(19)
(11)EP 3 553 059 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
13.10.2021 Bulletin 2021/41

(21)Application number: 16923536.3

(22)Date of filing:  13.12.2016
(51)International Patent Classification (IPC): 
C07D 487/04(2006.01)
A61P 21/02(2006.01)
A61P 25/08(2006.01)
A61P 25/22(2006.01)
A61K 9/19(2006.01)
A61K 31/5517(2006.01)
A61P 23/00(2006.01)
A61P 25/20(2006.01)
A61K 9/08(2006.01)
(52)Cooperative Patent Classification (CPC):
A61K 31/5517; A61K 9/08; C07D 487/04; A61K 9/19; A61P 21/02; A61P 23/00; A61P 25/08; A61P 25/22; A61P 25/20
(86)International application number:
PCT/CN2016/109564
(87)International publication number:
WO 2018/103119 (14.06.2018 Gazette  2018/24)

(54)

8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1,2-A][1,4]BENZODIAZEPINE-4-PROPANOIC ACID METHYL ESTER (REMIMAZOLAM, CNS 7056) HYDROBROMIDE (1:1) SALT FOR INJECTION FOR SEDATION AND ANESTHESIA

8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1,2-A][1,4]BENZODIAZEPINE-4-PROPANSÄUREMETHYLESTER (REMIMAZOLAM, CNS 7056) HYDROBROMIDE (1:1) SALZ ZUR INJEKTION FÜR SEDIERUNG UND ANÄSTHESIE

SÉL HYDROBROMIDE (1:1) DU ESTER MÉTHYLIQUE DU ACIDE PROPANOIQUE DE 8-BROMO-1-MÉTHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1,2-A][1,4]BENZODIAZEPINE (RÉMIMAZOLAM, CNS 7056) (1:1) POUR L'INJECTION POUR SÉDATION OU ANESTHÉSIE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 09.12.2016 CN 201611132114

(43)Date of publication of application:
16.10.2019 Bulletin 2019/42

(73)Proprietor: Chengdu Brilliant Pharmaceutical Co., Ltd.
Chengdu, Sichuan 610041 (CN)

(72)Inventors:
  • HUANG, Haoxi
    Chengdu Sichuan 610041 (CN)
  • ZHUO, Guoqing
    Chengdu Sichuan 610041 (CN)
  • SHANG, Guoning
    Chengdu Sichuan 610041 (CN)
  • LIANG, Zhen
    Chengdu Sichuan 610041 (CN)
  • CHU, Ting
    Chengdu Sichuan 610041 (CN)
  • CHEN, Cuicui
    Chengdu Sichuan 610041 (CN)
  • LUO, Ming
    Chengdu Sichuan 610041 (CN)
  • LI, Yingfu
    Chengdu Sichuan 610041 (CN)
  • SU, Zhonghai
    Chengdu Sichuan 610041 (CN)

(74)Representative: Held, Stephan 
Meissner Bolte Patentanwälte Rechtsanwälte Partnerschaft mbB Widenmayerstraße 47
80538 München
80538 München (DE)


(56)References cited: : 
WO-A1-2008/007071
CN-A- 104 768 557
CN-A- 106 380 470
WO-A1-2015/076340
CN-A- 104 968 348
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    Cross-Reference to Related Application



    [0001] The present invention claims the priority of the prior application CN201611132114.7 filed on Dec. 09, 2016.

    Technical field



    [0002] The present invention relates to hydrobromide of benzodiazepine derivative, preparation method and use thereof, and belongs to the field of medical chemistry.

    Background art



    [0003] Remimazolam, the chemical name of which is methyl 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl] propionate, has the structure represented by formula (I):



    [0004] The compound is currently known to be a short-acting Central Nervous System (CNS) inhibitor with sedative, hypnotic, anxiolytic, muscle-relaxing and anticonvulsant effects. At present, it is mostly used for intravenous administration in the following clinical treatment regimens: for pre-operative sedation, anxiolytic and amnestic use during surgery; for conscious sedation during short-term diagnosis, surgery or endoscopic procedures; as a component for induction and maintenance of general anesthesia before and/or at the same time of administering other anesthetics and analgesia; for ICU sedation and the like. It is reported in the patent application CN101501019 that the free base of the compound has poor stability, and is only suitable for storage at a low temperature of 5°C, and, under the condition of 40°C/75% relative humidity (open), the sample is deliquescent, discolored, and significantly reduced in content.

    [0005] In view of the stability problem with the free base of the compound, salts of the compound have been studied by researchers in multiple countries. For example, the patent applications CN101501019B and WO2008/007081 A1 respectively reported besylate and esylate of the compound of the formula (I). It is shown that the above salts have good thermal stability, low hygroscopicity and high water solubility. Moreover, CN104968348A clearly indicated that the above-mentioned besylate and esylate are the most preferred salts of the compound of the formula (I).

    [0006] Immediately thereafter, CN103221414B proposed a tosylate of the compound of the formula (I), and indicated that the tosylate is less toxic than besylate, and some crystal forms thereof behave better in thermal stability, water solubility, etc.

    [0007] By sorting the prior art information, the following related contents can be obtained (Table 1):
    Table 1
    NameCompanyPatent No.Properties
    Remimazolam besylate (CNS-7056) PAION CN200780028964.5 CN201310166860.8 Solubility in water: 8.3 mg/ml; degradation 0.5% at 40 degrees, RH75% closed, 4 weeks
    Remimazolam tosylate (HR-7056) Jiangsu Hengrui CN201280003321.6 Solubility in water: about 10, 11 mg/ml; influence factor tests show that the most stable crystal form still behaves not ideal under light conditions, with degradation more than 1.5% in 10 days. The patent states that the salt is less toxic than benzene sulfonic acid
    Remimazolam esylate Cambridge(GB) US20100075955 Solubility in water: 7.8 mg/ml; degradation 0.2% at 40 degrees, RH75% closed, 4 weeks
    Remimazolam GSK WO 00/69836 Almost insoluble in water; degradation 1.5-8%, and yellowing at 40 degrees, RH75% closed and 60 degrees open, 34 days


    [0008] It can be seen from the above table, neither the free base of remimazolam nor known salt derivatives of remimazolam has a water solubility higher than 11 mg/ml. The solubility is only in the range of sparingly soluble, which will increase its safety risk in clinical use, and require long-term vibration dissolution during clinical redissolution, and may also leave insoluble materials, resulting in inaccurate drug dosage and potential safety risks. In addition, when used for indications which require a large amount of drug, such as general anesthesia, the amount of diluent will be increased, resulting in extreme inconvenience in clinical use. Therefore, the solubility of known salt derivatives of remimazolam is a major disadvantage and needs to be further improved.

