WO2018103119A1 - 一种苯并二氮杂衍生物的氢溴酸盐及其制备方法和用途 - Google Patents

一种苯并二氮杂衍生物的氢溴酸盐及其制备方法和用途 Download PDF

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WO2018103119A1
WO2018103119A1 PCT/CN2016/109564 CN2016109564W WO2018103119A1 WO 2018103119 A1 WO2018103119 A1 WO 2018103119A1 CN 2016109564 W CN2016109564 W CN 2016109564W WO 2018103119 A1 WO2018103119 A1 WO 2018103119A1
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compound
formula
preparation
hydrobromide salt
hydrobromide
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PCT/CN2016/109564
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English (en)
French (fr)
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黄浩喜
卓国清
商国宁
梁臻
储婷
陈翠翠
罗鸣
李英富
苏忠海
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成都倍特药业有限公司
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Priority to EP16923536.3A priority Critical patent/EP3553059B1/en
Priority to US16/467,866 priority patent/US10618904B2/en
Priority to JP2019530024A priority patent/JP6843243B2/ja
Publication of WO2018103119A1 publication Critical patent/WO2018103119A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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

Definitions

  • the invention relates to a benzodiazepine
  • Remimazol the structure of which is represented by formula (I), the chemical name is 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole [1,2 -a][1,4]benzodiazepine 4-yl]methyl propionate.
  • the compound is currently known to be a short-acting Central Nervous System (CNS) inhibitor with sedative, hypnotic, muscle-relaxing and anticonvulsant effects.
  • CNS Central Nervous System
  • ICU sedation ICU sedation and the like.
  • the salt of the compound Due to the stability of the free base of the compound, the salt of the compound has been studied by a multinational researcher.
  • the patent application CN101501019B and WO2008/007081A1 respectively report the besylate and ethanesulfonate of the compound of the formula (I).
  • the above salts have good thermal stability, low hygroscopicity and high water solubility, and it is clearly recognized in CN104968348A that the above-mentioned besylate and ethanesulfonate are the most preferred compounds of the formula (I). Salt.
  • CN103221414B proposes a tosylate salt of a compound of formula (I) and indicates that the tosylate salt is less toxic than the besylate salt, and that some of the crystal forms are more thermally stable, water soluble, etc. For the good.
  • the object of the present invention is to improve the solubility of remiazolam to a degree that is easily soluble in water (30-100 mg/ml).
  • the inventors have conducted research from various aspects, such as the crystal form of existing salts, preparation excipients, new salt formation types, etc., hoping to find improved water solubility, while ensuring better A viable means of drug formation.
  • screening studies on existing salt crystal forms and formulation excipients ended in failure and no more suitable methods were found.
  • sulfate, hydrobromide, and hydrochloride have polymorphism.
  • Sulfate has high hygroscopicity or low crystallinity, and is not easy to be used.
  • the solubility of 1,5-naphthalenedisulfonic acid and 2-naphthalenesulfonic acid is low, while the crystallinity of methanesulfonic acid is low, and it is not easy to form a drug.
  • the hydrobromide salt of the compound of formula (I) has excellent solubility (>100 mg/ml), which is significantly superior to the current commercially available or developed compounds of the compound.
  • Other salt products are especially suitable for the preparation of injections, and the stability under various crystal forms is relatively good (see Table 3).
  • the present invention actually provides a hydrobromide salt of a compound of formula I:
  • the present inventors have also found in the study that the hydrobromide salt of the compound of formula (I) exists in a variety of crystal forms, and the inventors have found four crystal forms up to the present, which are named I, II, III and alpha crystal forms, respectively.
  • the inventors compared the physical and chemical properties of different crystal forms, and finally found that the ⁇ crystal form has the most excellent stability and still maintains good water solubility. Based on the above-mentioned good solubility, the crystal form can be prepared. Paired main drug dissolved
  • a preparation having a high degree of demand e.g., an injection
  • the injection may not be limited to an injection powder (powder needle), or a liquid injection (water needle) may be prepared.
  • Other conditions for the degradation of impurities are mainly:
  • the impurity activity is 1/300 of the compound of formula (I). If the above compound or a salt derivative thereof is inferior in stability, it is liable to be degraded, and the pharmacological activity is lowered, and the toxic side effect may be caused to the human body. Whether the stability is good or not is also a key factor in selecting the crystal form of the compound.
  • the hydrobromide salt of the compound of formula (I) is present in the alpha form. Comparing the ⁇ crystal form with the X-ray powder diffraction patterns (Cu-ka radiation) of the other three crystal forms, it can be found that the ⁇ crystal form is obvious at about 13.7 ⁇ 0.2, 16.0 ⁇ 0.2, 19.2 ⁇ 0.2° 2 ⁇ at the same time. In the differential scanning calorimetry of the characteristic peak and ⁇ crystal form, there is a melting endothermic peak at 170 ° C ⁇ 2 ° C. Therefore, in the present invention, the above-described powder diffraction characteristic peak and DSC melting peak are used to define the structure of the ⁇ crystal form, and on the basis of this definition, the ⁇ crystal form can be clearly distinguished from the other three crystal forms.
