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    • 专利摘要:
    Procedure for obtaining amorphous remimazolam besilate. The present invention relates to a lyophilization process for obtaining amorphous remimazolam besilate without contamination of crystalline material of said product. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2803099A1
    申请号:ES201930677
    申请日:2019-07-22
    公开日:2021-01-22
    发明作者:Casals Carles Sanchez；Rodriguez Alicia Dobarro
    申请人:Moehs Iberica SL；
    IPC主号:
    专利说明:

    [0002] Procedure for obtaining amorphous remimazolam besilate
    [0004] Field of the invention
    [0006] The present invention relates to a process for obtaining amorphous remimazolam besilate.
    [0008] Background of the invention
    [0010] Remimazolam, CNS 7056 or 3 - {(4S) -8-bromo-1-methyl-6- (pyridin-2-yl) -4H-imidazo [1,2-a] [1,4] benzodiazepin-4- Methyl yl} propanoate is a benzodiazepine developed by Paion, which has the following chemical structure:
    [0015] Remimazolam is a short-acting central nervous system depressant. It has anxiolytic, amnesiating, sedative, muscle relaxant and anti-seizure properties. Due to these properties it is suitable for use in anesthetic practice and in intensive care, such as in preoperative sedation, anxiolysis, amnesic use for perioperative cases, sedation in a conscious state during short diagnostic, operative or endoscopic procedures, as a component for the induction and maintenance of general anesthesia, before and / or concomitant with the administration of other anesthetic agents, as well as in intensive care sedation. The most suitable administration of this compound is intravenously.
    [0017] EP 1 183 243 B1 discloses remimazolam and its preparation process in Example Ic-8.
    [0018] Patent document WO 2008/007071 A1 reveals that remimazolam (in free base form) is stable when stored at 5 ° C, but behaves like a deliquescent solid when stored at 40 ° C and 75% relative humidity (in open vial) or at 60 ° C and ambient humidity (in a closed vial), appreciably decreasing the initial remimazolam content and turning yellow to orange. According to document WO 2008/007071 A1, the study by high-performance liquid chromatography (HPLC ) of remimazolam suggests that the degradation is due to the formation of the impurity corresponding to the hydrolysis of the ester methyl.
    [0020] In document WO 2008/007071 A1 it is proposed to solve said problem of stability to the storage of remimazolam by means of the formation of the besylate salt (benzenesulfonic acid salt) of said product in the form of a highly crystalline solid, easily isolatable and presenting good thermal properties, low hygroscopicity and good aqueous solubility. Specifically, WO 2008/007071 A1 discloses the monobesylate salt of remimazolam, where the molar ratio of benzenesulfonic acid and remimazolam is 1: 1, in various crystalline forms designated Form 1, Form 2, Form 3 and Form 4.
    [0022] In WO 2008/007071 A1 (example 5) a polymorphism study of remimazolam besilate is described in which the salt was subjected to maturation tests of crystalline form 1 in fifteen different solvents and their corresponding aqueous mixtures. In most cases, either form 1 or an oil was obtained. Only remimazolam besilate was obtained as an amorphous solid by using isopropanol, dichloromethane, or an aqueous THF solution. However, WO 2008/007071 A1 does not include any characterization data on the amorphous form obtained or on its purity or stability. By reproducing the examples that according to WO 2008/007071 A1 yielded the amorphous form of remimazolam besilate, the present inventors have not obtained this solid form but rather a crystalline form of the solid, specifically form 2.
    [0024] EP 2 852 389 B1 relates to stable lyophilized compositions of benzodiazepines, including remimazolam. Said document explains that lyophilization is a known technique for stabilizing water-labile compounds. However, it also explains that the lyophilization of remimazolam besilate alone (without excipients) did not give satisfactory results of stability of said salt. In document EP 2852389 B1 it is proposed to solve the problem of lack of stability of remimazolam besilate providing lyophilized compositions comprising a hygroscopic excipient and / or dextran, the lyophilized formulation being partially amorphous.
    [0026] In the examples of EP 2 852 389 B1 the crystalline material is evaluated in a lyophilized formulation of remimazolam besilate and lactose monohydrate. Studies carried out on said formulation demonstrated the presence of crystalline material, specifically remimazolam besylate salt in crystalline form, in this lyophilized formulation.
    [0028] The main advantage of products in the form of amorphous solids over their crystalline equivalents is that they have improved solubility and bioavailability. However, their main disadvantage is that they are less stable than crystalline solids and evolve into a crystalline form over time. The problem derived from the presence of crystalline remimazolam besilate in an amorphous remimazolam besilate matrix is precisely that said amorphous compound does not remain stable when stored, but instead evolves into one of the crystalline forms of the besilate salt.
    [0030] Therefore, there is a need in the state of the art for a process for the preparation of remimazolam besilate in amorphous form that allows to obtain said product without contamination of crystalline forms of the besilate salt. Amorphous remimazolam besilate without contamination of crystalline forms is advantageous as it remains more stable on storage.
    [0032] Summary of the invention
    [0034] As shown in the examples, the inventors have performed multiple experiments to try to obtain amorphous remimazolam besylate without product contamination in crystalline form, including various crystallization / precipitation tests with combinations of solvents and variety of conditions, as well as drying tests. by spraying, without being able to obtain the amorphous product free of crystalline material. Surprisingly, despite the unsatisfactory stability results described in EP 2 852 389 B1 for lyophilized remimazolam besylate, the inventors have discovered a lyophilization process for the preparation of stable amorphous remimazolam besilate, without contamination of crystalline forms of said product.