    Contents of the invention



    [0009] In view of the existing water solubility problem with the free base of remimazolam and its related salts, the object of the present invention is to improve the solubility of remimazolam to a degree that is easily soluble in water (30-100 mg/ml). In order to achieve the above water solubility goal, the inventors have conducted studies from various aspects, e.g., crystal forms of existing salts, preparation excipients, formation of new salt types, etc., hoping to find a feasible means that can improve water solubility while ensuring better druggability. However, the screening study on crystal forms of existing salts, preparation excipients ended in failure and no more suitable method was found. In the study of various salt types, a total of more than 20 types of acid salts were involved in the screening of the preliminary test, and 8 salt types were found out, among which sulfate, 2-naphthalenesulfonate, mesylate, oxalate, hydrobromide, hydrochloride, 1,5-naphthalene disulfonate are crystalline, and ethanedisulfonate is amorphous. After further study on the above salts, the results are obtained as follows:
    Table 2
    CompoundCrystal formCrystallinityCategorySalt forming ratiomp. (°C)Hygroscopicity (%)Solubility in water (mg/mL)Polymorphism
    HPLCIC
    Free base amorphous amorphous amorphous NA NA NA 1.7 almost insoluble NA
    Sulfate (bi)sulfate form 1 relatively low anhydrate 1:1 1:1 124 0.1 >100 2
    (bi)sulfate form 2 general anhydrate 1:2 1:1 186 24.9 >100
    Ethanedisulfonate amorphous amorphous amorphous decomposed NA NA 26 >100 NA
    Hydrochloride hydrochloride form 1 general hydrate NA 1:1 194 2.8 >100 2
    1,5-naphthalene disulfonate crystal form 1 crystal form 1 anhydrate 1:1 NA   15.9 1 1
    2-naphthalenesulfonate crystal form 1 crystal form 1 anhydrate 1:1 NA 193 2.1 1 1
    Hydrobromide crystal form α crystal form α anhydrate NA 1:1 170 2.5 >100 4
    crystal form 1 crystal form 1 hydrate NA 1:1 161 4.6 >100
    crystal form 2 crystal form 2 hydrate NA 1:1 173   >100
    crystal form 3 crystal form 3 hydrate NA 1:1 163 5 >100
    Mesylate Mesylate form 1 relatively low anhydrate decomposed NA 165 24 >100 1


    [0010] Among them, sulfate, hydrobromide, hydrochloride have polymorphism. Sulfate has high hygroscopicity or relatively low crystallinity, and is not easy to form a drug. 1,5-Naphthalene disulfonate and 2-naphthalenesulfonate have relatively low solubility, while mesylate has relatively low crystallinity, and is not easy to form a drug.

    [0011] As can be seen from the above table, the solubility and other properties of hydrochloride and hydrobromide are relatively ideal. Among 1,356 chemically-defined organic drugs marketed before 2006 that are included in the US FDA Orange Book (Progress in Pharmaceutical Sciences, 2012, Vol. 36, No. 4,151), there are 523 (38.6%) drugs that are acid addition salts, of which the most frequently used acid to form salts with organic bases is hydrochloric acid (53.4%). It can be seen that, among the numerous acid addition salt-based drugs currently on the market, hydrochloride is preferred.

    [0012] However, the analytic results of the stability of hydrochloride indicate that the most widely used hydrochloride has extremely poor stability:
    Table 3
    FormulationHydrochloride (moisture 8.58%)
    Itempuritypurity differenceappearance
    0 day 96.84 / white-like solid
    5 days light-open 96.37 0.47 light yellow solid
    light-closed 94.69 2.15 white-like solid
    60°C-open 94.01 2.83 white-like solid
    60°C -closed 11.97 84.87 black solid
    40°C -open 18.52 78.32 brown solid
    40°C -closed 87.42 9.42 light brown solid
    75%RH 96.75 0.09 white-like solid
    92.5%RH 82.67 14.17 light yellow solid (obvious moisture absorption)


    [0013] It can be seen from Table 3 that, although hydrochloride has good water solubility, its stability is extremely poor, so hydrochloride is abandoned.

    [0014] The present inventors unexpectedly found in the long-term study of the above various salts that hydrobromide of the compound of the formula (I) has excellent solubility (>100 mg/ml), is significantly superior to other currently marketed or developed salts of the compound, is especially suitable for the preparation of injections and also has relatively good stability in various crystal forms (see Table 3). For the above reasons, the present invention actually provides a hydrobromide of the compound of the formula I:

    wherein, the stoichiometric ratio of the compound of the formula (I) to hydrobromic acid is 1:1.

    [0015] The present inventors also found in the study that the hydrobromide of the compound of the formula (I) exists in various crystal forms, and, up to now, four crystal forms which are respectively named as I, II, III and α crystal forms have been found. The inventors studied and compared the physical and chemical properties of different crystal forms, and finally found that α crystal form has the best stability, and still retains good water solubility. Based on the above-mentioned good solubility, the crystal form can be prepared into a preparation (such as an injection) that has a relatively high requirement on the solubility of main drug, and in view of its good stability, the injection may not be limited to a powder for injection (powder-injection), but that a liquid injection (water-injection) can also be prepared.

