WO2022198361A1 - 一种达比加群酯乙酯盐酸盐新晶型及其制备方法和应用 - Google Patents

一种达比加群酯乙酯盐酸盐新晶型及其制备方法和应用 Download PDF

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WO2022198361A1
WO2022198361A1 PCT/CN2021/082000 CN2021082000W WO2022198361A1 WO 2022198361 A1 WO2022198361 A1 WO 2022198361A1 CN 2021082000 W CN2021082000 W CN 2021082000W WO 2022198361 A1 WO2022198361 A1 WO 2022198361A1
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crystal form
ethyl ester
dabigatran etexilate
dabigatran
new crystal
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PCT/CN2021/082000
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English (en)
French (fr)
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贾慧娟
侯伟
王艳鑫
贾天格
任晓慧
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天津睿创康泰生物技术有限公司
北京睿创康泰医药研究院有限公司
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Priority to PCT/CN2021/082000 priority Critical patent/WO2022198361A1/zh
Priority to CN202180095865.9A priority patent/CN117043150A/zh
Publication of WO2022198361A1 publication Critical patent/WO2022198361A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the technical field of chemical pharmacy, in particular to a new crystal form of dabigatran etexilate ethyl ester hydrochloride and a preparation method and application thereof.
  • Cardiovascular and cerebrovascular diseases are a general term for cardiovascular and cerebrovascular diseases, which generally refer to ischemic or hemorrhagic diseases of the heart, brain and whole body caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. disease. Cardiovascular and cerebrovascular disease is a common disease that seriously threatens the health of human beings, especially the middle-aged and elderly people over 50 years old. It has the characteristics of high morbidity, high disability and high mortality.
  • cardiovascular and cerebrovascular diseases such as cerebral thrombosis, cerebral infarction, various embolisms, myocardial infarction, coronary heart disease, atherosclerosis and other cardiovascular and cerebrovascular diseases claim the lives of 12 million people, which is close to a quarter of the total number of deaths in the world. Become the "Number One Health Killer” that surpasses malignant tumors.
  • thrombootic disease is one of the main forms of cardiovascular and cerebrovascular diseases. The diseases caused by the two pathological processes of thrombosis and thromboembolism are clinically called thrombotic diseases.
  • Thrombosis refers to a semi-clot-like substance formed on the surface of the blood vessel or the intima of the heart by blood components during the blood flow process, causing stenosis and occlusion of the blood vessel cavity, causing ischemia and infarction of major organs and causing various dysfunctions. a disease.
  • Thrombotic diseases are characterized by high morbidity, high recurrence rate, high disability rate, and high mortality rate.
  • PCI percutaneous coronary intervention
  • Antithrombotic drugs are receiving more and more attention. attention, the market size has steadily increased.
  • Antithrombotic drugs are used for the prevention and treatment of thromboembolic diseases and can be divided into antiplatelet aggregation drugs, anticoagulant drugs and thrombolytic drugs.
  • Dabigatran etexilate capsules are a new generation of non-vitamin K antagonist oral anticoagulant drugs for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This is the first oral anticoagulant with long-term indications since warfarin was approved for marketing. Pradaxa capsules were developed by Boehringer Ingelheim and approved by the US FDA in October 2010, and have entered dozens of countries around the world so far.
  • Pradaxa capsules are indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation; treating deep vein thrombosis and pulmonary embolism; reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism and for deep vein thrombosis after hip replacement Prevention of thrombosis and pulmonary embolism.
  • the active ingredient of Pradaxa capsules is the mesylate of dabigatran etexilate (Dabigatran E texilate M esylate, hereinafter referred to as DEM), and its chemical name is 3-[[[2-[[[4-[[[( Ethyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl Ester mesylate, the chemical formula is C 34 H 41 N 7 O 5 ⁇ CH 4 O 3 S, the molecular weight is 723.86, and the CAS# is 872728-81-9.
  • the structural formula of DEM is shown in formula (I).
  • Dabigatran etexilate is a novel, chemically synthesized direct thrombin inhibitor, a prodrug of dabigatran (Dabigatran, BIBR953), a non-peptide thrombin inhibitor.
  • the structure is shown in formula (II).
  • Dabigatran etexilate mesylate capsules are converted into dabigatran with direct anticoagulant activity after oral absorption through gastrointestinal tract. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing the cleavage of fibrinogen to fibrin, thereby blocking the final step of the coagulation cascade network and thrombus formation.
  • Dabigatran dissociates from the fibrin-thrombin conjugate and exerts a reversible anticoagulant effect.
  • DEM is a white to yellow crystalline powder. Soluble in methanol, slightly soluble in isopropanol, slightly soluble in ethanol. The solubility of DEM free base in aqueous solution is pH-dependent. When the pH of the aqueous solution is less than 1, its solubility exceeds 80 mg/mL. As the pH increases, its solubility decreases sharply.
  • the existing prodrug, dabigatran etexilate mesylate, is used as a medicinal active ingredient of an oral anticoagulant under physiological pH (pH1.0-pH7.4) conditions.
  • the low pH stomach enters the high pH intestinal tract, and its solubility drops sharply, which in turn causes the drug to precipitate into a solid state in the digestive tract and cannot be absorbed, resulting in a very low oral bioavailability, about 3% to 7%.
  • the prior art mainly involves two schemes, one is a pharmaceutical composition. It contains acidic substances that can adjust the pH value of the microenvironment during the drug release process. Such acidic substances include acidic amino acids, organic acids, inorganic acids, and acidic salts, etc.
  • the selected preparation process generally separates the acidic substances from the DEM is isolated to avoid direct contact between acidic substances and drug molecules, which may cause drug degradation.
  • this method is effective in solving the problems caused by drugs entering the small intestine from the stomach after oral administration. Precipitation of the drug due to increased pH is helpful; this solution has the advantage that the oral bioavailability of Pradaxa capsules is less affected by the patient taking the drug after eating or concurrently taking a PPI inhibitor (which increases gastric pH).
  • a PPI inhibitor which increases gastric pH.
  • the acid particles coated with the barrier coating must be uniform, nearly spherical and with low surface roughness, to avoid the barrier layer falling off or the barrier defect caused by the rough surface caused by the oversized acidic particles, which will destroy the shelf life of the product. , high rejection rate, high production cost, and difficult to control the production process.
  • Another solution is to prepare a solid dispersion of DEM through a new formulation technology, such as spray drying technology or hot melt extrusion technology, to change the DEM crystalline drug into an amorphous drug to improve the solubility of the drug.
  • Aqueous or amphiphilic macromolecular carriers can be used to inhibit the precipitation of drugs with increasing pH; or DEM or free form can be prepared into a self-emulsifying system, which can be compressed into tablets or encapsulated after being adsorbed by an adsorbent.
  • Dabigatran ethyl was once used as the preparation process intermediate and in vivo active metabolic intermediate of the marketed drug dabigatran etexilate. ) shown.
  • dabigatran etexilate (BIBR1048) is metabolized under the action of intestinal mucosal cells and liver ester hydrolase to produce two intermediates, an inactive metabolic intermediate (BIBR1087) and an active metabolic intermediate (BIBR951). Dabigatran etexilate and BIBR1087 are both substrates of efflux protein P-gp, while dabigatran etexilate (BIBR951) is neither a substrate nor an inducer of efflux protein P-gp.
  • dabigatran etexilate According to the chemical structures of dabigatran etexilate, BIBR1087 and BIBR951, dabigatran etexilate free base and BIBR1087 have similar dissolution behavior, and their solubility is pH-dependent, pH4.5 ⁇ pH7.4, and the solubility is lower than 0.01 mg/ml.
  • Dabigatran ethyl has high solubility (25°C) in the pH range of human digestive tract (pH 1.0-7.4), and dabigatran ethyl is used as a medicinal active ingredient without solving the problem of solubility.
  • the active ingredient of the existing listed product Paradax capsule is dabigatran etexilate.
  • dabigatran etexilate is the substrate of P-gp efflux protein, and the absorption of dabigatran etexilate in the gastrointestinal tract is incomplete. Therefore, the oral bioavailability of the marketed Paradax capsules is only 3% to 7%.
  • dabigatran and dabigatran ethyl are neither substrates of P-pg nor inhibitors or inducers of P-gp.
  • oral administration of dabigatran etexilate capsules while taking ketoconazole (P-gp inhibitor) increased the Cmax and AUC of dabigatran by 135% and 138%, respectively; while once daily rifampicin (P-gp inhibitor) -gp inducer) 600 mg for 6 consecutive days, taking dabigatran etexilate capsules on the seventh day, its AUC and Cmax decreased by 66% and 67%, respectively.
  • the current crystal forms of dabigatran etexilate are all used as a synthetic intermediate for the preparation of dabigatran etexilate APIs, and have problems such as poor stability, low yield, and low purity, which affect its clinical application. If a stable pharmaceutical crystal form can be developed, it is the key to solve the major problems existing in the prior art.
  • the technical problem to be solved by the present invention is to provide a new crystal form of dabigatran etexilate ethyl ester hydrochloride and its preparation method and application, and the new crystal form of dabigatran etexilate ethyl ester hydrochloride prepared
  • the physical stability and chemical stability are good, and at the same time, compared with dabigatran etexilate mesylate, it has better water solubility in the physiological pH range.
  • the present invention provides a new crystal form of dabigatran etexilate ethyl ester hydrochloride, the X-ray powder diffraction pattern has diffraction peaks at 2 ⁇ 0.2°, and the 2 ⁇ is at least selected from 5.42 ⁇ 0.2 Any of °, 9.08 ⁇ 0.2°, 11.88 ⁇ 0.2°, and 14.14 ⁇ 0.2°.
  • the invention prepares a new crystal form of dabigatran etexilate hydrochloride with good physical stability and chemical stability, so that dabigatran ethyl can be used as a prodrug of dabigatran, and Bigatran ethyl ester has obvious advantages from the structure of the compound, good solubility under pH1.0-pH7.4, non-P-gp, substrate or inhibitor or inducer of P450 enzymes, and then solves the problem of current problems. There are technical problems.