    [0035] Therefore, in a first aspect, the present invention relates to a process for the preparation of amorphous remimazolam besilate comprising the following steps: a) providing a solution consisting essentially of remimazolam besilate and a solvent selected from the group consisting of organic solvent miscible in water, water and mixtures thereof, and
    [0036] b) lyophilizing the solution provided in step a), wherein the lyophilization comprises b1) freezing the solution provided in step a) at a temperature lower than -45 ° C, and b2) removing the solvent from the product obtained in step b1) by heating from the temperature of said product to a temperature of 10 ° C to 40 ° C, at a pressure lower than 101325 Pa (1.01325 bar) and for a period of time of less than 5 days.
    [0038] In a second aspect, the present invention relates to stable amorphous remimazolam besilate characterized in that it presents a powder X-ray diffractogram that presents a broad peak between 10 and 40 ° 20 ± 2 ° 0.
    [0040] Description of the drawings
    [0042] Figure 1 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Example 1.3.
    [0044] Figure 2 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Example 1.5.
    [0046] Figure 3 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Example 1.6.
    [0048] Figure 4 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Comparative Example 3.
    [0050] Figure 5 shows the differential scanning calorimetry (DSC) diagram of the remimazolam besilate obtained in comparative example 3.
    [0052] Figure 6 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in comparative example 4.1.
    [0053] Figure 7 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Comparative Example 4.2.
    [0055] Figure 8 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Comparative Example 4.3.
    [0057] Figure 9 shows the X-ray powder diffractogram (XRPD) of the remimazolam besylate obtained in Comparative Example 3 after one week of storage at 40 ° C and 80% RH.
    [0059] Figure 10 shows the differential scanning calorimetry (DSC) diagram of the remimazolam besylate obtained in comparative example 3 after one week of storage at 40 ° C and 80% RH.
    [0061] Figure 11 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in Comparative Example 3 after one month of storage at 4 ° C.
    [0063] Figure 12 shows the X-ray powder diffractogram (XRPD) of remimazolam besilate obtained in test 1.5 after 15 days of storage at 40 ° C and 80% RH.
    [0065] Figure 13 shows the differential scanning calorimetry (DSC) diagram of remimazolam besilate obtained in test 1.5 after 15 days of storage at 40 ° C and 80% RH.
    [0067] Figure 14 shows the X-ray powder diffractogram (XRPD) of remimazolam besilate obtained in test 1.6 after 15 days of storage at 40 ° C and 80% RH.
    [0069] Figure 15 shows the differential scanning calorimetry (DSC) diagram of remimazolam besilate obtained in test 1.6 after 15 days of storage at 40 ° C and 80% RH.
    [0071] Figure 16 shows the X-ray powder diffractogram (XRPD) of remimazolam besilate obtained in test 1.5 after 30 days of storage at 40 ° C and 80% RH.
    [0073] Figure 17 shows the differential scanning calorimetry (DSC) diagram of remimazolam besilate obtained in test 1.5 after 30 days of storage at 40 ° C and 80% RH.
    [0074] Figure 18 shows the X-ray powder diffractogram (XRPD) of the remimazolam besilate obtained in test 1.6 after 30 days of storage at 40 ° C and 80% RH.
    [0076] Figure 19 shows the differential scanning calorimetry (DSC) diagram of remimazolam besilate obtained in test 1.6 after 30 days of storage at 40 ° C and 80% RH.
    [0078] Detailed description of the invention
    [0080] In a first aspect, the present invention relates to a process for the preparation of amorphous remimazolam besilate comprising the following steps: a) providing a solution consisting essentially of remimazolam besylate and a solvent selected from the group consisting of organic solvent miscible in water, water and mixtures thereof, and
    [0081] b) lyophilizing the solution provided in step a), wherein the lyophilization comprises b1) freezing the solution provided in step a) at a temperature lower than -45 ° C, and b2) removing the solvent from the product obtained in step b1) by heating from the temperature of said product to a temperature of 10 ° C to 40 ° C, at a pressure lower than 101325 Pa (1.01325 bar) and for a period of time of less than 5 days.
    [0083] Remimazolam besylate refers to the salt of remimazolam and benzenesulfonic acid in a molar ratio of 1: 1. Therefore, remimazolam besilate is a compound of formula (I):
    [0088] In the context of the present invention, the term "amorphous" or "amorphous solid" refers to a solid state of matter, in particular remimazolam besylate, in which the particles that make up the solid lack an ordered structure. These solids lack well-defined shapes. This classification contrasts with that of crystalline solids, whose atoms are arranged in a regular and orderly manner forming crystal lattices. In a crystalline solid the arrangement of its atoms is symmetrical. For that reason, its X-ray diffraction pattern shows several very well defined peaks at certain angles. In an amorphous solid, the atoms are arranged randomly, due to which few peaks are observed in its diffraction pattern, generally one, which is characterized by a large angular width. In particular, amorphous remimazolam besylate is characterized by an X-ray powder diffractogram showing a broad peak between 10 and 40 ° 20 ± 2 ° 0. The X-ray diffractogram can be recorded using a powder diffraction system with a copper anode emitting CuKa radiation with a wavelength of 1.541838 Á, in particular, following the method described in the examples.
    [0090] The expression "crystalline remimazolam besilate" refers to remimazolam besilate in the form of a crystalline solid, that is, in which the atoms are arranged in a regular and orderly manner forming crystalline lattices. Therefore, the X-ray diffraction pattern of crystalline forms show several very well defined peaks at certain angles In particular, crystalline remimazolam besylate refers to Form 1, Form 2, Form 3 and Form 4 defined in WO 2008/007071 A1.
    [0092] In the context of the present invention, the expression "a solution consisting essentially of remimazolam besilate and a solvent" is used to characterize solutions in which the sum of the amounts by weight of remimazolam besilate and solvent represents at least 95 %, more preferably at least 97%, more preferably at least 99%, more preferably at least 99.5% and more preferably at least 99.9% by weight of the solution.