    [0016] The current study showed that the light degradation impurity of the compound of the formula (I) has the structure:

    while the degradation impurity under other conditions is mainly

    the impurity having an activity which is 1/300 of that of the compound of formula (I). If the above compound or salt derivative thereof is inferior in stability, and is liable to be degraded, it may cause a reduction in pharmacological activity, and may even cause a certain toxic side effect to human body. Whether the stability is good or not is also a key factor in selecting the crystal form of the compound.

    [0017] Accordingly, it is preferred in the present invention that the hydrobromide of the compound of the formula (I) is present in the form of α crystal form. By comparing the X-ray powder diffraction pattern (Cu-ka radiation) of the α crystal form with those of other three crystal forms, it is found that the α crystal form has distinct characteristic peaks at angle 2θ of about 13.7±0.2, 16.0±0.2, 19.2±0.2 degrees. In the differential scanning calorimetry of the α crystal form, there is a melting endothermic peak at 170°C±2°C. Therefore, in the present invention, the structure of the α crystal form is defined by the above-mentioned powder diffraction characteristic peaks and DSC melting peak, and on the basis of this definition, the α crystal form can be clearly distinguished from other three crystal forms.

    [0018] Of course, in addition to the above three distinct distinguishing characteristic peaks, the X-ray powder diffraction pattern of the α crystal form includes characteristic peaks at angle 2θ of about 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 degrees.

    [0019] The X-ray powder diffraction pattern of the α crystal form prepared in the specific embodiments of the present invention is as shown in Figure 3 or 4, and the DSC spectrum is as shown in Figure 5.

    [0020] According to the EMEA document [20080124 EMEA A letter on the assessment of genotoxic impurities], it is pointed out that there is a potential risk with lower sulfonic acids such as benzene sulfonic acid and toluene sulfonic acid, that is, if an alcohol is used in the process, it may lead to the production of genotoxic impurity - besylate or tosylate, and likewise, the use of an alcohol-cleaned reaction tank or storage tank may also increase this risk. Therefore, in addition to the above-mentioned advantages of water solubility and stability, hydrobromide may also have a great advantage in terms of safety, because hydrobromic acid has low toxicity, and bromide ion is one of the 16 trace elements in human body.

    [0021] The present invention also provides a preparation method of the α crystal form of the hydrobromide as described above, which comprises the following steps:
    1. (1) reacting a compound of the formula I with hydrobromic acid in a solvent system consisting of isopropanol and water to obtain crystal form III, preferably with an aqueous solution of hydrobromic acid in isopropanol to precipitate out crystal form III, or crystallizing hydrobromide in isopropanol solvent to obtain crystal form III;
    2. (2) exposing the crystal form III to a gas having a high relative humidity at a certain temperature until the crystal form III is transformed into α crystal form.


    [0022] Wherein, in the step (2), the temperature is between 50 and 60°C.

    [0023] Wherein, in the step (2), the high relative humidity means a relative humidity of 65% or more. Further, the high relative humidity means a relative humidity of 75% or more.

    [0024] In a specific embodiment of the present invention, the gas is air.

    [0025] The above-mentioned transformation method may also be referred to as gas phase-mediated transformation, which is different from solvent-mediated transformation, and the medium for gas phase-mediated transformation is a gas. The transformation time can be from several hours to several days, weeks or months, depending on the relative humidity and temperature, which can be determined by conventional analysis means.

    [0026] Based on their excellent solubility (>100 mg/ml), the hydrobromide of the compound of the formula (I) and its various crystal forms can be used to prepare injections, which can better meet the requirements of injections for the solubility of raw materials. Accordingly, the present invention also provides use of the hydrobromide for the preparation of an injection having a sedative or hypnotic effect.

    [0027] The sedative or hypnotic effect mentioned in the present invention is directed to mammals. At the same time, the drug also has certain effects of anti-anxiety, inducing muscle relaxation, anticonvulsant, and anesthesia. For the specific administration dose, reference may be made to the effective dose of remimazolam in the prior art.

    [0028] Further, the present invention provides a pharmaceutical composition comprising a hydrobromide as described above. Of course, in addition to hydrobromide, pharmaceutically acceptable excipients may also be included in the composition.

    [0029] "Pharmaceutically acceptable" as used in the present invention is meant to include any substance that does not interfere with the effectiveness of biological activity of active ingredient and is non-toxic to the host to which it is administered.

    [0030] "Excipient" is a general term for all additional materials other than main drug in a pharmaceutical preparation. Excipient should have the following properties: (1) non-toxic to human body, with almost no side effects; (2) chemically stable, not susceptible to temperature, pH, preservation time, etc.; (3) not incompatible with the main drug, not affecting the efficacy and quality inspection of the main drug; (4) incapable of interacting with the packaging material.

    [0031] In a specific embodiment of the invention, the pharmaceutical composition is in the form of a preparation for injection.

    [0032] Among them, the injection is selected from the group consisting of a liquid injection (water-injection), a sterile powder for injection (powder-injection) or a tablet for injection (i.e., a molded tablet or a machine tablet made from a drug by sterile operation method, which, when used, is dissolved in water for injection, for subcutaneous or intramuscular injection).

    [0033] Among them, the powder for injection contains at least an excipient in addition to the hydrobromide of the compound of the 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, solubility or dissolution of drugs, the delivery of drugs by targeted route of administration, or contribute to the stability. The excipient of the present invention may be selected from the group consisting of carbohydrates, inorganic salts, and polymers, or a combination of two or more thereof. Among them, the carbohydrate includes monosaccharides, oligosaccharides or polysaccharides. Monosaccharide is a sugar that cannot be further hydrolyzed. It is a basic unit of making up molecules of various disaccharides and polysaccharides. It can be divided into triose, tetrose, pentose, hexose, etc. Monosaccharides in nature are mainly pentose and hexose. For example, glucose is aldohexose and fructose is ketohexose.

    [0034] Oligosaccharide, also known as oligose, is a polymer resulted from condensation of a few (2-10) monosaccharides.