  • the X-ray powder diffraction pattern of the alpha crystal form also includes about 8.2 ⁇ 0.2, 10.3 ⁇ 0.2, 12.6 ⁇ 0.2, 15.1 ⁇ 0.2, 20.7 ⁇ 0.2, 22.8 ⁇ Characteristic peaks at 0.2, 23.2 ⁇ 0.2, 25.5 ⁇ 0.2, 26.2 ⁇ 0.2, 27.7 ⁇ 0.2, 28.4 ⁇ 0.2, 30.7 ⁇ 0.2 degrees 2 ⁇ .
  • Fig. 3 or 4 The X-ray powder diffraction pattern of the alpha crystal form prepared in the specific embodiment of the present invention is shown in Fig. 3 or 4, and the DSC spectrum is shown in Fig. 5.
  • the invention also provides a preparation method of the above-mentioned hydrobromide ⁇ crystal form, which comprises the following steps:
  • a compound of the formula I which is reacted with hydrobromic acid to form a solvent system consisting of isopropanol and water.
  • Preparing Form III preferably reacting with aqueous hydrobromic acid in isopropanol to precipitate Form III, or crystallizing the hydrobromide salt in isopropanol solvent to obtain Form III;
  • Crystal III is taken and exposed to a gas having a high relative humidity at a certain temperature until crystal III is crystallized to the ⁇ crystal form.
  • the temperature is between 50 and 60 °C.
  • the high relative humidity means that the relative humidity is 65% or more.
  • the high relative humidity means that the relative humidity is 75% or more.
  • the gas is air.
  • the above crystal transformation method may also be referred to as gas phase-mediated crystal transformation, and is different from solvent-mediated transformation, and the medium for gas phase-mediated transformation is a gas.
  • the crystallizing time can range from a few hours to days, weeks or months depending on the relative humidity and temperature, which can be determined by conventional means of detection.
  • the hydrobromide salt of the compound of the formula (I) Based on the excellent solubility (>100 mg/ml) of the hydrobromide salt of the compound of the formula (I) and its different crystal forms, it can be used for the preparation of an injection, which can better meet the requirements of the injection for the solubility of the raw material. Accordingly, the present invention also provides the use of the hydrobromide salt for the preparation of an injection having a sedative or hypnotic effect.
  • the sedative or hypnotic effects of the present invention are directed to mammals.
  • the drug also has certain anti-anxiety, induced muscle relaxation, anticonvulsant, anesthesia.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrobromide salt as described above.
  • pharmaceutically acceptable excipients may also be included in the composition.
  • “Pharmaceutically acceptable” as used in the present invention is meant to include any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and that is non-toxic to the host to which it is administered.
  • auxiliary materials should have the following properties: (1) no toxic effect on human body, few side effects; (2) stable chemical properties, not susceptible to temperature, pH, The effect of preservation time, etc.; (3) no contraindications with the main drug, does not affect the efficacy and quality inspection of the main drug; (4) does not interact with the packaging material.
  • the pharmaceutical composition is in the form of an injectable preparation.
  • the injection is selected from the group consisting of a liquid injection (water needle), a sterile powder for injection (powder needle) or a tablet for injection (refers to a stencil or a machine tablet prepared by a sterile operation method for a medicine, and is used for temporary use) Dissolved in water for injection for subcutaneous or intramuscular injection).
  • the powder for injection contains at least an excipient in addition to the hydrobromide salt of the compound of formula I.
  • the excipient in the present invention is an ingredient intentionally added to a drug, which should not have pharmacological properties in the amount used, but the excipient may contribute to the processing, dissolution or dissolution of the drug, through the target.
  • the drug is delivered to the route of administration or contributes to stability.
  • the excipient of the present invention may be selected from one or a combination of two or more of a carbohydrate, an inorganic salt, and a polymer.
  • carbohydrates include monosaccharides, oligosaccharides or polysaccharides.
  • Monosaccharides are sugars that cannot be hydrolyzed, and are the basic unit of molecules that make up various disaccharides and polysaccharides. It is divided into triose, butyrate, pentose, hexose, etc.
  • the monosaccharides in nature are mainly pentose and hexose. For example, glucose is aldohexose and fructose is ketohexose.
  • Oligosaccharides also known as oligosaccharides, are polymers in which a few monosaccharides (2-10) are condensed.
  • a polysaccharide is a polymeric sugar polymer carbohydrate composed of a sugar chain bound by a glycosidic bond and having at least 10 monosaccharides.
  • the mass ratio of the compound of the formula I to the excipient is (1:0.5) to (1:200). Based on considerations of cost, concentration of active ingredient, etc., it is proposed in the present invention to set the mass ratio of the compound of the formula I to the excipient to be 1:5 to 1:86.
  • the sterile powder for injection in the present invention can be obtained by a conventional process such as aseptic dispensing or freeze drying.
  • the carbohydrate-based excipient is selected from the group consisting of lactose, maltose, sucrose, mannitol, glucose, or a combination of two or more thereof.
  • the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, and the like.
