HK1253589B - Hydrobromate of benzodiazepine derivative, preparation method and use thereof - Google Patents

Description

A hydrobromide of a benzodiazepine derivative and its preparation method and use

Technical Field

The present invention relates to a hydrobromide of a benzodiazepine derivative and a preparation method and application thereof, belonging to the field of medicinal chemistry.

Background Art

Remimazolam, whose structure is shown in formula (I), has a chemical name of methyl 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionate.

This compound is known to be a short-acting central nervous system (CNS) depressant with sedative-hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. It is currently used for intravenous administration in the following clinical treatment options: preoperative sedation, anxiolysis, and amnesia during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia before and/or concurrently with other anesthetics and analgesics; and ICU sedation. Patent application CN101501019 reports that the free base of this compound has poor stability and is only suitable for storage at 5°C. At 40°C/75% relative humidity (open air), the sample deliquesces, changes color, and its content decreases significantly.

Due to the stability issues of the free base of this compound, researchers in many countries have studied the salts of this compound. For example, patent applications CN101501019B and WO2008/007081 A1 report the benzenesulfonate and ethanesulfonate salts of the compound of formula (I), respectively, and show that the above salts have good thermal stability, low hygroscopicity and high water solubility. In addition, CN104968348A clearly states that the above benzenesulfonate and ethanesulfonate salts are the most preferred salts of the compound of formula (I).

Soon after, CN103221414B proposed a tosylate salt of the compound of formula (I), and stated that the tosylate salt was less toxic than the benzenesulfonate salt, and that certain crystal forms had better thermal stability and water solubility.

By arranging the existing technical information, the following relevant contents can be obtained (Table 1):

Table 1

As can be seen from the table above, both the free base of remimazolam and its known salt derivatives have a water solubility of no more than 11 mg/ml, placing them only slightly soluble. This increases safety risks in clinical use. Reconstitution during clinical use requires prolonged shaking and may also leave residual insoluble material, leading to inaccurate drug dosing and potential safety risks. Furthermore, for high-demand indications such as general anesthesia, the amount of diluent required increases, causing extreme inconvenience in clinical use. Therefore, the solubility of remimazolam's known salt derivatives is a significant disadvantage and urgently needs further improvement.

Summary of the Invention

In view of the water solubility problem of the existing remimazolam free base and its related salts, the purpose of the present invention is to improve the solubility of remimazolam to a level that is easily soluble in water (30-100 mg/ml). In order to achieve the above-mentioned water-soluble goal, the inventor has conducted research from many aspects, such as the crystal form of existing salts, formulation excipients, new salt types, etc., hoping to find a feasible means to improve water solubility while ensuring better drugability. However, the screening research on the existing salt crystal form and formulation excipients ultimately ended in failure, and no more suitable method was found. In the study of various salts, a total of more than 20 acid salts were screened during the preliminary experiments, and 8 salt forms were found, among which 7 salts such as sulfate, 2-naphthalenesulfonate, methanesulfonate, oxalate, hydrobromide, hydrochloride, 1,5-naphthalene disulfonate were in crystalline form, and ethane disulfonate was amorphous. Further research was made on the above-mentioned salts, and the results are as follows:

Table 2

Among them, sulfate, hydrobromide, and hydrochloride exhibit polymorphism. Sulfate is highly hygroscopic or has low crystallinity, making it difficult to develop into a drug. 1,5-naphthalenedisulfonic acid and 2-naphthalenesulfonic acid have low solubility, while methanesulfonic acid has low crystallinity, making it difficult to develop into a drug.

As can be seen from the table above, hydrochloride and hydrobromide salts have relatively ideal solubility and other properties. Of the 1,356 chemically well-defined organic drugs marketed before 2006, as listed in the US FDA Orange Book [Progress in Pharmaceutical Sciences, 2012, Vol. 36, No. 4-151], 523 (38.6%) form salts with acids. Of these, hydrochloric acid is the most frequently used acid for salt formation with organic bases (53.4%). This demonstrates that hydrochloride salts are a superior choice among the many acid salts currently on the market.

However, when analyzing and studying the stability of the hydrochloride salt, the inventors found that the most widely used hydrochloride salt had poor stability for this compound:

Table 3

As shown in Table 3, although the hydrochloride has good water solubility, it has very poor stability, so the hydrochloride was abandoned.