    [0035] Polysaccharide is a polymeric high molecular carbohydrate composed of sugar chains bound by glycosidic bonds and resulted from more than 10 monosaccharides.

    [0036] The mass ratio of the compound of the formula (I) to the excipient is (1:0.5)∼(1:200). In view of cost, concentration of active ingredient, etc., it is proposed in the present invention that the mass ratio of the compound of the formula (I) to the excipient be 1:5 to 1:86.

    [0037] The sterile powder for injection in the present invention can be obtained by a conventional process such as aseptic dispensing or freeze drying.

    [0038] In a specific embodiment of the present invention, the carbohydrate-based excipient is selected from the group consisting of lactose, maltose, sucrose, mannitol, and glucose, or a combination of two or more thereof. In a specific embodiment of the present invention, the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride and the like. Of course, at present, in lyophilized powder for injection, inorganic salts are often used in combination with carbohydrates. Therefore, in actual operation, the type of excipient in the present invention can be conventionally selected according to known theory. For example, it is possible to use lactose, mannitol or glucose alone or a combination of two or more thereof, or to further add an inorganic salt such as sodium chloride on the basis of using one or more carbohydrates.

    [0039] In the course of study, the present inventors found that, when a lyophilized powder for injection is prepared using the hydrobromide of the compound of the formula (I) as raw material, a plurality of different excipients can be selected to achieve good stability and resolubility, and the lyophilized powder for injection is superior to remimazolam besylate lyophilized powder for injection (CN201380036582.2). This finding is sufficient to demonstrate that the remimazolam hydrobromide provided by the present invention is more suitable for the preparation of lyophilized powder for injections.

    [0040] It is apparent that, on the basis of the above contents of the present invention, various other forms of modifications, substitutions or changes may be made in accordance with the common technical knowledge and means in the art, without departing from the basic technical idea of the present invention.

    [0041] The above contents of the present invention will be further described in detail below by way of specific embodiments.

    Description of figures



    [0042] 

    Figure 1 is an X-ray powder diffraction pattern of crystal form III of the hydrobromide of the compound of the formula (I);

    Figure 2 is a DSC spectrum of crystal form III of the hydrobromide of the compound of the formula (I);

    Figure 3 is an X-ray powder diffraction pattern of α crystal form of the hydrobromide of the compound of the formula (I);

    Figure 4 is an X-ray powder diffraction pattern of α crystal form of the hydrobromide of the compound of the formula (I);

    Figure 5 is a DSC/TGA spectrum of α crystal form of the hydrobromide of the compound of the formula (I);

    Figure 6 is a DVS spectrum of α crystal form of the hydrobromide of the compound of the formula (I);

    Figure 7 is an X-ray powder diffraction pattern of crystal form I of the hydrobromide of the compound of the formula (I);

    Figure 8 is a DSC spectrum of crystal form I of the hydrobromide of the compound of the formula (I);

    Figure 9 is a TGA spectrum of crystal form I of the hydrobromide of the compound of the formula (I);

    Figure 10 is an X-ray powder diffraction pattern of crystal form II of the hydrobromide of the compound of the formula (I);

    Figure 11 is a DSC spectrum of crystal form II of the hydrobromide of the compound of the formula (I);

    Figure 12 is a TGA spectrum of crystal form II of the hydrobromide of the compound of the formula (I).


    Specific mode for carrying out the invention



    [0043] The raw material, the compound of the formula (I) (remimazolam), used in the present invention can be commercially obtained, or can be prepared according to a known method (e.g., patents US200, 700, 934, 75A, etc.).


    Example 1 Preparation of crystal form III of the hydrobromide of the compound of the formula (I)



    [0044] 1.8 g of the compound of the formula (I) was accurately weighed into a 100 mL three-necked flask, 8.2 mL of isopropanol was added and stirred till complete dissolution; 0.83 g of an 47% aqueous solution of hydrobromic acid was dissolved in 6.3 mL of isopropanol, and added dropwise to the solution of the compound of the formula (I) in isopropanol; the resulting mixture was stirred and crystallized, filtered, and dried under reduced pressure at 55°C to obtain a hydrobromide of the compound of the formula (I).

    [0045] The X-ray diffraction pattern of the crystal was shown in Figure 1, the DSC and TGA spectra were shown in Figure 2, and the melting point is 163°C. This crystal form was defined as crystal form III of the hydrobromide of the compound of the formula (I).

    Example 2: Preparation of α crystal form of the hydrobromide of the compound of the formula (I)



    [0046] The crystal form III of the hydrobromide could be transformed in a non-flowing gas with a certain humidity, especially in the air with a humidity of 75% or more, which was mediated through gas phase interface, to obtain α crystal form. The method had the advantages: not solvent mediated, no loss, and no solvent residue.

    [0047] Specifically, 200 mg of the crystal form III of the hydrobromide of the compound of the formula (I) obtained above in Example 1 was placed open under the conditions of 50∼55°C - RH 75% for 20 hours. The X-ray diffraction pattern of the crystal sample was shown in Figure 3, at about 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. The product was identified as α crystal form of the hydrobromide of the compound of the formula (I). IC: the bromide ion content was 15.74%, and the salt forming ratio of hydrobromic acid was confirmed to be 1:1; solvent residue: isopropanol 0.01%.

    Example 3: Preparation of α crystal form of the hydrobromide of the compound of the formula (I)



    [0048] 500 mg of the crystal form III of the hydrobromide of the compound of the formula (I) obtained above in Example 1 was placed open under the conditions of 55∼60°C - RH 75% for 60 hours. The X-ray diffraction pattern and the DSC spectrum of the crystal sample were studied and compared. The product was determined to be α crystal form of the hydrobromide of the compound of the formula (I).

    [0049] The X-ray diffraction pattern was shown in Figure 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; the DSC/TGA spectrum was shown in Figure 5, showing a melting point 170°C; as the sample was not further dried after transformation at 75% humidity, it contained 4.3% free water, which was embodied by a weight loss platform of 60.78-79.45°C in TGA; in addition, the DVS spectrum showed the ability to combine with water at a certain humidity, and the product was a crystal form without crystal water. The product was determined to be α crystal form of the hydrobromide of the compound of the formula (I).

