A method for preparing the nonhydrated crystal form of ripocidil monosuccinate

Abstract

This invention relates to a method for preparing the nonhydrated crystalline form of reboxil monosuccinate. The method includes adding reboxil and succinic acid simultaneously or separately to two mixed solvents in an alcohol / alcohol or alcohol / alkane mixture, stirring to induce crystallization, filtering, and drying. The method of this invention features mild reaction conditions, convenient operation, low energy consumption, and is suitable for large-scale production. The nonhydrated reboxil monosuccinate obtained by the method of this invention has a uniform particle size and concentrated particle distribution, which helps to ensure the uniformity of formulation content and the stability of dissolution behavior, thereby ensuring drug quality.

Description

Technical Field

[0001] This invention relates to a method for preparing the nonhydrated crystal form of ribocidolitin monosuccinate. Background Technology

[0002] Reboxil succinate is a CDK4 / 6 inhibitor for breast cancer treatment developed by Novartis. Reboxil succinate, in combination with an aromatase inhibitor, is used as initial treatment for premenopausal or perimenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. When using endocrine therapy, it should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist. Reboxil succinate tablets were launched in the United States on March 13, 2017, under the brand name Kisqali; and in China on January 19, 2023, under the brand name Kelilong.

[0003] Reboxil succinate is a salt composed of the free base reboxil and succinic acid. Its chemical structural formula is as follows:

[0004] The original patent CN105384741B by Novartis, a Swiss company, discloses an hydrated and a hydrated form of reboxil monosuccinate. The hydrated form has a solubility of 30 mg / ml in water, while the hydrated form has a solubility of less than 0.5 mg / ml. The marketed drug, reboxil succinate tablets, uses the hydrated form.

[0005] The crystal form preparation process disclosed in patent CN105384741B has the following risks or problems: 1) The non-hydrate crystal form preparation method described in the patent is carried out under harsh conditions in an isopropanol solution at 80±3℃, which increases the risk of amidation and esterification byproducts; 2) The patent describes adding seed crystals under strict control of suitable temperature, appropriate time and a certain amount of succinic acid in the process. This method is relatively complex to operate and has low controllability. Other crystal forms may be generated during the crystallization process, which may affect the purity of the product crystal form; 3) The patent describes the use of a large amount of solvent in the preparation process and the additional use of seed crystals. In addition, the preparation process requires high temperature control and has high energy consumption. Therefore, the material cost and production cost of the process described in the patent are high.

[0006] To overcome the shortcomings of existing technologies, this invention provides a method for preparing the non-hydrated crystalline form of ribocidil monosuccinate. This method involves one-step crystallization, is simple to operate, operates under mild conditions, has low production costs, and possesses high economic value. Summary of the Invention

[0007] This invention provides a method for preparing the nonhydrated crystal form of ribocidolitin monosuccinate, thereby overcoming the shortcomings of the prior art.

[0008] According to the purpose of this invention, the present invention provides a method for preparing the crystal form, the method comprising: adding ribocidil and succinic acid separately or simultaneously to two mixed solvents in an alcohol / alcohol or alcohol / alkane mixture, stirring to induce crystallization, filtering and separating, and vacuum drying the wet product to obtain the nonhydrated crystal form of ribocidil monosuccinate.

[0009] in: Preferably, the amount of the mixed solvent is 35 v / w to 55 v / w.

[0010] Furthermore, the amount of the mixed solvent used is 40 v / w to 45 v / w.

[0011] The solvent ratio and amount affect crystal purity and production cost.

[0012] Preferably, the alcohol solvents include, but are not limited to, ethanol, isopropanol, n-butanol, etc., and the alkane solvents include, but are not limited to, n-hexane, n-heptane, etc.

[0013] Furthermore, the mixed solvent is preferably selected from ethanol and n-butanol, ethanol and isopropanol, or ethanol and n-hexane.

[0014] Preferably, the molar ratio of reboxil and succinic acid is 1:1.05 to 1:2.2.

[0015] Furthermore, the molar ratio of reboxil and succinic acid is 1:1.1 to 1:1.5.

[0016] Insufficient succinic acid can easily lead to the formation of a mixture of ribocic acid hemisuccinate and monosuccinate; excessive succinic acid can result in succinic acid residue, affecting product quality.

[0017] Preferably, the crystallization temperature range is 10℃~60℃.