  • the new crystal form of dabigatran etexilate ethyl hydrochloride according to the present invention is hydrochloride monohydrate, and its theoretical water content is 3.25%.
  • the compound of formula (IV) has sufficient crystallinity and good physicochemical stability.
  • the 2 ⁇ is at least selected from 5.42 ⁇ 0.2°, 9.08 ⁇ 0.2°, 11.88 ⁇ 0.2°, 14.14 ⁇ 0.2°, 16.20 ⁇ 0.2°, 17.02 ⁇ 0.2°, 17.58 ⁇ 0.2°, 19.58 ⁇ 0.2° , any one of 20.43 ⁇ 0.2°, 21.28 ⁇ 0.2°, and 21.74 ⁇ 0.2°.
  • the crystal form of dabigatran etexilate ethyl ester hydrochloride monohydrate, using Cu-K ⁇ radiation and X-ray powder diffraction (XRPD) pattern represented by diffraction angle 2 ⁇ shows at least one, more preferably at least one Two, still more preferably at least four, and most preferably all are selected from about the following characteristic peaks: 5.4 ⁇ 0.2°, 9.1 ⁇ 0.2°, 11.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 17.0 ⁇ 0.2°, 17.6 ⁇ 0.2° , 19.6 ⁇ 0.2°, 20.8 ⁇ 0.2°, 21.3 ⁇ 0.2°, 23.2 ⁇ 0.2°, 24.8 ⁇ 0.2°, 27.3 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the new crystal form of dabigatran etexilate ethyl ester hydrochloride, using Cu-K ⁇ radiation and X-ray powder diffraction (XRPD) pattern represented by diffraction angle 2 ⁇ has the following The characteristic peaks and their relative intensities shown in Table 1, the diffraction angle 2 ⁇ error is ⁇ 0.2°:
  • the X-ray powder diffraction (XRPD) pattern of the new crystal form of dabigatran etexilate hydrochloride is shown in FIG. 1 .
  • the new crystal form of dabigatran etexilate hydrochloride according to the present invention has characteristic peaks at the following positions in the infrared absorption (IR) spectrum measured by KBr tablet: 3408.91 ⁇ 5cm -1 , 3244.57 ⁇ 5cm -1 , 3035.26 ⁇ 5cm -1 , 1641.13 ⁇ 5cm -1 , 1607.38 ⁇ 5cm -1 , 1480.57 ⁇ 5cm -1 , 1178.76 ⁇ 5cm -1 , 832.31 ⁇ 5cm -1 , 739.95 ⁇ 5cm -1 .
  • IR infrared absorption
  • the new crystal form of dabigatran etexilate ethyl ester hydrochloride has an absorption peak at the following position in the infrared absorption (IR) spectrum measured by KBr tablet: 3408.91 ⁇ 5cm- 1 , 3360.73 ⁇ 5cm -1 , 3244.57 ⁇ 5cm -1 , 3035.26 ⁇ 5cm -1 , 2764.09 ⁇ 5cm -1 , 1720.59 ⁇ 5cm -1 , 1675.29 ⁇ 5cm -1 , 1641.13 ⁇ 5cm -1 , 1607.38 ⁇ 5cm -1 , 1480.57 ⁇ 5cm -1 , 1405.00 ⁇ 5cm -1 , 1330.64 ⁇ 5cm -1 , 1291.98 ⁇ 5cm -1 , 1178.76 ⁇ 5cm -1 , 1076.02 ⁇ 5cm -1 , 1032.47 ⁇ 5cm -1 , 832.31
  • the new crystal form of dabigatran etexilate hydrochloride of the present invention has an infrared absorption (IR) spectrum as shown in FIG. 2 .
  • the differential scanning calorimetry (DSC) spectrum of the new crystal form of dabigatran etexilate hydrochloride according to the present invention has two endothermic peaks in the range of 105.0°C to 155.0°C, and the peaks are 139.8°C and 155.0°C respectively. 149.6°C.
  • the new crystal form of dabigatran etexilate ethyl ester hydrochloride of the present invention has a differential scanning calorimetry (DSC) spectrum as shown in FIG. 3 .
  • thermogravimetric analysis (TGA) spectrum of the new crystal form of dabigatran etexilate hydrochloride according to the present invention shows that the weight loss is about 3.2% at 105.1°C to 150.5°C.
  • the new crystal form of dabigatran etexilate hydrochloride of the present invention has a thermogravimetric analysis (TGA) spectrum as shown in FIG. 4 .
  • TGA thermogravimetric analysis
  • thermogravimetric analysis (TGA) spectrum and the water content displayed by the moisture meter (instrument model: Metrohm 915-KF) is 3.26%, it shows that the new crystal form of dabigatran etexilate ethyl ester of the present invention is a monohydrate exist in physical form.
  • hydrochloride content of the new crystal form of dabigatran etexilate ethyl described in the present invention measured by potentiometric titration is 6.58%.
  • the new crystal form of dabigatran etexilate ethyl ester hydrochloride of the present invention has the hydrogen nuclear magnetic resonance spectrum (HNMR) as shown in FIG. 5 .
  • the new crystal form of dabigatran etexilate ethyl hydrochloride according to the present invention has a molar ratio of dabigatran ethyl ester and hydrogen chloride of 1:1.
  • the present invention provides a method for preparing the above-mentioned new crystal form of dabigatran etexilate ethyl ester hydrochloride, comprising the following steps:
  • the dabigatran ethyl ester is dispersed in water, stirred to dissolve, crystallized, the obtained solid is separated and dried to obtain a new crystal form of dabigatran etexilate ethyl ester hydrochloride.
  • the temperature of the stirring solution is 30-100°C; more preferably, it is 60-70°C.
  • the temperature of the crystallization is -10 to 40°C; more preferably, 20 to 30°C; further preferably, 25°C.
  • the drying temperature is 20-140°C; more preferably, it is 50-60°C.
  • the above preparation method can not only prepare the new crystal form of the crude dabigatran ethyl ester crystallization, but also has a strong impurity removal effect, and the obtained crystal can be used as an intermediate of dabigatran etexilate or a
  • the use of the ester as a medicinal active ingredient simplifies the purification steps of the subsequent process and improves the yield and the quality of the medicinal active ingredient.
  • the source of the crude dabigatran ethyl ester is not particularly limited in the present invention, and it can be generally commercially available, or can be prepared by a method well known to those skilled in the art.
  • the crude dabigatran ethyl ester is prepared according to the disclosed method, such as the method described in the patent documents such as J.Med.Chem.2002,45,1757-1766, WO2014012880A1, etc. Prepared by the Pinner reaction for the starting material.
  • the new crystal form of dabigatran etexilate hydrochloride provided by the present invention can be formulated into a pharmaceutical composition suitable for mammalian medical use.
  • the compositions may conventionally be presented in unit dosage form and prepared by any method known in the art of pharmacy.
  • the pharmaceutical composition of the present invention comprises a therapeutically effective amount of the new crystal form of dabigatran etexilate hydrochloride as an active agent, and one or more inert pharmaceutically acceptable carriers, optionally any other treatment ingredients, stabilizers, etc.
  • the carrier must be pharmaceutically acceptable, which means that the carrier is compatible with the other ingredients of the formulation and does not adversely cause harm to its recipient.
  • the active agents of the present invention are formulated into compositions suitable for oral, rectal, topical, nasal, ocular or parenteral administration (including intraperitoneal, intravenous, subcutaneous or intramuscular injection) dosage form.
  • the present invention provides a pharmaceutical composition, comprising the above-mentioned new crystal form of dabigatran etexilate ethyl hydrochloride, or the new crystal form of dabigatran etexilate ethyl hydrochloride prepared by the above preparation method, and Pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.
  • the dosage form of the composition can be selected from suitable dosage forms known to those skilled in the art, such as injection, lyophilized powder for injection, oral solid preparation, external patch, gel and the like.
  • the oral solid preparation is selected from ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, granules/dry suspensions, films, sublingual tablets, transdermal patches, etc.
  • Excipients may be (but are not limited to): binders such as hydroxypropylcellulose, povidone or hydroxypropylmethylcellulose; fillers such as microcrystalline cellulose, pregelatinized starch , starch, mannitol, or lactose; disintegrants, such as croscarmellose sodium, crospovidone, or sodium starch glycolate; lubricants, such as magnesium stearate, stearic acid, or other metallic stearin acid salts; sweeteners such as sucrose, fructose, lactose or aspartame; and/or flavoring agents such as peppermint, oil of wintergreen or cherry flavoring.
  • binders such as hydroxypropylcellulose, povidone or hydroxypropylmethylcellulose
  • fillers such as microcrystalline cellulose, pregelatinized starch , starch, mannitol, or lactose
  • disintegrants such as croscarmellose sodium, crospovidone, or sodium starch
  • the unit dosage form When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol.
  • a liquid carrier such as vegetable oil or polyethylene glycol.
  • Various other materials may be present in the form of coatings or in other forms that alter the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, polymers, waxes, shellac or sugar and the like.
  • any materials employed in the preparation of any unit dosage form will typically be pharmaceutically acceptable and substantially nontoxic in the amounts employed.
  • Solutions or emulsions for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents, such as water for injection, saline solution, oils, polyethylene glycols, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents , such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as EDTA; buffers, such as acetate, citrate, or phosphate, and Tonicity-adjusting agents such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Prepared into injection, lyophilized powder for injection or infusion.
  • Formulations for rectal administration can be presented as a suppository with a suitable base comprising, for example, cocoa butter or salicylates.
  • the compounds used according to the invention are suitable for delivery in the form of a pressurized pack or a spray formed by a nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorodifluoromethane, Chlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorodifluoromethane, Chlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined by providing a valve for delivering a metered amount.
  • Gelatin capsules and kits for use in inhalers or insufflators and the like can be formulated to contain a powder mix of the present compound with a suitable powder base such as lactose or starch.
  • the active agent may be delivered in a pharmaceutically acceptable ophthalmic carrier such that the compound remains in contact with the surface of the eye for a period of time sufficient to allow the compound to penetrate the cornea and internal regions of the eye, including, for example, the anterior Atrium, posterior chamber, vitreous, aqueous humor, vitreous humor, cornea, iris/ciliary body, lens, choroid/retina and sclera.
