Pirospirone-salicylic acid crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a new crystal form of piperaspirone, in particular to a piperaspirone-salicylic acid crystal form as well as a preparation method and application thereof. The novel piperaspirone crystal form provided by the invention contains one molecule of piperaspirone and one molecule of salicylic acid, the preparation method is simple to operate, the crystallization process is easy to control, and the reproducibility is good. After the two components form eutectic crystals, the solubility, stability and dissolution rate of the piperaspirone can be remarkably enhanced, and the piperaspirone eutectic crystals can be better applied to piperaspirone preparations.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to the crystalline form of piperopirone-salicylic acid, its preparation method, and its application. Background Technology

[0002] Perospirone, chemically named N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis-cyclohexanedicarboximide, is a structural imide with the following structural formula:

[0003]

[0004] Piperipelone is an atypical antipsychotic drug developed by Sumitomo Pharmaceutical Co., Ltd. of Japan. It was registered in Japan in February 2000, first marketed in Japan in February 2001, and officially entered clinical trials in my country in 2009. Piperipelone hydrochloride hydrate belongs to the second-generation atypical antipsychotics and is a dual antagonist of serotonin 2A receptor (5-HT2A) and dopamine D2 receptor (D2). Its core mechanism of action lies in the simultaneous antagonism of serotonin receptors and dopamine D2 receptors. This drug can also enhance dopamine release from the prefrontal cortex by stimulating some serotonin receptors, a process that helps improve cognitive function. Therefore, it is effective against behavioral abnormalities caused by dopamine and serotonin system dysregulation and can significantly alleviate both positive and negative symptoms of schizophrenia. When administered orally, it preferentially and selectively acts on relevant receptors in the central nervous system, regulating dopamine and serotonin neurotransmission and thus improving schizophrenia symptoms.

[0005] A key characteristic of piperopirone hydrochloride hydrate is its regional selectivity: it primarily acts on the mesolimbic system, with minimal effect on the basal ganglia. This selectivity allows it to exert a potent antipsychotic effect while significantly reducing the risk of extrapyramidal reactions (EPS).

[0006] Compared to traditional, typical antipsychotic drugs, piperobelone hydrochloride hydrate exhibits multiple advantages: fewer side effects, effectiveness against negative symptoms, and improvement of cognitive impairment in patients. Thanks to these advantages, it can significantly improve treatment adherence and long-term prognosis in patients with mental disorders. In the current field of psychotropic drug treatment, piperobelone hydrochloride hydrate is widely recognized as a promising atypical antipsychotic due to its broad therapeutic effects, superior safety profile, and good tolerability.

[0007] Currently, peropillone is mainly available as peropillone hydrochloride, which has shown good clinical efficacy. However, it also has limitations in its application. At normal therapeutic doses, it can cause a range of adverse reactions, such as extrapyramidal symptoms (EPS), sedation, drowsiness, and endocrine disturbances like elevated prolactin levels. To increase the availability of more salt crystal forms, optimize therapeutic efficacy, and reduce specific adverse reactions (such as the acute onset of EPS or elevated prolactin levels), it is important to regulate solubility and dissolution rate for different routes of administration. Summary of the Invention

[0008] The purpose of this invention is to address the shortcomings of existing technologies by providing a perospirone drug cocrystal and its preparation method, thereby solving the problems mentioned in the background section. This invention aims to provide a novel crystalline form of perospirone with low hygroscopicity, namely, the perospirone-salicylic acid crystal form. Furthermore, this invention provides a method for preparing the perospirone-salicylic acid crystal form, which is simple, convenient, and suitable for industrial production.

[0009] The specific technical content of this invention is as follows:

[0010] On one hand, the present invention provides a piperospirone-salicylic acid crystal form, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at at least 4.5±0.2°, 11.1±0.2°, 13.4±0.2°, 13.9±0.2°, 17.4±0.2°, and 19.6±0.2°.

[0011] Preferably, the piperopirone-salicylic acid crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 4.5±0.2°, 8.9±0.2°, 11.1±0.2°, 13.4±0.2°, 13.9±0.2°, 16.6±0.2°, 16.9±0.2°, 17.4±0.2°, 19.6±0.2°, 24.7±0.2°, 25.2±0.2°, 25.5±0.2°, and 29.0±0.2°.