    Example 4: Preparation of crystal form I of the hydrobromide of the compound of the formula (I)



    [0050] 44 mg (0.10 mmol) of the compound of the formula (I) was accurately weighed into a 10 mL single-necked flask, 0.4 mL of ethyl acetate was added and stirred till complete dissolution, the reaction temperature was lowered to 4°C, and then 1.1 mL of a solution of hydrobromic acid in methanol (1 mol/L, 0.11 mmol) was added dropwise to the solution of the compound of the formula (I) in ethyl acetate, stirred and crystallized, suction filtered, rinsed with ethyl acetate, and dried under reduced pressure at 30°C to obtain a hydrobromide of the compound of the formula (I), white solid 42 mg, yield 81%.

    [0051] The X-ray diffraction pattern of the crystal was shown in Figure 7, and the DSC spectrum was shown in Figure 8, having characteristic absorption peaks at around 70°C, 162°C and 180°C. This crystal form was defined as crystal form I of the hydrobromide of the compound of the formula (I). The TGA spectrum of the crystal form I of the hydrobromide of the compound of the formula (I) was shown in Figure 9.

    Example 5: Preparation of crystal form II of the hydrobromide of the compound of the formula (I)



    [0052] 22.26 mg of the compound of formula (I) was accurately weighed into a 1 mL centrifuge tube, 100 µL of acetone was added and stirred till complete dissolution, then 10 mg of a 47% aqueous solution of hydrobromic acid was dissolved in 75 µL of acetone and added dropwise to the solution of the compound of the formula (I) in acetone, stirred and crystallized, centrifuged, and dried under reduced pressure at 30°C to obtain a hydrobromide of the compound of the formula (I), white solid 20 mg, yield 76%.

    [0053] The X-ray diffraction spectrum of the crystal was shown in Figure 10, and the DSC spectrum was shown in Figure 11, having characteristic absorption peaks at around 69°C, 90°C, 173°C and 188°C. This crystal form was defined as crystal form II of the hydrobromide of the compound of the formula (I). The TGA spectrum of the crystal form II of the hydrobromide of the compound of the formula (I) was shown in Figure 12.

    Example 6 Comparison between α crystal form and other crystal forms of the present invention



    [0054] The α crystal form of the hydrobromide of the compound of the formula (I) was compared with other crystal forms, the results shown in Table 4:
    Table 4
    Name (batch No.):RML-007-056-1-zjRML-007-056-1RML-007-049-1RML-002-066-1
    α crystal formcrystal form 3crystal form 2crystal form 1
    Itempuritypurity differencepuritypurity differencepuritypurity differencepuritypurity difference
    0 day 99.76 / 99.79 / 99.87 / 99.48 /
    10 days light-open 99.55 -0.21 92.5 -7.29 98.41 -1.46 94.17 -5.31
    light-closed 99.78 0.02 99.78 -0.01 99.81 -0.06 99.48 0
    60°C-open 99.72 -0.04 99.59 -0.2 99.64 -0.23 99.45 -0.03
    60°C -closed 99.78 0.02 99.66 -0.13 99.84 -0.03 99.46 -0.02
    40°C -open 99.77 0.01 99.71 -0.08 99.06 -0.81 99.49 0.01
    40°C -closed 99.78 0.02 99.75 -0.04 99.6 -0.27 99.48 0
    75%RH 99.77 0.01 99.78 -0.01 99.82 -0.05 99.5 0.02
    92.5%RH 99.77 0.01 99.76 -0.03 98.92 -0.95 99.48 0
    30 days light-open 99.26 -0.5 93.4 -6.39 98.14 -1.73 82.17 -17.31
    light-closed 99.78 0.02 99.76 -0.03 99.83 -0.04 99.35 -0.13
    60°C -open 99.7 -0.06 99.55 -0.24 99.57 -0.3 99.13 -0.35
    60°C -closed 99.74 -0.02 99.56 -0.23 99.8 -0.07 99.32 -0.16
    40°C -open 99.74 -0.02 99.67 -0.12 97.47 -2.4 99.15 -0.33
    40°C -closed 99.75 -0.01 99.74 -0.05 99.02 -0.85 99.33 -0.15
    75%RH 99.79 0.03 99.78 -0.01 99.83 -0.04 99.38 -0.1
    92.5%RH 99.76 0 99.73 -0.06 99.47 -0.4 99.31 -0.17


    [0055] As can be seen from the above table, the α crystal form prepared in the present invention still could retain good stability under the conditions of strong light, high heat and high humidity, and was apparently superior to the other three crystal forms.

    Example 7 Comparison in stability between the α crystal form of the present invention and the original innovative crystal form



    [0056] Crystal form I of besylate of the compound of the formula (I) was prepared according to the patents CN200780028964.5 and CN201310166860.8, and the obtained crystal form had characteristic peaks at about 7.19, 7.79, 9.38, 12.08, 14.06, 14.40, 14.72, 15.59.

    [0057] The stability of the crystal form of the original innovative besylate was compared with that of the α crystal form of the hydrobromide of the present invention, the results shown in Table 5:
    Table 5
    Name:Hydrobromide (α crystal form)Besylate (crystal form I)
    Itempuritypurity differencepuritypurity difference
    0 day 99.76 / 99.24 /
    10 days light-open 99.55 -0.21 98.8 -0.44
    light-closed 99.78 0.02 99.18 -0.06
    60°C-open 99.72 -0.04 99.18 -0.06
    60°C -closed 99.78 0.02 99.07 -0.17
    40°C-open 99.77 0.01 99.21 -0.03
    40°C -closed 99.78 0.02 99.23 -0.01
    75%RH 99.77 0.01 99.23 -0.01
    92.5%RH 99.77 0.01 99.23 -0.01
    30 days light-open 99.26 -0.5 98.09 -1.15
    light-closed 99.78 0.02 99.16 -0.08
    60°C -open 99.7 -0.06 99.14 -0.1
    60°C -closed 99.74 -0.02 99.15 -0.09
    40°C -open 99.74 -0.02 99.12 -0.12
    40°C -closed 99.75 -0.01 99.13 -0.11
    75%RH 99.79 0.03 99.15 -0.09
    92.5%RH 99.76 0 99.14 -0.1


    [0058] As can be seen from the above table, the α crystal form prepared in the present invention exhibited better stability than the crystal form of the original innovative besylate under the conditions of strong light, high heat and high humidity. In addition, it can be seen from the published data that the stability of the α crystal form prepared in the present invention was also better than that of the crystal form of tosylate in CN103221414B.

