WO2024040668A1 - Palbociclib saccharinate crystal form and preparation method therefor - Google Patents

Abstract

A Palbociclib saccharinate crystal form and a preparation method therefor. A prepared Palbociclib saccharinate crystal form α has excellent physical and chemical stability, high solubility, and good dissolution, fluidity and bioavailability. The Palbociclib saccharinate crystal form α has mild preparation conditions, simple operations, good process reproducibility, and high purity, so as to achieve controllable industrial production conditions, thereby facilitating large-scale industrialization.

Description

A kind of palbociclib saccharin salt crystal form and preparation method thereof Technical field

The present application belongs to the field of pharmaceutical crystal forms, and specifically relates to a palbociclib saccharin salt crystal form and a preparation method thereof.

Background technique

Palbociclib is the first selective cyclin-dependent kinase inhibitor (CDK) 4/6 inhibitor in China developed by Pfizer. It was approved by the US FDA on February 3, 2015 and launched in July 2018. On the 31st, it was approved by China’s National Medical Products Administration (NMPA) and became the first CDK4/6 inhibitor marketed in China for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative localized tumors. For advanced or metastatic breast cancer, it can be used in combination with aromatase inhibitors as initial endocrine therapy in postmenopausal women. The chemical structural formula of palbociclib is shown below:

Palbociclib free base has poor water solubility (9 μg/mL) and low bioavailability, so its salt form needs to be studied. Chinese patent CN200480023494.X reports various salt forms of palbociclib, including isethionate, monohydrochloride, dihydrochloride and monomethanesulfonate. According to the patent report, palbociclib monohydrochloride has poor crystallinity and may pose potential risks in industrial production; palbociclib dihydrochloride and monomethanesulfonate are highly hygroscopic and are not suitable for For solid drug development; isethionate has lower hygroscopicity and greater water solubility, making it the most suitable solid form for development. Pfizer used isethionate in clinical phase I/II trials for development. However, in clinical phase II, it was found that the isethionate API is sticky and has poor powder flowability, making it difficult to prepare capsules with uniform content. Complying with the standards, when filling large-scale commercial batches of capsules, there will be problems with poor fluidity and difficulty in automatically filling capsules. Therefore, Pfizer gave up the commercial development of isethionate and used the free base crystal form A in late-stage clinical trials. Since the extremely poor water solubility of the free base limits its bioavailability, there is a need to develop a salt form that is highly bioavailable and suitable for commercial production.

Contents of the invention

The present application aims to provide a palbociclib saccharin salt crystal form α and a preparation method thereof. The palbociclib saccharin salt crystal form α has good crystal form stability and chemical stability. Unexpectedly, the saccharin salt It also has lower hygroscopicity, higher fluidity and bioavailability, overcomes the shortcomings of palbociclib free base and existing salt forms, and can be better used in preparation production.

The present application provides a palbociclib saccharin salt crystal form α, in which the molar ratio of palbociclib and saccharin is 1:1, and the structure is shown in formula (I).

Further, the palbociclib saccharin salt crystal form α described in this application has an X-ray powder diffraction pattern at 2θ angle of 8.55±0.2°, 10.63±0.2°, 11.59±0.2°, 14.63±0.2°, and 16.02± There are characteristic peaks at 0.2°, 21.10±0.2°, 22.97±0.2° and 24.45±0.2°.

Further, the X-ray powder diffraction pattern of the palbociclib saccharin salt crystal form α at the 2θ angle is 5.24±0.2°, 8.55±0.2°, 10.63±0.2°, 11.59±0.2°, 13.44±0.2°, 14.63 ±0.2°, 16.02±0.2°, 16.72±0.2°, 19.48±0.2°, 19.89±0.2°, 21.10±0.2°, 22.21±0.2°, 22.97±0.2°, 24.45±0.2° and 26.40±0.2°. Characteristic peaks.

Furthermore, the X-ray powder diffraction pattern of the palbociclib saccharin salt crystal form α at the 2θ angle is 5.24±0.2°, 8.55±0.2°, 10.63±0.2°, 11.59±0.2°, 13.44±0.2°, 14.63±0.2°, 16.02±0.2°, 16.72±0.2°, 19.48±0.2°, 19.89±0.2°, 21.10±0.2°, 22.21±0.2°, 22.97±0.2°, 24.45±0.2° and 26.40±0.2° There are characteristic diffraction peaks.