During the long-term research on the above-mentioned various salts, the present invention unexpectedly discovered that the hydrobromide salt of the compound of formula (I) has excellent solubility (>100 mg/ml), significantly better than other salt products currently available on the market or in development, and is particularly suitable for the preparation of injections. In addition, the stability of various crystalline forms is relatively good (see Table 3). Based on the above reasons, the present invention actually provides the hydrobromide salt of the compound shown in formula I:

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

The present invention also discovered during research that the hydrobromide salt of the compound of formula (I) exists in multiple crystal forms. The inventors have discovered four crystal forms to date, namely I, II, III, and α crystal forms. The inventors studied and compared the physical and chemical properties of the different crystal forms and ultimately found that the α crystal form has the best stability and still maintains good water solubility. Based on such good solubility, this crystal form can be prepared into preparations with high requirements for the solubility of the main drug (such as injections). At the same time, given its good stability, injections do not need to be limited to powders for injection (powder injections), and liquid injections (water injections) can also be prepared.

Current research has revealed that the structure of the impurities degraded by light in the compound of formula (I) is: The activity of these impurities, which is 1/300 of that of the compound of formula (I), is significantly lower under other conditions. If these compounds or their salt derivatives have poor stability, they are susceptible to degradation, which can lead to reduced pharmacological activity at best and potentially toxic side effects in the human body at worst. Good stability is also a key factor in selecting a compound's crystalline form.

Therefore, the present invention preferably presents the hydrobromide salt of the compound of formula (I) in the α-crystalline form. Comparison of the X-ray powder diffraction patterns (Cu-Ka radiation) of the α-crystalline form with the other three crystalline forms reveals that the α-crystalline form exhibits distinct characteristic peaks at approximately 13.7±0.2, 16.0±0.2, and 19.2±0.2 degrees 2θ. Differential scanning calorimetry analysis of the α-crystalline form reveals a melting endotherm at 170°C±2°C. Therefore, the present invention uses the aforementioned powder diffraction characteristic peaks and DSC melting peaks to define the structure of the α-crystalline form. Based on this definition, the α-crystalline form can be clearly distinguished from the other three crystalline forms.

Of course, in addition to the three obvious distinguishing characteristic peaks mentioned above, the X-ray powder diffraction pattern of the α crystal form also includes characteristic peaks located at approximately 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, and 30.7±0.2 degrees 2θ.

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

According to the EMEA document [20080124 EMEA Letter on Requesting a Genotoxic Impurity Assessment], low-level sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid pose a potential risk: the use of alcohols in the process can lead to the formation of genotoxic impurities such as benzenesulfonate or toluenesulfonate. Similarly, the use of alcohols to clean reaction vessels or storage tanks may also increase this risk. Therefore, in addition to the aforementioned advantages of water solubility and stability, hydrobromic acid's low toxicity and the fact that bromide ion is one of 16 trace elements required by the human body may also offer significant safety advantages.

The present invention also provides a method for preparing the above-mentioned hydrobromide α-crystalline form, which comprises the following steps:

(1) taking the compound of formula I, reacting it with hydrobromic acid, and preparing it into Form III in a solvent system consisting of isopropanol and water, preferably reacting it with an aqueous solution of hydrobromic acid in isopropanol to precipitate Form III, or crystallizing the hydrobromide salt in isopropanol solvent to obtain Form III;

(2) Taking crystal III, exposing it to a gas with high relative humidity at a certain temperature until crystal III transforms into the α-crystalline form.

Wherein, in step (2), the temperature is 50-60°C.

Wherein, in step (2), the high relative humidity refers to a relative humidity of above 65%.

Furthermore, the high relative humidity refers to a relative humidity above 75%.

In one embodiment of the present invention, the gas is air.

This crystallization method, also known as vapor-mediated crystallization, differs from solvent-mediated crystallization in that the medium used is a gas. Crystallization times can range from hours to days, weeks, or even months, depending on relative humidity and temperature. This time can be determined using conventional monitoring methods.

