Novel molecular assembly of axitinib

Abstract

The present invention relates to a molecular assembly which is a novel axitinib polymorph in which axitinib is physically bound.

Description

Novel molecular complex of axitinib

[0001] The present invention relates to a novel axitinib molecular complex.

[0002] Axitinib is a compound having the structure of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole, represented by the following chemical formula 1. It is a tyrosine kinase inhibitor and is a drug used to treat kidney cancer, Inlyta, by Pfizer. ® ) is well known as the main ingredient.

[0003]

[0004] Axitinib is known to have several polymorphs, but the known polymorphs are thermodynamically unstable or photochemically unstable, so new polymorphs are continuously being studied.

[0005] For example, in 2006, Pfizer stated that Form IV (US Application Publication 2006-0094763) of axitinib was the most thermodynamically stable polymorph, but later introduced Form XXV, XLI (EP 2134702 B2) and stated that Form XXV, XLI are more thermally stable than Form IV in terms of density, heat of fusion, and solubility. In addition, Form XXV, XLI are said to have improved photostability, a more regular crystal shape, no tendency to form aggregates, and bulk flow properties that prevent sticking to probes in tanks. These improved properties are advantageous in purification processing and manufacturing, and the filtering process, which took a long time of 26 hours when manufacturing Form IV, was shortened to 4 hours when manufacturing Form XXV, XLI. Additionally, it is said that in the manufacturing of Form XXV and XLI, ethanol was used, which resulted in lower flash points and no toxicity issues compared to the Form IV manufacturing process using n-heptane.

[0006] In this way, new polymorphs of axitinib are continuously being studied, taking into account the manufacturing process and stability.

[0007] [Prior Art Literature]

[0008] [Patent Document]

[0009] (Patent Document 1) US 2006-0094763 A1

[0010] (Patent Document 2) EP 2134702 B2

[0011] The present invention introduces a molecular complex in which axitinib is physically bound, which is not only easy to manufacture but also has excellent solubility and stability.

[0012] Accordingly, the purpose of the present invention is to provide a novel molecular complex of axitinib, which is easy to manufacture and has excellent solubility and stability, and a manufacturing process thereof.

[0013] To achieve the above purpose,

[0014] The present invention is a molecular complex in which axitinib is physically bound,

[0015] The X-ray powder diffraction spectrum of the above molecular assembly provides a molecular assembly having X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1°.

[0016] In addition, the molecular assembly of the present invention can have a differential scanning calorimetry (DSC) profile characterized by a glass transition at a single endothermic temperature of 220.4±2.0°C when measured under DSC conditions of a heating rate of 10°C / min, 99.999% N2, and 30-250°C.

[0017] Additionally, the molecular aggregate of the present invention may have an average particle diameter of 3 to 12 μm.

[0018] In addition, the molecular complex of the present invention may have a solubility of 3.0 mg / mL or more in a solubility concentration at pH 1 and 0.1 mg / mL or more in a solubility concentration at pH 2.

[0019] The novel molecular complex of axitinib according to the present invention has the advantage of having superior solubility and stability compared to conventional general axitinib.

[0020] In addition, the pharmaceutical composition comprising the molecular complex of the axitinib of the present invention has the advantage of being easily dissolved and absorbed and having excellent bioavailability.

[0021] Figure 1 is a DSC of Axitinib API, which is comparative example 1.

[0022] Figure 2 is a DSC of Axitinib SCAI-Form, which is Example 1 of the present invention.

[0023] Figure 3 is an XRD of Axitinib API, Comparative Example 1.

[0024] Figure 4 is an XRD of Axitinib SCAI-Form, which is Example 1 of the present invention.

[0025] Figure 5 is an SEM of Axitinib API, Comparative Example 1.

[0026] Figure 6 is an SEM of Axitinib SCAI-Form, which is Example 1 of the present invention.

[0027] Terminology

[0028] The term “precursor” as used herein refers to a precursor or precursor used to produce axitinib according to the present invention. That is, the precursor of axitinib according to the present invention refers to axitinib or a salt of axitinib to which no shear stress is applied.

[0029] The term “molecular aggregate” as used herein refers to a molecular aggregate in which axitinib is physically bound, and when the molecular aggregate is formed into a composition by being incorporated into water, the molecular aggregate in the composition may have an aggregated structure.

[0030] The term “aspect ratio” used herein refers to a value obtained by dividing the length of a particle by the thickness of the particle. “Length of a particle” refers to the longest diameter among the diameters of a particle measured in the present invention. “Thickness of a particle” refers to the shortest diameter among the diameters of a particle measured in the present invention. Therefore, the aspect ratio is calculated as the ratio of these.

