A process for preparing a crystalline form II of buspirone hydrochloride

Abstract

The application relates to the technical field of drug crystallization, in particular to a preparation method of a crystal form II of buspirone hydrochloride. The technical scheme of the application is as follows: buspirone is put into water, the liquid-solid ratio is 1-3:1, and the temperature is controlled at 20-40 DEG C. Then, 1-1.5 equivalent of concentrated hydrochloric acid is added dropwise, and then stirring is continuously carried out for 2 hours, during which constant temperature needs to be controlled. Filtration is carried out, and the filtrate is collected. Subsequently, an alcohol solvent is added into the filtrate. Then, freezing is carried out at-20 DEG C to-50 DEG C. The frozen sample is vacuum freeze-dried in a freeze dryer, and the crystal form II of buspirone hydrochloride is obtained. The concentrated hydrochloric acid is characterized in that the dropwise adding time is 0.5-2 hours. The alcohol solvent is characterized in that the alcohol solvent is one of ethanol, isopropyl alcohol, n-propyl alcohol and n-butyl alcohol. The alcohol solvent in the fourth step is characterized in that the adding amount of the alcohol solvent is 0.05-0.2 times the feeding amount. The freeze-drying condition in the sixth step is characterized in that the cold trap temperature is-50 DEG C to-80 DEG C, and the pressure is 10 Pa to 40 Pa.

Description

Technical Field

[0001] This invention relates to the field of drug crystallization technology, and specifically to a method for preparing buspirone hydrochloride crystal form II. Background Technology

[0002] Buspirone hydrochloride is a novel non-benzodiazepine anxiolytic drug with the chemical name 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione. It can alter anxiety by activating serotonin (5-HT) 1A receptors in the brain and has a wide and significant therapeutic effect on anxiety disorders. Its advantages include no drug tolerance, no risk of abuse, and no obvious sedative effect while anxiolytically anti-anxious.

[0003] Buspirone hydrochloride oral formulations are rapidly absorbed, reaching peak plasma concentration in approximately 0.5 to 1 hour, with a minimum half-life of only 2 hours. Therefore, to maintain effective plasma concentrations, the dosing interval must be shortened, increasing the frequency of administration. This significantly increases the toxicity of metabolites and the incidence of adverse reactions. Furthermore, increased dosing frequency also significantly reduces patient adherence. The treatment course for buspirone hydrochloride is generally several months to a year. Therefore, if it could be processed into a sustained-release formulation to reduce dosing frequency and maintain stable plasma concentrations, it would undoubtedly bring significant benefits to patients.

[0004] In recent years, there has been an increasing amount of research on sustained-release and controlled-release formulations of buspirone hydrochloride. However, the vast majority of these studies achieve controlled release by modifying the formulation, such as patent CN1977845 protecting a sustained-release microsphere of buspirone hydrochloride; patent CN100363003 protecting a sustained-release tablet of buspirone hydrochloride; and CN117257747 protecting a sustained-release matrix of buspirone hydrochloride, etc. These approaches significantly increase the complexity of the formulation process, leading to higher formulation costs and increasing the burden of medication on patients. Furthermore, they also present problems such as excessively high energy consumption and serious emissions of waste.

[0005] Controlling the dissolution and release rate of a drug through crystal form control is a novel approach. Currently known crystal forms of buspirone hydrochloride include crystal form I and crystal form II, protected in the original manufacturer's patents US5015646 and US4810789; and crystal forms A, B, and C, mentioned by Du Qing et al. in their research on the polymorphism of buspirone hydrochloride. Studies have shown that crystal form C and the original manufacturer's crystal form II are the same crystal form, with a melting point around 203℃. This crystal form is the most stable of buspirone hydrochloride, exhibiting the lowest dissolution and release rate, and is most favorable for the processing of sustained-release formulations.