    [0094] The process of the present invention makes it possible to obtain amorphous remimazolam besilate that is stable over time due to the absence of crystalline forms. Said stability refers to the fact that the product does not evolve to crystalline forms when stored, in particular when stored at 40 ° C and 80% relative humidity and / or when stored at 25 ° C and 60% relative humidity for at least 15 days, preferably for at least 30 days, more preferably when stored for at least 15 days at 40 ° C and 80% relative humidity, even more preferably for at least 30 days. The presence / absence of crystalline forms can be determined by X-ray powder diffraction analysis, in particular using a powder diffraction system with a copper anode emitting CuKa radiation with a wavelength of 1.541838 Á, following the experimental protocol described in the examples. In particular, amorphous remimazolam besylate is characterized by a powder X-ray diffractogram showing a broad peak between 10 and 40 ° 20 ± 2 ° 0, while the X-ray diffraction pattern of crystalline forms shows various Very well defined peaks at certain angles, in particular according to X-ray powder diffractograms shown in WO 2008/007071 A1 for crystalline remimazolam besylate form 1, form 2, form 3 and form 4.
    [0096] The first step of the process of the invention, step a), is to provide a solution consisting essentially of remimazolam besylate and a solvent selected from the group consisting of water-miscible organic solvent, water, and mixtures thereof.
    [0098] Any form of remimazolam besilate can be used, be it an amorphous solid, or a crystalline solid, such as those designated as Form 1, Form 2, Form 3 and Form 4 in WO 2008/007071 A1, as well as mixtures of any of said solid forms. This document also describes the procedure for obtaining said crystalline forms. Preferably, in step a) of the present invention, Form 1 (as designated in WO 2008/007071 A1) of remimazolam besilate is used.
    [0100] The solvent used for the dissolution of step a) is selected from the group consisting of water-miscible organic solvent, water, and mixtures thereof.
    [0102] The expression "water-miscible organic solvent" refers to a liquid compound that contains carbon and that when mixed with water in any proportion at a temperature between 20 and 25 ° C, a mixture is obtained that has a single liquid phase. Examples of water-miscible organic solvents are acetonitrile, dimethylsulfoxide, methanol, ethanol, and isopropanol, preferably acetonitrile.
    [0104] The solvent mixtures may have two or more solvents, such as 2, 3 or 4 solvents, preferably two solvents, more preferably where one of the solvents in the mixture is water or acetonitrile, even more preferably where one of the solvents of the mixture is water. The solvents in the mixture can be in any volumetric ratio between them. In particular when mixtures of water and another solvent selected from acetonitrile and dimethylsulfoxide are used. In particular, when mixtures of water and another solvent selected from methanol, ethanol and isopropanol are used, the water content is at least 70%.
    [0105] Preferably, the solvent of step a) is selected from the group consisting of water, acetonitrile and mixtures thereof, more preferably the solvent is water.
    [0107] In mixtures of water and acetonitrile, said solvents can be in any volumetric ratio between them, for example in a volume ratio of water to acetonitrile of 0.1: 1 to 10: 1, preferably 0.2: 1 to 5 : 1, more preferably 0.25: 1 to 4: 1, more preferably 0.3: 1 to 3: 1, more preferably 0.5: 1 to 2: 1, more preferably 0.6: 1 to 1.5: 1, more preferably 0.8: 1 to 1.2: 1, still more preferably 0.9: 1 to 1.1: 1, most preferred 1: 1.
    [0109] More preferably, the solvent of step a) is selected from the group consisting of water, acetonitrile and a mixture of water and acetonitrile in a volume ratio of 0.5: 1 to 2: 1.
    [0111] In a particular embodiment, the concentration of remimazolam besilate in the solution provided in step a) is 5 to 15 mg / mL (mg of remimazolam besilate / mL of solution), more preferably 7 to 13 mg / mL.
    [0113] The next stage of the process of the invention, stage b), is to lyophilize the solution provided in the previous stage, stage a).
    [0115] The term "lyophilization" or "lyophilization" refers to a process that aims to separate water, an organic solvent or a mixture thereof from a solution, which in the present invention contains remimazolam besilate as solute, by freezing the dissolution and subsequent sublimation of the frozen solvent (solid). The term "sublimation" or "sublimate" refers to the process of changing from a solid state to a gaseous state without going through the liquid state. Lyophilization involves a step of freezing the solution by below its eutectic point (which is the minimum temperature at which all the components of the solution freeze) and a step of sublimation of the solvent (water, organic solvent or mixture thereof) of the frozen product and removal of the sublimated solvent. the sublimation and removal of the solvent is carried out under reduced pressure, that is, pressure below 101325 Pa.
    [0117] Step b) lyophilization of the process of the present invention comprises:
    [0118] b1) freezing the solution provided in step a) at a temperature below -45 ° C, and b2) removing the solvent from the product obtained in step b1) by heating from the temperature of said product to a temperature of 10 ° C to 40 ° C, at a pressure lower than 101325 Pa (1.01325 bar) and for a period time less than 5 days.
    [0120] Step b1) of freezing the solution provided in step a) at a temperature lower than -45 ° C can be carried out by cooling the solution from step a) to the temperature below -45 ° C, for example by using of liquid nitrogen or a mixture of dry ice (solid CO 2 ) and acetone, until the solution freezes completely.
    [0122] In a preferred embodiment, the freezing temperature of step b1) is lower than -55 ° C; preferably the freezing temperature of step b1) is -55 ° C to -85 ° C; more preferably -55 ° C to -65 ° C or -75 ° C to -85 ° C; even more preferably -58 ° C to -62 ° C or -78 ° C to -82 ° C.
    [0124] Preferably the temperature of step b1) is maintained from 10 minutes to 36 hours, more preferably from 10 minutes to 1 hour or from 15 hours to 30 hours; even more preferably 10 minutes to 40 minutes or 20 hours to 25 hours.
