crystal.Yield 47.4mg, yield 90%.
Embodiment 9
1.01mg macitentan is taken to add in the water saturation solution of 1.0mL nitromethanes in 5mL vials, formed suspended
Liquid, 60 DEG C are stirred 1 day, are separated by filtration, are washed with water 2 times, when room temperature in vacuo drying 48 is small, obtain macitentan nitromethane
Compound crystal.Yield 0.45mg, yield 42%.
There is the sample of embodiment 8,9 XRPD collection of illustrative plates the same or similar with 7 sample of embodiment and nucleus magnetic hydrogen spectrum (not to show
Go out).The sample and 7 sample of embodiment for illustrating embodiment 8,9 are identical crystal.
Embodiment 10
9.9mg macitentan is taken in 5mL vials, adds in 3.3mL methyl tertiary butyl ether(MTBE)s, solution is formed, with 0.45 μ
M organic filter membrane filtrations, filtrate stand 2 days at room temperature, and white crystal is precipitated, and centrifugation when room temperature in vacuo drying 24 is small, obtains horse
Replace smooth methyl tertbutyl etherate crystal in west.Yield 8.0mg, yield 77%.
XRPD collection of illustrative plates is as shown in figure 11.
1HNMR(CDCl3):δ8.51(s,2H),8.50(s,1H),7.60-7.61(m,2H),7.18-7.19(m, 2H),
5.62 (t, J=6.2Hz, 1H), 4.74-4.76 (m, 2H), 4.63-4.65 (m, 2H), 3.62 (s, 1H), 2.99 (q, J=
6.8Hz, 2H), 1.58-1.64 (m, 12H), 1.22 (s, 4H), 0.97 (t, J=7.4Hz, 3H).Display：It is prepared with preparation example 1
Crystal form I compare, macitentan methyl tertbutyl etherate crystal contains methyl tertiary butyl ether(MTBE), and per molecule macitentan containing about
1/3 methyl tertiary butyl ether(MTBE) molecule.
Embodiment 11
5.1mg macitentan is taken in 5mL vials, adds in 2.5mL methyl tertiary butyl ether(MTBE)s, solution is formed, with 0.45 μ
M organic filter membrane filtrations stand 1 day at 40 DEG C of filtrate, and white crystal is precipitated, and centrifugation when room temperature in vacuo drying 1 is small, obtains horse
Replace smooth methyl tertbutyl etherate crystal in west.Yield 3.2mg, yield 60%.
Embodiment 12
14.9mg macitentan is taken in 20mL vials, adds in 15mL methyl tertiary butyl ether(MTBE)s, solution is formed, with 0.45
μm organic filter membrane filtration, filtrate stand 14 days at room temperature, and white crystal is precipitated, and centrifugation when room temperature in vacuo drying 72 is small, obtains
Macitentan methyl tertbutyl etherate crystal.Yield 12.8mg, yield 82%.
The sample of embodiment 11,12 has XRPD collection of illustrative plates the same or similar with 10 sample of embodiment and nucleus magnetic hydrogen spectrum (not
It shows).The sample and 10 sample of embodiment for illustrating embodiment 11,12 are identical crystal.
Embodiment 13
10mg macitentan crystal forms II is taken to be placed in 10mL cillin bottles to seal, room temperature preservation 3 months respectively carries out before and after placement
XRPD is characterized.XRPD collection of illustrative plates is as shown in figure 12, display：It is constant that macitentan crystal form II places front and rear stable crystal form at room temperature.
Embodiment 14
Macitentan methyl tertbutyl etherate crystal prepared by the present invention is after 40 DEG C of desolventizings, sampling detection.Its
XRPD collection of illustrative plates is similar to Fig. 1, and macitentan crystal form I is had been converted to after showing its desolventizing.
Embodiment 15
At 70 DEG C after desolventizing, sampling detects macitentan methylate crystal prepared by the present invention.Its XRPD schemes
Spectrum is similar to Fig. 3, is changed into macitentan crystal form II after showing its desolventizing.
Embodiment 16
At 40 DEG C after desolventizing, sampling detects macitentan nitromethane compound crystal prepared by the present invention.Its
XRPD collection of illustrative plates is changed into amorphous article after showing its desolventizing.
Embodiment 17
Crystal form I prepared by preparation example 1 and crystal form II prepared by the present invention is taken to carry out solubility contrast experiment.