[0012] Preferably, the piperopirone-salicylic acid eutectic is subjected to Cu-Kα radiation, and its characteristic peaks conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0013] Preferably, the perostelone-salicylic acid crystal form has the molecular formula C0. 31 H 40N4O6S has the following crystallographic parameters: monoclinic crystal system, space group C2 / c, cell parameters: a=41.0332(4), b=8.89500(10), c=18.0306(2), α=90°, β=98.869(4)°, γ=90°, and cell volume V=6078.86(12).

[0014] On the other hand, the present invention provides a method for preparing piperoprin-salicylic acid crystal form, comprising the following steps:

[0015] Piperidone and salicylic acid were dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand to volatilize and crystallize, and then filtered and dried to obtain the piperospirone-salicylic acid crystal form.

[0016] Preferably, the mixed solvent is selected from a mixed solvent of methanol and isopropanol, ethanol, acetonitrile, water, acetone and n-butanol, and particularly preferably a mixed solvent of methanol and isopropanol and water.

[0017] Preferably, the mass-to-volume ratio of perospirone to solvent is 42.6:2 to 4; more preferably 42.6:3, in mg / mL.

[0018] Preferably, the molar ratio of piperospirone to salicylic acid is 1:1 to 3, more preferably 1:2.

[0019] Preferably, the heating temperature is 40-60°C, more preferably 50°C.

[0020] The cooling crystallization temperature is 0–30°C, preferably 20–25°C.

[0021] The drying temperature is 45–65°C.

[0022] The raw material perospirone used in the preparation method can be prepared according to any method in the prior art or purchased from commercially available products.

[0023] Finally, the present invention provides a pharmaceutical composition comprising the piperopirone-salicylic acid crystal form described herein and other pharmaceutically feasible components.

[0024] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0025] Confirmation of crystal structure

[0026] The X-ray crystal data for the perospirolone-salicylic acid crystal form test described in this invention were collected on a Rigaku XtaLABSynergy instrument in Japan at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected in an ω-scan manner with Lp correction. The structure was analyzed using a direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained through theoretical hydrogenation. The structure was refined using the least squares method.

[0027] The crystallographic data of the crystalline form of piperopirone-salicylic acid prepared in this invention (as shown in Table 1) are as follows: monoclinic crystal system, space group C2 / c, cell parameters: a=41.0332(4), b=8.89500(10), c=18.0306(2), α=90°, β=98.869(4)°, γ=90°, cell volume V=6078.86(12).

[0028] Table 1. Main crystallographic data of piperoprin-salicylic acid crystal forms

[0029]

[0030]

[0031] The ORTEP diagram of the perospirone-salicylic acid crystal form of the present invention shows that this crystalline form contains one molecule of perospirone and one molecule of salicylic acid, as shown in the attached diagram. Figure 3 As shown. The hydrogen bond diagram of piperopirone-salicylic acid of the present invention is attached. Figure 4 As shown. Based on the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 And Table 2.

[0032] Table 2 PXRD peaks of the piperospirone-salicylic acid crystal form

[0033]

[0034] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0035] This invention provides, for the first time, a perospirone-salicylic acid crystal form, the preparation method of which is simple to operate, the crystallization process is easy to control, and has good reproducibility. The formation of a eutectic between the two significantly enhances the solubility of perospirone, demonstrating strong pharmaceutical value. Attached Figure Description

[0036] Figure 1 PXRD pattern of piperospirone-salicylic acid crystal form.

[0037] Figure 2 TGA / DSC image of the piperospirone-salicylic acid crystal form;

[0038] Figure 3 ORTEP diagram of the crystalline form of piperospirone-salicylic acid.

[0039] Figure 4 Hydrogen bond diagram of the piperospirone-salicylic acid crystal form. Detailed Implementation

[0040] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0041] Example 1

[0042] Piperidone (42.6 mg, 0.1 mol) and salicylic acid (27.6 mg, 0.2 mol) were dissolved in a mixed solvent of 1 mL methanol, 1 mL isopropanol and 1 mL water. The solution was heated and stirred in a water bath at 50 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding piperospirone-salicylic acid with a yield of 97.2% and a purity of 99.98%.

