WO2016155578A1 - 达格列净的新晶型及其制备方法 - Google Patents

达格列净的新晶型及其制备方法 Download PDF

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WO2016155578A1
WO2016155578A1 PCT/CN2016/077405 CN2016077405W WO2016155578A1 WO 2016155578 A1 WO2016155578 A1 WO 2016155578A1 CN 2016077405 W CN2016077405 W CN 2016077405W WO 2016155578 A1 WO2016155578 A1 WO 2016155578A1
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preparation
ray powder
powder diffraction
diffraction pattern
crystal form
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PCT/CN2016/077405
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English (en)
French (fr)
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陈敏华
张炎锋
杨朝惠
陆飞
杨存波
张晓宇
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苏州晶云药物科技有限公司
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • the invention relates to the field of chemical medicine, in particular to a novel crystal form of dapagliflozin and a preparation method thereof.
  • SGLT has two subtypes, SGLT1 and SGLT2, which are distributed in the small intestine mucosa and renal tubules, and can transport glucose into the blood. Daggliflozin inhibits SGLT2 activity and reduces glucose reabsorption in the renal tubules, thereby lowering blood glucose levels.
  • Patent CN101479287B discloses several solid forms of dapagliflozin, including its marketed crystalline form (S) propylene glycol monohydrate form SC-3, other alcohol solvates and eutectic of dapagliflozin and amino acid; patent CN102167715 Co-crystals of dapagliflozin and proline, tryptophan or phenylalanine are disclosed; patent CN103958491A discloses two hydrate crystal forms of dapagliflozin.
  • the crystalline form (S) propylene glycol monohydrate form SC-3 listed in dapagliflozin is a solvate, and the solvent (S) propylene glycol is a chiral molecule, which is toxic to the brain, digestive system, blood, and expensive. Caused an increase in the cost of drugs.
  • the invention provides a hydrate crystal form of dapagliflozin, avoids the risk of easy conversion of the marketed drug solvate, and the hydrate is non-toxic, environmentally friendly, and the preparation process is simple, and the production cost of the drug can be greatly reduced. , has a strong social and economic value.
  • the solubility and wettability of the hydrate crystal form provided by the invention are in compliance with the medicinal requirements, the stability is good, the storage is stable, the crystal transformation is prevented during the development process, and the solubility, dissolution rate, bioavailability and efficacy of the drug are avoided. change.
  • the compound of the formula (I) provided by the invention has good crystal form stability, solubility and wettability meet the requirements of medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 15.8 ° ⁇ 0.2 °, 19.8 ° ⁇ 0.2 °, and 28.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has characteristic peaks at one or two or three of 2theta values of 8.8° ⁇ 0.2°, 27.1° ⁇ 0.2°, and 31.9° ⁇ 0.2°. .
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 8.8 ° ⁇ 0.2 °, 27.1 ° ⁇ 0.2 °, and 31.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has characteristic peaks at one or two or three of 2theta values of 24.1 ° ⁇ 0.2 °, 8.1 ° ⁇ 0.2 °, and 32.9 ° ⁇ 0.2 °. .
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 24.1 ° ⁇ 0.2 °, 8.1 ° ⁇ 0.2 °, and 32.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a value of 8.1 ° ⁇ 0.2 °, 8.8 ° ⁇ 0.2 °, 15.8 ° ⁇ 0.2 °, 19.8 ° ⁇ 0.2 °, 24.1 °. There are characteristic peaks at ⁇ 0.2°, 27.1° ⁇ 0.2°, 28.7° ⁇ 0.2°, 31.9° ⁇ 0.2°, and 32.9° ⁇ 0.2°.
  • the X-ray powder diffraction spectrum of Form I of the present invention has characteristic peak, d value and relative intensity data at a position where the diffraction angle 2 ⁇ is:
  • the X-ray powder diffraction pattern of Form I provided by the present invention is substantially as shown in FIG.
  • crystal form I provided by the present invention begins to exhibit an endothermic peak when heated to 50 ° C to 60 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the crystal form I provided by the present invention has a weight loss gradient of about 5.6% when heated to 160 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG. 3 .