Respectively at adding about 10mg samples and 250mL purified waters in 500mL vials, respectively in ultrasonic (40Khz ultrasound work(
Rate) 15 minutes, about 110mL suspensions is respectively taken within 60 minutes to filter, filtrate is taken to be settled to 100mL, be placed in round-bottomed flask be spin-dried for it is molten
Agent adds a small amount of acetonitrile sample dissolution to be transferred in 10mL volumetric flasks, and is transferred to acetonitrile rinse flask 2 times, then by rinse liquid
In same 10mL volumetric flasks, with acetonitrile constant volume, HPLC concentration is directly surveyed after filtering.It the results are shown in Table 1.
Embodiment 18
Crystal form I prepared by preparation example 1 and crystal form II prepared by the present invention is taken to carry out solubility contrast experiment.
Respectively at adding 60mg samples, 0.2g lauryl sodium sulfate and 50mL purified waters in 100mL vials, respectively super
Sound (40Khz ultrasonic powers) respectively takes about 15mL suspensions to filter for 15 minutes, 60 minutes, and filtrate is taken to be settled to 10mL, is placed in round bottom
Solvent is spin-dried in flask, a small amount of acetonitrile sample dissolution is added to be transferred in 10mL volumetric flasks, and with acetonitrile rinse flask 2 times, then will
Rinse liquid is transferred in same 10mL volumetric flasks, and with acetonitrile constant volume, HPLC concentration is directly surveyed after filtering.It the results are shown in Table 1.
Embodiment 19
Take crystal form I, methylate crystal, crystal form II, the nitromethane compound crystal of the invention prepared prepared by preparation example 1
Solubility contrast experiment is carried out with methyl tertbutyl etherate crystal.
Respectively at adding 200mg samples, 1.0g lauryl sodium sulfate and 50mL purified waters in 100mL vials, exist respectively
Ultrasonic (40Khz ultrasonic powers) respectively takes about 15mL suspensions to filter for 15 minutes, 60 minutes, and filtrate is taken to be settled to 10mL, is placed in circle
Solvent is spin-dried in the flask of bottom, a small amount of acetonitrile sample dissolution is added to be transferred in 10mL volumetric flasks, and with acetonitrile rinse flask 2 times, then
Rinse liquid is transferred in same 10mL volumetric flasks, with acetonitrile constant volume, HPLC concentration is directly surveyed after filtering.It the results are shown in Table 1.
Embodiment 20
Crystal form I prepared by preparation example 1 and crystal form II prepared by the present invention is taken to carry out solubility contrast experiment.
Respectively at adding 60mg samples, 0.2g Tween-80s and 50mL purified waters in 100mL vials, respectively in ultrasound
(40Khz ultrasonic powers) respectively takes about 15mL suspensions to filter for 15 minutes, 60 minutes, and filtrate is taken to be settled to 10mL, is placed in round bottom burning
Solvent is spin-dried in bottle, a small amount of acetonitrile sample dissolution is added to be transferred in 10mL volumetric flasks, and with acetonitrile rinse flask 2 times, then will moisten
Washing lotion is transferred in same 10mL volumetric flasks, and with acetonitrile constant volume, HPLC concentration is directly surveyed after filtering.It the results are shown in Table 1.
Embodiment 21
Crystal form I prepared by preparation example 1 and crystal form II prepared by the present invention is taken to carry out solubility contrast experiment.
Respectively at adding 60mg samples, 1.0g Tween-80s and 50mL purified waters in 100mL vials, respectively in ultrasound
(40Khz ultrasonic powers) respectively takes about 15mL suspensions to filter for 15 minutes, 60 minutes, takes filtrate constant volume 10mL, is placed in round-bottomed flask
In be spin-dried for solvent, a small amount of acetonitrile sample dissolution is added to be transferred in 10mL volumetric flasks, and with acetonitrile rinse flask 2 times, then by rinse
Liquid is transferred in same 10mL volumetric flasks, and with acetonitrile constant volume, HPLC concentration is directly surveyed after filtering.It the results are shown in Table 1.
1 solubility comparative experimental data of table counts
From table 1：Crystal form I and crystal form II are almost insoluble in pure water, but in addition surfactant sodium dodecyl base sulphur
In the case of sour sodium or Tween-80, the solubility of crystal form II in water is much larger than the solubility of crystal form I in water, and methanolizing
Object crystal, the solubility of nitromethane compound crystal and methyl tertbutyl etherate crystal in water are than crystal form I and crystal form II
Solubility in water is good.