[0006] Currently, the preparation processes for buspirone hydrochloride crystal form II are all quite complex: original patents US4810789 and US5015646 indicate that crystal form II can only be stably obtained above 95°C; M. Sheikhzadeh et al., in their academic paper "Solid-State Characterization of Buspirone Hydrochloride Polymorphs," provided a method for preparing crystal form II at 40-50°C, but this requires additional nitrogen protection. Clearly, current crystal form II preparation processes suffer from cumbersome operation, demanding equipment requirements, and high energy consumption and production costs.

[0007] In summary, seeking a stable, simple, and environmentally friendly process for preparing crystal form II using a non-toxic solvent system is of great significance. This invention, through a scientifically designed system, can stably prepare crystal form II while achieving the goals of a simple, easily industrialized process, environmentally friendly solvents, low emissions of waste, and high production capacity. This invention undoubtedly possesses significant economic, environmental, and social benefits. Summary of the Invention

[0008] This invention provides a method for preparing buspirone hydrochloride crystal form II. This method features a simple preparation process, stable crystal form, an environmentally friendly solvent system, and ease of industrial production.

[0009] Detailed Implementation Plan

[0010] Add buspirone to water with a liquid-to-solid ratio of 1 to 3:1 and control the temperature at 20 to 40°C.

[0011] Add 1 to 1.5 equivalents of concentrated hydrochloric acid dropwise, and then continue stirring for 2 hours, during which the temperature needs to be kept constant.

[0012] Filter and collect the filtrate.

[0013] Add an alcohol solvent to the filtrate.

[0014] The above solution was frozen at -20℃ to -50℃.

[0015] The frozen sample is obtained by vacuum freeze-drying in a freeze dryer.

[0016] More specifically:

[0017] The concentrated hydrochloric acid is added dropwise over a period of 0.5 to 2 hours in the second step.

[0018] The alcohol solvent mentioned in step four is one of ethanol, isopropanol, n-propanol, and n-butanol.

[0019] The amount of alcohol solvent added in step four is 0.05 to 0.2 times the amount of feed.

[0020] The freeze-drying conditions described in step six are a cold trap temperature of -50℃ to -80℃ and a pressure of 10Pa to 40Pa. Attached Figure Description

[0021] Figure 1 X-ray powder diffraction (XRD) pattern of crystal form II in Example 2

[0022] Figure 2 Differential scanning calorimetry (DSC) chart of crystal form II in Example 2 Detailed Implementation

[0023] Example

[0024] 100 g of buspirone and 200 ml of purified water were added to a crystallizer, and the temperature was maintained at 30°C with continuous stirring until homogeneous. 1.5 equivalents of concentrated hydrochloric acid were added to the crystallizer at a uniform rate over 2 hours. After the addition was complete, the temperature was maintained at 30°C with stirring for another 2 hours. The mixture was filtered, and the filtrate was collected. 5 ml of isopropanol was added to the filtrate, and the mixture was stirred until homogeneous before freezing at -20°C. The frozen sample was then placed in a freeze dryer and freeze-dried at a cold trap temperature of -60°C and a pressure of 10 Pa to obtain the final product. XRD analysis confirmed that the product was buspirone hydrochloride crystal form II, and the HPLC purity was 99.83%.

[0025] Example

[0026] 100 g of buspirone and 250 ml of purified water were added to a crystallizer, and the temperature was maintained at 40°C with continuous stirring until homogeneous. 1.3 equivalents of concentrated hydrochloric acid were added to the crystallizer at a uniform rate over 1 hour. After the addition was complete, the temperature was maintained at 40°C and the mixture was stirred for 1.5 hours. The mixture was filtered, and the filtrate was collected. 4 ml of ethanol was added to the filtrate, and the mixture was stirred until homogeneous before freezing at -50°C. The frozen sample was then placed in a freeze dryer and freeze-dried at a cold trap temperature of -80°C and a pressure of 40 Pa to obtain the final product. XRD analysis confirmed that the product was buspirone hydrochloride crystal form II, and the HPLC purity was 99.88%.