  • the crystalline form I provided by the present invention is a hydrate containing 1 to 2 moles of water per mole of the crystalline form I.
  • Another object of the present invention is to provide a process for the preparation of Form I comprising the addition of a compound of formula (I) to an aqueous crystallization solvent, by volatilization, heating, temperature reduction, anti-solvent addition or suspension agitation.
  • the aqueous crystallizing solvent includes, but is not limited to, water or a binary mixed system of water and an alcohol, a ketone, or an ether solvent; preferably water.
  • the above preparation method has an operating temperature of -20 ° C to 28 ° C, preferably room temperature.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin Form I and a pharmaceutically acceptable adjuvant.
  • a therapeutically effective amount of dapagliflozin Form I is mixed or combined with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is prepared in a manner well known in the pharmaceutical arts. of.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release;
  • dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agents, patches; dosage forms suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • the crystalline form of the present invention has unexpectedly low hygroscopicity and stability in water or aqueous ethanol solution, it is especially suitable for preparation into tablets, suspensions, capsules, disintegrating tablets, immediate release, and slow release. Release and controlled release tablets; further preferred are tablets, suspensions and capsules.
  • a pharmaceutically acceptable excipient in the above pharmaceutical composition, in the case of a solid oral dosage form including but not limited to: a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, Calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, poly Ethylene glycol or the like; a disintegrating agent such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; a lubricant such as stearic acid , magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; complex forming agents, such as
  • pharmacies available Acceptable excipients include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.
  • the coating is applied to the tablet, for example to provide a shellac barrier coating, a sugar coating or a polymeric coating, a polymer in the coating layer such as hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl Cellulose, methacrylic polymer, hydroxypropyl cellulose or starch may also include anti-adherents such as silica, talc, opacifiers such as titanium dioxide, colorants such as iron oxide-based colorants.
  • suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, and the like; aqueous or nonaqueous sterile suspensions may be employed Containing suspending agents and thickeners; excipients suitable for aqueous suspensions include synthetic or natural gums such as gum arabic, arborvitae, alginate, dextran, sodium carboxymethylcellulose, methylcellulose , polyvinylpyrrolidone or gelatin.
  • the excipient of the aqueous or non-aqueous sterile injectable solution is usually sterile water, physiological saline or aqueous dextrose, may contain buffers, antioxidants, bacteriostatic agents and enable The pharmaceutical composition is isotonic with a blood solute.
  • Each excipient must be acceptable, compatible with the other ingredients in the formulation, and not deleterious to the patient.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art.
  • the crystalline form I of dapagliflozin of the present invention is admixed with one or more pharmaceutically acceptable excipients, optionally with one or more other pharmaceutically active ingredients.
  • tablets, capsules, granules can be prepared by a process such as mixing, granulating, tableting or filling capsules; powders are prepared by mixing finely divided pharmaceutically active ingredients and excipients; solution and syrup
  • the agent can be prepared by dissolving the pharmaceutically active ingredient in a suitably flavored water or aqueous solution; the suspension can be prepared by dispersing the pharmaceutically active ingredient in a pharmaceutically acceptable carrier.
  • wet granulation process for solid preparations which is exemplified by wet granulation of tablets by mixing dry solids such as active ingredients, fillers, binders, etc., with a wetting agent such as water or alcohol Wet, the wetted solid is made into agglomerates or granules, and wet granulation is continued until the desired uniform particle size is obtained, followed by drying of the granulated product. The resulting dried granules are then mixed with a disintegrant, a lubricant, an anti-adhesive, etc., and compressed in a tablet machine; alternatively, coated with a suitable coating powder.
  • a wet granulation process for solid preparations which is exemplified by wet granulation of tablets by mixing dry solids such as active ingredients, fillers, binders, etc., with a wetting agent such as water or alcohol Wet, the wetted solid is made into agglomerates or granules, and wet granulation is
  • the dapagliflozin Form I provided by the present invention has advantageous properties suitable for the above dosage forms.