    [0126] Preferably, the freezing temperature of step b1) is -55 ° C to -65 ° C and is kept in this temperature range from 15 hours to 30 hours, or where the freezing temperature of step b1) is from -75 ° C to -85 ° C and is kept in this temperature range from 10 minutes to 1 hour.
    [0128] Preferably, the freezing temperature of step b1) is from -58 ° C to -62 ° C and is kept in this temperature range from 20 hours to 25 hours, or where the freezing temperature of step b1) is from -78 ° C to -82 ° C and is kept in this temperature range from 10 minutes to 40 minutes.
    [0130] Once stage b1) is finished, the next stage of lyophilization is carried out, stage b2), in which the solvent (water, water-miscible organic solvent or a mixture thereof as defined above) is eliminated from the product obtained (frozen) in step b1) by heating from the temperature of said product to a temperature of 10 ° C to 40 ° C, at a pressure lower than 101325 Pa (1.01325 bar) and for a shorter period of time to 5 days.
    [0131] The term "remove" means to totally or partially reduce the solvent content of the frozen product obtained in step b1). Said removal of the solvent yields a product that has a solvent content of less than 5%, preferably a solvent content of less than 3 % by weight, more preferably less than 2% by weight, more preferably less than 1% by weight, more preferably less than 0.5% by weight, wherein the weight percentage is weight of solvent present in the product obtained after step b2) with respect to the total weight of the product obtained in step b2) The percentage of solvent present in the product obtained in step b2) can be determined by thermogravimetry analysis or by Karl-Fisher volumetric titration analysis.
    [0133] The procedure to determine the percentage of solvent present in the product obtained in step b2) by thermogravimetric analysis can be carried out using a thermobalance (for example, Mettler Toledo TGA / SDTA851e model) placing the sample to be analyzed in an alumina crucible of 70 microliters with a nitrogen flow over the sample of 50 mL / min. The heating of the sample is carried out from 30 to 300 ° C with an increase in temperature by gradient of 10 ° C / min. Before analyzing the sample, a blank is performed under the same conditions, which is subtracted from the result of the sample analysis.
    [0135] Alternatively, the procedure to determine the percentage of solvent present in the product obtained in step b2) when said solvent is water can also be carried out by means of Karl-Fischer titration analysis. In this case, a volumetric titrator (for example, Mettler Toledo V30 model) can be used, placing the sample to be analyzed exactly weighed in the titration beaker and performing the titration with the corresponding reagent of known concentration in mg / mL (for example, Hydranal 5K Composite) until reaching the final titration point.
    [0137] Preferably, the pressure in step b2) is from 0.01 Pa (0.0001 mbar) to 101000 Pa (1.01 bar); more preferably the pressure in step b2) is from 0.01 Pa (0.0001 mbar) to 100 Pa (1 mbar) or from 50000 Pa (0.5 bar) to 101000 Pa (1.01 bar); even more preferably the pressure in step b2) is from 0.05 Pa (0.0005 mbar) to 50 Pa (0.5 mbar) or from 90,000 Pa (0.9 bar) to 101000 Pa (1.01 bar) .
    [0139] Preferably, the heating in step b2) is carried out to a temperature of 15 to 30 ° C, more preferably to a temperature of 20 to 25 ° C.
    [0140] Preferably, the temperature variation in step b2) of the process of the invention is from 0.5 to 1.5 ° C / minute, more preferably from 0.8 to 1.2 ° C / min, even more preferably from 0 , 9 at 1.1 ° C / min.
    [0142] Step b2) is carried out until all the solvent has been removed, provided that it lasts for less than 5 days. Preferably, step b2) is carried out for a time period of less than 4 days, more preferably less than 3 days, more preferably 20 to 60 hours, even more preferably 20 to 30 hours or 40 to 60 hours.
    [0144] In a preferred embodiment, step b2) is carried out at a pressure of 50000 Pa (0.5 bar) to 101000 Pa (1.01 bar) for a period of time of 20 to 30 hours; more preferably at a pressure of 90,000 Pa (0.9 bar) to 101,000 Pa (1.01 bar) for a period of time of 20 to 30 hours.
    [0146] In a particular embodiment, the freezing temperature of step b1) is from -75 ° C to -85 ° C and is maintained in this temperature range from 10 minutes to 1 hour, and step b2) is carried out at a pressure of 50000 Pa (0.5 bar) to 101000 Pa (1.01 bar) for a period of time from 20 to 30 hours, with heating to a temperature of 15 to 30 ° C.
    [0148] In another preferred embodiment, step b2) is carried out at a pressure of 0.01 Pa (0.0001 mbar) to 100 Pa (1 mbar) for a period of time of 40 to 50 hours; more preferably at a pressure of 0.05 Pa (0.0005 mbar) to 50 Pa (0.5 mbar) for a period of time of 40 to 50 hours.
    [0150] In a particular embodiment, the freezing temperature of stage b1) is from -55 ° C to -65 ° C and is kept in this temperature range from 20 to 30 hours, and stage b2) is carried out at a pressure of 0.01 Pa (0.0001 mbar) to 100 Pa (1 mbar) for a period of time of 40 to 50 hours, with heating to a temperature of 15 to 30 ° C, more preferably to a temperature of 15 to 25 ° C.
    [0152] Preferably, step b2) of the process of the invention comprises:
    [0153] (i) maintain a temperature of -30 ° C to -20 ° C and a pressure of 10 Pa (0.1 mbar) to 50 Pa (0.5 mbar) for a period of time from 15 to 24 h,
    [0154] (ii) maintain a temperature of -5 ° C to 5 ° C and a pressure of 10 Pa (0.1 mbar) to 50 Pa (0.5 mbar) for a period of time from 6 to 18 h,
    [0155] (iii) maintain a temperature of 8 ° C to 15 ° C and a pressure of 10 Pa (0.1 mbar) to 50 Pa (0.5 mbar) for a period of time from 12 to 24 h, and
    [0156] (iv) maintain a temperature of 15 ° C to 25 ° C and a pressure of 0.01Pa (0.0001 mbar) to 1 Pa (0.01 mbar) for a period of time from 3 to 18 h.