[0018] Furthermore, the crystallization temperature range is 20~40℃.

[0019] Furthermore, the crystallization temperature range is 20~30℃.

[0020] If the crystallization temperature is too high, impurities are easily generated and the yield is low; if the crystallization temperature is too low, impurities in the product are difficult to remove.

[0021] Preferably, the volume ratio of the two mixed solvents in the mixed solvent is 1:1 to 1:2.75.

[0022] Furthermore, the ratio of the mixed solvent is from 1:1 to 1:1.8.

[0023] Preferably, the crystallization time is 1 to 16 hours.

[0024] Furthermore, the crystallization time is 1 to 3 hours.

[0025] Compared with existing technologies, the advantages of the method for preparing the nonhydrated crystal form of ripocidil monosuccinate described in this invention are as follows: (1) Simplified process and convenient operation: The process does not require the addition of seed crystals, and the target crystal form can be prepared by conventional operations such as stirring, dissolving, crystallizing, filtering and drying, which greatly reduces the complexity of the process and the difficulty of operation.

[0026] (2) Significantly low production cost: The entire process is carried out at room temperature, which reduces production energy consumption; no seed crystals are used in the process, which reduces material costs; the total amount of solvent used is reduced from 44v / w in the original patent to 40v / w, which reduces solvent costs.

[0027] (3) Reduced risk of impurities: The process is mild throughout, making it less likely to produce amides or esters, thus reducing the risk of product non-compliance.

[0028] (4) Uniform and controllable particle size of the product: The uniformity of the particle size of the active pharmaceutical ingredient has a significant impact on the quality of the drug. The reboxil succinate nonhydrate obtained by the process described in this invention does not require pulverization, and has D90=13.255μm, D50=5.647μm, D10=3.063μm, and a particle size distribution width (SPAN) of 1.80. This indicates that the product obtained by the preparation method of this invention has uniform particle size and concentrated particle distribution, which helps to ensure the uniformity of the formulation content, the stability of dissolution behavior, and promotes the improvement of drug quality consistency and efficacy reliability. In contrast, the reboxil succinate nonhydrate prepared according to the original patent CN105384741B has D90=75.941μm, D50=8.397μm, D10=3.771μm, and a particle size distribution width (SPAN) of 8.59, indicating that the product has poor particle size uniformity.

[0029] This invention simplifies the process and reduces costs while effectively improving the key quality attributes of the product, thereby enhancing the safety and market competitiveness of the drug. Attached Figure Description

[0030] Figure 1 The image shows the X-ray powder diffraction pattern of the ripocidole monosuccinic acid crystal form prepared according to the method in Example 1 of this invention.

[0031] Figure 2 The image shows the TGA pattern of the ripocidole monosuccinic acid crystal form obtained according to the method in Example 1 of this invention.

[0032] Figure 3The image shows the DSC diagram of the ripocidole monosuccinic acid crystal form obtained according to the method in Example 1 of this invention.

[0033] Figure 4 The particle size distribution diagram is shown for the ripocidole monosuccinic acid crystal form prepared according to the method in Example 1 of this invention.

[0034] Figure 5 This is a particle size distribution diagram of the ripocitrate monosuccinic acid crystal form obtained according to the original patented method.

[0035] Figure 6 The image shows the liquid chromatography detection spectrum of ripocidole monosuccinic acid prepared according to the method in Example 1 of this invention. Detailed Implementation

[0036] Example

[0037] In a reaction flask, add 0.6 g of succinic acid, 20 ml of anhydrous ethanol, and 20 ml of n-hexane. Stir until the succinic acid is completely dissolved and set aside. In another reaction flask, add 2.0 g of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dicarboxamide (reboxil), 20 ml of anhydrous ethanol, and 20 ml of n-hexane. Stir until homogeneous, then add the prepared succinic acid solution dropwise. After the addition is complete, maintain the temperature at 20-30°C and stir for 1 hour. Filter and vacuum dry to obtain the non-hydrated crystal form of reboxil monosuccinate, with a yield of 90.1% and a purity of 99.93%. Example