  • the present invention provides the use of dapagliflozin Form I for the preparation of a medicament for the prevention, delay or treatment of SGLT2 with or without mediated, in particular for the treatment of diabetic pharmaceutical preparations.
  • Still another object of the present invention is to provide use of dapagliflozin Form I or a pharmaceutical composition thereof for the preparation of a hypoglycemic pharmaceutical preparation for the treatment of Type II diabetes.
  • the crystalline form I provided by the present invention is more stable than the (S) propylene glycol monohydrate form SC-3 of the patent CN101479287B. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form moisture permeability and solubility provided by the invention meet the requirements of the drug effect, no special drying conditions are needed in the preparation process, the preparation process and the post-treatment process of the drug are simplified, and the humidity is not easily affected, and the storage conditions are not demanding and convenient. Long-term storage greatly reduces the cost of material storage and quality control, and has strong economic value. Among them, no special drying conditions are required, which means that the sample can be placed at room temperature after filtration, and no special drying conditions such as heating or vacuum are required.
  • the crystal form of the present invention can also be dried at a higher temperature, for example, 40 ° C, or to 50 ° C, or to 60 ° C, drying time can be 2 to 48 hours, or overnight, drying can be in a fume hood, It is carried out in a forced air oven or vacuum oven.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used in the present invention refers to a biological response or drug that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent that is reacted.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or exhibiting a disease or condition of the disease, disorder or disorder; and (3) Ameliorating the disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a condition or symptom of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual
  • inhibiting the disease for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • the novel Form I of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Polymorphic forms of the drug can be obtained by methods including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, solvent loss, volatilization, heat cooling, vapor diffusion, and sublimation. Sometimes, different methods may also achieve the same crystallization. Polymorphs can be detected, discovered, and classified by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), optical microscopy, hygroscopicity, and the like.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the crystal form of the present invention is obtained by volatilization, heating and cooling, anti-solvent addition or suspension stirring.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of Form I of the present invention, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms or amorphous forms of dapagliflozin or a salt thereof, including but not limited to, for example, the known crystalline forms disclosed in CN101479287B.
  • Form I of the invention may be administered as a separate active agent, or they may be administered in combination with other active agents, including other compounds that have the same or similar therapeutic activity and that are determined to be safe and effective for such combination administration.
  • co-administration of the two (or more) active agents allows for a significant reduction in the dosage of each active agent used, thereby reducing the side effects seen, including but not limited to Those disclosed in the specification of the prior art document CN101628905B.
  • oral suspensions are also specifically mentioned, an advantage of this form of administration is that the patient does not have to swallow a solid form, especially for elderly people, children or patients with oral or throat damage who may have difficulty swallowing solid forms.
  • Suspensions are two-phase systems formed by dispersing solid particles in a liquid. Crystals that retain their original solid form in the aqueous or aqueous carrier of the suspension are expected to be more advantageous in maintaining the stability of the properties of the drug product.
  • Other components in the oral suspensions may include buffers, surfactants, viscosity modifiers, preservatives, antioxidants, colorants, flavoring agents, taste masking agents, and the like.
  • Figure 1 is an XRPD pattern of Daphine Net Form I of the present invention
  • Figure 2 is a DSC chart of Daphine Net Form I of the present invention.
  • Figure 3 is a TGA diagram of Daglipepsin Form I of the present invention.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer, wherein room temperature means 25 ° C ⁇ 3 ° C.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the water content in the crystal form I of the present invention is calculated based on the TGA weight loss estimation.
  • the dapagliflozin solid i.e., the compound of formula (I) used in the following examples was prepared according to the method disclosed in the patent document CN101628905B.
  • the (S) propylene glycol monohydrate form SC-3 crystal form is prepared according to the method disclosed in CN101479287B.