    [0158] In particular, stages (i) - (iv) are carried out sequentially, that is, first stage (i) is carried out, then stage (ii), then stage (iii) and finally stage (iv).
    [0160] In a particular embodiment, the freezing temperature of stage b1) is from -55 ° C to -65 ° C and is maintained in this temperature range from 20 to 30 hours, and stage b2) comprises stages (i) - (iv) described above.
    [0162] Preferably, the temperature variation in step b2) of the process of the invention is from 0.5 to 1.5 ° C / minute, more preferably from 0.8 to 1.2 ° C / min, even more preferably from 0 , 9 at 1.1 ° C / min.
    [0164] In a preferred embodiment, the lyophilization of step b) of the process of the invention is carried out in the absence of a hygroscopic excipient selected from the group consisting of lactose, mannitol, trehalose, sucrose, maltose, dextran, povidone, glycine and mixture thereof, that is, the mentioned hygroscopic excipients are not present in the remimazolam besilate solution provided in stage a), frozen in stage b1) and treated in stage b2) does not contain any of the aforementioned hygroscopic excipients .
    [0166] In a particular embodiment, the lyophilization of step b) of the process of the invention is carried out in the absence of a hygroscopic excipient selected from the group consisting of carbohydrates and / or organic polymers.
    [0168] The term "carbohydrate" refers to an organic compound of the empirical formula Cm (H 2 O) n. Structurally, carbohydrates can be described as polyhydroxylated aldehydes and ketones. Carbohydrates are divided into four chemical groups: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Carbohydrates defined herein include all carbohydrate modifications, derivatives, and analogs such as acidic saccharides containing carboxyl groups, phosphate groups, and / or sulfuric ester groups. Examples of carbohydrates are amylose, amylopectin, alginate, dextrans, starches, mono-, di-, and oligosaccharides. Examples of disaccharides are lactose, maltose, sucrose and trehalose. Examples of polysaccharides are dextrans. The organic polymer is preferably a polyacrylate or vinyl polymer, more preferably polyvinylpyrrolidone (or povidone)
    [0170] Lyophilization can be carried out in a lyophilizer, which is an apparatus that generally comprises the following elements: a dry chamber, a condenser with a refrigeration circuit and a vacuum system.
    [0172] The dry chamber or lyophilization chamber is the place where the solution to be lyophilized is placed. It can have different shapes with compartments where the sublimation takes place, passing the water from solid to steam. The closure is hermetic and works under reduced pressure.
    [0174] The condenser with a refrigeration circuit communicates with the dry chamber and is where the vapor that is produced in the sublimation condenses. A refrigerant keeps it at a lower temperature than the dry chamber (generally between -50 and -125 ° C).
    [0176] The vacuum system produces a vacuum (reduced pressure, that is, pressure less than 101325 Pa) with an oil pump that works connected to a trap so that solvent vapors do not pass into it. The vacuum system first removes air from the dry chamber when starting the lyophilization process, and then aids in sublimation.
    [0178] The lyophilizer also comprises a temperature regulation system that allows reaching the desired freezing temperatures of the product to be lyophilized as well as a temperature regulation system that allows it to reach at least 40 ° C.
    [0180] A further aspect of the present invention is directed to stable amorphous remimazolam besylate characterized by an X-ray powder diffractogram exhibiting a broad peak between 10 and 40 ° 20 ± 2 ° 0, preferably a powder X-ray diffractogram substantially as the one shown in Figure 1,2 or 3.
    [0182] The term "stable" refers to the fact that amorphous remimazolam besylate does not evolve to crystalline forms when stored, particularly when stored at 40 ° C and 80% relative humidity and / or when stored at 25 ° C and 60% relative humidity. relative humidity for at least 15 days, preferably for at least 30 days, more preferably when stored for at least 15 days at 40 ° C and 80% relative humidity, even more preferably for at least 30 days.
    [0183] The presence / absence of crystalline forms can be determined by X-ray powder diffraction analysis, in particular using a powder diffraction system with a copper anode emitting CuKa radiation with a wavelength of 1.541838 Á, following the experimental protocol described in the examples. In particular, amorphous remimazolam besylate is characterized by a powder X-ray diffractogram showing a broad peak between 10 and 40 ° 20 ± 2 ° 0, while the X-ray diffraction pattern of crystalline forms shows various Very well defined peaks at certain angles, in particular according to X-ray powder diffractograms shown in WO 2008/007071 A1 for crystalline remimazolam besylate form 1, form 2, form 3 and form 4.
    [0185] Preferably, the stable amorphous remimazolam besylate is characterized by an X-ray diffractogram with absence of characteristic peaks of crystalline form 1, that is, absence of peaks at 7.3, 7.8, 9.4, 12.1, 14.1, 14.7 and / or 15.6 ° 20 ± 0.2 °, absence of characteristic peaks of crystalline form 2, that is, absence of peaks at 8.6, 10.5, 12.0, 13.1, 14.415.9 and / or 16.2 ° 20 ± 0.2 °, absence of characteristic peaks of crystalline form 3, that is, absence of peaks at 7.6, 11.2, 12.4, 14.6, 15.2, 16.4 and / or 17.7 ° 20 ± 0.2 °, and absence of characteristic peaks of crystalline form 4, that is, absence of peaks at 7.6, 10.8 , 15.2, 15.9 and / or 22.0 ° 20 ± 0.2 °.
    [0187] The present invention also relates to the amorphous remimazolam besylate obtainable by the lyophilization process of the first aspect, described above.
    [0189] In order to facilitate the understanding of the foregoing ideas, some examples of the experimental procedures and embodiments of the present invention are described below. These examples are for illustrative purposes only.