Furthermore, the X-ray powder diffraction pattern of the palbociclib saccharin salt crystal form α is basically as shown in Figure 1.

Furthermore, the thermogravimetric analysis chart of palbociclib saccharin salt crystal form α is basically as shown in Figure 2, and its weight loss in the range of 30°C-105°C is 0.87%.

Furthermore, the single crystal structure of the palbociclib saccharin salt crystal form α is shown in Figure 3.

This application also relates to a method for preparing palbociclib saccharin salt crystal form α, specifically: dissolving saccharin in an alcohol solvent, adding palbociclib, stirring, filtering, and drying to obtain palbociclib saccharin salt crystal form α .

Further, the alcohol solvent is selected from methanol, ethanol or isopropanol, preferably ethanol; the molar ratio of palbociclib and saccharin is 1: (0.9-1.1), preferably 1:1.

Furthermore, the preparation method specifically includes: dissolving saccharin in ethanol, adding palbociclib, fully stirring at 40° C. for 3-24 hours, filtering, and drying to obtain palbociclib saccharin salt crystal form α.

In the preparation method of palbociclib saccharin salt described in the present application, the palbociclib added is palbociclib free base crystal form A.

The present application also relates to the use of the palbociclib saccharin salt in the preparation of CDK4/6 inhibitors for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.

The beneficial effects brought by this application include:

1. The palbociclib saccharin salt crystal form α prepared by this application has excellent physical stability and chemical stability.

2. Compared with palbociclib free base, the saccharin salt crystal form α prepared in this application has higher solubility, and pharmaceutical preparations prepared with saccharin salt crystal form α have better dissolution and bioavailability.

3. Compared with palbociclib free base and isethionate, the saccharin salt crystal form α of the present application has better dispersion and fluidity, and is less prone to adhesion and agglomeration during automatic filling of capsules. The capsules have better content uniformity and are more conducive to large-scale commercial production.

4. Compared with palbociclib hydrochloride and mesylate, the saccharin salt crystal form α of the present application has lower hygroscopicity and is more conducive to the production and storage of raw materials and preparations.

5. The preparation conditions of palbociclib saccharin salt crystal form α of the present application are mild, simple to operate, good process reproducibility, and high purity, making industrial production conditions controllable and conducive to large-scale industrialization.

Description of drawings

Figure 1 is the XRD pattern of palbociclib saccharin salt crystal form α obtained in Example 1.

Figure 2 is a TGA spectrum of palbociclib saccharin salt crystal form α obtained in Example 1.

Figure 3 is a single crystal structure diagram of palbociclib saccharin salt crystal form α obtained in Example 1.

Figure 4 shows the XRD comparison patterns of palbociclib saccharin salt crystal form α before and after accelerated stability.

Figure 5 is the XRD pattern of palbociclib monoisethionate.

Figure 6 is the XRD pattern of palbociclib monohydrochloride.

Figure 7 is the XRD pattern of palbociclib dihydrochloride.

Figure 8 is the XRD pattern of palbociclib monomethanesulfonate.

Figure 9 is the XRD pattern of palbociclib monobenzenesulfonate.

Figure 10 is the XRD pattern of palbociclib diphenylsulfonate.

Figure 11 is the XRD pattern of palbociclib mono-p-toluenesulfonate.

Figure 12 is the DVS curve of palbociclib free base crystal form A.

Figure 13 is the DVS curve of palbociclib saccharin salt crystal form α.

Figure 14 is the DVS curve of palbociclib monoisethionate.

Figure 15 is the DVS curve of palbociclib monohydrochloride.

Figure 16 is the DVS curve of palbociclib dihydrochloride.

Figure 17 is the DVS curve of palbociclib monomethanesulfonate.

Figure 18 is the DVS curve of palbociclib monobenzene sulfonate.

Figure 19 is the DVS curve of palbociclib diphenylsulfonate.

Figure 20 is the DVS curve of palbociclib mono-p-toluenesulfonate.