  • lactose, mannitol, glucose, or a combination of two or more thereof may be used alone, or an inorganic salt such as sodium chloride may be further added in the presence of a single or a plurality of carbohydrates.
  • Figure 1 is an X-ray powder diffraction spectrum of the hydrobromide salt III form of the compound of the formula (I);
  • Figure 2 is a DSC spectrum of the hydrobromide salt III form of the compound of formula (I);
  • Figure 3 is an X-ray powder diffraction spectrum of the hydrobromide alpha crystal form of the compound of formula (I);
  • Figure 4 is an X-ray powder diffraction spectrum of the hydrobromide alpha crystal form of the compound of formula (I);
  • Figure 5 is a DSC/TGA spectrum of the hydrobromide alpha crystal form of the compound of formula (I)
  • Figure 6 is a DVS spectrum of the hydrobromide alpha crystal form of the compound of formula (I)
  • Figure 7 is an X-ray powder diffraction spectrum of the hydrobromide salt I form of the compound of the formula (I);
  • Figure 8 is a DSC spectrum of the hydrobromide salt I form of the compound of formula (I);
  • Figure 9 is a TGA spectrum of the hydrobromide salt I form of the compound of formula (I);
  • Figure 10 is an X-ray powder diffraction spectrum of the hydrobromide salt II form of the compound of the formula (I);
  • Figure 11 is a DSC spectrum of the hydrobromide salt II form of the compound of formula (I);
  • Figure 12 is a TGA spectrum of the hydrobromide II crystal form of the compound of formula (I);
  • the raw material of the compound of the formula (I) used in the present invention can be obtained by purchasing a commercially available product, or can be produced according to a known method (e.g., patents US200, 700, 934, 75A, etc.).
  • the hydrobromide III crystal form compound can be crystallized in a non-flowing gas of a certain humidity to obtain an ⁇ crystal form, especially in air having a humidity of 75% or more, which is mediated by a gas phase interface to undergo crystal transformation. .
  • the advantage of this method is that it is not mediated by the solvent, no loss occurs, and no solvent residue is introduced.
  • the X-ray diffraction spectrum is shown in Fig. 4, at about 6.96, 8.24, 10.48, 12.77, 13.61, 13.85, 15.20, 16.05, 16.28, 17.70, 19.40, 20.80, 22.85, 23.23, 24.05, 24.92, 25.55, 26.25, 27.79, 28.45, 30.70, DSC / TGA diagram shown in Figure 5, showing a melting point of 170 ° C, the sample is not further dried after crystal transformation at 75% humidity, containing 4.3% free water, reflected in the TGA 60.78-79.45 ° C A weightless platform; in addition, the DVS spectrum shows the ability to combine with water at a certain humidity, and is a crystalline crystal.
  • the product is identified as the hydrobromide alpha crystalline form of the compound of formula (I).
  • the X-ray diffraction spectrum of the crystal is shown in Fig. 7, and the DSC spectrum is shown in Fig. 8. There are characteristic absorption peaks at 70 ° C, 162 ° C and 180 ° C, and the crystal form is defined as hydrobromic acid of the compound of the formula (I). Salt I crystal form.
  • the TGA spectrum of the hydrobromide salt I form of the compound of formula (I) is shown in Figure 9.
  • the X-ray diffraction spectrum of the crystal is shown in Fig. 10.
  • the DSC spectrum is shown in Fig. 11.
  • Hydrobromide II crystal form is shown in Figure 12.
  • the ⁇ crystal form prepared by the invention can still ensure good stability under the conditions of strong light, high heat and high humidity, and is obviously superior to the other three crystal forms.
  • the benzenesulfonate I crystal form of the compound of the formula (I) is prepared by referring to the patents CN200780028964.5 and CN201310166860.8, and the obtained crystal forms are about 7.19, 7.79, 9.38, 12.08, 14.06, 14.40, 14.72, 15.59. There are characteristic peaks.
  • the ⁇ crystal form prepared by the invention exhibits better stability than the original crystalline form of the besylate salt under the conditions of strong light, high heat and high humidity.
  • the ⁇ crystal form prepared by the present invention is also more stable than the tosylate crystal form in CN103221414B.
  • Prescription 1 The remiazolam hydrobromide salt is directly dispensed into a brown vial under aseptic conditions, and the lid is obtained.
  • Prescription 2 ⁇ 10 Dissolve the excipient and remiazolam hydrobromide in water for injection, stir until dissolved, adjust the pH value of the solution with hydrochloric acid/sodium hydroxide, dispense into a vial, freeze-dry, ie Got it.
  • Prescriptions 9, 10 are prepared according to the process reported in the patent CN201380036582.2, respectively, to prepare remiazolam hydrobromide, remazolium benzene sulfonate freeze-dried powder needles, the two freeze-dried powder needles are compared as follows:
  • the accelerated placement condition is 40 °C
  • the long-term placement condition is 25 °C.
  • reconstitution time water for injection / glucose / physiological saline gently vortex to dissolve completely mixed, record the time spent completely dissolved.
  • the lyophilized powder of remazol hydrobromide in the present invention maintains good stability in both accelerated and long-term stability experiments, and its stability and resolubility are superior to those of ruthenium.