    [0191] Examples
    [0193] Analysis methods
    [0195] XRPD analysis was performed using a Siemens D-5000 model X-ray powder diffractometer equipped with a Copper anode. The radiation used is CuKa with a wavelength of 1.541838 Á. Scan parameters: 4-50 degrees 20, continuous scan, ratio: 1.2 degrees / minute. .
    [0197] Differential Scanning Calorimetry (DSC) analysis was performed on a Mettler Toledo 822e apparatus with STARe SW15.00 software. Parameters: heating range from 25 to 300 ° C with a ramp of 20 ° C / min and N 2 flow of 50 ml / min. The measurement is made with a closed perforated capsule.
    [0199] The thermogravimetry analysis to obtain the percentage by weight of water was carried out in a Mettler Toledo TGA / STDA851e thermobalance using approximately 3 mg of sample to be analyzed and a nitrogen flow of 50 mL / min. The sample was heated from 30 to 300 ° C with a ramp of 10 ° C / min. Previously, a blank was made under the same analysis conditions and it was subtracted from the result obtained for the sample.
    [0201] The purity of the products obtained was analyzed using the Ultra-High Resolution Liquid Chromatography (UHPLC) technique in a Waters brand apparatus, Acquity model, equipped with a photodiode detector and thermostatted oven for the column. A CSH C18 column (3 x 50 mm and 1.7 µm) and the mobile phases A (KH 2 PO 4 5 mM pH 2) and B (acetonitrile) were used with the following analysis conditions:
    [0202] - Flow: (mL / min): 0.5
    [0203] - Te column (° C): 40
    [0204] - Wavelength (nm): 230
    [0205] - Injection volume (^ L): 1
    [0206] - Acquisition time (min): 10
    [0207] - Diluent: acetonitrile / water (1: 1)
    [0208] - Gradient:
    [0210]
    [0213] Example 1. Obtaining amorphous remimazolam besilate by lyophilization
    [0214] In the lyophilization tests, remimazolam besilate obtained by the procedure disclosed in example 7 of document WO 2019/072944 A, which corresponds to Form 1, has been used as starting material.
    [0216] The lyophilization tests were performed either in a Telstar brand lyophilizer, LyoQuest series (protocol A) or in a Telstar brand lyophilizer, LyoBeta 35 series (protocol B).
    [0218] In the A protocol the freezing temperature was -80 ° C. The drying time was 24 hours, during which the temperature was allowed to evolve from -80 ° C to 25 ° C. The temperature variation ramp was 1 ° C / min. The vacuum pressure during drying was 100000 Pa (1.0 bar).
    [0220] In protocol B the freezing temperature was -60 ° C. The drying time was divided into primary drying (18 hours at -25 ° C, 8 hours at 0 ° C and 15 hours at 10 ° C) and secondary drying (5 hours at 20 ° C). The temperature variation ramps were established at 1 ° C / min. The vacuum pressure during drying was 20 Pa (0.2 mbar) during primary drying and 0.1 Pa (0.001 mbar) during secondary drying.
    [0222] The solid resulting in each of the tests was stored under a N 2 atmosphere.
    [0224] The particular conditions of tests 1.1-1.5 as well as the results obtained are shown in Table 1, where RM refers to remimazolam and RM-acid refers to the carboxylic acid product obtained by hydrolysis of the remimazolam methyl ester. In the solvent column, the solvent used, the concentration of remimazolam besilate in the solution and the volume of solution are indicated.
    [0226] Table 1
    [0228]
    [0229]
    [0232] In all the tests carried out, the amorphous form of the remimazolam besilate salt was obtained, without observing the presence of any crystalline form, either Form 1, Form 2, Form 3 or Form 4 described in WO 2008/007071 A1. Additionally, in the tests using protocol B and water as solvent, the amorphous form of the besylate salt of remimazolam was obtained with a water content that varies between 0.1% and 0.4% by weight. Particularly in test 1.6 a percentage of water corresponding to 0.22% was obtained.
    [0234] Comparative Example 2. Attempt to obtain an amorphous form by precipitation
    [0236] In the precipitation tests, remimazolam besilate obtained through the procedure disclosed in example 7 of document WO 2019/072944 A, which corresponds to Form 1, has been used as starting material.
    [0237] Different precipitation tests were performed to try to obtain the amorphous form of remimazolam besilate following procedure protocols C, D and E, as described below:
    [0239] Protocol C: xg of remimazolam besilate were dissolved in the amount of solvent or mixture of solvents indicated in Table 2 (1 Vol refers to 1 mL of the corresponding solvent for each 1 mg of initial remimazolam besilate) at a temperature of approximately 50 ° C. The solution thus obtained was added to the antisolvent previously heated to a temperature of approximately 50 ° C. Precipitation of a solid was observed practically immediately and the mixture thus obtained was cooled to the temperature of about 0 ° C. The solid resulting in each of the tests was filtered and dried in an oven, being stored in a N 2 atmosphere until its analysis of XRPD.
    [0241] Protocol D: xg of remimazolam besilate were dissolved in the amount of solvent or mixture of solvents indicated in Table 2 (1 Vol refers to 1 mL of the corresponding solvent for each 1 mg of initial remimazolam besilate) at a temperature of approximately 50 ° C. The solution thus obtained was added to the antisolvent previously cooled to a temperature of approximately 0 ° C. Precipitation of a solid is observed practically immediately (with the exception of test 10) and the mixture thus obtained was kept for 30 minutes at a temperature of approximately 0 ° C. The solid resulting in each of the tests was filtered and dried in an oven, being stored in a N 2 atmosphere until its analysis of XRPD.