    Example 8 Formulation and preparation process of remimazolam hydrobromide sterile powder for injection



    [0059] According to the formulation of Table 6, a sterile powder was prepared according to the following preparation process, and the physical and chemical parameters of various formulations were compared.

    Preparation process:



    [0060] Formulation 1: remimazolam hydrobromide was directly dispensed into a brown vial under aseptic conditions, and covered.

    [0061] Formulations 2∼10: Excipient and remimazolam hydrobromide were dissolved in water for injection, stirred until dissolution, the pH value of the solution was adjusted with hydrochloric acid/sodium hydroxide, and then the solution was dispensed into a vial, and lyophilized.
    Table 6 Remimazolam hydrobromide sterile powder for injection
    FormulationFormulation 1Formulation 2Formulation 3Formulation 4Formulation 5Formulation 6Formulation 7Formulation 8Formulation 9Formulation 10
    Material dose mg dose g dose g dose g dose g dose g dose g dose g dose g dose g
    remimazolam hydrobromide 29 5.9 29.6 11.8 9.0 1.8 1.8 1.8 25.7 /
    remimazolam besylate / / / / / / / / / 29.5
    Lactose / 1.5 / 50 250 / 130 / 375 375
    Mannitol / 1.0 125 / / 85 / 170 / /
    Glucose / / / 50 / / / 170 / /
    Sodium chloride / / / / / 5 / / / /
    Hydrochloric acid / sodium hydroxide to adjust the pH / 3.15 3.18 3.13 3.20 3.08 3.17 3.25 3.11 3.10
    Water for Injection / to 1000ml to 1000ml to 100ml to 1000ml to 1000ml to 1000ml to 1000ml to 1000ml to 1000ml


    [0062] The physical and chemical parameters of various formulations were given as follows:
    Table 7 Physical and chemical parameters of remimazolam hydrobromide sterile powder for injection
    Physical and chemical propertie sFormula tion 1Formula tion 2Formula tion 3Formula tion 4Formula tion 5Formula tion 6Formula tion 7Formula tion 8Formula tion 9Formula tion 10
    Descripti on white solid white solid white solid white solid white solid white solid white solid white solid white solid white solid
    Moisture ≤3% ≤3% ≤3% ≤3% ≤3% ≤3% ≤3% ≤3% ≤3% ≤3%
    Redissolu tion time within 30s within 30s within 30s within 30s within 30s within 30s within 30s within 30s within 30s 240s
    Appearan ce powdery good good good good good good Slight collapse good good


    [0063] Formulations 9, 10 were remimazolam hydrobromide lyophilized powder for injection, remimazolam besylate lyophilized powder for injection that were respectively prepared according to the process reported in the patent CN201380036582.2, and comparison was made between them as follows:
    Table 8 Comparison between remimazolam hydrobromide lyophilized powder for injection and original innovative remimazolam besylate lyophilized powder for injection
    NameRemimazolam hydrobromide lyophilized powder for injection (Formulation 9)Remimazolam besylate lyophilized powder for injection (Formulation 10)
    Itemdescriptionpuritypurity differenceredissolution timeDescriptionpuritypurity differenceredissolution time
    0 day white solid 99.84 / within 30s white solid 99.74 / 240s
    Accelerated 1 month white solid 99.78 -0.06 within 30s white solid 99.54 -0.20 240s
    Accelerated 2 months white solid 99.73 -0.11 within 30s white solid 99.32 -0.42 240s
    Accelerated 3 months white solid 99.67 -0.17 within 30s white solid 99.48 -0.26 240s
    Accelerated 6 months white solid 99.53 -0.31 within 30s white solid 98.78 -0.96 240s
    Long-term 3 months white solid 99.82 -0.02 within 30s white solid 99.63 -0.11 240s
    Long-term 6 months white solid 99.75 -0.09 within 30s white solid 99.53 -0.21 240s
    Notes: 1. Accelerated placement condition was 40°C; Long-term placement condition was 25°C
    2. Redissolution time: gently vibrating with water for injection / glucose / normal saline till complete dissolution and uniform mixture, and recording the time required for complete dissolution.


    [0064] As can be seen from the above table, the remimazolam hydrobromide lyophilized powder for injection of the present invention retained good stability in both accelerated stability test and long-term stability test, and it was superior in both stability and resolubility to the remimazolam besylate lyophilized powder for injection (CN201380036582.2).


    Claims

    1. A hydrobromide of the compound of the formula I:

    wherein the stoichiometric ratio of the compound of the formula (I) to hydrobromic acid is 1:1.
     
    2. The hydrobromide as claimed in claim 1, characterized in that the hydrobromide is present in the form of α crystal form, and the X-ray powder diffraction pattern obtained using Cu-ka radiation at least includes characteristic peaks at angle 2θ of about 13.7±0.2, 16.0±0.2, 19.2±0.2 degrees.
     
    3. The hydrobromide as claimed in claim 2, characterized in that the X-ray powder diffraction pattern of the α crystal form of the hydrobromide further includes characteristic peaks at angle 2θ of about 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 degrees.
     
    4. The hydrobromide as claimed in claim 2, characterized in that, in the differential scanning calorimetry of the α crystal form, there is a melting endothermic peak at 170°C±2°C.
     