  • Efazolium besylate lyophilized powder needle (CN201380036582.2).

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Abstract

本发明提供了3-[(4s)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1,2-a][1,4]苯并二氮杂-4-基]丙酸甲酯的氢溴酸盐及其相关晶型与制备方法和用途。该氢溴酸盐，溶解度极佳(>100mg/ml)，显著优于该化合物当前各市售或研发的其他盐类产品，尤其适合注射剂的制备，并且各种晶型形式下的稳定性也相对较好，具有良好的实用价值和市场前景。

Description

一种苯并二氮杂衍生物的氢溴酸盐及其制备方法和用途
本发明要求在先申请CN201611132114.7、申请日2016年12月09日的优先权，该在先申请中的所有内容都应被纳入参考。
技术领域
本发明涉及一种苯并二氮杂
Figure PCTCN2016109564-appb-000002
衍生物的氢溴酸盐及其制备方法和用途，属医药化学领域。
背景技术
瑞马唑仑，其结构如式(I)所示，化学名为3-[(4s)-8-溴-1-甲基-6-(2-吡啶基)-4H-咪唑[1,2-a][1,4]苯并二氮杂
Figure PCTCN2016109564-appb-000003
-4-基]丙酸甲酯。
Figure PCTCN2016109564-appb-000004
目前已知该化合物是短效中枢神经系统(CNS，Central Nervous System)抑制剂，具有包括镇静催眠、抗焦虑、肌肉松弛和抗惊厥作用。目前多用于以下临床治疗方案中的静脉给药：如手术期间中的手术前镇静、抗焦虑和遗忘用途；在短期诊断、手术或内窥镜程序期间的清醒性镇静；在施用其它麻醉剂和止痛剂之前和/或同时，作为用于全身麻醉的诱导和维持的组分；ICU镇静等。在专利申请CN101501019中报道，该化合物的游离碱稳定性较差，只适合于低温5℃保存，在40℃/75％相对湿度(开放)的条件下，样品潮解、变色，含量显著降低。
由于该化合物游离碱存在的稳定性问题，多国研发人员对该化合物的盐类进行了研究，如专利申请CN101501019B、WO2008/007081A1分别报道了式(I)化合物的苯磺酸盐、乙磺酸盐，并显示上述盐类有良好的热稳定性、低的吸湿性和高的水溶性，并且，CN104968348A中明确认为，上述苯磺酸盐、乙磺酸盐是式(I)化合物的最优选的盐类。
紧随其后，CN103221414B提出了一种式(I)化合物的托西酸盐，并表示该托西酸盐毒性低于苯磺酸盐，并且某些晶型的热稳定性、水溶性等更为良好。
将现有技术信息进行整理，可以得出如下相关内容(表1)：
表1
Figure PCTCN2016109564-appb-000005
由上表内容可以看出，不管是瑞马唑仑游离碱，还是瑞马唑仑的已知盐类衍生物，水溶性均不高于11mg/ml，仅仅处于微溶的范围，这会增加其在临床使用的安全风险，在临床使用复溶时需要长时间震荡溶解，还有可能残留不溶性原料，导致药物剂量不准确，以及潜在的安全性风险，另外，在用于全麻这种药物需求量较大的适应症上，会加大稀释剂的用量，造成临床使用的极度不便。故瑞马唑仑已知盐类衍生物溶解性是较大的劣势，亟待进一步改善。
发明内容
针对现有瑞马唑仑游离碱及其相关盐类存在的水溶性问题，本发明的目的是希望能够将瑞马唑仑的溶解性提高至易溶于水(30-100mg/ml)的程度。为了达到上述水溶性目标，发明人曾从多个方面入手进行了研究，例如现有盐类的晶型、制剂辅料、新的成盐类型等方面，希望能够找到提高水溶性，同时保证较好的成药性的可行手段。然而，对现有盐类晶型、制剂辅料的筛选研究最终以失败告终，并未找到更加合适的方法。而对多种盐类进行的研究中，前期试验过程中总共对20多种酸盐进行了筛选，发现有8种盐型，其中，硫酸盐、2-萘磺酸盐、甲磺酸盐、草酸盐、氢溴酸盐、盐酸盐、1,5-萘二磺酸盐等7种盐呈晶态形式，乙二磺酸盐呈现无定型。对上述盐类作出进一步的研究，结果如下表：
表2
Figure PCTCN2016109564-appb-000006
其中，硫酸盐、氢溴酸盐、盐酸盐存在多晶型现象。硫酸盐吸湿性高或结晶度较低，不易成药，1,5-萘二磺酸和2-萘磺酸的溶解度较低，而甲磺酸的结晶度较低，不易成药。