  • Pharmaceutically acceptable ophthalmic carriers can be, for example, ointments, vegetable oils or encapsulating materials.
  • the compounds of the present invention can also be injected directly into the vitreous humor and aqueous humor or by subconjunctival (Subtenon) injection.
  • the active agent can be delivered in a pharmaceutically acceptable topical carrier, which can be formulated as gels, patches, foams, ointments, creams, and the like.
  • the amount and timing of administration will depend on the subject being treated, the severity of the disease, the method of administration, and the judgment of the prescribing physician. Because patients vary from patient to patient, the guided dose is always given low and the doctor can slowly increase the dose to achieve what he believes to be effective treatment for the patient. In considering the level of treatment required, the physician must weigh various factors such as the patient's age, the presence of disease symptoms, and the presence of other diseases (eg, cardiovascular disease).
  • the present invention provides the above new crystal form of dabigatran etexilate ethyl hydrochloride, or the new crystal form of dabigatran etexilate ethyl hydrochloride prepared by the above preparation method, or the above pharmaceutical composition, which is used in the preparation of preventive , the application of medicines for the treatment or alleviation of acute thrombotic diseases and the resulting cardiovascular and cerebrovascular diseases.
  • the thrombotic diseases include arterial thromboembolic diseases, venous thromboembolic diseases.
  • the acute thrombotic diseases and the resulting cardiovascular and cerebrovascular diseases including but not limited to cerebral thrombosis, cerebral infarction, myocardial infarction, coronary heart disease, atherosclerosis, deep vein thrombosis, pulmonary embolism, heart failure, cardiogenic Shock, arrhythmia, disturbance of consciousness and hemiplegia, established venous thromboembolism, acute coronary syndrome, diseases caused by acute cerebral arterial thrombosis, acute mesenteric arterial thrombosis and acute limb arterial thrombosis, acute deep vein thrombosis, atrial fibrillation (AF), one or more of recurrent deep vein thrombosis, cerebral embolism, splenic embolism, and the like.
  • cerebral thrombosis cerebral infarction
  • myocardial infarction coronary heart disease
  • atherosclerosis deep vein thrombosis
  • pulmonary embolism heart failure
  • cardiogenic Shock arrhythmia
  • arrhythmia disturbance of
  • the above-mentioned new crystal form or composition of dabigatran etexilate hydrochloride provided by the present invention is suitable for:
  • the new crystal form of dabigatran etexilate hydrochloride does not need to use special techniques such as spray drying, hot-melt extrusion, nano-grinding to prepare amorphous or nano-crystals to improve solubility, and conventional oral solid preparation production Processes such as mixing, granulation (dry granulation or wet granulation) or no granulation, coating or non-coating, blending, tableting or encapsulation and conventional production processes for injectable products such as weighing, dissolving , filtration, canning, freeze-drying, nitrogen filling, and capping.
  • the injection product can be prepared in the form of pre-potting or pre-mixing through a pre-potting production line. The process is simple, controllable, low in cost, stable in quality, and suitable for large-scale industrial production.
  • the present invention also provides a pharmaceutical composition or injection for injection, which can be achieved by pre-filling or instant dissolving.
  • the present invention provides a method for preventing, treating or alleviating acute thrombotic diseases and cardiovascular and cerebrovascular diseases caused thereby, comprising the above-mentioned new crystal form of dabigatran etexilate ethyl ester hydrochloride, or a method prepared by the above-mentioned preparation method.
  • a new crystal form of dabigatran etexilate hydrochloride, or the above-mentioned pharmaceutical composition is contacted with a biological specimen.
  • the present invention provides a new crystal form of dabigatran etexilate ethyl ester hydrochloride, the X-ray powder diffraction pattern has diffraction peaks at 2 ⁇ 0.2°, and the 2 ⁇ is at least selected from 5.42. Any of ⁇ 0.2°, 9.08 ⁇ 0.2°, 11.88 ⁇ 0.2°, and 14.14 ⁇ 0.2°.
  • the above-mentioned new crystal form of dabigatran etexilate ethyl ester hydrochloride provided by the present invention can be used as a medicinal active ingredient, and it has the following advantages:
  • Fig. 1 is the X-ray powder diffraction pattern (XRPD) of the new crystal form of dabigatran etexilate ethyl ester hydrochloride prepared in Example 1;
  • Fig. 2 is the infrared spectrum analysis figure (IR) of the dabigatran etexilate ethyl ester hydrochloride new crystal form prepared by embodiment 1;
  • Fig. 3 is the differential scanning calorimetry (DSC) of the new crystal form of dabigatran etexilate ethyl ester hydrochloride prepared in Example 1;
  • Fig. 4 is the thermogravimetric analysis diagram (TGA) of the new crystal form of dabigatran etexilate hydrochloride prepared in Example 1;
  • Fig. 5 is the hydrogen nuclear magnetic resonance spectrum (H-NMR) of the new crystal form of dabigatran etexilate ethyl ester hydrochloride prepared in Example 1;
  • Fig. 6 is the HPLC spectrogram of the crude dabigatran ethyl ester containing ammonium chloride salt prepared in Preparation Example 1;
  • Fig. 7 is the HPLC spectrogram of the new crystal form of dabigatran etexilate hydrochloride prepared in Example 1;
  • Fig. 8 is the HPLC spectrogram of the crude dabigatran ethyl ester containing ammonium chloride salt prepared in Example 2;
  • Fig. 9 is the HPLC spectrogram of the dabigatran etexilate ethyl ester hydrochloride new crystal form prepared in Example 2;
  • Fig. 10 is the X-ray powder diffraction pattern (XRPD) of the crystal form of dabigatran etexilate ethyl ester hydrochloride 1.5 hydrate prepared in Example 3;
  • Fig. 11 is the HPLC spectrogram of the dabigatran ethyl ester anhydrate crystal form prepared by Comparative Example 1;
  • Figure 12 is the X-ray powder diffraction pattern (XRPD) of the dabigatran ethyl ester anhydrate crystal form prepared in Comparative Example 1;
  • Fig. 13 is the thermogravimetric analysis chart (TGA) of dabigatran ethyl ester anhydrate crystal form prepared by Comparative Example 1;
  • the dabigatran ethyl ester used in the present invention can be carried out Pinner reaction with the compound of formula VII as a raw material according to known methods, such as the methods described in J.MedChem.2002,45,1757-1766, WO2014012880A1 and other patent documents preparation.
  • the compound of formula VII can be obtained commercially from Pinghu Aibai Chemical Co., Ltd.
  • the other raw materials, reagents and solvents used in the present invention are not particularly limited, and commercially available conventional raw materials, reagents and solvents can be used.
  • X-ray powder diffraction (XRPD) data was collected, the instrument model used was: XD6, the test conditions were: CuK ⁇ light source, 36kV voltage, 20mA current, slit 1°, 1°, 0.3mm, sampling step width: 0.01, Scanning speed: 8°/min, acquisition software: MDI Jade 5.0.
  • IR Infrared spectral analysis
  • DSC Differential scanning calorimetry
  • thermogravimetric analysis (TGA) data the instrument model used is: SII-TG/DTA6200, analysis method parameters: temperature range: 30°C-245°C, scan rate: 10°C/min, protective gas: nitrogen, 200 ml /minute.
  • Hydrogen nuclear magnetic resonance (HNMR) data were collected, the instrument model used was: BrukerAVANCE600, the resonance frequency: 600 MHz, and the solvent used: deuterated dimethyl sulfoxide.
  • the liquid phase test conditions involved in the present invention are: the chromatographic column is an Agilent C18 reversed-phase column, 4.6mm ⁇ 150mm, 2.7 ⁇ m; mobile phase A: 0.02mol/L ammonium acetate buffer (containing 0.1% diethylamine), acetic acid Adjust pH to 5.5; mobile phase B: acetonitrile; detection wavelength: 307 nm; flow rate: 0.7 mL/min; injection volume: 10 ⁇ L; column temperature: 35 °C; liquid phase conditions are shown in Table 2:
  • Concentrated ammonia water adjusts the pH value of the system to 8.5 ⁇ 9.5, slowly warms up to room temperature and continues to stir for 10 hours, the system is concentrated under reduced pressure to about 5L, the solid is collected by filtration, and vacuum-dried at 50°C ⁇ 60°C for 4 hours to obtain 3.27Kg darbi Crude Gatran ethyl ester (HPLC: 86.039%, see Figure 8 for details)
  • the moisture content was 4.81% as measured by a cassette moisture analyzer, containing 1.5 crystal water.
  • the crystal form was confirmed by X-ray powder diffraction. See Fig. 10 for details. Combined with moisture data, it is confirmed that it is the crystal form of dabigatran ethyl hydrochloride 1.5 hydrate, and the theoretical water content of dabigatran ethyl ester hydrochloride 1.5 hydrate is 4.80%.
  • the X-ray powder diffraction (XRPD) pattern expressed as diffraction angle 2 ⁇ using Cu-K ⁇ radiation showed the following characteristic peaks: 8.5 ⁇ 0.2°, 10.6 ⁇ 0.2°, 12.8 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.7 ⁇ 0.2° , 17.5 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.3 ⁇ 0.2°, 24.2 ⁇ 0.2°, 28.6 ⁇ 0.2°.
  • the moisture is 0.24% by Karl Fischer moisture determination, and XRPD and TGA, see Figs. 12 and 13 for details, and it is determined to be the crystalline form of dabigatran etexilate ethyl ester.
  • Dabigatran etexilate ethyl ester hydrochloride anhydrous and dabigatran etexilate ethyl ester hydrochloride monohydrate were subjected to influencing factor experiments, and the materials of the two crystal forms were taken at high temperature of 50 °C ⁇ 2 °C and light. 4500LX ⁇ 500LX and high humidity RH75% ⁇ 5% were left bare for 14 days to investigate the physical and chemical stability of the two crystal forms. The results are as follows:
  • Dabigatran etexilate ethyl ester hydrochloride monohydrate and anhydrous were placed under the condition of 5000LX light for 14 days, and dabigatran etexilate ethyl ester hydrochloride monohydrate and anhydrate crystal forms were degraded to a certain extent , but the degradation of the anhydrate crystal form is slightly larger, and the character is also changed from a white powder at 0 days to a light yellow powder.