Based on the excellent solubility (>100 mg/ml) of the hydrobromide salt of the compound of formula (I) and its various crystalline forms, its use in the preparation of injections can better meet the solubility requirements of the raw materials for injections. Therefore, the present invention also provides the use of the hydrobromide salt in the preparation of an injection having a sedative or hypnotic effect.

The sedative or hypnotic effects described herein are produced in mammals. The drug also has certain anxiolytic, muscle relaxation, anticonvulsant, and anesthetic effects. For specific dosages, refer to the effective dosage of remimazolam in the prior art.

In addition, the present invention also provides a pharmaceutical composition comprising the hydrobromide salt as described above. Of course, in addition to the hydrobromide salt, the composition may also include pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable" as used herein includes any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

“Excipients” is a general term for all additional materials in pharmaceutical preparations other than the main drug. Excipients should have the following properties: (1) non-toxic to the human body and almost no side effects; (2) stable chemical properties, not easily affected by temperature, pH, storage time, etc.; (3) no incompatibility with the main drug, and no impact on the efficacy and quality inspection of the main drug; (4) no interaction with the packaging material.

In one embodiment of the present invention, the pharmaceutical composition is in the form of an injectable preparation.

Among them, the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablets for injection (referring to molded tablets or machine-pressed tablets made by aseptic operation of the drug, dissolved with injection water when used, for subcutaneous or intramuscular injection).

The powder for injection contains, in addition to the hydrobromide salt of the compound of Formula I, at least an excipient. The excipient herein is an ingredient intentionally added to a drug and should not have pharmacological properties in the amount used. However, the excipient may aid in drug processing, solubility or dissolution, drug delivery via targeted routes of administration, or contribute to stability.

The excipient of the present invention can be selected from one or a combination of two or more of carbohydrates, inorganic salts, and polymers, wherein carbohydrates include monosaccharides, oligosaccharides, or polysaccharides.

Monosaccharides are sugars that cannot be further hydrolyzed. They are the basic units of molecules that make up various disaccharides and polysaccharides. They can be divided into trioses, tetroses, pentoses, hexoses, etc. Monosaccharides in nature are mainly pentoses and hexoses. For example, glucose is an aldohexose and fructose is a ketohexose.

Oligosaccharides, also known as oligosaccharides, are polymers formed by the condensation of a small number of monosaccharides (2-10).

Polysaccharides are high-molecular carbohydrates composed of sugar chains linked by glycosidic bonds, with at least 10 monosaccharides.

The mass ratio of the compound of formula I to the excipient is (1:0.5) to (1:200). Based on considerations of cost, active ingredient concentration, etc., the present invention recommends setting the mass ratio of the compound of formula I to the excipient to 1:5 to 1:86.

The sterile powder for injection of the present invention can be obtained by conventional aseptic packaging or freeze-drying processes.

In one embodiment of the present invention, the carbohydrate excipient is selected from one or a combination of two or more of lactose, maltose, sucrose, mannitol, and glucose. In one embodiment of the present invention, the inorganic salt is selected from sodium chloride, potassium chloride, calcium chloride, and the like. Of course, inorganic salts are often used in combination with carbohydrates in freeze-dried powder injection formulations. Therefore, in the actual operation of the present invention, the selection of the type of excipient can be obtained by conventional screening based on known theories. For example, lactose, mannitol, and glucose can be used alone, or a combination of two or more thereof can be used, or an inorganic salt such as sodium chloride can be added to the presence of a single or multiple carbohydrates.

During research, the present invention discovered that when the hydrobromide salt of the compound of Formula I is used as a raw material to prepare a lyophilized powder injection, the selected excipients all achieve good stability and solubility, and are superior to the lyophilized powder injection of remimazolam besylate (CN201380036582.2). This finding is sufficient to demonstrate that the remimazolam hydrobromide salt provided by the present invention is more suitable for preparing a lyophilized powder injection.