从上表可以看出，盐酸盐和氢溴酸盐的溶解度及其他方面的性质都较为理想，美国FDA橙皮书收录【Progress in Pharmaceutical Sciences,2012，Vol.36，No.4151】的2006年前上市的1 356个化学结构明确的有机药物中，与酸成盐的药物523个(占38.6％)，其中，使用频率最高的与有机碱成盐的酸为盐酸(占53.4％)。由此可见，目前上市的诸多酸盐类药品中，盐酸盐是优势选择。
不过，在对盐酸盐的稳定性进行分析研究时，其结果却为发明人指出了使用比例最广的盐酸盐对于该化合物稳定性太差：
表3
Figure PCTCN2016109564-appb-000007
由表3可见，盐酸盐虽然水溶性良好，但是稳定性极差，因此放弃盐酸盐。
本发明在对上述多种盐类进行长期的研究过程中意外地发现，式(I)化合物的氢溴酸盐溶解度极佳(>100mg/ml)，显著优于该化合物当前各市售或研发的其他盐类产品，尤其适合注射剂的制备，并且各种晶型形式下的稳定性也相对较好(见表3)。基于上述原因，本发明实际提供了如式I所示化合物的氢溴酸盐：
Figure PCTCN2016109564-appb-000008
其中，式(I)化合物与氢溴酸的化学配比为1:1。
本发明在研究中还发现，式(I)化合物氢溴酸盐存在多种晶型，发明人截至当前已经发现了4种晶型，分别命名为I、II、III和α晶型。发明人对不同的晶型进行了理化性质的研究比对，最终发现α晶型的稳定性最为优异，且依然保持了良好的水溶性，基于上述如此良好的溶解性，可以将该晶型制备成对主药溶解 性有较高要求的制剂(如注射剂)，同时，鉴于其良好的稳定性，注射剂中也可以无需限定于注射用粉剂(粉针)，也可以制备液体注射剂(水针)。
目前研究发现，式(I)化合物的光照降解杂质结构：
Figure PCTCN2016109564-appb-000009
其他条件降解杂质主要是：
Figure PCTCN2016109564-appb-000010
该杂质活性为式(I)化合物的1/300。若上述化合物或其盐类衍生物稳定性较差，容易发生降解，轻则导致药效活性降低，重则可能对人体产生一定毒副作用。稳定性是否良好，也是选择化合物晶型的关键因素。
因此，本发明优选式(I)化合物氢溴酸盐以α晶型形式存在。将α晶型与其他三种晶型的X-射线粉末衍射图谱(Cu-ka辐射)进行比较可以发现，α晶型同时在约13.7±0.2、16.0±0.2、19.2±0.2度2θ处有明显的特征峰，α晶型的差示扫描量热分析中，在170℃±2℃有熔融吸热峰。因此，本发明中使用上述粉末衍射特征峰和DSC熔融峰对α晶型的结构进行限定，在此限定基础上，可以将α晶型与其他三种晶型明确区分。
当然，除了上述三个明显的区别特征峰外，α晶型的X-射线粉末衍射图谱中还包括位于约8.2±0.2、10.3±0.2、12.6±0.2、15.1±0.2、20.7±0.2、22.8±0.2、23.2±0.2、25.5±0.2、26.2±0.2、27.7±0.2、28.4±0.2、30.7±0.2度2θ处的特征峰。
本发明具体实施方式中制备的α晶型的X-射线粉末衍射图谱如图3或4所示，DSC谱图如图5所示。
另据EMEA文件【20080124EMEA关于要求进行基因毒性杂质评估的函件】指出苯磺酸与甲苯磺酸等低级磺酸类存在一个潜在风险，即若在工艺过程中使用醇类，可能导致基因毒性杂质苯磺酸酯或甲苯磺酸酯的产生，同理，使用醇类清洁的反应罐或储存罐也可能提高该风险。因此，除了上述水溶性和稳定性的优势以外，氢溴酸为低毒性，溴离子是人体16种微量元素之一，在安全性方面可能也存在很大优势。
本发明还提供了上述氢溴酸盐α晶型的制备方法，它包括如下操作步骤：
(1)取式I所示化合物，与氢溴酸反应，将其在异丙醇和水组成的溶剂系统 中制备成晶型III,优选地在异丙醇中与氢溴酸水溶液反应，析出晶型III，或将氢溴酸盐在异丙醇溶剂中结晶获得晶型III；
(2)取晶体III，在一定温度下暴露于具有高相对湿度的气体中，直至晶体III转晶至α晶型。
其中，步骤(2)中，所述温度在50-60℃。
其中，步骤(2)中，所述高相对湿度是指相对湿度在65％以上。
进一步地，所述高相对湿度是指相对湿度在75％以上。
本发明一个具体实施方式中，所述气体为空气。
上述转晶方法亦可称为气相介导转晶，不同于溶剂介导转晶，气相介导转晶的介质是气体。转晶时间可以为数小时到数天、数周或数月，这取决于相对湿度和温度，这一时间可以通过常规检测手段确定。
基于式(I)化合物氢溴酸盐及其不同晶型极佳的溶解性(>100mg/ml)，将其用于制备注射剂，能够更好的满足注射剂对原料溶解度的要求。因此，本发明还提供了将该氢溴酸盐用于制备具有镇静或催眠作用的注射剂中的用途。