  • Dabigatran ethyl ester was placed for 14 days under the conditions of high temperature of 50 °C, light, and high humidity of 75%.
  • the comparison results with 0-day XRPD are shown in Table 5:
  • the XRPD characteristic diffraction angle of the sample under high temperature and light for 14 days is significantly different from that of the sample. There was no significant change ( ⁇ 0.2 ⁇ ) compared with 0 days.
  • the crystal form of dabigatran etexilate ethyl ester hydrochloride monohydrate changed, and the characteristic diffraction angle of XRPD changed, which was consistent with that. The moisture measurement results were consistent.
  • the dabigatran etexilate ethyl ester hydrochloride monohydrate was placed in an artificial climate box at 25°C/RH80% for 24 hours in accordance with the "Guidelines for the hygroscopicity test of drugs", and the moisture-inducing weight gain was 0.85%. , is slightly hygroscopic.
  • the samples were taken out after wetting, and transferred to a desiccator at 25°C/RH20% for 24 hours or dried in an oven for 2 hours. All the added water was lost, and the stable monohydrate was still maintained. Therefore, dabigatran etexilate ethyl ester hydrochloride monohydrate has reversible hygroscopicity.
  • the XRPD analysis results also confirmed this reversible process from the crystal form.
  • the solubility of dabigatran etexilate hydrochloride monohydrate in different pH media is higher than that of dabigatran etexilate mesylate in corresponding pH media.

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Abstract

公开了一种达比加群酯乙酯盐酸盐新晶型，X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ至少选自5.42±0.2°、9.08±0.2°、11.88±0.2°和14.14±0.2°中的任意一个。公开的上述达比加群酯乙酯盐酸盐新晶型可作为药用活性成分使用，其具有以下优点：(1)物理稳定性及化学稳定性好；(2)生产成本可控；(3)生产过程中，具有极佳的纯化除杂效果，操作简便，收率高，利于工业化生产；(4)具有很好的水溶性，后续作为原料药应用无需采用特殊的增溶技术；(5)生理pH范围内，溶解度不具有pH依赖性。

Description

一种达比加群酯乙酯盐酸盐新晶型及其制备方法和应用 技术领域
本发明涉及化学制药技术领域，尤其涉及一种达比加群酯乙酯盐酸盐新晶型及其制备方法和应用。
背景技术
心脑血管疾病是心脏血管和脑血管疾病的统称，泛指由于高脂血症、血液黏稠、动脉粥样硬化、高血压等所导致的心脏、大脑及全身组织发生的缺血性或出血性疾病。心脑血管疾病是一种严重威胁人类，特别是50岁以上中老年人健康的常见病，具有高患病率、高致残率和高死亡率的特点。全球每年脑血栓、脑梗塞、各种栓塞、心肌梗塞、冠心病、动脉粥样硬化等心脑血管疾病夺走1200万人生命，接近世界总死亡人数的四分之一，心脑血管疾病已经成为超越恶性肿瘤的"头号健康杀手"。血栓性疾病是心脑血管病的主要形式之一。血栓形成和血栓栓塞两种病理过程所引起的疾病，临床上称为血栓性疾病。血栓是指血液成分在血液流动过程中，在血管或心脏内膜表面形成的一种半凝块状物质，造成血管腔狭窄与闭塞，使主要脏器发生缺血和梗塞而引发机能障碍的各种疾病。血栓性疾病具有高发病率、高复发率、高致残率、高死亡率的特征，随着经皮冠状动脉介入治疗(PCI)在临床上大规模展开，抗血栓药物受到越来越多的重视，市场规模稳步上升。抗血栓药物用于血栓栓塞性疾病的预防与治疗，可分为抗血小板聚集药、抗凝血药和溶栓药。
达比加群酯胶囊(Pradaxa)，是新一代非维生素K拮抗剂类口服抗凝药物，用于预防非瓣膜性房颤患者的卒中和全身性栓塞。这是自华法林获批上市以来，第一个取得长期适应症的口服抗凝药。Pradaxa胶囊由勃林格殷格翰公司开发，于2010年10月经美国FDA批准上市，至今已经进入全球几十个国家。Pradaxa胶囊适用于降低非瓣膜性房颤患者发生卒中和全身性栓塞的风险；治疗深静脉血栓形成和肺栓塞；减低深静脉血栓形成和肺栓塞复发的风险及用于髋关节置换术后深静脉血栓形成和肺栓塞的预防。Pradaxa胶囊的活性成分为达比加群酯的甲磺酸盐( Dabigatran  Etexilate  Mesylate,以下简称DEM)，其化学名称是3-[[[2-[[[4-[[[(己氧基)羰基]氨基]亚氨甲基]苯基]氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基](吡啶-2-基)氨基]丙酸乙酯甲磺 酸盐，化学式为C 34H 41N 7O 5·CH 4O 3S，分子量为723.86，CAS#为872728-81-9。DEM的结构式如式(I)所示。
达比加群酯是一种新型的、化学合成的直接凝血酶抑制剂，是达比加群(Dabigatran，BIBR953)的前体药物，属非肽类凝血酶抑制剂，达比加群的化学结构如式(II)所示。甲磺酸达比加群酯胶囊口服经胃肠吸收后，在体内转化为具有直接抗凝血活性的达比加群。达比加群结合凝血酶的纤维蛋白特异结合位点，阻止纤维蛋白原裂解为纤维蛋白，从而阻断了凝血瀑布网络的最后步骤及血栓形成。达比加群可从纤维蛋白-凝血酶结合体上解离，发挥可逆的抗凝作用。DEM为白色至黄色结晶性粉末。易溶于甲醇，略溶于异丙醇，微溶于乙醇。DEM游离碱在水溶液中的溶解度具有pH依赖性，当水溶液的pH小于1时，其溶解度超过80mg/mL，随着pH升高，其溶解度急剧下降，当水溶液的pH为3.0时，其溶解度约为0.8mg/mL；当水溶液的pH为4.0时，其溶解度约为0.08mg/mL；当水溶液的pH为6.0～7.4时，其溶解度约为0.003mg/mL，基本不溶。而DEM的LogD(pH1.50)＝0.41，吸收较差。
现有前体药物甲磺酸达比加群酯作为口服抗凝药的药用活性成分在生理pH(pH1.0～pH7.4)条件下，药物口服后，随着胃肠蠕动，逐渐由低pH的胃进入高pH肠道，其溶解度急剧下降，进而导致药物在消化道析出成固体状态无法吸收而造成口服生物利用度很低，约3％～7％。
Figure PCTCN2021082000-appb-000001
为解决DEM在高pH条件下溶解度及溶出度低的问题，避免药物口服后生物利用度受消化道pH的影响，从而影响药效，现有技术主要涉及两种方案，一种是药物组合物中包含可以调节药物释放过程微环境pH值的酸性物质，这种酸性物质包括酸性氨基酸、有机酸、无机酸以及偏酸性的盐等，选择的制备 工艺一般都通过物理隔离的方法将酸性物质与DEM隔离开，避免酸性物质与药物分子直接接触而造成药物降解；根据Pradaxa胶囊体外不同pH介质中的溶出曲线、药代动力学参数显示，这种方法对解决药物口服后由胃进入小肠后因pH值升高而造成药物析出有一定帮助；采用这种解决方案，优点是病人进食后服药或同时服用PPI抑制剂(升高了胃内pH)对Pradaxa胶囊的口服生物利用度影响较小。从工艺角度，无论是酸性物质作为丸芯，外喷隔离层、上带药层、包衣的工艺还是酸性物质单独制备包衣颗粒与含药颗粒一起装胶囊，其制备工艺均过于复杂。为了确保最终产品的稳定性，包隔离衣的酸性颗粒必须是均匀的、近乎球形及低的表面粗糙度，避免隔离层脱落或超大酸性粒子造成的粗糙表面带来的隔离缺陷破坏产品货架期稳定性，废品率高、生产成本高、生产工艺难于控制。另外一种方案是通过新的制剂技术，如喷雾干燥技术或热熔挤出技术制备DEM的固体分散体，将DEM晶型药物变成无定形药物来提高药物的溶解度，组合物中增加具有亲水性或两亲性的高分子载体来抑制药物随pH升高而析出；或者将DEM或游离体制备成自乳化系统，经过吸附剂吸附后压片或装胶囊。无论哪一种技术方案，最终都要面临一个问题就是上市后的货架期稳定性问题。
达比加群乙酯曾作为已上市药物甲磺酸达比加群酯的制备工艺中间体和体内活性代谢中间体，是目标活性成分达比加群的单前体药物，结构式如式(III)所示。
Figure PCTCN2021082000-appb-000002
根据Paradax胶囊美国FDA Pharmacology Review公布的信息，达比加群酯在体内的代谢过程如下：
Figure PCTCN2021082000-appb-000003
达比加群酯(BIBR1048)口服后，在肠粘膜细胞和肝脏酯水解酶的作用下代谢产生两个中间体，非活性代谢中间体(BIBR1087)及活性代谢中间体(BIBR951)。达比加群酯和BIBR1087均为外排蛋白P-gp的底物，而达比加群乙酯(BIBR951)不是外排蛋白P-gp的底物，也不是诱导剂。根据达比加群酯、BIBR1087、BIBR951的化学结构，达比加群酯游离碱和BIBR1087具有相似的溶解行为，其溶解度均具有pH依赖性，pH4.5～pH7.4，溶解度均低于0.01mg/ml。达比加群乙酯在人体消化道pH范围内(pH1.0-7.4)均具有较高的溶解度(25℃)，以达比加群乙酯作为药用活性成分，无需解决溶解度的问题。