[0031] When axinib is formed into a composition as a physically bonded molecular aggregate by allowing the molecular aggregate to be incorporated into water, the molecular aggregate in the composition may have an aggregated structure.

[0032]

[0033] Axitinib of the present invention

[0034] The present invention provides a molecular complex in which axitinib, a compound of the following chemical formula 1, is physically bound.

[0035] [Chemical Formula 1]

[0036]

[0037] The above molecular complex physically bound to the axitinib has an X-ray powder diffraction spectrum of the molecular complex having X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1°.

[0038]

[0039] In addition, the molecular assembly to which the axitinib of the present invention is physically bound can have a DSC profile having a glass transition at a single endothermic temperature of 220.4±2.0°C when measured under differential scanning calorimetry (DSC) conditions of a heating rate of 10°C / min, 99.999% N2, and 30-250°C. That is, while conventional general axitinib exhibits glass transitions at two endothermic temperatures of about 212.5°C and about 220.6°C based on the DSC profile, the molecular assembly to which the axitinib of the present invention is physically bound has a difference in that it has a DSC profile characterized by a glass transition at a single endothermic temperature of 220.4±2.0°C.

[0040] In addition, the molecular aggregate to which the axitinib of the present invention is physically bound may have an average particle diameter of 2.0 to 15 μm, preferably 3.0 μm or more, 5.0 μm or more, and 13.0 μm or less, 10.0 μm or less. If the average particle diameter of the molecular aggregate exceeds 15.0 μm, there is a problem that dispersibility is reduced and transparency and transmittance are reduced. In addition, if the average particle diameter of the molecular aggregate is less than 2.0 μm, there is a problem that manufacturing is difficult and performance is not expressed.

[0041]

[0042] In addition, the molecular complex to which the axitinib of the present invention is physically bound may have an aspect ratio value of 0.3 to 1.0. That is, in the case of conventional general axitinib, it has an aspect ratio value of less than 0.3 and has an elongated rod-shaped shape as shown in FIG. 5. In contrast, the molecular complex to which the axitinib of the present invention is physically bound has a physically bound structure of pure axitinib and thus exhibits a characteristic of having an aspect ratio value of 0.3 or more, and specifically, as disclosed in FIG. 6, there is a difference in that it has a relatively round shape.

[0043] The molecular complex to which the axitinib of the present invention is physically bound may have an aspect ratio of 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, 0.7 or more, 0.8 or more, 0.9 or more, and may have an aspect ratio of 1.0 or less, 0.9 or less, 0.8 or less.

[0044] In the present invention, the aspect ratio of the particle can be determined by measuring the length and thickness of the particle using any suitable measuring technique, preferably using a dynamic image analysis method performed according to the ISO 13322-2:2006 standard, and calculating the aspect ratio from the measured dimensions of the particle as described above.

[0045]

[0046] In addition, the molecular complex to which the axitinib of the present invention is physically bound may have a solubility of 3.0 mg / mL or more in a solubility concentration at pH 1 and 0.1 mg / mL or more in a solubility concentration at pH 2.

[0047] Specifically, the molecular complex to which the axitinib of the present invention is physically bound may have a solubility concentration at pH 1 of 3.0 mg / mL or more, 3.5 mg / mL or more, 4.0 mg / mL or more, or 4.3 mg / mL or more, and the upper limit may be 10.0 mg / mL or less, although there is no particular limitation thereon.

[0048] In addition, specifically, the molecular complex to which the axitinib of the present invention is physically bound may have a solubility concentration at pH 2 of 0.1 mg / mL or more, 0.3 mg / mL or more, 0.5 mg / mL or more, 1.0 mg / mL or more, 1.5 mg / mL or more, or 1.7 mg / mL or more, and the upper limit may be 5.0 mg / mL or less, although there is no particular limitation thereon.

[0049]

[0050] The solubility of the axitinib of the present invention may be 1.5 times or 2 times higher than that of the original axitinib itself.

[0051]

[0052] Method for manufacturing axitinib of the present invention

[0053] According to one embodiment of the present invention, axitinib can be prepared by applying shear stress to a solution containing axitinib or a salt of axitinib, which is a precursor of the structure.

[0054] The shear stress applied to the solution containing axitinib, which is a precursor of the above structure, may be either mechanical shear stress or ultrasonic application.