Embodiment 22
The preparation of tablet.Formula is shown in Table 2, is as follows：
(1) by bulk pharmaceutical chemicals (API, selected from macitentan crystal form II, macitentan methylate crystal, macitentan nitro
Methanides crystal or macitentan methyl tertbutyl etherate crystal) and lactose (water) be uniformly mixed.
(2) after polyvinylpyrrolidone is dissolved with suitable 50% ethanol water, it is added in said mixture, mistake
Sieve series wet granular.
(3) by wet granular is dry, after whole grain, with crospovidone and magnesium stearate mixing, tabletting.
2 tablet formulation of table
| Ingredient | Quality (mg/ pieces) |
| API | 8.0 |
| Lactose (water) | 182.9 |
| Polyvinylpyrrolidone | 4.1 |
| Crospovidone | 4.0 |
| Magnesium stearate | 1.0 |
| It is total | 200 |
Embodiment 23
The preparation of tablet.Formula is shown in Table 3, is as follows：
(1) by API (selected from macitentan crystal form II, macitentan methylate crystal, macitentan nitromethane compound
Crystal or macitentan methyl tertbutyl etherate crystal) and pregelatinized starch be uniformly mixed.
(2) magnesium stearate, mixing, tabletting are added in into said mixture.
3 tablet formulation of table
Embodiment 24
Crystal form I prepared by preparation example 1 and crystal form II prepared by the present invention are taken, carries out stability of crystal form tabletting experiment.
A) the tablet formulation dosage of table 4 is pressed, by API (crystal form I or crystal form II) and crosslinked polyvinylpyrrolidone, a water and milk
Sugar, magnesium stearate and microcrystalline cellulose are uniformly mixed, 4MPa lower sheetings；
4 tablet formulation of table
| Ingredient in tablets | Dosage (mg/ pieces) |
| API (crystal form I or crystal form II) | 10.0 |
| Crosslinked polyvinylpyrrolidone | 10.0 |
| Lactose monohydrate | 108.0 |
| Microcrystalline cellulose | 120.0 |
| Magnesium stearate | 2.0 |
| It is total | 250 |
B) by tablet, with agate mortar, gently grind into fine powder solid, progress XRPD characterizations compare it and are made before and after tablet
Crystal form variation.
XRPD the result is shown in Figure 1s 3 and Figure 14, display：Compared with the crystal form before tabletting, the crystalline substance of crystal form I and crystal form II after tabletting
Type does not change；The auxiliary material and technique of 24 tablet of embodiment are on the crystal form of crystal form I and crystal form II without influence.
Embodiment 25
The crystal form I tablets prepared by 24 method of embodiment and crystal form II tablets are taken, carries out dissolution rate comparative experiments.
With reference to《Chinese Pharmacopoeia》The leaching condition of " Benorilate Tablets " measures dissolution rate in 2010 editions, using paddle method, with 900mL
1% lauryl sodium sulfate (SDS) aqueous solution as dissolution medium, 37 DEG C, rotating speed of agitator 100r/min of temperature, respectively
3mL is sampled when 10min, 20min, 30min, 60min, is supplied after every sub-sampling with 1% SDS solution, when HPLC measures each
Between put sample concentration, calculate dissolution percentage.Dissolution data result is shown in Table 5.
5 crystal form I tablets of table, the dissolution data of crystal form II tablets
The results show of table 5：Dissolution percentage of the tablet in 30min of the crystal form II of the present invention up to more than 95%,
And dissolution percentage of the tablet of known crystal form I in 30min is less than 85%, therefore the dissolution of the tablet of the crystal form II of the present invention is fast
Rate is faster than the dissolution rate of the tablet of known crystal form I.Illustrate when preparing quick releasing formulation, the preparation of crystal form II of the invention is more easy to
Reach the requirement of product.
Cited all patent documents and non-patent publications in this specification, quoting in a manner of its full text
It is incorporated herein.
The general of the above-mentioned invention to involved in the application describes and the description of its specific embodiment should not be understood
For be to the inventive technique scheme form limitation.Those skilled in the art can not disobey according to disclosure herein
On the premise of the involved invention inscape of the back of the body, to above-mentioned general description or/and specific embodiment (including embodiment)
In public technology feature increased, reduced or combined, formed and belong to other technical solutions of the invention.