现有上市产品Paradax胶囊活性成分为达比加群酯，根据FDA Clinical Review，达比加群酯是P-gp外排蛋白的底物，达比加群酯在胃肠道中的吸收是不完全的，因此，已上市的Paradax胶囊口服生物利用度只有3％～7％，其主要原因有两个：一、pH依赖性，造成肠道吸收很少；二、P-gp外排蛋白的作用。这些因素同时也造成了现有上市产品Paradax个体内及个体间的变异很高。而达比加群和达比加群乙酯既不是P-pg的底物也不是P-gp的抑制剂或诱导剂。根据公开文献，口服达比加群酯胶囊的同时服用酮康唑(P-gp抑制剂)，达比加群的Cmax和AUC分别增加135％和138％；而每天一次服用利福平(P-gp诱导剂)600mg，连续服用6天，在第七天服用达比加群酯胶囊，其AUC和Cmax分别下降66％和67％。这种药物与药物之间的相互作用，临床使用过程中很容易发生严重不良反应，造成病人内脏器官出血或消化道出血等 风险，因此，根据达比加群的临床适应症，开发一个既无溶解度问题，又避免p-gp或P450酶影响而造成的体内PK高变异问题，对达比加群的临床应用与治疗非常重要。
目前的达比加群乙酯晶型，均作为制备达比加群酯原料药的一个合成中间体，存在稳定性差，收率低、纯度低等问题，影响了其临床应用。如能开发出稳定的药用晶型，是解决现有技术中存在的重大问题的关键。
发明内容
有鉴于此，本发明要解决的技术问题在于提供一种达比加群酯乙酯盐酸盐新晶型及其制备方法和应用，制备的达比加群酯乙酯盐酸盐新晶型物理稳定性及化学稳定性好，同时与甲磺酸达比加群酯相比，生理pH范围内具有较好的水溶性。
为达到上述目的，本发明提供了一种达比加群酯乙酯盐酸盐新晶型，X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ至少选自5.42±0.2°、9.08±0.2°、11.88±0.2°和14.14±0.2°中的任意一个。
本发明中，所述达比加群乙酯新晶型的结构式如式(Ⅳ)所示：
Figure PCTCN2021082000-appb-000004
本发明制备得到了物理稳定性和化学稳定性均较好的达比加群酯乙酯盐酸盐新晶型，使得达比加群乙酯可以作为达比加群的前体药物应用，达比加群乙酯从化合物的结构、pH1.0-pH7.4条件下良好的溶解度、非P-gp、P450酶的底物或抑制剂或诱导剂等特性均具有明显优势，进而解决了现有技术中存在的问题。
本发明所述达比加群酯乙酯盐酸盐的新晶型为盐酸盐一水合物，其理论含水量为3.25％。
在本发明的一个方面，所述式(IV)化合物，具有充分的结晶度和良好的物理化学稳定性。
本发明优选的，所述2θ至少选自5.42±0.2°、9.08±0.2°、11.88±0.2°、14.14±0.2°、16.20±0.2°、17.02±0.2°、17.58±0.2°、19.58±0.2°、20.43±0.2°、21.28±0.2°和21.74±0.2°中的任意一个。
本发明优选的，所述达比加群酯乙酯盐酸盐一水合物晶型，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图显示至少一个、更优选至少两个、再更优选至少四个、最优选全部选自约为以下特征峰：5.4±0.2°、9.1±0.2°、11.9±0.2°、16.2±0.2°、17.0±0.2°、17.6±0.2°、19.6±0.2°、20.8±0.2°、21.3±0.2°、23.2±0.2°、24.8±0.2°、27.3±0.2°。
在本发明更优选的一个实施方案中，所述达比加群酯乙酯盐酸盐新晶型，使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图谱，具有如下表1所示的特征峰及其相对强度，衍射角2θ误差为±0.2°：
表1 达比加群酯乙酯盐酸盐新晶型X-射线粉末衍射特征峰及相对强度
No. 衍射角2θ D I/Io No. 衍射角2θ D I/Io
1 5.420 16.2929 5.5 2 9.080 9.7312 6.5
3 11.880 7.4434 25.1 4 14.140 6.2581 4.9
5 16.200 5.4668 35.9 6 17.020 5.2053 100.0
7 17.580 5.0407 18.3 8 19.580 4.5301 20.0
9 20.430 4.3434 15.9 10 21.280 4.1718 43.6
11 21.740 4.0846 21.5 12 23.180 3.8340 32.0
13 23.519 3.7795 18.1 14 24.320 3.6568 23.3
15 24.800 3.5871 39.1 16 26.180 3.4011 16.1
17 27.300 3.2641 53.4 18 28.120 3.1707 10.5
19 28.540 3.1250 18.8 20 29.540 3.0214 11.2
21 29.940 2.9819 12.8 22 31.380 2.8483 9.0
23 32.400 2.7609 4.8 24 32.880 2.7217 14.9
25 34.220 2.6182 13.1 26 35.361 2.5363 3.1
27 35.900 2.4994 4.2 28 37.220 2.4137 5.1
29 38.680 2.3259 4.2 30 39.380 2.2862 3.2
31 39.901 2.2575 3.0 32 42.340 2.1329 6.0
33 48.000 1.8938 4.2 34 48.458 1.8770 2.8
35 50.340 1.8111 3.6 - - - -
本发明中，所述达比加群酯乙酯盐酸盐新晶型的X-射线粉末衍射(XRPD)图如图1所示。
本发明所述达比加群酯乙酯盐酸盐新晶型，使用KBr压片测得的红外吸收(IR)图谱在以下位置具有特征峰：3408.91±5cm -1、3244.57±5cm -1、3035.26±5cm -1、1641.13±5cm -1、1607.38±5cm -1、1480.57±5cm -1、1178.76±5cm -1、832.31±5cm -1、739.95±5cm -1。
在本发明优选的一个实施方案中，所述达比加群酯乙酯盐酸盐新晶型，用KBr压片测得的红外吸收(IR)图谱在以下位置具有吸收峰：3408.91±5cm -1、3360.73±5cm -1、3244.57±5cm -1、3035.26±5cm -1、2764.09±5cm -1、1720.59±5cm -1、1675.29±5cm -1、1641.13±5cm -1、1607.38±5cm -1、1480.57±5cm -1、1405.00±5cm -1、1330.64±5cm -1、1291.98±5cm -1、1178.76±5cm -1、1076.02±5cm -1、1032.47±5cm -1、832.31±5cm -1、739.95±5cm -1。
非限制性地，本发明的达比加群酯乙酯盐酸盐新晶型，具有如图2所示的红外吸收(IR)图谱。
本发明所述达比加群酯乙酯盐酸盐新晶型的差示扫描量热(DSC)谱图，在105.0℃～155.0℃范围内有两个吸热峰，峰值分别为139.8℃和149.6℃。非限制性地，本发明的达比加群酯乙酯盐酸盐新晶型，具有如图3所示的差示扫描量热(DSC)谱图。
本发明所述达比加群酯乙酯盐酸盐新晶型的热重分析(TGA)谱图，在105.1℃～150.5℃失重约为3.2％。
非限制性地，本发明的达比加群酯乙酯盐酸盐新晶型，具有如图4所示的热重分析(TGA)谱图。
根据热重分析(TGA)谱图，以及水分测量仪(仪器型号：Metrohm 915-KF)显示的含水量为3.26％，表明本发明所述达比加群酯乙酯的新晶型为一水合物形式存在。
本发明所述达比加群酯乙酯的新晶型采用电位滴定法测得盐酸盐含量为6.58％。
本发明所述的达比加群酯乙酯盐酸盐新晶型，核磁共振氢谱(HNMR)，在以下位置具有共振峰：HNMR(600MHz,DMSO)δ8.906(s，2H)，8.717 (s，2H)，8.393-8.382(d，1H，J＝4.8Hz)，7.683-7.668(d，2H，J＝9.0Hz)，7.566-7.537(t，1H，J＝7.8Hz)，7.478(s，1H)，7.466-7.448(t，1H，J＝5.4Hz)，7.411-7.397(d，1H，J＝8.4Hz)，7.162-7.145(d，1H，J＝8.4Hz)，7.130-7.109(m，1H)，6.904-6.891(d，1H，J＝7.8Hz),6.879-6.864(d，2H，J＝9.0Hz),4.651-4.642(d，2H，J＝5.4Hz)，4.237-4.213(t，2H，J＝7.2Hz)，3.993-3.957(q，2H，J＝7.2Hz)，3.778(s，3H)，2.696-2.672(t，2H，J＝7.2Hz)，1.134-1.110(t，3H，J＝7.2Hz)。
非限制性地，本发明的达比加群酯乙酯盐酸盐新晶型，具有如图5所示的核磁共振氢谱(HNMR)。
根据核磁共振氢谱(HNMR)谱图数据，表明本发明所述达比加群酯乙酯盐酸盐新晶型，达比加群乙酯与氯化氢的摩尔比为1:1。
本发明提供了上述达比加群酯乙酯盐酸盐新晶型的制备方法，包括以下步骤：
将达比加群乙酯分散在水中，搅拌溶清，析晶，分离所得固体并干燥，得到达比加群酯乙酯盐酸盐新晶型。
本发明优选的，所述搅拌溶清的温度为30～100℃；更优选为60～70℃。
本发明优选的，所述析晶的温度为-10～40℃；更优选为20～30℃；进一步优选为25℃。
本发明优选的，所述干燥的温度为20～140℃；更优选为50～60℃。
上述制备方法，除了可以对达比加群乙酯粗品结晶制备其新晶型，还具有很强的除杂效果，得到的晶体无论作为达比加群酯中间体使用，还是达比加群乙酯作为药用活性成分使用，都简化了后续工艺的纯化步骤，提高了收率和药用活性成分的质量。
本发明对所述达比加群乙酯粗品的来源并无特殊限定，可以为一般市售，或按照本领域技术人员熟知的方法自行制备。
本发明优选的，所述达比加群乙酯粗品按照公开的方法，如专利文献J.Med.Chem.2002,45,1757-1766，WO2014012880A1等专利文献中所记载的方法，以式VII化合物为原料进行Pinner反应制备。
Figure PCTCN2021082000-appb-000005