Abstract

本发明涉及一种II型糖尿病治疗药物达格列净的晶型I及其制备方法。所述晶型I，其特征在于X射线粉末衍射图在2theta值为15.8°±0.2°、19.8°±0.2°、28.7°±0.2°处具有特征峰。与现有技术相比，晶型I稳定性更好，有利于药品的长期储存放置，避免药物开发和储存中的转晶。制备方法操作简单，有利于工艺化生产中的成本控制，具有极高的经济价值。

Description

达格列净的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及一种达格列净的新晶型及其制备方法。
背景技术
(1S)-1,5-脱水-1-C-[4-氯-3-[(4-乙氧基苯基)甲基]苯基]-D-葡萄糖醇，又名达格列净，其化学结构式如式(I)所示，是由阿斯利康和百时美施贵宝公司联合开发的新型II型糖尿病药物。2012年11月12日，欧盟委员会审批达格列净上市，是全球首个SGLT2(选择性的可逆钠-葡萄糖协同转运蛋白2)抑制剂的新药，可独立于胰岛素外清除体内多余的葡萄糖。并且，达格列净于2014年1月8日获FDA审批上市，是FDA批准上市的第二个SGLT2抑制剂。SGLT有SGLT1和SGLT2两种亚型，分别分布于小肠黏膜和肾小管，能将葡萄糖转运进血液。达格列净可抑制SGLT2活性，减少肾小管中的葡萄糖重吸收，从而降低血糖浓度。
Figure PCTCN2016077405-appb-000001
专利CN101479287B公开了达格列净的几种固体形式，包含其上市晶型(S)丙二醇一水合物形式SC-3，其他醇类溶剂合物以及达格列净和氨基酸的共晶；专利CN102167715公开了达格列净和脯氨酸、色氨酸或苯丙氨酸的共晶；专利CN103958491A公开了达格列净的两个水合物晶型。
达格列净上市的晶型(S)丙二醇一水合物形式SC-3是溶剂合物，溶剂(S)丙二醇是手性分子，对脑、消化系统、血液存在一定的毒性，而且价格昂贵，造成药物成本提高。
本发明提供了达格列净的一种水合物晶型，避免了上市药物溶剂合物易转晶的风险，并且水合物无毒，对环境友好，其制备工艺简单，能大大降低药物生产成本，具有很强的社会经济价值。
本发明提供的水合物晶型溶解度、引湿性符合药用要求，稳定性好，能稳定储存，避免药物在开发过程中发生转晶，从而避免药物溶解度、溶出率、生物利用度以及药效的改变。
发明内容
本发明提供的式(I)化合物的晶型稳定性好，溶解度、引湿性符合药用要求，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
具体的，本发明的一个目的是提供式(I)化合物的晶型，在此命名为晶型I。
本发明提供的晶型I的X射线粉末衍射图在2theta值为15.8°±0.2°、19.8°±0.2°、28.7°±0.2°处具有特征峰。
进一步的，本发明提供的晶型I的X射线粉末衍射图在2theta值为8.8°±0.2°、27.1°±0.2°、31.9°±0.2°中的一处或两处或三处具有特征峰。
更进一步的，本发明提供的晶型I的X射线粉末衍射图在2theta值为8.8°±0.2°、27.1°±0.2°、31.9°±0.2°处具有特征峰。
进一步的，本发明提供的晶型I的X射线粉末衍射图在2theta值为24.1°±0.2°、8.1°±0.2°、32.9°±0.2°中的一处或两处或三处具有特征峰。
更进一步的，本发明提供的晶型I的X射线粉末衍射图在2theta值为24.1°±0.2°、8.1°±0.2°、32.9°±0.2°处具有特征峰。
在一个具体实施方案中，本发明提供的晶型I的X射线粉末衍射图在2theta值为8.1°±0.2°、8.8°±0.2°、15.8°±0.2°、19.8°±0.2°、24.1°±0.2°、27.1°±0.2°、28.7°±0.2°、31.9°±0.2°、32.9°±0.2°处具有特征峰。
进一步地，本发明的晶型I的X-射线粉末衍射谱图在衍射角2θ为以下位置处具有特征峰、d值和相对强度数据：
2theta d间隔 强度％
8.10 10.91 14.64
8.80 10.05 26.09
15.80 5.61 100.00
19.79 4.49 36.37
24.09 3.69 15.83
27.10 3.29 17.11
28.67 3.11 26.95
31.93 2.80 16.84
32.88 2.72 11.69
在另一个具体实施方案中，本发明提供的晶型I的X射线粉末衍射图基本如图1所示。