Detailed ways

The present application will be described in further detail below with reference to the examples, but this application is not limited. Any equivalent substitutions in the field made based on the disclosure of this application shall fall within the protection scope of this application.

The abbreviations used in this application are explained as follows:

XRD: X-ray powder diffraction

The X-ray powder diffraction (XRD) test described in this application is collected using a Malvern-PANalytical Empyrea powder diffractometer. The specific parameters are as follows:

TGA: Thermogravimetric Analyzer

The measurement of thermogravimetric analysis (TGA) described in this application was collected using METTLER TOLEDO model TGA-2. The heating rate was 10°C/min, the temperature range was 30-300°C, and the nitrogen purge rate during the test was 20mL. /min.

X-ray single crystal diffractometer

The single crystal diffraction data described in this application were collected using Rigaku XtaL AB-PRO single crystal X-ray diffractometer. The specific parameters are as follows:

Room temperature: 15~30℃.

Example 1: Preparation of palbociclib saccharin salt crystal form α

Dissolve 4.0g saccharin in 500mL ethanol at 40°C, add 10.0g palbociclib crystal form A (outsourced from Shandong Xuanhong Biomedicine), then continue stirring at 40°C for 3 hours, filter and dry to obtain 14.1 g yellow powdery solid.

This crystal form was named Form α.

The obtained sample was subjected to X-ray powder measurement using Cu-ka rays, and its pattern has the diffraction angle, interplanar spacing and relative intensity shown in Table 1:

Table 1 Diffraction angle, interplanar spacing and relative intensity of palbociclib saccharin salt crystal form α

The error of 2θ diffraction angle is ±0.20°.

Furthermore, the palbociclib saccharin salt crystal form α prepared in Example 1 has an X-ray powder diffraction pattern basically as shown in Figure 1 .

The thermogravimetric analysis (TGA) of the palbociclib saccharin salt crystal form α is shown in Figure 2, and its weight loss in the range of 30°C-105°C is 0.87%.

The single crystal structure of the palbociclib saccharin salt crystal form α is shown in Figure 3.

Example 2: Preparation of palbociclib saccharin salt crystal form α

Dissolve 16.3g saccharin in 2L ethanol at 40°C, add 40.0g palbociclib crystal form A (outsourced from Shandong Xuanhong Biomedicine), then continue stirring at 40°C for 12h, filter and dry to obtain 55.4 g yellow powdery solid. Its powder diffraction pattern and thermogravimetric analysis pattern are basically consistent with Example 1.

Example 3: Preparation of palbociclib saccharin salt crystal form α

Dissolve 32.7g saccharin in 4L ethanol at 40°C, add 80.0g palbociclib crystal form A (outsourced from Shandong Xuanhong Biomedicine), then continue stirring at 40°C for 24h, filter and dry to obtain 110.9 g yellow powdery solid. Its powder diffraction pattern and thermogravimetric analysis pattern are basically consistent with Example 1.

Example 4: Preparation of palbociclib saccharin salt form α single crystal

At 40°C, 30 mg of the saccharin salt crystal form α obtained in Example 1 was dissolved in a mixed solvent of 8 mL of isopropyl alcohol and 2 mL of methanol, and left to evaporate at 40°C to obtain a rhombus-shaped large particle single crystal sample. Its thermogravimetric analysis pattern and powder diffraction data are basically consistent with Example 1. Single crystal analysis was performed on this sample. Its unit cell parameters are shown in Table 2, and its single crystal structure is shown in Figure 3.

Table 2 Unit cell parameters of palbociclib saccharin salt crystal form α

Comparative Example 1: Preparation of palbociclib monoisethionate

At room temperature, 1.0g palbociclib (purchased from Shandong Xuanhong Biomedicine) and 0.28g isethionic acid (1eq) were added to 20 mL methanol, stirred at room temperature for 7 hours, filtered, and dried to obtain palbociclib. The powder diffraction pattern of Cilimon isethionate is shown in Figure 5.