    [0243] Protocol E: xg of remimazolam besilate were dissolved in the amount of solvent or mixture of solvents indicated in Table 2 (1V or 1Vol refers to 1 mL of the corresponding solvent for each 1 mg of initial remimazolam besilate) at the temperature of about 20 ° C. The solution thus obtained was added to the antisolvent previously cooled to a temperature of approximately 0 ° C. Precipitation of a solid is observed practically immediately and the mixture thus obtained was kept for 30 minutes at a temperature of approximately 0 ° C. The solid resulting in each of the tests was filtered and dried in an oven, being stored in a N 2 atmosphere until its analysis of XRPD.
    [0245] The particular conditions of the tests 2.1-2.14 as well as the results obtained are shown in Table 2.
    [0246] Table 2
    [0248]
    [0251] As can be seen, none of the tests yielded the amorphous form of remimazolam besilate. In one of the tests a solid was not obtained (test 2.10) and in the other tests (tests 2.1-2.9 and 2.11-2.14) either form 1 or form 2 described in WO 2008/007071 A1 was obtained.
    [0253] Comparative Example 3. Attempt to obtain an amorphous form by means of spray-drying
    [0255] The spray drying tests were carried out on a Büchi B-290 equipment, which allows air inlet temperatures of up to 220 ° C, maximum air flow rates of 35 m3 / h and a maximum compressed air flow rate of 800 L / h. The system consists of a closed circuit, where a dehumidifier and a solvent condenser are inserted between the inlet and outlet of drying air to the atomization equipment. The air circuit was initially filled with nitrogen and the feed mixture began to atomize at the moment when oxygen practically disappeared from the circuit.
    [0257] Different experimental tests were carried out using methanol or acetonitrile as solvents, different flow rates of compressed air (L / h) and different inlet and outlet temperatures (° C). The drying air flow rate was kept constant at 38 m3 / h in all tests.
    [0259] In the spray drying tests, remimazolam besilate obtained by the procedure disclosed in example 6 of document WO 2019/072944 A, which corresponds to Form 1, has been used as starting material.
    [0261] The particular conditions of the tests carried out (tests 3.1-3.4) as well as the results obtained are shown in Table 3.
    [0263] Table 3
    [0268] Only in one case, in test 3.2, a product was obtained with an amorphous structure. The solid obtained presented an amorphous structure with contamination of traces of crystalline forms, as can be verified by the presence of the signals at 15.8 and 16.2 degrees 20 in the X-ray diffraction pattern of Figure 4, corresponding to Form 2 of WO 2008/007071 A1. The DSC of this solid is reproduced in Figure 5. In the DSC the presence of amorphous form is clearly seen by the exotherm present in the range of between 130 and 140 ° C, which corresponds to the crystallization process of said form upon heating. The following endotherms correspond to the fusion of crystalline forms 1 and 3 and the endotherm of form 2 should come out a little earlier (180 ° C) than that of form 1 (190 ° C), but in this case a Quite wide endotherm, which makes it difficult to conclude by means of said technique the presence of the crystalline form 2 present as contamination of the amorphous form. However, contamination with crystalline forms was clearly seen in the X-ray diffraction pattern, as indicated above.
    [0270] Comparative Example 4. Reproduction of obtaining the amorphous form of the polymorphism study of Example 5 of patent EP 2081921 B1
    [0272] In order to reproduce the obtaining of the amorphous form as indicated in entries 3, 5 and 17 of table 11 (page 12 of the European patent EP 2 081 921 B1) the following experiments were carried out, considering them as representative of the description disclosed in Example 5, polymorphism study, of the mentioned European patent.
    [0274] At a temperature of approximately 20 ° C, 3 different samples of 5 g each corresponding to crystalline form 1 of remimazolam besilate (form 1 according to WO 2008/007071 A1) were mixed with 10 mL of isopropanol (test 4.1 ), 10 mL of dichloromethane (test 4.2) and 10 mL of a mixture of THF and 2.5% water (V / V) (test 4.3), respectively. The 3 mixtures obtained in this way were subjected to the following cycle carried out consecutively for 172 hours using a Mettler Toledo EasyMax 102 apparatus:
    [0275] a) heating to the temperature of 60-62 ° C in 30 minutes,
    [0276] b) hold for 10 minutes at a temperature of 60-62 ° C
    [0277] c) cooling to the temperature of 20-25 ° C in 15 minutes
    [0278] d) hold for 10 minutes at a temperature of 20-25 ° C
    [0280] Once the indicated cycles had finished, the solvent of each of the three mixtures obtained was evaporated on a rotary evaporator with the bath temperature at approximately 35 ° C and the 3 resulting solids were analyzed by XRPD and UHPLC).
    [0281] The three tests led to obtaining crystalline form 2 of remimazolam besilate (form 2 according to WO 2008/007071 A1), without observing the presence of the amorphous form of said salt, as can be seen in the XRPD of the solids obtained in each of the tests 4.1 (Figure 6), 4.2 (Figure 7) and 4.3 (Figure 8). UHPLC analysis revealed the following purity for the products obtained, where RM refers to remimazolam and RM-acid refers to the carboxylic acid product obtained by hydrolysis of the methyl ester of remimazolam:
    [0282] - Test 4.1: Remimazolam: 99.64%; RM-acid: 0.22%
    [0283] - Test 4.2: Remimazolam: 99.74%; RM-acid: 0.17%
    [0284] - Test 4.3: Remimazolam: 90.92%; RM-acid: 8.53%
    [0286] Example 5. Stability study
    [0288] The remimazolam besylate obtained in comparative example 3 (amorphous form contaminated with traces of crystalline form 2) was stored at 40 ° C and 80% RH. After one week of storage under these conditions, the crystalline form 2 described in WO 2008/007071 A1) is obtained without observing the presence of the initial form, as can be seen in the XRPD (Figure 9) and in the DSC (Figure 10 ).
    [0290] The remimazolam besylate obtained in comparative example 3 (amorphous form contaminated with traces of crystalline form 2) was also stored at 4 ° C. After one month of storage under these conditions, the crystalline form 2 described in WO 2008/007071 A1 is obtained without observing the presence of the initial form, as can be seen in the XRPD (Figure 11).