Claims (13)
1. the methylate crystal of structural formula macitentan as follows,
It is characterized in that, radiated using Cu-K α, the X-ray powder diffraction of the methylate crystal is 8.9 in 2 θ of the angle of diffraction
±0.2°、11.3±0.2°、12.4±0.2°、13.9±0.2°、15.2±0.2°、18.6±0.2°、18.9±0.2°、19.3
There is characteristic peak at ± 0.2 °, 20.1 ± 0.2 °, 21.2 ± 0.2 °, 24.0 ± 0.2 ° and 25.3 ± 0.2 °.
2. the methylate crystal of macitentan according to claim 1, which is characterized in that the methylate crystal
X-ray powder diffraction has characteristic peak and its relative intensity at following 2 θ of the angle of diffraction：
3. the preparation method of the methylate crystal of macitentan any one of claim 1~2, comprises the following steps：
Macitentan is suspended in methanol and forms suspension, is stirred crystallization, then separates the solid of precipitation, room temperature in vacuo is done
It is dry, obtain the methylate crystal of the macitentan；The dosage of the macitentan is that 10-250mg is added in per ml methanol
Macitentan；The recrystallization temperature is room temperature to 60 DEG C.
4. the preparation method of macitentan methylate crystal according to claim 3, which is characterized in that the Ma Xi is replaced
Smooth dosage is that 10-100mg macitentan is added in per ml methanol.
5. the preparation method of macitentan methylate crystal according to claim 3, which is characterized in that the crystallization temperature
It spends for room temperature.
6. the preparation method of macitentan methylate crystal according to claim 3, which is characterized in that during the crystallization
Between be 1-14 days.
7. the preparation method of macitentan methylate crystal according to claim 6, which is characterized in that during the crystallization
Between be 1-7 days.
8. the preparation method of macitentan methylate crystal according to claim 3, which is characterized in that when described dry
Between for 1-72 it is small when.
9. the preparation method of macitentan methylate crystal according to claim 8, which is characterized in that when described dry
Between for 1-24 it is small when.
10. a kind of pharmaceutical composition, the methanol of macitentan any one of the claim 1~2 comprising therapeutically effective amount
Compound crystal and at least one pharmaceutically acceptable carrier.
11. pharmaceutical composition according to claim 10, which is characterized in that described pharmaceutical composition is oral formulations or note
Penetrate preparation.
12. pharmaceutical composition according to claim 11, which is characterized in that the oral formulations are solid orally ingestible,
The solid orally ingestible is tablet, capsule, granule, pill or powder.
13. any one of methylate crystal or claim 10-12 of macitentan any one of claim 1~2
The pharmaceutical composition is being prepared for treating pulmonary hypertension, pulmonary hypertension, coronary heart disease, heart failure, kidney failure, brain
Ischemic, cerebral angiospasm, dementia, antimigraine, subarachnoid hemorrhage, thunder Na Shi syndromes, portal hypertension, artery sclerosis
Disease, the restenosis of postangioplasty, cancer, asthma drug in purposes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310237972 | 2013-06-14 | ||
| CN2013102379728 | 2013-06-14 | ||
| CN201480001614.XA CN104411691B (en) | 2013-06-14 | 2014-05-22 | ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480001614.XA Division CN104411691B (en) | 2013-06-14 | 2014-05-22 | ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105693624A CN105693624A (en) | 2016-06-22 |
| CN105693624B true CN105693624B (en) | 2018-05-18 |
Family
ID=52021638
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480001614.XA Active CN104411691B (en) | 2013-06-14 | 2014-05-22 | ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes |
| CN201610072641.7A Active CN105693624B (en) | 2013-06-14 | 2014-05-22 | Macitentan crystal and preparation method thereof, its pharmaceutical composition and purposes |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480001614.XA Active CN104411691B (en) | 2013-06-14 | 2014-05-22 | ACT-064992 crystal and preparation method thereof, its pharmaceutical composition and purposes |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN104411691B (en) |
| WO (1) | WO2014198178A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104897833B (en) * | 2015-05-15 | 2017-03-01 | 成都克莱蒙医药科技有限公司 | A kind of detection method of ACT-064992 intermediate and its application |
| CN106924190A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of ACT-064992 microballoon and preparation method thereof |
| CN107868055B (en) * | 2016-09-28 | 2020-02-07 | 普济生物科技（台州）有限公司 | Preparation method of macitentan |