进一步地，本发明提供的晶型I在加热至50℃～60℃时开始出现吸热峰，其差示扫描量热分析图基本如图2所示。
更进一步地，本发明提供的晶型I在加热至160℃时具有约5.6％的重量损失梯度，其热重分析图基本如图3所示。
更进一步的，本发明提供的晶型I是水合物，每摩尔的晶型I中含有1～2摩尔的水。
本发明的另一个目的是提供晶型I的制备方法，包括将式(I)化合物加入含水的析晶溶剂中，通过挥发、加热降温、反溶剂添加或悬浮搅拌制得。
更进一步的，所述含水的析晶溶剂包括但不限于水或水和醇类、酮类、醚类溶剂的二元混合体系；优选为水。
以上制备方法的操作温度为-20℃～28℃，优选室温。
本发明的另一个目的是提供一种包含有效治疗量的达格列净晶型I和药用辅料的药物组合物。一般是将治疗有效量的达格列净晶型I与一种或多种药用辅料混合或组合制成药物组合物或制剂，该药物组合物或制剂是以制药领域中熟知的方式进行制备的。
上述药物组合物可制成一定的剂型，通过适合的途径给药。例如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。优选地，由于本发明的晶型具有出人意料的低吸湿性和在水中或乙醇水溶液中的稳定性，因此，尤其适合制备成片剂、混悬剂、胶囊剂、崩解片、即释、缓释和控释片剂；进一步优选为片剂、混悬剂和胶囊剂。
上述药物组合物中药学上可接受的赋形剂，在固体口服剂型的情况下，包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上 可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。任选地，对片剂涂覆包衣层，例如提供虫胶隔离包衣、糖衣或聚合物包衣，包衣层中的聚合物例如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、甲基丙烯酸类聚合物、羟丙基纤维素或淀粉，还可以包括抗粘着剂如二氧化硅、滑石粉，乳浊剂如二氧化钛，着色剂如氧化铁类着色剂。在液体口服剂型的情况下，合适的赋形剂包括水、油类、醇类、二醇类、调味剂、防腐剂、稳定剂、着色剂等；水或非水的无菌混悬剂可含有悬浮剂和增稠剂；适用于水性混悬剂的赋形剂包括合成胶或天然胶例如阿拉伯树胶、苍耳树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。在胃肠外给药剂型的情况下，水或非水的无菌注射溶液的赋形剂通常为无菌水、生理盐水或葡萄糖水溶液，可以含有缓冲剂、抗氧化剂、抑菌剂和能够使该药物组合物与血液等渗的溶质。每一种赋形剂必须是可接受的，能与配方中的其他成分兼容并且对于患者无害。
所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备药物组合物时，将本发明达格列净晶型I与一种或多种药学上可接受的赋形剂相混合，任选地与一种或多种其他的药物活性成分相混合。例如，片剂、胶囊剂、颗粒剂可以通过混合、制粒、压片或填充胶囊等工艺来制备；粉剂通过将研细到合适大小的药物活性成分及赋形剂混合来制备；溶液和糖浆剂可通过将药物活性成分溶解于适当调味的水或水性溶液中来制备；混悬剂可通过将药物活性成分分散于药学上可接受的载体中来制备。
特别提及的是固体制剂的湿法制粒工艺，以片剂的湿法制粒为例，制备工艺是：混合活性成分、填充剂、粘合剂等干固体，用润湿剂例如水或醇润湿，将该润湿的固体制成凝聚物或颗粒剂，继续湿法制粒，直到获得所要求的均匀粒径，随后干燥该颗粒产物。然后将得到的干燥颗粒与崩解剂、润滑剂、抗粘着剂等混合，在制片机中压片；可选地，用适当的包衣粉进行包衣。
本发明提供的达格列净晶型I具有适用于上述剂型的有利性质。
此外，本发明提供达格列净晶型I在制备预防、延缓或治疗SGLT2参与或不参与介导的疾病，特别是治疗糖尿病药物制剂的用途。
本发明的又一个目的是提供达格列净晶型I或其药用组合物用于制备治疗Ⅱ型糖尿病的降血糖药物制剂中的用途。
本发明的有益效果为：
本发明提供的晶型I比专利CN101479287B中(S)丙二醇一水合物形式SC-3的稳定性更好。能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变。