本发明所述镇静或催眠作用，是针对哺乳动物产生。同时，该药物还具有一定的抗焦虑、诱导肌肉松弛、抗惊厥、麻醉的功效。具体给药剂量，可以参见现有技术中瑞马唑仑的有效用药剂量。
另外，本发明还提供了一种药物组合物，其含有如上所述的氢溴酸盐。当然，除了氢溴酸盐外，组合物中还可以包括及药学上可接受的辅料。
本发明中所述“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。
“辅料”是药物制剂中除主药以外的一切附加材料的总称，辅料应当具备如下性质：(1)对人体无毒害作用，几无副作用；(2)化学性质稳定，不易受温度、pH、保存时间等的影响；(3)与主药无配伍禁忌，不影响主药的疗效和质量检查；(4)不与包装材料相互发生作用。
本发明一个具体实施方式中，所述药物组合物以注射用制剂形式存在。
其中，所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片，临用时用注射用水溶解，供皮下或肌肉注射之用)。
其中，所述注射用粉剂的中除含有式I化合物的氢溴酸盐外，还至少含有赋形剂。本发明中所述赋形剂，为有意加到药物中的成分，其在所用的量上不应具有药理学特性，但是，赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给药途径递药或有助于稳定性。
本发明所述赋形剂可以选自碳水化合物、无机盐、聚合物中的一种或两种以上的组合。其中碳水化合物包括单糖、寡糖或多糖类等。
单糖就是不能再水解的糖类，是构成各种二糖和多糖的分子的基本单位，可 分为丙糖、丁糖、戊糖、己糖等，自然界的单糖主要是戊糖和己糖，例如，葡萄糖为己醛糖，果糖为己酮糖。
寡糖又称为低聚糖，是少数单糖(2—10个)缩合的聚合物。
多糖是由糖苷键结合的糖链，至少要超过10个的单糖组成的聚合糖高分子碳水化合物。
其中，式I化合物与赋形剂的质量比为(1：0.5)～(1：200)。基于对成本、有效成分浓度等的考虑，本发明中建议将式I化合物与赋形剂的质量比设为1：5～1：86。
本发明中所述注射用无菌粉末可通过常规的无菌分装或冷冻干燥等工艺获得。
本发明一个具体实施方式中，所述碳水化合物类赋形剂选自乳糖、麦芽糖、蔗糖、甘露醇、葡萄糖中的一种或两种以上的组合。本发明一个具体实施方式中，所述无机盐类选自氯化钠、氯化钾、氯化钙等。当然，目前在冻干粉针制剂中，常常将无机盐类与碳水化合物联合使用，因此，本发明在实际操作过程中，对赋形剂种类的选择可以遵循已知理论进行常规筛选而获得。例如，可以单独使用乳糖、甘露醇、葡萄糖，或者使用它们两者以上的组合物，又或者在单独或多个碳水化合物存在的基础上再加入氯化钠等无机盐。
本发明在研究过程中发现，采用式I化合物氢溴酸盐来作为原料制备冻干粉针剂时，选用多种不同的赋形剂均能够达到良好的稳定性和复溶性，且优于瑞马唑仑苯磺酸盐冻干粉针(CN201380036582.2)。这一发现，足以说明本发明提供的瑞马唑仑氢溴酸盐更适合用于制备冻干粉针剂。
显然，根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。
以下通过具体实施例的形式，对本发明的上述内容再做进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为式(I)化合物氢溴酸盐Ⅲ晶型的X-射线粉末衍射谱图；
图2为式(I)化合物氢溴酸盐Ⅲ晶型的DSC谱图；
图3为式(I)化合物氢溴酸盐α晶型的X-射线粉末衍射谱图；
图4为式(I)化合物氢溴酸盐α晶型的X-射线粉末衍射谱图；
图5为式(I)化合物氢溴酸盐α晶型的DSC/TGA谱图
图6为式(I)化合物氢溴酸盐α晶型的DVS谱图
图7为式(I)化合物氢溴酸盐Ⅰ晶型的X-射线粉末衍射谱图；
图8为式(I)化合物氢溴酸盐Ⅰ晶型的DSC谱图；
图9为式(I)化合物氢溴酸盐Ⅰ晶型的TGA谱图；
图10为式(I)化合物氢溴酸盐Ⅱ晶型的X-射线粉末衍射谱图；
图11为式(I)化合物氢溴酸盐Ⅱ晶型的DSC谱图；
图12为式(I)化合物氢溴酸盐Ⅱ晶型的TGA谱图；
具体实施方式
本发明使用的式(I)化合物原料瑞马唑仑，可以通过购买市售产品获得，也可以按照已知方法进行制备(如专利US200，700，934，75A等)。
Figure PCTCN2016109564-appb-000011
实施例1式(I)化合物的氢溴酸盐III晶型的制备
向100mL三口瓶中准确称取式(I)化合物1.8g，加入8.2mL异丙醇搅拌使其全部溶解，然后将0.83g 47％的氢溴酸水溶液溶于6.3mL异丙醇中，并滴加到式(I)化合物的异丙醇溶液中，搅拌析晶，过滤，55℃减压干燥得式(I)化合物的氢溴酸盐。