Comparative Example 2: Preparation of palbociclib monohydrochloride

At room temperature, add 1.0g palbociclib (purchased from Shandong Xuanhong Biopharmaceutical) into 15mL acetone, slowly add 1.12mL HCL/EA solution (2mol/L) dropwise, stir at room temperature for 6h, and filter. After drying, palbociclib monohydrochloride is obtained, and its powder diffraction pattern is shown in Figure 6.

Comparative Example 3: Preparation of palbociclib dihydrochloride

At room temperature, add 1.0g palbociclib (outsourced from Shandong Xuanhong Biopharmaceutical) to 35 mL acetone, slowly add 2.24 mL HCL/EA solution (2 mol/L) dropwise, stir at room temperature for 6 hours, and filter. After drying, palbociclib dihydrochloride is obtained, and its powder diffraction pattern is shown in Figure 7.

Comparative Example 4: Preparation of palbociclib monomethanesulfonate

At room temperature, 1.0g palbociclib (purchased from Shandong Xuanhong Biopharmaceutical) was added to 20 mL acetone, 0.21g methanesulfonic acid (1eq) was slowly added dropwise, stirred at room temperature for 6 hours, filtered, and dried to obtain palbociclib. The powder diffraction pattern of bociclib monomethane sulfonate is shown in Figure 8.

Comparative Example 5: Preparation of palbociclib monobenzene sulfonate

At room temperature, add 1.0g palbociclib (outsourced from Shandong Xuanhong Biopharmaceutical) to 15mL methanol, dissolve 0.35g benzenesulfonic acid (1eq) in 2mL methanol, and slowly add palbociclib methanol dropwise The solution was then stirred at room temperature for 6 hours, filtered, and dried to obtain palbociclib monobenzenesulfonate, whose powder diffraction pattern is shown in Figure 9.

Comparative Example 6: Preparation of palbociclib diphenylsulfonate

At room temperature, add 1.0g palbociclib (outsourced from Shandong Xuanhong Biopharmaceutical) to 45mL methanol, dissolve 0.70g benzenesulfonic acid (2eq) in 2mL methanol, and slowly add palbociclib methanol dropwise solution, then stirred at room temperature for 6 hours, filtered, and dried to obtain palbociclib diphenylsulfonate, whose powder diffraction pattern is shown in Figure 10.

Comparative Example 7: Preparation of palbociclib mono-p-toluenesulfonate

At room temperature, add 1.0g palbociclib (outsourced from Shandong Xuanhong Biopharmaceutical) to 20 mL acetonitrile, dissolve 0.43g p-toluenesulfonic acid (1eq) in 2 mL acetonitrile, and slowly add it dropwise to the solution of palbociclib. in acetonitrile solution, then stirred at room temperature for 6 hours, filtered, and dried to obtain palbociclib mono-p-toluenesulfonate, whose powder diffraction pattern is shown in Figure 11.

Test Example 1: Accelerated Stability Investigation

In order to examine the stability of palbociclib saccharin salt crystal form α prepared in this application, the crystal form α samples prepared in Example 1 were placed under two accelerated test conditions of 25°C, 60% RH and 40°C, 75% RH. For 3 months, samples were taken in January, February, and March to test XRD and HPLC, and compared with the results on day 0. The results are shown in Table 3 and Figure 4:

Table 3 Accelerated stability test data of saccharin salt crystal form α

It can be seen from Table 3 and Figure 4 that palbociclib saccharin salt crystal form α has good physical and chemical stability under accelerated test conditions.

Test Example 2: Investigation of Hygroscopicity

In order to examine the hygroscopicity of palbociclib free base, saccharin salt crystal form α, isethionate, hydrochloride, methanesulfonate, benzenesulfonate and p-toluenesulfonate, the purchased free base was separately Alkali crystal form A, saccharin salt crystal form α prepared in Example 1, monoisethionate prepared in Comparative Example 1, monohydrochloride prepared in Comparative Example 2, dihydrochloride prepared in Comparative Example 3, The monomethanesulfonate prepared in Example 4, the monobenzenesulfonate prepared in Comparative Example 5, the diphenylsulfonate prepared in Comparative Example 6 and the mono-p-toluenesulfonate prepared in Comparative Example 7 were placed in a dynamic moisture adsorption instrument. , examine the weight change of the sample in the humidity range of 0-98%-0. The hygroscopicity results of palbociclib free base and different salt forms at 80% to 98% humidity are shown in Table 4, and the corresponding DVS curve is shown in Figure 12-21:

Table 4 Hygroscopicity of palbociclib free base and different salt forms at 80% RH to 98% RH

It can be seen from Table 4 and Figure 12-21 that palbociclib saccharin salt crystal form α and free base crystal form A have extremely low hygroscopicity, while hydrochloride, methanesulfonate, benzenesulfonate, etc. Different degrees of hygroscopicity.