本发明提供的晶型引湿性、溶解度符合药效要求，在制备工艺中无需特殊的干燥条件，简化了药物的制备工艺和后处理工艺，且不易受湿度影响，对储存条件要求不苛刻，便于长期贮存，大大降低了物料储存以及质量控制方面的成本，具有很强的经济价值。其中，无需特殊的干燥条件是指样品过滤后在室温放置即可，无需加热或真空等特殊干燥条件。当然，本发明的晶型也可以在更高的温度下进行干燥，例如40℃，或者到50℃，或者到60℃，干燥时间可以为2～48小时，或者过夜，干燥可以在通风橱、鼓风烘箱或真空烘箱里进行。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
本发明中所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本发明中所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
在一些实施方案中，本发明的新晶型I是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
药物的多晶型可通过包括但不限于如下的方法获得：熔融重结晶、熔融冷却、溶剂重结晶、失溶剂、挥发、加热降温、蒸汽扩散和升华。有时，不同的方法也可能获得相同的结晶。多晶型可以通过X射线粉末衍射(XRPD)、差示扫描量热分析(DSC)、热重分析(TGA)、光学显微镜技术、吸湿性等来检测、发现和归类。而本发明晶型是通过挥发、加热降温、反溶剂添加或悬浮搅拌制得的。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明的晶型I，以及至少一种药学上可接受的赋形剂。此外，所述药物组合物还可以包含其它可药用的达格列净或其盐的晶型或无定型物，这些晶型包括但不限于例如CN101479287B中所披露的已知晶型。任选地，本发明的晶型I可以作为单独的活性剂施用，或者它们可以与其它活性剂组合施用，包括具有相同或相似治疗活性并且对于此类组合施用确定为安全且有效的其它化合物。在特别的实施方案中，两种(或多种)活性剂的共同施用使得可以显著降低所用的每种活性剂的剂量，从而降低所见的副作用，这种药物联合使用的方案包括但不限于现有技术文献CN101628905B说明书中所披露的那些。
此外，还特别提及的是口服混悬剂，这种给药形式的一个优点是患者可以不必吞咽固体形式，尤其对于吞咽固体形式可能有困难的老年人、儿童或口腔、咽喉损伤的患者。混悬剂是将固体颗粒分散在液体中形成的两相系统，在混悬剂的水或水性载体中仍保持其原有的固体形式的晶体预期将更有利于保持药物产品性质的稳定。口服混悬剂中的其他组分可包括缓冲剂、表面活性剂、粘度调节剂、防腐剂、抗氧化剂、着色剂、调味剂、味道掩盖剂等。
附图说明
图1为本发明达格列净晶型I的XRPD图；
图2为本发明达格列净晶型I的DSC图；
图3为本发明达格列净晶型I的TGA图；
图4为专利CN101479287B中的(S)丙二醇一水合物形式SC-3在水中搅拌后检测的XRPD图。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施，其中室温是指25℃±3℃。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Figure PCTCN2016077405-appb-000002
1.540598；
Figure PCTCN2016077405-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
其中，本发明晶型I中的含水量是根据TGA失重推测算出。
以下实施例中使用的达格列净固体(即，式(I)化合物)依据专利文献CN101628905B中所公开的方法制得。
实施例1
式(I)化合物晶型I的制备方法：
将80.0mg式(I)化合物加入1.0mL水中，得到悬浊液，将该悬浊液在室温条件下搅拌24小时，过滤，收集固体，并在室温下干燥既得。经检测，所得固体为晶型I。
本实施例得到的晶型I的X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，其TGA图如图3。
表1
2theta d间隔 强度％
8.10 10.91 14.64
8.80 10.05 26.09
11.15 7.93 13.65
11.83 7.48 18.70
15.80 5.61 100.00
16.26 5.45 12.99
17.68 5.02 5.48
18.82 4.72 4.00
19.49 4.56 8.46