实验结果表明，本发明提供的上述达比加群酯乙酯盐酸盐新晶型在生理pH水溶液中具有较好的溶解度，作为药用活性成分使用，可以很方便地根据使用目的的不同制备成注射液、注射用冻干粉针剂及口服固体制剂、外用贴剂、凝胶剂等。
本发明提供的达比加群酯乙酯盐酸盐新晶型可以被配制成适于哺乳动物医疗用途的药物组合物。组合物可以常规地存在于单位剂型中，并通过药学领域中的任何方法制备。本发明的药物组合物包括治疗有效量的达比加群酯乙酯盐酸盐新晶型作为活性剂，以及一种或多种惰性的药学上可接受的载体、可选的任何其他的治疗成分、稳定剂等。载体必须是药学上可接受的，这是指载体与配制剂中的其他成分相容并且不会不利地对其接收者造成损害。本发明的活性剂所配制成的组合物包括适合口服给药、直肠给药、局部给药、鼻腔给药、眼部给药或肠道外给药(包括腹腔、静脉、皮下或肌肉注射)的剂型。
基于此，本发明提供了一种药物组合物，包括上述达比加群酯乙酯盐酸盐新晶型，或上述制备方法制备的达比加群酯乙酯盐酸盐新晶型，以及药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
所述组合物的剂型可以选自注射液、注射用冻干粉针剂、口服固体制剂、外用贴剂、凝胶剂等本领域技术人员熟知的适用剂型。
本发明优选的，所述口服固体制剂选自普通片剂或胶囊剂、缓释片剂或缓释胶囊剂、控释片剂或胶囊剂、颗粒剂/干混悬剂、膜剂、舌下片、透皮贴剂等。
具体的，对经口治疗性施用来说，可以与一种或一种以上赋形剂组合，并且以可吞食片、颊含片、糖衣片、胶囊、酏剂、悬浮液、糖浆、粉片等形式使用。赋形剂可以是(但不限于)：粘合剂，诸如羟丙基纤维素、聚维酮(povidone)或羟丙基甲基纤维素；填充剂，诸如微晶纤维素、预胶化淀粉、淀粉、甘露糖醇或乳糖；崩解剂，诸如交联羧甲纤维素钠、交联聚维酮或羟基乙酸淀粉钠； 润滑剂，诸如硬脂酸镁、硬脂酸或其它金属硬脂酸盐；甜味剂，诸如蔗糖、果糖、乳糖或阿斯巴甜(aspartame)；和/或调味剂，诸如胡椒薄荷、冬青油或樱桃调味剂。
当单位剂型是胶囊时，除以上类型的材料之外，其还可以含有液体载体，诸如蔬菜油或聚乙二醇。各种其它材料可以包衣形式或以改变固体单位剂型的物理形式的其它形式存在。举例来说，片剂、丸剂或胶囊可以用明胶、聚合物、蜡、虫胶或糖等等包覆。当然，用于制备任何单位剂型的任何材料在所采用的量下典型地都将是医药学上可接受且实质上无毒的。
用于肠胃外、皮内或皮下施用的溶液或乳液可包括以下组分：无菌稀释剂，例如注射用水、盐水溶液、油、聚乙二醇、甘油、丙二醇或其它合成的溶剂；抗菌剂，例如苄醇或对羟基苯甲酸甲酯；抗氧化剂，例如抗坏血酸或亚硫酸氢钠；螯合剂，例如乙二胺四乙酸；缓冲剂，例如乙酸盐、柠檬酸盐或磷酸盐，和用于调节张力的剂，例如氯化钠或葡萄糖。pH可用酸或碱调节，例如盐酸或氢氧化钠。肠胃外制备物可封闭在由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。制备成注射液、注射用冻干粉针剂或输液。
用于经直肠施用的调配物可以表现为具有包含例如可可脂或水杨酸酯的合适基质的栓剂。
对于鼻腔给药或吸入式给药，根据本发明使用的化合物适合以加压包装或喷雾器形成的喷雾形式来输送，并使用合适的推进剂，例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体。当采用加压喷雾时，可以通过提供用来输送经计量的量的阀来确定剂量单位。用于吸入器或吹入器等的明胶胶囊和药盒可被配制成包含本化合物与合适的粉末基料(例如乳糖或淀粉)的粉末混合物。
对于向眼部给药，活性剂可在药学上可接受的眼用载体中被输送，以使化合物保持与眼睛表面接触足够长的时间，来允许化合物渗透眼睛的角膜和内部区域，包括例如前房、后房、玻璃体、房水、玻璃液、角膜、虹膜/睫状体、晶状体、脉络膜/视网膜和巩膜。药学上可接受的眼用载体可以例如是油膏、植物油或封装材料。本发明的化合物也可被直接注射进玻璃液和房水或者进行结膜下(Subtenon)注射。
对于透皮或皮肤给药，活性剂可在药学上可接受的外用载体中被输送，可以制备成凝胶剂、贴片、泡沫剂、软膏、乳膏等。
用药的量和时间取决于被治疗的对象、疾病严重程度、给药方法以及处方医生的判断。因为患者与患者各不相同，所以指导性的剂量总是给得较低而医生可以慢慢增加剂量以达到其认为是对患者有效的治疗。在考虑所需的治疗程度时，医生必须权衡各种因素如患者年龄、存在的疾病症状、以及存在的其它疾病(例如心血管疾病)等。
本发明提供了上述达比加群酯乙酯盐酸盐新晶型，或上述制备方法制备的达比加群酯乙酯盐酸盐新晶型，或上述药物组合物，在制备用于预防、治疗或减轻急性血栓性疾病和由此引发的心脑血管疾病的药物中的应用。
所述血栓性疾病包括动脉血栓栓塞性疾病，静脉血栓栓塞性疾病。
所述急性血栓性疾病和由此引发的心脑血管疾病，包括但不限于脑血栓、脑梗塞、心肌梗塞、冠心病、动脉粥样硬化、深静脉血栓、肺栓塞、心力衰竭、心源性休克、心律失常、意识障碍及偏瘫、已经形成的静脉血栓栓塞、急性冠状动脉综合症、急性脑动脉血栓引起的疾病、急性肠系膜动脉血栓及急性肢体动脉血栓、急性深静脉血栓、心房纤维性震颤(AF)、复发的深静脉血栓、脑栓塞、脾栓塞等中的一种或多种。
具体的，本发明提供的上述达比加群酯乙酯盐酸盐新晶型或组合物，适用于：
(1)降低非瓣膜性房颤患者发生卒中和全身性栓塞的风险；
(2)预防及治疗深静脉血栓形成和肺栓塞；
(3)减少深静脉血栓形成和肺栓塞复发的风险及用于髋关节置换术后深静脉血栓形成和肺栓塞的预防；
(4)髋关节和膝关节置换手术的短期应用；
(5)预防心肌梗塞后血栓栓塞并发症(卒中或体循环栓塞)；
(6)预防房颤、心膜瓣疾病或人工膜瓣置换术后引起地血栓栓塞并发症(卒中或体循环栓塞)。
本发明提供的达比加群酯乙酯盐酸盐新晶型，不需要采用喷雾干燥、热熔挤出、纳米研磨等特殊技术制备无定形或纳米晶来提高溶解度，常规的口服固 体制剂生产工艺如混合、制粒(干法制粒或湿法制粒)或不制粒，包衣或不包衣、总混、压片或装胶囊以及常规的注射用产品的生产工艺，如称量、溶解、过滤、罐装、冻干、充氮、压盖即可。或者通过预灌封生产线制备成预灌封或预混的形式制备注射产品，工艺简单、可控，成本低，质量稳定，适合工业化大生产。
本发明还提供一种供注射用的药用组合物或注射液，这种注射液可以通过预灌封形式实现，也可以通过即时溶解实现。
本发明提供了一种预防、治疗或减轻急性血栓性疾病和由此引发的心脑血管疾病的方法，包括将上述达比加群酯乙酯盐酸盐新晶型，或上述制备方法制备的达比加群酯乙酯盐酸盐新晶型，或上述药物组合物与生物标本接触。
与现有技术相比，本发明提供了一种达比加群酯乙酯盐酸盐新晶型，X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ至少选自5.42±0.2°、9.08±0.2°、11.88±0.2°和14.14±0.2°中的任意一个。
本发明提供的上述达比加群酯乙酯盐酸盐新晶型可作为药用活性成分使用，其具有以下优点：
(1)物理稳定性及化学稳定性好；
(2)生产成本可控；
(3)生产过程中，具有极佳的纯化除杂效果，操作简便，收率高，利于工业化生产；
(4)具有很好的水溶性，后续作为原料药应用无需采用特殊的增溶技术；
(5)生理pH范围内，具有较好的溶解度。
附图说明
图1为实施例1制备的达比加群酯乙酯盐酸盐新晶型的X-射线粉末衍射图(XRPD)；
图2为实施例1制备的达比加群酯乙酯盐酸盐新晶型的红外光谱分析图(IR)；
图3为实施例1制备的达比加群酯乙酯盐酸盐新晶型的差示扫描量热图(DSC)；
图4为实施例1制备的达比加群酯乙酯盐酸盐新晶型热重分析图(TGA)；
图5为实施例1实施例1制备的达比加群酯乙酯盐酸盐新晶型的核磁共振氢谱图(H-NMR)；
图6为制备例1制备的含有氯化铵盐的达比加群乙酯粗品的HPLC谱图；
图7为实施例1制备的达比加群酯乙酯盐酸盐新晶型的HPLC谱图；
图8为实施例2制备的含有氯化铵盐的达比加群乙酯粗品的HPLC谱图；
图9为实施例2制备的达比加群酯乙酯盐酸盐新晶型的HPLC谱图；
图10为实施例3制备的达比加群酯乙酯盐酸盐1.5水合物晶型的X-射线粉末衍射图(XRPD)；
图11为对比例1制备的达比加群乙酯无水物晶型的HPLC谱图；
图12为对比例1制备的达比加群乙酯无水物晶型的X-射线粉末衍射图(XRPD)；
图13为对比例1制备的达比加群乙酯无水物晶型的热重分析图(TGA)；
图14为对比例2制备的达比加群酯的HPLC谱图。
具体实施方式
为了进一步说明本发明，下面结合实施例对本发明提供的达比加群酯乙酯盐酸盐新晶型及其制备方法和应用进行详细描述。
本发明所使用的达比加群乙酯，可以按照已知方法，例如J.MedChem.2002,45,1757-1766，WO2014012880A1等专利文献中所记载的方法，以式VII化合物为原料进行Pinner反应制备。
式VII化合物可以从平湖市艾柏化工有限公司商购获得。
本发明所使用的其他原料、试剂、溶剂没有特别的限制，可采用商购的常规原料、试剂、溶剂。
采集数据所用的仪器及方法：
采集X-射线粉末衍射(XRPD)数据，所使用的仪器型号为：XD6，测试条件为：CuKα光源，36kV电压，20mA电流，狭缝1°，1°，0.3mm，采样步宽：0.01，扫描速度：8°/min，采集软件为：MDI Jade 5.0。
采集红外光谱分析(IR)数据，所使用的仪器型号为：Spectrum 65，测试 条件为：KBr压片法，扫描范围400-4000cm -1。
采集差示扫描量热(DSC)数据，所使用的仪器型号为：SII-DSC6220，分析方法参数：温度范围：30℃-250℃，扫描速率：10℃/分钟，保护气体：氮气，50毫升/分钟。
采集热重分析(TGA)数据，所使用的仪器型号为：SII-TG/DTA6200，分析方法参数：温度范围：30℃-245℃，扫描速率：10℃/分钟，保护气体：氮气，200毫升/分钟。
采集核磁共振氢谱(HNMR)数据，所使用的仪器型号为：BrukerAVANCE600，共振频率：600MHz，使用溶剂：氘代二甲基亚砜。
本发明涉及的液相测试条件为：色谱柱为安捷伦C18反相柱，4.6mm×150mm，2.7μm；流动相A：0.02mol/L乙酸铵缓冲液(含0.1％二乙胺)，用乙酸调节pH至5.5；流动相B：乙腈；检测波长：307nm；流速：0.7mL/min；进样量：10μL；柱温：35℃；液相条件如表2所示：
表2 液相参数
t(min) 0 5 8 16 23 30 35 35.1 45
A(％) 95 95 80 75 60 10 10 95 95
B(％) 5 5 20 24 40 90 90 5 5