Test Example 3: Investigation of powder fluidity

In order to examine the powder properties of palbociclib free base, saccharin salt crystal form α and isethionate, the purchased free base crystal form A, the saccharin salt crystal form α prepared in Example 3 and the comparative example were respectively 1. The prepared monoisethionate is placed in a comprehensive powder tester to test its angle of repose and bulk density. The results are shown in Table 5:

Table 5 Comparison of powder properties of palbociclib free base crystal form A, monoisethionate salt and saccharin salt crystal form α

Sample type	Angle of repose/°	Collapse angle/°	Bulk density/g·cm -3	Tap density/g·cm -3	Compression
Free base crystal form A	44.26	39.77	0.32	0.60	47.00%
isethionate	66.52	63.35	0.26	0.67	61.00%
Saccharin salt crystal form α	34.55	26.81	0.28	0.47	40.00%

As can be seen from Table 5, compared with the free base and isethionate, the saccharin salt crystal form α has a smaller angle of repose, indicating that it has better fluidity and will avoid adhesion and agglomeration during automatic filling of capsules. The possibility is lower, and the content uniformity of capsules is high, which is more conducive to large-scale commercial production.

Test Example 4: Investigation of Equilibrium Solubility

In order to examine the solubility of palbociclib saccharin salt crystal form α and free base crystal form A prepared in this application in different media, excess saccharin salt crystal form α and free base crystal form A were dissolved in different pH solutions at 37°C. In the aqueous solution, take the supernatant at 0.5h, 2h, 4h, 6h, 18h and 24h to test its concentration. The results are shown in Tables 6 and 7:

Table 6 Equilibrium solubility of saccharin salt crystal form α in different media

Note: n.d represents main peak overload.

Table 7 Equilibrium solubility of free base crystal form A in different media

Note: n.d represents main peak overload.

It can be seen from Table 6 and Table 7 that in pure water and a medium of pH 6.8, the solubility of palbociclib saccharin salt crystal form α is much higher than that of the free base crystal form A; in a medium of pH 1.0, the solubility of palbociclib saccharin salt crystal form α The solubility of the crystalline form α of the celery saccharin salt is comparable to the solubility of the free base crystalline form A.

Test Example 5: Dissolution Investigation

In order to examine the dissolution rates of palbociclib saccharin salt crystal form α and free base crystal form A prepared in this application in different media, the saccharin salt crystal form α prepared in Example 2 and the purchased free base crystal form A were respectively prepared into The dissolution rates of three sizes of capsules, 75 mg, 100 mg and 125 mg, in pH 1.0 and pH 6.8 media were investigated. The results are shown in Tables 8 and 9:

Table 8 Dissolution results in pH1.0 medium

Table 9 Dissolution results in pH6.8 medium

It can be seen from Table 8 and Table 9 that in the medium of pH 1.0, the dissolution rates of capsules of different specifications prepared by the palbociclib saccharin salt crystal form α are similar to those of the free base crystal form A; in the medium of pH 6.8, The dissolution rates of capsules of different specifications prepared from palbociclib saccharin salt crystal form α are significantly higher than those of the free base crystal form A.

Test Example 6: Investigation of bioavailability in beagle dogs

(1) Test purpose

The concentration levels and pharmacokinetic characteristics of the API in the plasma of beagle dogs after a single oral administration of different specifications of capsules prepared from saccharin salt crystal form α and free base crystal form A at the same dosage were investigated.

(2)Materials and methods

①Tested drug

75 mg capsule prepared from palbociclib saccharin salt crystalline form α;

125 mg capsule prepared from palbociclib saccharin salt crystalline form α;

75 mg capsule prepared from palbociclib free base crystal form A;

125 mg capsule prepared from palbociclib free base crystal form A;

②Experimental animals

4 beagles.