    5. A preparation method of the α crystal form of the hydrobromide as claimed in any one of claims 2 to 4, which comprises the following steps:

    (1) reacting a compound of the formula I with hydrobromic acid in a solvent system consisting of isopropanol and water to obtain crystal form III of a hydrobromide;

    (2) exposing the crystal form III to a gas, preferably air, having a high relative humidity, preferably a relative humidity of 65% or more, more preferably a relative humidity of 75% or more, at a certain temperature, preferably the temperature of between 50 and 60°C, until the crystal form III is transformed into α crystal form.


     
    6. The preparation method as claimed in claim 5, characterized in that the step (1) is carried out by reacting with an aqueous solution of hydrobromic acid in isopropanol to precipitate out crystal form III, or crystallizing hydrobromide in isopropanol solvent to obtain crystal form III.
     
    7. Use of the hydrobromide as claimed in any one of claims 1 to 4 in the manufacture of an injection having the effect of sedation, hypnosis, anti-anxiety, inducing muscle relaxation, anticonvulsant or anesthesia.
     
    8. A pharmaceutical composition, characterized in that it is a preparation for injection comprising the hydrobromide as claimed in any one of claims 1 to 4.
     
    9. The pharmaceutical composition as claimed in claim 8, characterized in that the preparation for injection is selected from the group consisting of a liquid injection, a sterile powder for injection.
     
    10. The pharmaceutical composition as claimed in claim 9, characterized in that the sterile powder for injection contains at least an excipient, preferably an excipient selected from the group consisting of carbohydrates, inorganic salts, and polymers, or a combination of two or more thereof, in addition to the hydrobromide of the compound of the formula (I).
     
    11. The pharmaceutical composition as claimed in claim 10, characterized in that the carbohydrate is selected from the group consisting of monosaccharides, oligosaccharides or polysaccharides.
     
    12. The pharmaceutical composition as claimed in claim 11, characterized in that the carbohydrate is selected from the group consisting of lactose, maltose, sucrose, mannitol, glucose, glucan.
     
    13. The pharmaceutical composition as claimed in claim 10, characterized in that the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride.
     
    14. The pharmaceutical composition as claimed in claim 10, characterized in that the mass ratio of the compound of the formula (I) to the excipient is 1:0.5 ∼ 1:200.
     
    15. The pharmaceutical composition as claimed in claim 14, characterized in that the mass ratio of the compound of the formula (I) to the excipient is 1:5 to 1:86.
     


    Ansprüche

    1. Hydrobromid der Verbindung der Formulierung I:

    wobei das stöchiometrische Verhältnis der Verbindung der Formulierung (I) zur Hydrobromid-Säure 1:1 beträgt.
     
    2. Hydrobromid nach Anspruch 1, dadurch gekennzeichnet, dass das Hydrobromid in der α-Kristallform vorliegt, und dass das Röntgenstrahlen-Pulverbeugungsdiagramm, das unter Verwendung von Cu-Kα-Strahlung erhalten wird, wenigstens charakteristische Peaks bei einem 2θ-Winkel von etwa 13,7 ± 0,2, 16,0 ± 0,2 und 19,2 ± 0,2 Grad aufweist.
     
    3. Hydrobromid nach Anspruch 2, dadurch gekennzeichnet, dass das Röntgenstrahlen-Pulverbeugungsdiagramm der α-Kristallform des Hydrobromids ferner charakteristische Peaks bei einem 2θ-Winkel von etwa 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 und 30,7 ± 0,2 Grad aufweist.
     
    4. Hydrobromid nach Anspruch 2, dadurch gekennzeichnet, dass in der Differenzialkalorimetrie der α-Kristallform ein endothermer Schmelzpeak bei 170 °C ± 2 °C liegt.
     
    5. Herstellungsverfahren der α-Kristallform des Hydrobromids nach einem der Ansprüche 2 bis 4, wobei das Verfahren die folgenden Schritte umfasst:

    (1) Reagieren einer Verbindung der Formulierung I mit Hydrobromidsäure in einem Lösungsmittelsystem, das aus Isopropanol und Wasser besteht, um die Kristallform III eines Hydrobromids zu erhalten;

    (2) Aussetzen der Kristallform III einem Gas, vorzugsweise Luft, die eine relativ hohe Feuchtigkeit, vorzugsweise eine relative Feuchtigkeit von 65 % oder mehr, stärker bevorzugt eine relative Feuchtigkeit von 75 % oder mehr bei einer bestimmten Temperatur, vorzugsweise bei der Temperatur zwischen 50 und 60 °C hat, bis die Kristallform III in eine α-Kristallform umgewandelt wurde.


     
    6. Herstellungsverfahren nach Anspruch 5, dadurch gekennzeichnet, dass der Schritt (1) ausgeführt wird, indem eine Reaktion mit einer wässrigen Lösung von Hydrobromid-Säure in Isopropanol ausgeführt wird, um die Kristallform III auszufällen, oder indem eine Kristallisierung von Hydrobromid in Isopropanol-Lösungsmittel ausgeführt wird, um die Kristallform III zu erhalten.
     
    7. Verwendung von Hydrobromid nach einem der Ansprüche 1 bis 4 zur Zubereitung einer Injektion, die eine Wirkung zur Beruhigung, zur Hypnose, zur Angstlösung, zum Auslösen einer Muskelentspannung, zur Krampflösung und/oder zur Betäubung hat.
     
    8. Pharmazeutische Rezeptur, dadurch gekennzeichnet, dass diese eine Zubereitung zur Injektion ist, die das Hydrobromid nach einem der Ansprüche 1 bis 4 umfasst.
     
    9. Pharmazeutische Rezeptur der Anspruch 8, dadurch gekennzeichnet, dass die Zubereitung zur Injektion aus der Gruppe ausgewählt wird, die aus einer Flüssigkeitsinjektion und einem sterilen Pulver zur Injektion besteht.
     