[0027] Example

[0028] 100 g of buspirone and 100 ml of purified water were added to a crystallizer, and the temperature was maintained at 35°C with continuous stirring until homogeneous. One equivalent of concentrated hydrochloric acid was added to the crystallizer at a uniform rate over 2 h. After the addition was complete, the temperature was maintained at 35°C and the mixture was stirred for 1.5 h. The mixture was filtered, and the filtrate was collected. 8 ml of n-propanol was added to the filtrate, and the mixture was stirred until homogeneous before freezing at -30°C. The frozen sample was then placed in a freeze dryer and freeze-dried at a cold trap temperature of -60°C and a pressure of 20 Pa to obtain the final product. XRD analysis confirmed that the product was buspirone hydrochloride crystal form II, and the HPLC purity was 99.81%. Example

[0029] 100 g of buspirone and 300 ml of purified water were added to a crystallizer, and the temperature was maintained at 20°C with continuous stirring until homogeneous. 1.1 equivalents of concentrated hydrochloric acid were added to the crystallizer at a uniform rate over 1.5 h. After the addition was complete, the temperature was maintained at 30°C and the mixture was stirred for 1 h. The mixture was filtered, and the filtrate was collected. 6 ml of isopropanol was added to the filtrate, and the mixture was stirred until homogeneous before freezing at -420°C. The frozen sample was then placed in a freeze dryer and freeze-dried at a cold trap temperature of -50°C and a pressure of 30 Pa. The product was identified by XRD as buspirone hydrochloride crystal form II, and the HPLC purity was 99.90%. Example

[0030] 100 g of buspirone and 150 ml of purified water were added to a crystallizer, and the temperature was maintained at 30°C with continuous stirring until homogeneous. 1.2 equivalents of concentrated hydrochloric acid were added to the crystallizer at a uniform rate over 0.5 h. After the addition was complete, the temperature was maintained at 30°C and the mixture was stirred for 1 h. The mixture was filtered, and the filtrate was collected. 3 ml of n-butanol was added to the filtrate, and the mixture was stirred until homogeneous before freezing at -35°C. The frozen sample was then placed in a freeze dryer and freeze-dried at a cold trap temperature of -70°C and a pressure of 40 Pa to obtain the final product. XRD analysis confirmed that the product was buspirone hydrochloride crystal form II, and the HPLC purity was 99.85%.

[0031] The method for preparing buspirone hydrochloride crystal form II disclosed and proposed in this invention can be implemented by those skilled in the art by appropriately modifying the process parameters, based on the content of this invention. This invention has described the method and product through multiple embodiments. Those skilled in the art can obviously modify or appropriately combine the crystallization process described in this invention without departing from the content and parameter scope of this invention to reproduce the technology of this invention. It should be particularly noted that all similar modifications or substitutions are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this invention.

Claims

1. A method for preparing buspirone hydrochloride crystal form II, characterized in that... Includes the following steps: Step 1: Add buspirone to water at a liquid-to-solid ratio of 1 to 3:1 and control the temperature at 20 to 40°C; Step 2: Add 1 to 1.5 equivalents of concentrated hydrochloric acid dropwise over 0.5 to 2 hours, then continue stirring for 2 hours, maintaining a constant temperature throughout the process. Step 3: Filtration, collecting the filtrate; Step 4: Add an alcohol solvent to the filtrate, wherein the alcohol solvent is one of ethanol, isopropanol, n-propanol, and n-butanol; the amount of alcohol solvent added is 0.05 to 0.2 times the amount of buspirone fed. Step 5: Place the above solution in 20℃~ Freeze at 50℃; Step 6: Freeze-dry the frozen sample under vacuum in a freeze dryer. The freeze-drying conditions are: cold trap temperature. 50℃~ 80℃, pressure 10Pa~40Pa.

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