19.79 4.49 36.37
20.05 4.43 12.60
23.28 3.82 3.49
23.82 3.74 8.16
24.09 3.69 15.83
25.09 3.55 22.43
25.62 3.48 8.64
27.10 3.29 17.11
27.60 3.23 9.25
28.67 3.11 26.95
29.86 2.99 11.29
30.94 2.89 5.00
31.93 2.80 16.84
32.88 2.72 11.69
34.16 2.63 3.49
36.07 2.49 3.21
37.84 2.38 2.59
38.43 2.34 4.37
38.95 2.31 3.24
实施例2
式(I)化合物晶型I与专利CN101479287B中的(S)丙二醇一水合物形式SC-3晶型稳定性对比研究：
其中，(S)丙二醇一水合物形式SC-3晶型根据CN101479287B中所公开的方法制得。
取80mg CN101479287B中的(S)丙二醇一水合物形式SC-3，加入到1.0mL水中，得到悬浊液，在4℃条件下搅拌，过滤，收集固体，并在室温下干燥。所得固体检测XRPD，如图4所示。结果如表2：
表2
Figure PCTCN2016077405-appb-000004
结果表明，在4℃条件下，专利CN101479287B中的(S)丙二醇一水合物形式SC-3转为本发明的晶型I。因此，在4℃条件下，本发明的晶型I比专利CN101479287B中的(S)丙二醇一水合物形式SC-3更稳定。

Claims (13)

  1. 一种式(I)化合物的晶型I，
    Figure PCTCN2016077405-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为15.8°±0.2°、19.8°±0.2°、28.7°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为8.8°±0.2°、27.1°±0.2°、31.9°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求2所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为8.8°±0.2°、27.1°±0.2°、31.9°±0.2°处具有特征峰。
  4. 根据权利要求1-3所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为24.1°±0.2°、8.1°±0.2°、32.9°±0.2°中的一处或两处或三处具有特征峰。
  5. 根据权利要求4所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为24.1°±0.2°、8.1°±0.2°、32.9°±0.2°处具有特征峰。
  6. 根据权利要求1-5任一项所述的晶型I，其特征在于，其X射线粉末衍射图在2theta值为8.1°±0.2°、8.8°±0.2°、15.8°±0.2°、19.8°±0.2°、24.1°±0.2°、27.1°±0.2°、28.7°±0.2°、31.9°±0.2°、32.9°±0.2°处具有特征峰。
  7. 一种式(I)化合物晶型I的制备方法，其特征在于，将式(I)化合物加入含水的析晶溶剂中，通过挥发、加热降温、反溶剂添加或悬浮搅拌制得晶型I。
  8. 根据权利要求7所述的制备方法，其特征在于，所述含水的析晶溶剂包括水或水和醇类、酮类、醚类溶剂的二元混合体系。
  9. 根据权利要求8所述的析晶溶剂，其特征在于，所述含水的析晶溶剂为水。
  10. 一种药用组合物，所述药用组合物包含有效量的权利要求1至6任意一项所述的晶型I及药学上可接受的赋形剂。
  11. 根据权利要求1至6任意一项所述的晶型I或根据权利要求10所述的药用组合物在制备预防、延缓或治疗SGLT2参与或不参与介导的疾病的药物制剂中的用途。
  12. 权利要求1至6任意一项所述的晶型I或根据权利要求10所述的药用组合物在制备治疗糖尿病的药物制剂中的用途。
  13. 根据权利要求1至6任意一项所述的晶型I或根据权利要求10所述的药用组合物在制备治疗Ⅱ型糖尿病的降血糖药物制剂中的用途。
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