应当说明的是，本发明技术方案中所涉及的数值或数值端点，其含义或意义的保护范围并不局限于数字本身，本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许误差范围，例如实验误差、测量误差、统计误差和随机误差等等，而这些误差范围均包含在本发明的范围之内。
为了进一步对本发明进行说明，下面将通过具体实施例进行说明，但是以下的实施例对本发明的保护范围不构成任何限制。
制备例1 达比加群乙酯粗品的制备
向1000mL三口瓶中加入400mL无水乙醇开启搅拌，加入40.00g式VII化合物搅拌至体系溶清。控制体系温度在0℃～5℃通入HCl气体2小时，缓慢恢复至室温继续搅拌25小时，用浓氨水(25％)调节体系pH值到8.5～9.5继续搅拌6小时，将体系减压浓缩干燥，得到65.31g含有氯化铵盐的达比加群 乙酯粗品(HPLC：89.912％，详见图6)。
实施例1 达比加群酯乙酯新晶型的制备
向1000mL三口瓶中加入500mL纯化水，开启搅拌，加入50.00g制备例1中所得达比加群乙酯粗品，搅拌并升温至60℃～70℃至体系溶清。将此溶液缓慢降温至25℃保温析晶5小时，过滤，收集的固体在50℃～60℃真空干燥4小时，得到30.31g白色固体(HPLC:99.263％，详见图7)，通过水分测量仪(仪器型号：Metrohm 915-KF)显示的含水量为3.26％。
通过X-射线粉末衍射图(XRPD)、红外光谱分析图(IR)、差示扫描量热图(DSC)、热重分析图(TGA)、核磁共振氢谱图(H-NMR)进行表征，结果详见图1-5。
HNMR(600MHz,DMSO)δ8.906(s，2H)，8.717(s，2H)，8.393-8.382(d，1H，J＝4.8Hz)，7.683-7.668(d，2H，J＝9.0Hz)，7.566-7.537(t，1H，J＝7.8Hz)，7.478(s，1H)，7.466-7.448(t，1H，J＝5.4Hz)，7.411-7.397(d，1H，J＝8.4Hz)，7.162-7.145(d，1H，J＝8.4Hz)，7.130-7.109(m，1H)，6.904-6.891(d，1H，J＝7.8Hz),6.879-6.864(d，2H，J＝9.0Hz),4.651-4.642(d，2H，J＝5.4Hz)，4.237-4.213(t，2H，J＝7.2Hz)，3.993-3.957(q，2H，J＝7.2Hz)，3.778(s，3H)，2.696-2.672(t，2H，J＝7.2Hz)，1.134-1.110(t，3H，J＝7.2Hz)。确认得到的白色固体为达比加群乙酯的新晶型。
实施例2 达比加群乙酯新晶型的制备
向50L双层夹套反应釜中加入25L无水乙醇开启搅拌，加入2.50Kg的式VII化合物继续搅拌至体系溶清。控制体系温度在0℃～5℃通入HCl气体6小时，保温搅拌4小时后缓慢升温至室温继续搅拌25小时，通入氮气置换HCl气体1小时，将体系降温至0℃～5℃，用浓氨水调节体系pH值到8.5～9.5，缓慢升温至室温继续搅拌10小时，将体系减压浓缩至约5L，过滤收集固体，在50℃～60℃下真空干燥4小时，得到3.27Kg达比加群乙酯粗品(HPLC:86.039％％，详见图8)
向50L双层夹套反应釜中加入3.20L纯化水开启搅拌，加入3.20Kg上述制备的达比加群乙酯粗品，升温至60℃～70℃搅拌至体系溶清。将此溶液缓慢降温至25℃保温析晶10小时，过滤，收集的固体在50℃～60℃真空干燥4小 时，得到2.42Kg白色固体(HPLC:99.209％，详见图9)，通过水分测量仪(仪器型号：Metrohm 915-KF)显示的含水量为3.26％，为达比加群酯乙酯盐酸盐一水合物。
实施例3 达比加群酯乙酯盐酸盐1.5水合物晶型的制备
将上述制备的达比加群酯乙酯盐酸盐一水合物适量，平铺于平皿中，敞口放置在高湿环境中24小时。
通过卡式水份测定仪测定水份为4.81％，含1.5个结晶水。通过X-射线粉末衍射确认晶型。详见图10，结合水份数据确认为达比加群乙酯盐酸盐1.5水合物晶型，达比加群乙酯盐酸盐1.5水合物理论含水量4.80％。
使用Cu-Kɑ辐射以衍射角2θ表示的X-射线粉末衍射(XRPD)图显示具有以下特征峰：8.5±0.2°、10.6±0.2°、12.8±0.2°、14.2±0.2°、16.7±0.2°、17.5±0.2°、18.1±0.2°、18.6±0.2°、19.3±0.2°、24.2±0.2°、28.6±0.2°。
对比例1 达比加群乙酯无水物晶型的制备
向1000mL三口瓶中加入500mL异丙醇和37mL纯化水，开启搅拌，加入50.00g实施例2中所得达比加群酯乙酯粗品，搅拌并升温至75℃～85℃至体系溶清。将此溶液缓慢降温至0℃～5℃保温析晶2小时，过滤用25mL异丙醇漂洗两次，收集固体在45℃～50℃真空干燥4小时，得到24.00g白色固体(HPLC:98.566％，详见图11)，通过卡尔费休水分测定水分为0.24％，以及XRPD和TGA，详见图12和13，确定为达比加群酯乙酯无水物晶型。
对比例2 达比加群酯的制备
向1000mL三口瓶中加入500mL的四氢呋喃和100mL的纯化水，开启搅拌，加入53.0g实施例2中所得达比加群酯乙酯盐酸盐新晶型的纯品(HPLC：99.209％)搅拌溶清后加入39.7g碳酸钾，然后在室温下滴加16.54g氯甲酸正己酯，滴加完毕后体系在室温下继续搅拌4个小时，减压蒸除溶剂，残余物加入500mL乙酸乙酯溶解，用150mL饱和食盐水洗涤三次，有机相减压蒸除溶剂，残余物用乙腈重结晶得到45g白色固体，熔点为128.1℃～129.3℃(HPLC:99.730％，详见图14)。
实验例1 达比加群酯乙酯盐酸盐一水合物影响因素实验
将达比加群酯乙酯盐酸盐无水物与达比加群酯乙酯盐酸盐一水物进行影 响因素实验，取两种晶型的物料分别于高温50℃±2℃、光照4500LX±500LX、高湿RH75％±5％条件下裸放14天，考察两种晶型的物理稳定性及化学稳定性，结果如下所示：
(1)化学稳定性
表3 达比加群酯乙酯盐酸盐无水物、一水物影响因素14天结果对比
Figure PCTCN2021082000-appb-000006
Figure PCTCN2021082000-appb-000007
由表3可以看出，达比加群酯乙酯盐酸盐一水合物在各影响因素条件下裸放14天，除光照条件杂质略有增长，其他考察条件下有关物质测定结果与0天检测结果相比，未见显著增长。表明本发明制备的达比加群酯乙酯盐酸盐新晶型化学稳定性良好。达比加群酯乙酯盐酸盐一水合物和无水物光照5000LX条件下放置14天，达比加群酯乙酯盐酸盐一水合物和无水物晶型均有一定程度的降解，但无水物晶型降解的幅度略大些，性状也由0天的白色粉末变为淡黄色粉末。
(2)物理稳定性
表4 达比加群酯乙酯盐酸盐无水物、一水物引湿性、熔点变化
Figure PCTCN2021082000-appb-000008
Figure PCTCN2021082000-appb-000009
由表4可以看出，达比加群酯乙酯盐酸盐一水物于高湿RH75％条件下裸放14天，水分值由3.51％增加到4.88％，即由一个结晶水吸水变成1.5个结晶水(理论值4.875％)。取RH75％条件下放置14天样品敞口置于25℃干燥器内，2小时后检测水分，水分值为3.34％(一水合物理论值3.25％)，即达比加群乙酯盐酸盐一水合物具有可逆引湿性。达比加群乙酯盐酸盐无水物置高湿RH75％条件下14天，水分由0天的0.45％增加到0.56％。
达比加群乙酯经影响因素高温50℃、光照、高湿75％条件放置14天，与0天XRPD对比结果如表5所示：
表5 达比加群酯乙酯盐酸盐一水合物晶型影响因素试验结果
Figure PCTCN2021082000-appb-000010
Figure PCTCN2021082000-appb-000011
根据达比加群酯乙酯盐酸盐一水合物经影响因素高温50℃、光照5000LX、高湿RH75％条件下考察14天，其中高温、光照条件下考察14天样品的XRPD特征衍射角与0天相比无明显变化(±0.2゜)，高湿RH75％条件下放置14天，达比加群酯乙酯盐酸盐一水合物晶型发生改变，XRPD特征衍射角发生变化，这与水分测定结果一致。高湿RH75％条件下放置14天样品置25℃干燥器内2小时，达比加群酯乙酯盐酸盐1.5水合物又失水变成达比加群乙酯盐酸盐一水合物，其XRPD特征衍射角与0天样品无明显差异。
(3)可逆引湿性试验
称取达比加群乙酯盐酸盐一水物适量，按照《2020年版中国药典》四部通则9103《药物引湿性指导原则》进行药物引湿性试验，试验结束后立即检测引湿增重、水份、并取样密封好送XRPD分析；其余样品分成两份，一份敞口放置在25℃/RH20％干燥器中24小时，另一份放置在鼓风干燥箱中60℃烘干2小时，试验结束分别检测水份和XRPD，结果如表6所示。
表6 达比加群酯乙酯盐酸盐一水合物晶型可逆引湿性试验结果
Figure PCTCN2021082000-appb-000012
Figure PCTCN2021082000-appb-000013
根据引湿性试验结果，达比加群酯乙酯盐酸盐一水物按照《药物引湿性试验指导原则》于25℃/RH80％的人工气候箱中放置24小时，引湿增重为0.85％， 为略有引湿性。引湿后样品取出，转移至25℃/RH20％的干燥器中放置24小时或在烘箱中干燥2小时，增加的水份又全部失掉，仍然维持稳定的一水合物。因此，达比加群酯乙酯盐酸盐一水物具有可逆引湿性。XRPD分析结果同样从晶型上证实了这一可逆过程。
实验例2 达比加群酯乙酯盐酸盐一水合物溶解度试验
取达比加群酯乙酯盐酸盐一水合物适量，分别加pH1.0盐酸、pH3.0柠檬酸盐缓冲液、pH4.5醋酸盐缓冲液及pH6.8磷酸盐缓冲液，置25℃恒温空气浴摇床中振摇，分别于12h、24h，13000rpm/min离心10分钟，取上清液分析，结果见下表：
表7：溶解度考察
Figure PCTCN2021082000-appb-000014
注1：数据来自文献。
根据测定结果，达比加群乙酯盐酸盐一水合物在不同pH介质中的溶解度均高于甲磺酸达比加群酯在对应pH介质中的溶解度。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指 出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (13)

  1. 一种达比加群酯乙酯盐酸盐新晶型，其特征在于，X-射线粉末衍射图在2θ±0.2°位置有衍射峰，所述2θ至少选自5.42±0.2°、9.08±0.2°、11.88±0.2°和14.14±0.2°中的任意一个。