③Test method

Take palbociclib capsules and give them orally to beagle dogs, and take 0.1 mL of blood from the jugular vein before and 15 minutes, 30 minutes, 1 hour, 2 hours, -4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 30 hours, and 48 hours after administration. In an EDTA-K2 tube, centrifuge at 3000r/min for 10min to separate the plasma and store it in a -80°C refrigerator.

④LC/MS/MS biological sample analysis:

Take 50 μL of plasma and mix with 5 mL of working solution or blank diluent, add 150 μL of acetonitrile precipitant containing internal standard, vortex for 2 min, centrifuge at 12000 r/min for 10 min, take 20 μL of supernatant and 200 μL of acetonitrile aqueous solution (acetonitrile: water = 1:1 ) After mixing, inject 5 μL volume for analysis.

⑤Test results:

The main pharmacokinetic parameters in the plasma of beagle dogs after a single oral administration of palbociclib capsules of different specifications are shown in Table 10:

Table 10 Main pharmacokinetic parameters in plasma after single oral administration of different capsules in beagle dogs

As can be seen from Table 10, among the 75 mg and 125 mg capsules, the maximum blood concentration in beagle dogs that were orally administered saccharin salt capsules was significantly higher than that of free base capsules; the above experimental results show that saccharin salt has better bioavailability .

It is obvious to those of ordinary skill in the art that various modifications and changes can be made to the compounds of the present application and their preparation methods without departing from the spirit or scope of the present application. Therefore, the protection scope of the present application covers Various modifications and changes can be made to the present application as long as the modifications or changes are within the scope covered by the claims and equivalent embodiments thereof.

Claims (10)

1. A palbociclib saccharin salt crystal form α having the structure of formula (I), characterized in that the molar ratio of palbociclib and saccharin in the crystal form α is 1:1.

   
2. The palbociclib saccharin salt crystal form α according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal form α is 8.55±0.2°, 10.63±0.2°, and 11.59±0.2° at 2θ angle. There are characteristic peaks at , 14.63±0.2°, 16.02±0.2°, 21.10±0.2°, 22.97±0.2° and 24.45±0.2°.
3. The palbociclib saccharin salt crystal form α according to claim 2, characterized in that the X-ray powder diffraction pattern of the crystal form α is 5.24±0.2°, 8.55±0.2°, and 10.63±0.2° at the 2θ angle. , 11.59±0.2°, 13.44±0.2°, 14.63±0.2°, 16.02±0.2°, 16.72±0.2°, 19.48±0.2°, 19.89±0.2°, 21.10±0.2°, 22.21±0.2°, 22.97±0.2° There are characteristic peaks at , 24.45±0.2° and 26.40±0.2°.
4. The palbociclib saccharin salt crystal form α according to claim 2, characterized in that the X-ray powder diffraction pattern of the crystal form α is basically as shown in Figure 1.
5. The palbociclib saccharin salt crystal form α according to claim 1, characterized in that the thermogravimetric analysis pattern of the crystal form α is basically as shown in Figure 2.
6. The palbociclib saccharin salt crystal form α according to claim 1, characterized in that the single crystal structure of the crystal form α is as shown in Figure 3.
7. A method for preparing palbociclib saccharin salt crystal form α according to any one of claims 1 to 6, characterized in that saccharin is dissolved in an alcoholic solvent, palbociclib is added, stirred, filtered, and dried to obtain Palbociclib saccharin salt crystalline form α.
8. The method of claim 7, wherein the alcohol solvent is selected from methanol, ethanol or isopropyl alcohol; the molar ratio of palbociclib and saccharin is 1: (0.9-1.1).
9. The method according to claim 7, characterized in that saccharin is dissolved in ethanol, palbociclib is added, fully stirred at 40° C. for 3-24 hours, filtered, and dried to obtain palbociclib saccharin salt crystal form α.
10. The use of the palbociclib saccharin salt crystal form α according to any one of claims 1 to 6 in the preparation of a CDK4/6 inhibitor; the CDK4/6 inhibitor is used for the treatment of hormone receptor positive, Human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.

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