[0043] Example 2

[0044] Piperidone (42.6 mg, 0.1 mol) and salicylic acid (13.8 mg, 0.1 mol) were dissolved in a mixed solvent of 0.5 mL methanol, 0.5 mL acetonitrile, and 1 mL water. The solution was heated and stirred in a water bath at 40 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding piperospirone-salicylic acid with a yield of 94.3% and a purity of 99.72%.

[0045] Example 3

[0046] Piperidone (42.6 mg, 0.1 mol) and salicylic acid (55.2 mg, 0.4 mol) were dissolved in a mixed solvent of 1 mL methanol, 1 mL n-butanol and 2 mL water. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding piperospirone-salicylic acid with a yield of 95.6% and a purity of 99.61%.

[0047] Example 4

[0048] Piperidone (42.6 mg, 0.1 mol) and salicylic acid (11.0 mg, 0.08 mol) were dissolved in a mixed solvent of 0.5 mL methanol, 0.5 mL acetone and 0.8 mL water. The solution was heated and stirred in a water bath at 35 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding piperospirone-salicylic acid with a yield of 85.8% and a purity of 98.85%.

[0049] Example 5

[0050] Piperidone (42.6 mg, 0.1 mol) and salicylic acid (59.3 mg, 4.3 mol) were dissolved in a mixed solvent of 1.5 mL methanol, 1.5 mL isopropanol and 1.5 mL water. The solution was heated in a water bath at 65 °C and stirred until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding piperospirone-salicylic acid with a yield of 88.8% and a purity of 98.40%.

[0051] Comparative Example 1

[0052] Dissolve 57.20 g of free base of piperospirone (HPLC content 98.0%) in 215 ml of acetonitrile, add hydrochloric acid dropwise, and continue stirring until salt is fully formed. Filter and dry the filter cake in an oven to obtain crude piperospirone hydrochloride.

[0053] Add 5.90g of crude piperospirone hydrochloride to 24.8mL of 80% ethanol solution, heat to dissolve and clarify, then cool to -5℃~0℃, stir, and wait for the crystals to fully precipitate. Filter and wash with 80% ethanol; dry the filter cake at 50℃ to obtain 6.16g of piperospirone hydrochloride dihydrate crystal form B product.

[0054] Verification Experiment

[0055] 1. Stability test

[0056] The stability test conditions included: (1) High temperature: about 200 mg of the test sample was placed in a drying oven at 60℃; (2) Photodegradation: about 200 mg of the test sample was placed in an environment with an illuminance of 4500±500 lx; ​​(3) High humidity degradation: about 200 mg of the test sample was placed under high humidity (RH 75%, RH 92.5%) conditions. The stability test results are shown in Table 3.

[0057] Table 3 Stability test results

[0058] Placement conditions Placement time Example 1 Comparative Example 1 Sample before placement 99.98％ 99.94％ High temperature test 10 99.97％ 99.92％ High humidity test 10 99.96％ 99.91％ Strong light irradiation experiment 10 99.95％ 99.91％

[0059] The experimental results in Table 3 show that the purity of the piperopirone salicylic acid crystal form prepared in this invention did not change significantly under high heat, high humidity, and light conditions. In contrast, the purity of Comparative Example 1 decreased under high heat, high humidity, and light conditions. Similar experimental results were obtained in Examples 1-5.

[0060] 2. Solubility test

[0061] 10 ml of each of the following media (0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer) was measured into a vial. An excess of the sample to be tested was added, and the vial was sealed and placed in a 25°C constant temperature water bath with stirring for 30 min. The solution was filtered through an aqueous microporous membrane, and the filtrate was collected. The concentrations of piperospiron salicylic acid and piperospiron hydrochloride dihydrate in the solution were determined by high performance liquid chromatography (HPLC) to obtain the solubility. The results are shown in Table 4.

[0062] Table 4 Solubility in different media

[0063]

[0064] Solubility test results show that the solubility of the piperopirone salicylic acid prepared by this invention is significantly improved compared to the available crystal forms disclosed in the prior art. Further investigation revealed similar solubility test results for Examples 1-5.