该结晶的X-射线衍射谱图见附图1，DSC和TGA图谱见附图2，熔点在163℃，定义该晶型为式(I)化合物的氢溴酸盐Ⅲ晶型。
实施例2：式(I)化合物的氢溴酸盐α晶型的制备
氢溴酸盐Ⅲ晶型化合物在非流动状态的一定湿度的气体中，可以发生转晶，获得α晶型，特别是在湿度75％以上的空气中，通过气相界面介导，发生晶型转化。该法的优点是不通过溶剂介导，不发生损失，且不引入溶剂残留。
具体地，将上述实施例1中的式(I)化合物的氢溴酸盐Ⅲ晶型化合物200mg，在50～55℃-RH75％条件下敞口放置20小时。该结晶样品的X-射线衍射谱图见图3，在约6.85、8.16、10.25、12.63、13.48、13.73、15.01、16.05、16.25、17.59、19.15、20.65、22.74、23.18、23.95、24.75、25.40、26.16、27.69、28.30、30.65确定产物为式(I)化合物的氢溴酸盐α晶型。IC：溴离子含量15.74％，确认氢溴酸成盐比例1:1；溶剂残留：异丙醇0.01％。
实施例3：式(I)化合物的氢溴酸盐α晶型的制备
将上述实施例1中的式(I)化合物的氢溴酸盐Ⅲ晶型化合物500mg，在55～60℃-RH75％条件下敞口放置60小时。该结晶样品的X-射线衍射谱图和DSC谱图经研究比对，确定产物为式(I)化合物的氢溴酸盐α晶型。
X-射线衍射谱图见图4，在约6.96、8.24、10.48、12.77、13.61、13.85、15.20、16.05、16.28、17.70、19.40、20.80、22.85、23.23、24.05、24.92、25.55、26.25、27.79、28.45、30.70，DSC/TGA图见附图5，显示熔点为170℃，该样品由于在75％湿度下转晶后没有进一步干燥，含有4.3％的游离水，体现在TGA上的60.78-79.45℃的一个失重平台；另外，DVS图谱显示在一定湿度下有和水结合的能力，为无结晶水晶型。确定产物为式(I)化合物的氢溴酸盐α晶型。
实施例4：式(I)化合物的氢溴酸盐Ⅰ晶型的制备
向10mL单口瓶中准确称取式(I)化合物44mg(0.10mmol)，加入0.4mL乙酸乙酯搅拌使其全部溶解，反应温度降至4℃，然后将1.1mL氢溴酸的甲醇溶液(1mol/L,0.11mmol)滴加到式(I)化合物的乙酸乙酯溶液中，搅拌析晶，抽滤，乙酸乙酯淋洗，30℃减压干燥得式(I)化合物的氢溴酸盐，白色固体42mg，收率81％。
该结晶的X-射线衍射谱图见附图7，DSC图谱见附图8，在70℃、162℃和180℃附近有特征吸收峰，定义该晶型为式(I)化合物的氢溴酸盐的Ⅰ晶型。式(I)化合物氢溴酸盐Ⅰ晶型的TGA谱图见附图9。
实施例5：式(I)化合物的氢溴酸盐Ⅱ晶型的制备
向1mL离心管中准确称取式(I)化合物22.26mg，加入100μL丙酮搅拌使其全部溶解，然后将10mg 47％的氢溴酸水溶液溶于75μL丙酮中，并滴加到式(I)化合物的丙酮溶液中，搅拌析晶，离心，30℃减压干燥得式(I)化合物的氢溴酸盐，白色固体20mg，收率76％。
该结晶的X-射线衍射谱图见附图10，DSC图谱见附图11，在69℃、90℃、173℃及188℃附近有特征吸收峰，定义该晶型为式(I)化合物的氢溴酸盐Ⅱ晶型。式(I)化合物氢溴酸盐Ⅱ晶型的TGA谱图见附图12。
实施例6本发明α晶型与其他晶型的比较
将式(I)化合物氢溴酸盐的α晶型与其他晶型进行比较，结果见表4：
表4
Figure PCTCN2016109564-appb-000012
由上表可以看出，本发明制备的α晶型在强光、高热和高湿等因素条件下，仍然能够保证良好的稳定性，且明显优于其他三种晶型。
实施例7本发明α晶型与原盐晶型的稳定性对照
参照专利CN200780028964.5和CN201310166860.8制备式(I)化合物的苯磺酸盐Ⅰ晶型，所得晶型在约7.19、7.79、9.38、12.08、14.06、14.40、14.72、15.59 处有特征峰。
将该原研苯磺酸盐晶型与本发明氢溴酸盐α晶型进行如下稳定性比较，结果见表5：
表5
Figure PCTCN2016109564-appb-000013
由上表可以看出，本发明制备的α晶型在强光、高热和高湿等因素条件下，都表现出了比原研苯磺酸盐晶型更好的稳定性。另外，从公开的数据来看，本发明制备的α晶型稳定性也比CN103221414B中的托西酸盐晶型更好。
实施例8注射用瑞马唑仑氢溴酸盐无菌粉末处方及工艺
按照表6的处方，采用如下制备工艺，制备无菌粉末，并对各处方的理化指标进行对比。
制备工艺：
处方1：在无菌条件下将瑞马唑仑氢溴酸盐直接分装至棕色西林瓶中，扎盖即得。