Obviously, based on the above contents of the present invention, according to the common technical knowledge and means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

The above content of the present invention will be further described in detail below through the form of specific embodiments. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following embodiments. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an X-ray powder diffraction spectrum of the hydrobromide salt of the compound of formula (I) in crystalline form III;

FIG2 is a DSC spectrum of the hydrobromide salt of the compound of formula (I) in crystalline form III;

FIG3 is an X-ray powder diffraction spectrum of the α-crystalline form of the hydrobromide salt of the compound of formula (I);

FIG4 is an X-ray powder diffraction spectrum of the α-crystalline form of the hydrobromide salt of the compound of formula (I);

FIG5 is a DSC/TGA spectrum of the α-crystalline form of the hydrobromide salt of the compound of formula (I)

FIG6 is a DVS spectrum of the α-crystalline form of the hydrobromide salt of the compound of formula (I)

FIG7 is an X-ray powder diffraction spectrum of the hydrobromide salt of the compound of formula (I) in Form I;

FIG8 is a DSC spectrum of the hydrobromide salt of the compound of formula (I) in Form I;

FIG9 is a TGA spectrum of the hydrobromide salt of the compound of formula (I) in Form I;

FIG10 is an X-ray powder diffraction spectrum of the hydrobromide salt of the compound of formula (I) in crystalline form II;

FIG11 is a DSC spectrum of the hydrobromide salt of the compound of formula (I) in crystalline form II;

FIG12 is a TGA spectrum of the hydrobromide salt of the compound of formula (I) in crystalline form II;

DETAILED DESCRIPTION

The raw material of the compound of formula (I) remimazolam used in the present invention can be obtained by purchasing commercial products or prepared according to known methods (such as patents US200,700,934,75A, etc.).

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

1.8 g of the compound of formula (I) was accurately weighed into a 100 mL three-necked flask, and 8.2 mL of isopropanol was added and stirred to dissolve it completely. Then, 0.83 g of a 47% aqueous solution of hydrobromic acid was dissolved in 6.3 mL of isopropanol and added dropwise to the isopropanol solution of the compound of formula (I). The mixture was stirred for crystallization, filtered, and dried under reduced pressure at 55°C to obtain the hydrobromide salt of the compound of formula (I).

The X-ray diffraction spectrum of the crystal is shown in Figure 1, and the DSC and TGA spectra are shown in Figure 2. The melting point is 163°C, and the crystal form is defined as the hydrobromide salt III crystal form of the compound of formula (I).

Example 2: Preparation of the α-crystalline hydrobromide salt of the compound of formula (I)

The hydrobromide crystal form III can undergo crystal transformation to the α-form in a non-flowing atmosphere at a certain humidity. This transformation occurs, particularly in air with a humidity above 75%, through the gas-phase interface. This method has the advantage of not involving solvent, resulting in no losses or residual solvent.

Specifically, 200 mg of the hydrobromide salt of the compound of formula (I) in Example 1 above, Form III, was left unattended at 50-55°C and 75% relative humidity for 20 hours. The X-ray diffraction spectrum of this crystalline sample is shown in Figure 3 . At approximately 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, and 30.65, the product was confirmed to be the hydrobromide salt of the compound of formula (I), Form α. IC: bromide ion content 15.74%, confirming a 1:1 ratio of hydrobromic acid to salt; residual solvent: 0.01% isopropyl alcohol.

Example 3: Preparation of the α-crystalline hydrobromide salt of the compound of formula (I)

500 mg of the hydrobromide salt of the compound of formula (I) in Example 1 was stored in an open atmosphere at 55-60°C and 75% relative humidity for 60 hours. Comparison of the X-ray diffraction pattern and DSC spectrum of the crystalline sample confirmed that the product was the hydrobromide salt of the compound of formula (I), α-form.

The X-ray diffraction spectrum is shown in Figure 4, with peaks at approximately 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, and 30.70. The DSC/TGA diagram is shown in Figure 5, showing a melting point of 170°C. Since this sample was not further dried after crystallization at 75% humidity, it contained 4.3% free water, as evidenced by a weight loss plateau at 60.78-79.45°C on the TGA. Furthermore, the DVS spectrum showed the ability to bind water at a certain humidity, indicating an amorphous crystalline form. The product was confirmed to be the α-crystalline hydrobromide salt of the compound of formula (I).