[0065] 3. In vitro dissolution test

[0066] 1. Experimental Materials: The piperospirone salicylic acid crystal form and piperospirone hydrochloride dihydrate obtained in the examples were prepared into tablets using the same conventional wet granulation process in the art. In vitro dissolution was tested. The formulation is as follows:

[0067] Table 5 Piperipelone Prescription

[0068] Piperipelone Hydrochloride 0.1kg starch 0.2kg Hydroxypropyl methylcellulose K100 0.2kg Hydroxypropyl methylcellulose K4M 0.4kg Polyethylene glycol 6000 0.2kg microcrystalline cellulose 0.89kg magnesium stearate 0.01kg

[0069] The method for manufacturing tablets is as follows:

[0070] Disperse 0.1 kg of piperospiron hydrochloride in molten polyethylene glycol 6000 at 57°C, mix well, allow to cool, grind finely, and pass through a 100-mesh sieve. Mix with the prescribed amounts of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K100, dextrin, and CaHPO4, and moisten with 80% ethanol. Perform wet granulation, passing through an 18-mesh sieve. Dry the wet granules at 50–60°C for 4 hours, then extrude and sieve through a 30–40-mesh sieve to prepare granules. Add the prescribed amount of magnesium stearate, mix well, and compress into tablets at a pressure of 4–6 kg. Based on a dosage of 10,000 tablets, the sustained-release formulation is 10 mg / tablet, with the active ingredient being 2.5 times that of ordinary tablets, and a sustained release time of 12 hours.

[0071] Dissolution conditions: The dissolution was performed according to the second method (paddle method) of Dissolution and Release Determination, Part IV, General Chapter 4, 0931, of the Chinese Pharmacopoeia 2020. A pH 6.8 phosphate buffer solution was selected as the dissolution medium, with a volume of 1000 mL and a rotation speed of 50 rpm. Dissolution was measured at 5, 10, 15, 30, 45, and 60 min. Accelerated dissolution conditions were: temperature 40℃ ± 2℃ and relative humidity 75% ± 5%.

[0072] Table 6 Dissolution rates of tablets from each example

[0073]

[0074] The novel crystalline form of piperopirone presented in this application exhibits excellent solubility and in vitro dissolution, providing a new option for the development of piperopirone formulations.

[0075] In summary, the piperospirone-salicylic acid crystal form prepared by this invention has better solubility, stability, and dissolution rate, making it better suited for piperospirone formulations.

Claims

1. A novel crystalline form of piperospirone, characterized in that, The molar ratio of piperospirone to salicylic acid in the crystal unit structure is 1:

1.

2. The new crystalline form of piperopirone according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in terms of angle, has characteristic diffraction peaks at 0.5±0.2°, 11.1±0.2°, 13.4±0.2°, 13.9±0.2°, 17.4±0.2°, and 19.6±0.2°.

3. The new crystalline form of piperopirone according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in angles, shows diffraction peaks at 4.5±0.2°, 8.9±0.2°, 11.1±0.2°, 13.4±0.2°, 13.9±0.2°, 16.6±0.2°, 16.9±0.2°, 17.4±0.2°, 19.6±0.2°, 24.7±0.2°, 25.2±0.2°, 25.5±0.2°, and 29.0±0.2°.

4. The new crystalline form of piperopirone according to claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

5. The new crystalline form of piperopirone according to claim 1, characterized in that, Its crystallographic parameters are: monoclinic crystal system, space group C2 / c, cell parameters are: a=41.0332(4), b=8.89500(10), c=18.0306(2), α=90°, β=98.869(4)°, γ=90°, and cell volume V=6078.86(12).

6. A method for preparing a new crystalline form of piperospirone according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: dissolving piperospiron and salicylic acid in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand to volatilize and crystallize, filtering and drying to obtain the piperospiron-salicylic acid crystal form.

7. The method according to claim 6, characterized in that, The mixed solvent is selected from a mixture of methanol and isopropanol, ethanol, acetonitrile, water, acetone and n-butanol.

8. The method according to claim 6, characterized in that, The mass-to-volume ratio of perospirone to solvent is 42.6:2 to 4; preferably 42.6:3, in mg / mL.

9. The method according to claim 6, characterized in that, The molar ratio of perospirone to salicylic acid is 1:1 to 3.

10. The method according to claim 6, characterized in that, The heating temperature is 40–60°C; the cooling and crystallization temperature is 0–30°C.

Images