处方2～10：将赋形剂及瑞马唑仑氢溴酸盐溶于注射用水中，搅拌至溶解，用盐酸/氢氧化钠调整溶液pH值，分装入西林瓶，经冷冻干燥，即得。
表6注射用瑞马唑仑氢溴酸盐无菌粉末
Figure PCTCN2016109564-appb-000014
各处方理化指标如下：
表7注射用瑞马唑仑氢溴酸盐无菌粉末理化指标
Figure PCTCN2016109564-appb-000015
处方9、10为按照专利CN201380036582.2报导的工艺，分别制备瑞马唑仑氢溴酸盐、瑞马唑仑苯磺酸盐冻干粉针，两种冻干粉针比较如下：
表8瑞马唑仑氢溴酸盐冻干粉针与原研瑞马唑仑苯磺酸盐冻干粉针比较
Figure PCTCN2016109564-appb-000016
注：1、加速放置条件为40℃，长期放置条件为25℃
2、复溶时间：注射用水/葡萄糖/生理盐水温和地涡旋至溶解完全混合均匀，记录完全溶解所花的时间。
从上表可以看出，本发明将瑞马唑仑氢溴酸盐的冻干粉针，在加速和长期稳定性实验中都保持了良好的稳定性，其稳定性和复溶性都优于瑞马唑仑苯磺酸盐冻干粉针(CN201380036582.2)。

Claims (20)

  1. 如式I所示化合物的氢溴酸盐：
    Figure PCTCN2016109564-appb-100001
    式(I)化合物与氢溴酸的化学配比为1:1。
  2. 根据权利要求1所述的氢溴酸盐，其特征在于：所述氢溴酸盐以α晶型形式存在，使用Cu-ka辐射，得到的X-射线粉末衍射图谱中，至少包括位于约13.7±0.2、16.0±0.2、19.2±0.2度2θ处的特征峰。
  3. 根据权利要求2所述的氢溴酸盐，其特征在于：所述氢溴酸盐的α晶型的X-射线粉末衍射图谱中还包括位于约8.2±0.2、10.3±0.2、12.6±0.2、15.1±0.2、20.7±0.2、22.8±0.2、23.2±0.2、25.5±0.2、26.2±0.2、27.7±0.2、28.4±0.2、30.7±0.2度2θ处的特征峰。
  4. 根据权利要求2所述的氢溴酸盐，其特征在于：所述α晶型的差示扫描量热分析中，在170℃±2℃有熔融吸热峰。
  5. 权利要求2～4任意一项所述氢溴酸盐α晶型的制备方法，其特征在于：它包括如下操作步骤：
    (1)取式I所示化合物，与氢溴酸反应，将其在异丙醇和水组成的溶剂系统中，制备成氢溴酸盐的晶型III；；
    (2)取晶型III，在一定温度下暴露于具有高相对湿度的气体中，直至晶体III转晶至α晶型。
  6. 根据权利要求5所述的制备方法，其特征在于：步骤(1)的具体操作为：在异丙醇中与氢溴酸水溶液反应，析出晶型III；或将氢溴酸盐在异丙醇溶剂中结晶获得晶型III。
  7. 根据权利要求5所述的制备方法，其特征在于：步骤(2)中，所述温度在50-60℃。
  8. 根据权利要求5所述的制备方法，其特征在于：步骤(2)中，所述高相对湿度是指相对湿度在65％以上。
  9. 根据权利要求8所述的制备方法，其特征在于：所述高相对湿度是指相对湿度在75％以上。
  10. 根据权利要求5所述的制备方法，其特征在于：步骤(2)中，所述气体为空气。
  11. 权利要求1～4任意一项所述氢溴酸盐在制备具有镇静、催眠、抗焦虑、 诱导肌肉松弛、抗惊厥或麻醉作用的注射剂中的用途。
  12. 一种药物组合物，其特征在于：它是含有权利要求1～4任意一项所述氢溴酸盐的注射用制剂。
  13. 根据权利要求12所述的药物组合物，其特征在于：所述注射用制剂选自为注射液、注射用无菌粉末等。
  14. 根据权利要求13所述的药物组合物，其特征在于：所述注射用无菌粉末除含有式I化合物的氢溴酸盐，还包含至少一种赋形剂。
  15. 根据权利要求14所述的药物组合物，其特征在于：所述的赋形剂选自糖类、无机盐类、聚合物类中的一种或两种以上的组合。
  16. 根据权利要求15所述的药物组合物，其特征在于：所述的糖类选自单糖类、寡糖类或多糖类。
  17. 根据权利要求16所述的药物组合物，其特征在于：所述的糖类选自乳糖、麦芽糖、蔗糖、甘露醇、葡萄糖、葡聚糖等。
  18. 根据权利要求15所述的药物组合物，其特征在于：所述无机盐类选自氯化钠、氯化钾、氯化钙等。
  19. 根据权利要求14所述的药物组合物，其特征在于：式I化合物与赋形剂的质量比为1：0.5～1：200。
  20. 根据权利要求19所述的药物组合物，其特征在于：式I化合物与赋形剂的质量比为1：5～1：86。
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