[0038] In a reaction flask, 0.6 g of succinic acid, 20 ml of anhydrous ethanol, and 22.5 ml of n-hexane were added and stirred until the succinic acid was completely dissolved. In another reaction flask, 2.0 g of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dicarboxamide (reboxil), 20 ml of anhydrous ethanol, and 22.5 ml of n-hexane were added and stirred until homogeneous. The prepared succinic acid solution was then added dropwise. After the addition was complete, the mixture was kept at 20-30°C and stirred for 3 hours. The mixture was then filtered and dried under vacuum to obtain the ahydrated crystalline form of reboxil monosuccinate, with a yield of 87.6% and a purity of 99.86%. Example

[0039] In a reaction flask, 0.8 g of succinic acid, 20 ml of anhydrous ethanol, and 20 ml of n-hexane were added and stirred until the succinic acid was completely dissolved. In another reaction flask, 2.0 g of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dicarboxamide (reboxil), 20 ml of anhydrous ethanol, and 20 ml of n-heptane were added and stirred until homogeneous. The prepared succinic acid solution was then added dropwise. After the addition was complete, the mixture was kept at 40-50 °C and stirred for 3 hours. The mixture was then filtered and dried under vacuum to obtain the non-hydrated crystalline form of reboxil monosuccinate, with a yield of 88.2% and a purity of 99.80%. Example

[0040] 1.0 g of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dicarboxamide (reboxil), 0.38 g of succinic acid, 20 ml of anhydrous ethanol and 20 ml of n-butanol were added to the reaction flask. The mixture was kept at 20-30 °C and stirred for 1 h. After filtration and vacuum drying, the nonhydrated crystal form of reboxil monosuccinate was obtained with a yield of 83.5% and a purity of 99.76%. Example

[0041] 1.0 g of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dicarboxamide (reboxil), 0.38 g of succinic acid, 20 ml of anhydrous ethanol and 20 ml of isopropanol were added to the reaction flask. The mixture was kept at 30-40 °C and stirred for 3 h. After filtration and vacuum drying, the nonhydrated crystal form of reboxil monosuccinate was obtained with a yield of 88.7% and a purity of 99.88%.

Claims

1. A method for preparing the nonhydrated crystal form of ripocylin monosuccinate, characterized in that, Ripocidide and succinic acid are added separately or simultaneously to two mixed solvents, stirred to crystallize, filtered, and vacuum dried to obtain the nonhydrated crystal form of ripocidide monosuccinate. The two mixed solvents are selected from different alcohols or alcohols and alkanes, and the amount of the mixed solvent is 35 v / w to 55 v / w.

2. The method according to claim 1, characterized in that, The two mixed solvents are selected from ethanol and n-butanol, ethanol and isopropanol, and ethanol and n-hexane.

3. The method according to claim 2, characterized in that, The molar ratio of ribocidil to succinic acid is 1:1.05 to 1:2.

2.

4. The method according to claim 3, characterized in that, The crystallization temperature range is 10℃~60℃, preferably 20~40℃, and more preferably 20~30℃.

5. The method according to claim 4, characterized in that, The ratio of the two mixed solvents is from 1:1 to 1:2.

75.

6. The method according to claim 5, characterized in that, The solvent usage is 40 v / w to 45 v / w.

7. The method according to claim 6, characterized in that, The crystallization time is 1 to 16 hours.

8. The method according to any one of claims 2-7, characterized in that, The molar ratio of ribocidil to succinic acid is 1:1.1 to 1:1.5; the crystallization temperature range is 20℃ to 30℃; the ratio of the mixed solvent is 1:1 to 1:1.8; the solvent dosage is 40v / w to 45v / w; and the crystallization time is 1 to 3 hours.

9. The method according to claim 8, characterized in that, Succinic acid was added to anhydrous ethanol and n-hexane and stirred until completely dissolved. The solution was then set aside. Ripocidide was added to anhydrous ethanol and n-hexane and stirred until homogeneous. The prepared succinic acid solution was then added dropwise. After the addition was complete, the solution was kept at 20-30℃ and stirred for 1-3 hours. The solution was then filtered and dried under vacuum to obtain the nonhydrated form of ripocidide monosuccinate.

10. The method according to claim 8, characterized in that, Succinic acid and reboxil are added to anhydrous ethanol and n-butanol or anhydrous ethanol and isopropanol, stirred until completely dissolved, kept at 20-30℃ and stirred for 1-3 hours, filtered, and vacuum dried to obtain the nonhydrated crystal form of reboxil monosuccinate.

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