| WO2018153925A1 (en) * | 2017-02-22 | 2018-08-30 | Amneal Pharmaceuticals Company Gmbh | Stable pharmaceutical compositions comprising macitentan |
| TW202103703A (en) * | 2019-04-05 | 2021-02-01 | 瑞士商艾克泰聯製藥有限公司 | Methods for treating portopulmonary hypertension |
| US20220249381A1 (en) * | 2019-07-05 | 2022-08-11 | TECNIMEDE - Sociedade Técnico-medicinal, SA | Compressed macitentan compositions, methods and uses thereof |
| EP4297754A1 (en) * | 2021-02-26 | 2024-01-03 | Actelion Pharmaceuticals Ltd | Methods for treating pulmonary hypertension in patients with left ventricular assist device implantation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101262847A (en) * | 2005-09-12 | 2008-09-10 | 埃科特莱茵药品有限公司 | Stable pharmaceutical composition comprising a pyrimidine-sulfamide |
| CN101511365A (en) * | 2006-08-29 | 2009-08-19 | 埃科特莱茵药品有限公司 | Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100432070C (en) * | 2000-12-18 | 2008-11-12 | 埃科特莱茵药品有限公司 | Novel sulfamides and their use as endothelin receptor antagonists |
-
2014
- 2014-05-22 CN CN201480001614.XA patent/CN104411691B/en active Active
- 2014-05-22 WO PCT/CN2014/078137 patent/WO2014198178A1/en active Application Filing
- 2014-05-22 CN CN201610072641.7A patent/CN105693624B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101262847A (en) * | 2005-09-12 | 2008-09-10 | 埃科特莱茵药品有限公司 | Stable pharmaceutical composition comprising a pyrimidine-sulfamide |
| CN101511365A (en) * | 2006-08-29 | 2009-08-19 | 埃科特莱茵药品有限公司 | Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| "The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist";Martin H. Bolli等;《Journal of Medicinal Chemistry》;20120803;第55卷(第17期);第7849-7861页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105693624A (en) | 2016-06-22 |
| WO2014198178A1 (en) | 2014-12-18 |
| CN104411691B (en) | 2016-05-25 |
| CN104411691A (en) | 2015-03-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105693624B (en) | Macitentan crystal and preparation method thereof, its pharmaceutical composition and purposes | |
| CN104603123B (en) | Solid-state form of bent Ge Lieting and its production and use | |
| CN105073740B (en) | The salt and crystal formation or amorphous article of a kind of compound, its preparation method, the pharmaceutical composition containing them and purposes | |
| CN105121409B (en) | Crystalline form of dolutegravir sodium salt and preparation method therefor | |
| CN106187926B (en) | Carboxylic acids URAT1 inhibitor, preparation method and its purposes in hyperuricemia and gout treatment of the structure containing diarylmethanes | |
| US9556164B2 (en) | Salts of Dasatinib in crystalline form | |
| CN106543085A (en) | Solid-state form of the miscellaneous Shandong amine of grace and its production and use | |
| US8796279B2 (en) | 4′-demethylepipodophyllotoxin derivative, preparation method and use thereof | |
| CN105801568B (en) | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition | |
| CN105229001B (en) | Crystal form of oxazolidinone antibiotics and preparation method, composition and use thereof | |
| CN106928228B (en) | Ao Gelieting salt and its crystal form, their preparation method and pharmaceutical composition | |
| CN105228988B (en) | Crystal of bent Ge Lieting hemisuccinic acids salt and preparation method thereof and pharmaceutical composition | |
| CN104936947B (en) | Lorcaserin salt and its crystal, Preparation Method And The Use | |
| TW200301114A (en) | Crystals of taxane derivative and process for the production thereof | |
| CN105308043B (en) | Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes | |
| CN104955816B (en) | Crystal formation that a kind of Ansai is bent and preparation method thereof, its pharmaceutical composition and purposes | |
| CN105384730A (en) | Empagliflozin crystal forms, preparation methods and uses thereof, and pharmaceutical composition | |
| US11926586B2 (en) | Process for the preparation of ferric organic compounds | |
| CN105315266A (en) | Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid | |
| CN104603117B (en) | Amine salt and its crystal | |
| CN103755767B (en) | Polymorph of CDDO ethyl ester and application thereof | |
| JPH02121924A (en) | Carcinostatic agent effect-enhancing agent | |
| CN108727391A (en) | PARP inhibitor compounds are amorphous and its preparation method and application | |
| CN104736521A (en) | Crystal form of regorafenib salt and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191018 Address after: 318000 room 3-1-202, Tengda new village, Jiaojiang District, Taizhou City, Zhejiang Province Patentee after: Ni Yun 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. |