Example 4: Preparation of Form I of the Hydrobromide Salt of the Compound of Formula (I)

Accurately weigh 44 mg (0.10 mmol) of the compound of formula (I) into a 10 mL single-necked flask, add 0.4 mL of ethyl acetate and stir to dissolve it completely. The reaction temperature is lowered to 4°C, and then 1.1 mL of a methanol solution of hydrobromic acid (1 mol/L, 0.11 mmol) is added dropwise to the ethyl acetate solution of the compound of formula (I). The mixture is stirred for crystallization, filtered, washed with ethyl acetate, and dried under reduced pressure at 30°C to obtain the hydrobromide salt of the compound of formula (I) as a white solid (42 mg, yield 81%).

The X-ray diffraction spectrum of the crystals is shown in Figure 7 , and the DSC spectrum is shown in Figure 8 . Characteristic absorption peaks are observed near 70°C, 162°C, and 180°C, defining the crystal form as Form I of the hydrobromide salt of the compound of Formula (I). A TGA spectrum of Form I of the hydrobromide salt of the compound of Formula (I) is shown in Figure 9 .

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

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 to dissolve it completely, then 10 mg of a 47% aqueous solution of hydrobromic acid was dissolved in 75 μL of acetone and added dropwise to the acetone solution of the compound of formula (I), stirred for crystallization, centrifuged, and dried under reduced pressure at 30°C to obtain the hydrobromide salt of the compound of formula (I), 20 mg of a white solid, with a yield of 76%.

The X-ray diffraction spectrum of the crystals is shown in Figure 10, and the DSC spectrum is shown in Figure 11. Characteristic absorption peaks are observed near 69°C, 90°C, 173°C, and 188°C, defining the crystal form as Form II of the hydrobromide salt of the compound of Formula (I). A TGA spectrum of Form II of the hydrobromide salt of the compound of Formula (I) is shown in Figure 12.

Example 6 Comparison of the α-crystal form of the present invention with other crystal forms

The α-crystalline form of the hydrobromide salt of the compound of formula (I) was compared with other crystalline forms. The results are shown in Table 4:

Table 4

As can be seen from the above table, the α crystal form prepared by the present invention can still ensure good stability under conditions of strong light, high heat and high humidity, and is significantly better than the other three crystal forms.

Example 7 Stability comparison between the α-crystal form of the present invention and the original salt crystal form

The benzenesulfonate salt form I of the compound of formula (I) was prepared with reference to patents CN200780028964.5 and CN201310166860.8, and the obtained form had characteristic peaks at approximately 7.19, 7.79, 9.38, 12.08, 14.06, 14.40, 14.72, and 15.59.

The stability of the original benzenesulfonate crystalline form and the hydrobromide α crystalline form of the present invention were compared as follows. The results are shown in Table 5:

Table 5

As can be seen from the table above, the α-crystal prepared by the present invention exhibits better stability than the original benzenesulfonate salt crystal form under conditions such as strong light, high heat, and high humidity. In addition, based on publicly available data, the α-crystal prepared by the present invention is also more stable than the tosylate salt crystal form in CN103221414B.

Example 8 Remimazolam Hydrobromide Sterile Powder for Injection and Process

According to the prescription in Table 6, sterile powder was prepared using the following preparation process, and the physical and chemical indicators of each prescription were compared.

Preparation process:

Prescription 1: Aseptically dispense remimazolam hydrobromide directly into brown penicillin bottles and seal the cap.

Prescriptions 2 to 10: Dissolve the excipients and remimazolam hydrobromide in water for injection, stir until dissolved, adjust the pH value of the solution with hydrochloric acid/sodium hydroxide, divide into vials, and freeze-dry to obtain the product.

Table 6 Remimazolam Hydrobromide Sterile Powder for Injection

The physicochemical indicators of each prescription are as follows:

Table 7 Physical and chemical indicators of sterile powder of remimazolam hydrobromide for injection

Prescriptions 9 and 10 are prepared according to the process reported in patent CN201380036582.2 to prepare remimazolam hydrobromide and remimazolam besylate lyophilized powder injections, respectively. The two lyophilized powder injections are compared as follows:

Table 8 Comparison between Remimazolam Hydrobromide Lyophilized Powder Injection and Original Research Remimazolam Besylate Lyophilized Powder Injection

Note: 1. Accelerated storage condition is 40℃, long-term storage condition is 25℃

2. Reconstitution time: Gently vortex the water for injection/glucose/normal saline until it is completely dissolved and mixed evenly. Record the time taken for complete dissolution.