  2. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，所述2θ至少选自5.42±0.2°、9.08±0.2°、11.88±0.2°、14.14±0.2°、16.20±0.2°、17.02±0.2°、17.58±0.2°、19.58±0.2°、20.43±0.2°、21.28±0.2°和21.74±0.2°中的任意一个。
  3. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，X-射线粉末衍射图如图1所示。
  4. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，红外光谱在以下位置具有特征吸收峰：3408.91±5cm -1、3244.57±5cm -1、3035.26±5cm -1、1641.13±5cm -1、1607.38±5cm -1、1480.57±5cm -1、1178.76±5cm -1、832.31±5cm -1、739.95±5cm -1。
  5. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，差示扫描量热谱图在105.0～155.0℃有两个吸热峰，峰值分别为139.8℃和149.6℃。
  6. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，热重分析谱图在105.1～150.5℃失重为3.2％。
  7. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，所述晶型为一水合物；
    所述水的理论含量为3.25wt％；
    所述新晶型中，达比加群乙酯与氯化氢的摩尔比为1:1。
  8. 根据权利要求1所述的达比加群酯乙酯盐酸盐新晶型，其特征在于，核磁共振氢谱以下位置具有共振峰：HNMR(600MHz,DMSO)δ8.906(s，2H)，8.717(s，2H)，8.393-8.382(d，1H，J＝4.8Hz)，7.683-7.668(d，2H，J＝9.0Hz)，7.566-7.537(t，1H，J＝7.8Hz)，7.478(s，1H)，7.466-7.448(t，1H，J＝5.4Hz)，7.411-7.397(d，1H，J＝8.4Hz)，7.162-7.145(d，1H，J＝8.4Hz)，7.130-7.109 (m，1H)，6.904-6.891(d，1H，J＝7.8Hz),6.879-6.864(d，2H，J＝9.0Hz),4.651-4.642(d，2H，J＝5.4Hz)，4.237-4.213(t，2H，J＝7.2Hz)，3.993-3.957(q，2H，J＝7.2Hz)，3.778(s，3H)，2.696-2.672(t，2H，J＝7.2Hz)，1.134-1.110(t，3H，J＝7.2Hz)。
  9. 权利要求1～8任一项所述的达比加群酯乙酯盐酸盐新晶型的制备方法，包括以下步骤：
    将达比加群乙酯分散在水中，搅拌溶清，析晶，分离所得固体并干燥，得到达比加群酯乙酯盐酸盐新晶型。
  10. 根据权利要求9所述的制备方法，其特征在于，所述搅拌溶清的温度为30～100℃；
    所述析晶的温度为-10～40℃；
    所述干燥的温度为20～140℃。
  11. 药物组合物，包括权利要求1～8任一项所述的达比加群酯乙酯盐酸盐新晶型，或权利要求9～10任一项所述的制备方法制备的达比加群酯乙酯盐酸盐新晶型，以及药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
  12. 权利要求1～8任一项所述的达比加群酯乙酯盐酸盐新晶型，或权利要求9～10任一项所述的制备方法制备的达比加群酯乙酯盐酸盐新晶型，或权利要求11所述的药物组合物，在制备用于预防、治疗或减轻急性血栓性疾病和由此引发的心脑血管疾病的药物中的应用。
  13. 根据权利要求12所述的应用，其特征在于，所述急性血栓性疾病和由此引发的心脑血管疾病包括脑血栓、脑梗塞、心肌梗塞、冠心病、动脉粥样硬化、深静脉血栓、肺栓塞、心力衰竭、心源性休克、心律失常、意识障碍及偏瘫、已经形成的静脉血栓栓塞、急性冠状动脉综合症、急性脑动脉血栓引起的疾病、急性肠系膜动脉血栓及急性肢体动脉血栓、急性深静脉血栓、心房纤维性震颤、复发的深静脉血栓、脑栓塞、脾栓塞中的一种或多种。
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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045900A1 (en) * 2008-10-24 2010-04-29 Zentiva, K.S. A method for the preparation of dabigatran and its intermediates
WO2012077136A2 (en) * 2010-12-06 2012-06-14 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
WO2013111163A2 (en) * 2012-01-20 2013-08-01 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
WO2014020555A2 (en) * 2012-08-01 2014-02-06 Alembic Pharmaceuticals Limited An improved process for the preparation of dabigatran etexilate mesylate
WO2014041559A2 (en) * 2012-08-27 2014-03-20 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dabigatran etexilate and intermediates thereof
WO2014192030A2 (en) * 2013-05-29 2014-12-04 Laurus Labs Private Limited An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof
CN105153118A (zh) * 2015-09-24 2015-12-16 青岛黄海制药有限责任公司 一种甲磺酸达比加群酯制备过程中中间体的中控方法
CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
CN105566297A (zh) * 2015-12-31 2016-05-11 哈药集团技术中心 一种达比加群酯甲磺酸盐的制备方法
WO2016132296A1 (en) * 2015-02-18 2016-08-25 Piramal Enterprises Limited A process for the preparation of an intermediate of dabigatran etexilate
CN106543144A (zh) * 2016-09-29 2017-03-29 成都丽凯手性技术有限公司 一种达比加群酯的工业化制备方法
CN109125274A (zh) * 2017-06-28 2019-01-04 上海美悦生物科技发展有限公司 注射用苯并咪唑类药用酸组合物及其制备方法和用途

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010045900A1 (en) * 2008-10-24 2010-04-29 Zentiva, K.S. A method for the preparation of dabigatran and its intermediates
WO2012077136A2 (en) * 2010-12-06 2012-06-14 Msn Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
WO2013111163A2 (en) * 2012-01-20 2013-08-01 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
WO2014020555A2 (en) * 2012-08-01 2014-02-06 Alembic Pharmaceuticals Limited An improved process for the preparation of dabigatran etexilate mesylate
WO2014041559A2 (en) * 2012-08-27 2014-03-20 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dabigatran etexilate and intermediates thereof
WO2014192030A2 (en) * 2013-05-29 2014-12-04 Laurus Labs Private Limited An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof
WO2016132296A1 (en) * 2015-02-18 2016-08-25 Piramal Enterprises Limited A process for the preparation of an intermediate of dabigatran etexilate
CN105294651A (zh) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 一种用于合成制备达比加群酯脒化中间体的方法
CN105153118A (zh) * 2015-09-24 2015-12-16 青岛黄海制药有限责任公司 一种甲磺酸达比加群酯制备过程中中间体的中控方法
CN105566297A (zh) * 2015-12-31 2016-05-11 哈药集团技术中心 一种达比加群酯甲磺酸盐的制备方法
CN106543144A (zh) * 2016-09-29 2017-03-29 成都丽凯手性技术有限公司 一种达比加群酯的工业化制备方法
CN109125274A (zh) * 2017-06-28 2019-01-04 上海美悦生物科技发展有限公司 注射用苯并咪唑类药用酸组合物及其制备方法和用途

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