    [0292] However, when remimazolam besilate is obtained in amorphous form without observing the presence of a crystalline form, said amorphous form is stable over time and does not evolve towards conversion to a crystalline form. This is evidenced in the stability results of the product in amorphous form obtained according to tests 1.5 (lyophilization in acetonitrile) and 1.6 (lyophilization in water) indicated in Table 1. To determine said stability, it was stored in climatic chambers under two different conditions: a) temperature of 40 ° C and 80% relative humidity and b) temperature of 25 ° C and 60% relative humidity. The product stored under conditions a) for 15 days and for 30 days continues to maintain the initial characteristics in terms of amorphous form, as shown in the XRPD and DSC patterns determined at the aforementioned 15 days (Figures 12 to 15) thus as at the 30 days mentioned (Figures 16-19).
    权利要求:
    Claims (18)
    [1]
    1. Procedure for the preparation of amorphous remimazolam besilate comprising the following steps:
    a) providing a solution consisting essentially of remimazolam besilate and a solvent selected from the group consisting of water-miscible organic solvent, water, and mixtures thereof, and
    b) lyophilizing the solution provided in step a), wherein the lyophilization comprises b1) freezing the solution provided in step a) at a temperature lower than -45 ° C, and b2) removing the solvent from the product obtained in step b1) by heating from the temperature of said product to a temperature of 10 ° C to 40 ° C, at a pressure lower than 101325 Pa and for a period of time less than 5 days.
    [2]
    2. Process according to claim 1, wherein the solvent of the remimazolam besylate solution provided in step a) is selected from the group consisting of water, acetonitrile and mixtures thereof.
    [3]
    Process according to any one of the preceding claims, in which the concentration of remimazolam besilate in the solution provided in step a) is 5 to 15 mg / mL.
    [4]
    4. Process according to any one of the preceding claims, in which the freezing temperature of step b1) is lower than -55 ° C.
    [5]
    5. Process according to claim 4, in which the freezing temperature of step b1) is -55 ° C to -85 ° C.
    [6]
    6. Process according to claim 5, in which the freezing temperature of step b1) is -55 ° C to -65 ° C or -75 ° C to -85 ° C.
    [7]
    7. Process according to any one of the preceding claims, in which the temperature of step b1) is maintained from 10 minutes to 36 hours.
    [8]
    8. Process according to claim 7, wherein the temperature of step b1) is maintained from 10 minutes to 1 hour or from 15 hours to 30 hours.
    [9]
    9. Process according to any one of the preceding claims, in which the freezing temperature of step b1) is from -55 ° C to -65 ° C and is maintained in this temperature range from 15 hours to 30 hours, or wherein the freezing temperature of step b) is -75 ° C to -85 ° C and is kept in this temperature range from 10 minutes to 1 hour.
    [10]
    Process according to any one of the preceding claims, in which the pressure in step b2) is from 0.01 Pa to 101000 Pa.
    [11]
    11. Process according to claim 10, in which the pressure in step b2) is from 0.01 Pa to 100 Pa or from 50000 Pa to 101000 Pa.
    [12]
    12. Process according to any one of the preceding claims, in which heating in step b2) is carried out to a temperature of 15 to 30 ° C.
    [13]
    Process according to any one of the preceding claims, in which step b2) is carried out for a period of time from 20 to 60 hours.
    [14]
    Process according to any one of the preceding claims, in which step b2) is carried out at a pressure of 50,000 Pa to 101,000 Pa for a period of time from 20 to 30 hours.
    [15]
    15. Process according to any one of claims 1 to 13, wherein in step b2) it is carried out at a pressure of 0.01 Pa to 100 Pa for a period of time of 40 to 60 hours.
    [16]
    16. Process according to claim 15, in which step b2) comprises:
    (i) maintain a temperature of -30 ° C to -20 ° C and a pressure of 10 Pa to 50 Pa for a period of time from 15 to 24 h,
    (ii) maintain a temperature of -5 ° C to 5 ° C and a pressure of 10 Pa to 50 Pa for a period of time from 6 to 18 h,
    (iii) maintain a temperature of 8 ° C to 15 ° C and a pressure of 10 Pa to 50 Pa for a period of time from 12 to 24 h, and
    (iv) maintain a temperature of 15 ° C to 25 ° C and a pressure of 0.01 Pa to 1 Pa for a period of time from 3 to 18 h.
    [17]
    17. Process according to any one of the preceding claims, in which the temperature variation in step b2) is from 0.5 to 1.5 ° C / minute.
    [18]
    18. Stable amorphous remimazolam besilate characterized in that it presents a powder X-ray diffractogram that presents a broad peak between 10 and 40 ° 20 ± 2 ° 0.
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    同族专利:
    公开号 | 公开日
    ES2803099A8|2021-03-04|
    ES2803099B2|2021-11-08|
    WO2021013826A1|2021-01-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2008007071A1|2006-07-10|2008-01-17|Cenes Limited|Short-acting benzodiazepine salts and their polymorphic forms|
    WO2013029431A1|2011-08-31|2013-03-07|江苏恒瑞医药股份有限公司|Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof|
    WO2013174883A1|2012-05-22|2013-11-28|Paion Uk Limited|Compositions comprising short-acting benzodiazepines|
    GB9911152D0|1999-05-14|1999-07-14|Glaxo Group Ltd|Short-acting benzodiazepines|
    ES2709298B2|2017-10-13|2019-08-21|Moehs Iberica Sl|PROCEDURE TO PREPARE METHYL ESTER ACID 3 - [ -8-BROMO-1-METHYL-6- -4H-IMIDAZO [1,2-A] [1,4] BENZODIAZEPIN-4 -IL] -PROPIONIC, AND USEFUL COMPOUNDS IN THAT PROCEDURE|
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