As can be seen from the above table, the lyophilized powder injection of remimazolam hydrobromide of the present invention maintains good stability in both accelerated and long-term stability experiments, and its stability and solubility are better than those of remimazolam besylate lyophilized powder injection (CN201380036582.2).

Claims (18)

1. The hydrobromide salt of the compound shown in Formula I: The chemical ratio of compound (I) to hydrobromic acid is 1:1; The hydrobromate exists in α-crystalline form. When subjected to Cu-ka radiation, the resulting X-ray powder diffraction pattern includes at least characteristic peaks located at approximately 13.7±0.2, 16.0±0.2, 19.2±0.2, 8.2±0.2, 10.3±0.2, 12.6±0.2, 15.1±0.2, 20.7±0.2, 23.2±0.2, and 25.5±0.2 degrees 2θ. 2. The hydrobromide according to claim 1, characterized in that: the X-ray powder diffraction pattern further includes characteristic peaks located at 22.8±0.2, 26.2±0.2, 27.7±0.2, 28.4±0.2, 30.7±0.2 degrees 2θ. 3. The hydrobromate according to claim 1, characterized in that: in the differential scanning calorimetry analysis of the α-crystal form, there is a melting endothermic peak at 170℃±2℃. 4. The method for preparing the α-crystal form of hydrobromide according to any one of claims 1-3, characterized in that it comprises the following steps: (1) Take the compound shown in Formula I and react it with hydrobromic acid to prepare the hydrobromide crystal form III in a solvent system composed of isopropanol and water; the specific operation is: react with hydrobromic acid aqueous solution in isopropanol to precipitate crystal form III; or crystallize the hydrobromide in isopropanol solvent to obtain crystal form III. (2) Take crystal form III and expose it to a gas with a relative humidity of more than 65% at 50-60℃ until crystal form III transforms into α crystal form. 5. The preparation method according to claim 4, characterized in that: the operation of step (1) is as follows: accurately weigh 1.8g of compound (I) into a 100mL three-necked flask, add 8.2mL of isopropanol and stir until completely dissolved, then dissolve 0.83g of 47% hydrobromic acid aqueous solution in 6.3mL of isopropanol and add it dropwise to the isopropanol solution of compound (I), stir to precipitate crystals, filter, and dry under reduced pressure at 55℃ to obtain crystal form III. 6. The preparation method according to claim 4, characterized in that: the X-ray diffraction pattern of crystal form III is shown in Figure 1, the DSC and TGA patterns are shown in Figure 2, and the melting point is 163℃. 7. The preparation method according to claim 4, wherein the gas in step (2) is air. 8. The preparation method according to claim 4, wherein the high relative humidity refers to a relative humidity of 75% or higher. 9. Use of the hydrobromide according to any one of claims 1 to 3 in the preparation of an injectable preparation having sedative, hypnotic, anxiolytic, muscle relaxant, anticonvulsant, or anesthetic effects. 10. A pharmaceutical composition, characterized in that it is an injectable formulation containing the hydrobromide according to any one of claims 1 to 3. 11. The pharmaceutical composition according to claim 10, wherein the injectable formulation is selected from injectable solutions and sterile powders for injection. 12. The pharmaceutical composition according to claim 11, characterized in that: the sterile powder for injection contains, in addition to the hydrobromide of the compound of formula I, at least one excipient. 13. The pharmaceutical composition according to claim 12, wherein the excipient is selected from one or more combinations of sugars, inorganic salts, and polymers. 14. The pharmaceutical composition according to claim 13, wherein the sugar is selected from monosaccharides, oligosaccharides or polysaccharides. 15. The pharmaceutical composition according to claim 13, wherein the sugar is selected from lactose, maltose, sucrose, mannitol, glucose, and dextran. 16. The pharmaceutical composition according to claim 13, wherein the inorganic salt is selected from sodium chloride, potassium chloride, and calcium chloride. 17. The pharmaceutical composition according to any one of claims 12 to 16, characterized in that the mass ratio of the compound of formula I to the excipient is 1:0.5 to 1:200. 18. The pharmaceutical composition according to claim 17, characterized in that the mass ratio of the compound of formula I to the excipient is 1:5 to 1:86.