    10. Pharmazeutische Rezeptur nach Anspruch 9, dadurch gekennzeichnet, dass das sterile Pulver zur Injektion wenigstens einen Hilfsstoff, vorzugsweise einen Hilfsstoff, der aus der Gruppe ausgewählt wird, die aus Kohlenhydraten, anorganischen Salzen und Polymeren oder einer Kombination von zwei oder mehr dieser Stoffe besteht, zusätzlich zum Hydrobromid der Verbindung der Formulierung (I) umfasst.
     
    11. Pharmazeutische Rezeptur nach Anspruch 10, dadurch gekennzeichnet, dass das Kohlenhydrat aus der Gruppe ausgewählt wird, die aus Monosacchariden, Oligosacchariden und Polysacchariden besteht.
     
    12. Pharmazeutische Rezeptur nach Anspruch 11, dadurch gekennzeichnet, dass das Kohlenhydrat aus der Gruppe ausgewählt wird, die aus Laktose, Maltose, Saccharose, Mannitol, Glukose und Glucan besteht.
     
    13. Pharmazeutische Rezeptur nach Anspruch 10, dadurch gekennzeichnet, dass das anorganische Salz aus der Gruppe ausgewählt wird, die aus Natriumchlorid, Kaliumchlorid und Kalziumchlorid besteht.
     
    14. Pharmazeutische Rezeptur nach Anspruch 10, dadurch gekennzeichnet, dass das Massenverhältnis der Verbindung der Formulierung (I) zum Hilfsstoff 1:0,5 ∼ 1:200 beträgt.
     
    15. Pharmazeutische Rezeptur nach Anspruch 14, dadurch gekennzeichnet, dass das Massenverhältnis der Verbindung der Formulierung (I) zum Hilfsstoff im Bereich von 1:5 bis 1:86 liegt.
     


    Revendications

    1. Bromhydrate du composé de formule I :

    dans lequel le rapport stœchiométrique du composé de formule (I) sur l'acide bromhydrique est de 1/1.
     
    2. Bromhydrate selon la revendication 1, caractérisé en ce que le bromhydrate est présent sous la forme d'une forme cristalline a, et le diagramme de diffraction des rayons X sur poudre obtenu à l'aide d'un rayonnement de Cu-Ka inclut au moins des pics caractéristiques à un angle 2θ d'environ 13,7 ± 0,2, 16,0 ± 0,2, 19,2 ± 0,2 degrés.
     
    3. Bromhydrate selon la revendication 2, caractérisé en ce que le diagramme de diffraction des rayons X sur poudre de la forme cristalline α du bromhydrate inclut en outre des pics caractéristiques à un angle 2θ d'environ 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 degrés.
     
    4. Bromhydrate selon la revendication 2, caractérisé en ce que, dans la calorimétrie différentielle à balayage de la forme cristalline α, il y a un pic endothermique de fusion à 170 °C ± 2 °C.
     
    5. Procédé de préparation de la forme cristalline α du bromhydrate selon l'une quelconque des revendications 2 à 4, qui comprend les étapes suivantes :

    (1) mise en réaction d'un composé de formule I avec de l'acide bromhydrique dans un système de solvant consistant en l'isopropanol et l'eau pour obtenir une forme cristalline III d'un bromhydrate ;

    (2) exposition de la forme cristalline III à un gaz, de préférence à l'air, ayant une humidité relative élevée, de préférence une humidité relative de 65 % ou plus, de manière davantage préférée une humidité relative de 75 % ou plus, à une certaine température, de préférence la température d'entre 50 et 60 °C, jusqu'à ce que la forme cristalline III soit transformée en forme cristalline a.


     
    6. Procédé de préparation selon la revendication 5, caractérisé en ce que l'étape (1) est réalisée par mise en réaction avec une solution aqueuse d'acide bromhydrique dans de l'isopropanol pour précipiter la forme cristalline III, ou cristallisation de bromhydrate dans un solvant isopropanol pour obtenir la forme cristalline III.
     
    7. Utilisation du bromhydrate selon l'une quelconque des revendications 1 à 4 dans la fabrication d'une injection ayant l'effet de sédation, d'hypnose, d'anti-anxiété, d'induction de relaxation musculaire, d'anticonvulsif ou d'anesthésie.
     
    8. Composition pharmaceutique caractérisée en ce qu'elle est une préparation pour injection comprenant le bromhydrate selon l'une quelconque des revendications 1 à 4.
     
    9. Composition pharmaceutique selon la revendication 8, caractérisée en ce que la préparation pour injection est sélectionnée dans le groupe consistant en une injection liquide, une poudre stérile pour injection.
     
    10. Composition pharmaceutique selon la revendication 9, caractérisée en ce que la poudre stérile pour injection contient au moins un excipient, de préférence un excipient sélectionné dans le groupe consistant en des hydrates de carbone, des sels inorganiques, et des polymères, ou une combinaison de deux ou plus de ceux-ci, en plus du bromhydrate du composé de formule (I).
     
    11. Composition pharmaceutique selon la revendication 10, caractérisée en ce que l'hydrate de carbone est sélectionné dans le groupe consistant en des monosaccharides, des oligosaccharides ou des polysaccharides.
     
    12. Composition pharmaceutique selon la revendication 11, caractérisée en ce que l'hydrate de carbone est sélectionné dans le groupe consistant en le lactose, le maltose, le sucrose, le mannitol, le glucose, le glucane.
     
    13. Composition pharmaceutique selon la revendication 10, caractérisée en ce que le sel inorganique est sélectionné dans le groupe consistant en le chlorure de sodium, le chlorure de potassium, le chlorure de calcium.
     
    14. Composition pharmaceutique selon la revendication 10, caractérisée en ce que le rapport en masse du composé de formule (I) sur l'excipient est de 1/0,5 à 1/200.
     
    15. Composition pharmaceutique selon la revendication 14, caractérisée en ce que le rapport en masse du composé de formule (I) sur l'excipient est de 1/5 à 1/86.
     




    Drawing



































    Cited references

    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description




    Non-patent literature cited in the description