[0055] The above mechanical shear stress may be applied by passing the solution through a silica-filled column or filter paper. The mechanical shear stress is described in detail below.

[0056] According to one embodiment of the present invention, the mechanical shear stress may be applied by passing a solution containing axitinib through a column filled with silica. When the solution containing axitinib passes through a column filled with silica or the like, the axitinib is subjected to very high shear stress by passing through a physically narrow region.

[0057] The above silica may be spherical or angular, but is not limited to its shape.

[0058] The size of the silica may be 0.01 to 100 μm, preferably 0.1 to 10 μm, and more preferably 2.5 to 3.7 μm. When the size of the silica is less than 0.01 μm or greater than 100 μm, even if the solution containing the axitinib passes through a column filled with silica, shear stress is not applied, so there may be no change in the structure.

[0059] A negative pressure of 0.1 bar to 1.0 bar or 0.2 bar to 0.9 bar can be applied to the lower portion of the silica-filled column. When the negative pressure applied to the lower portion of the silica-filled column is less than 0.1 bar, the time required for the solution containing axitinib to pass through the column increases, thereby delaying the manufacturing time of axitinib according to the present invention. In addition, when the negative pressure applied to the lower portion of the silica-filled column is more than 1.0 bar, the time required for the solution containing axitinib to pass through the column decreases, thereby shortening the manufacturing time of axitinib according to the present invention. However, since additional pump equipment is required, the manufacturing cost may increase.

[0060] According to another embodiment of the present invention, the mechanical shear stress may be applied by passing the solution containing the axitinib through one or more filter papers. Passing through the one or more filter papers physically exposes the axitinib to very high shear stress by passing through a narrow area.

[0061] The filter paper may be a single filter paper or two or more filter papers. If the filter paper is two or more filter papers, the filter papers may be arranged in a stacked manner. If the filter paper is two or more filter papers, a higher shear stress may be provided than that of a single filter paper.

[0062] The pore size of the filter paper may be 0.1 to 5.0 microns or 0.3 to 4.5 microns. When the pore size of the filter paper is less than 0.1 micron, the amount of the solution containing axitinib passing through or filtering the filter paper may be too small, so that the production speed of axitinib according to the present invention may be reduced, and when the pore size of the filter paper is greater than 5.0 microns, the solution containing axitinib may simply pass through the filter paper, so that shear stress may not be effectively applied.

[0063] Hereinafter, the present invention will be described in more detail through examples. It will be understood that the present invention is not limited to these examples.

[0064]

[0065] [Example]

[0066] Example 1. Method for manufacturing a novel axitinib polymorph (SCAI-Form)

[0067] A solution of axitinib with a concentration of approximately 0.1% was prepared by dissolving 16.0 g of axitinib [Shilpa, India] in 16.0 kg of ethanol (94.5% ethanol, Samjeon).

[0068] 270 g of SYLOID 244FP (GRACE, USA) was wetted with 4.32 kg of ethanol (94.5%, Ethanol, Samsung), and a 1.0 μm paper filter was attached to a 350 mm diameter Nutsche filter to prepare a SYLOID 244FP column with a height of approximately 1.4 cm by pouring the SYLOID 244FP solution wetted with ethanol into the Nutsche filter.

[0069] The SYLOID 244FP column was made solid by adding 1.08 kg of 94.5% ethanol prepared on the column using a vacuum. The prepared axitinib solution was added, and an additional 3.24 kg of 94.5% ethanol was passed through the column to recover the axitinib remaining in the SYLOID 244FP. The weight of the axitinib effluent at this time was approximately 21.86 kg.

[0070] The axitinib effluent was filtered using a 0.45 μm PVDF membrane filter and concentrated to a concentration of 3.0 mg / g using a rotary vacuum evaporator. After concentration was completed, the axitinib concentrate was filtered using a 0.2 μm PVDF membrane filter.

[0071] 53.0 kg of purified water was added to a 100 L reactor, and the prepared axitinib concentrate was slowly added while rapidly stirring the purified water. After the addition was complete, stirring was continued for an additional 30 minutes. The mixture was filtered using a 1.0 μm paper filter.

[0072] The filtered cake was decompressed under vacuum for 30 minutes and dried using nitrogen for 2 hours. In addition, it was dried in a vacuum oven at 25°C for 38 hours to obtain 14.07 g (Y. 88%) of axitinib as a white powder.

[0073]

[0074] Comparative Example 1. Axitinib API

[0075] Axitinib is a commercially available substance [Shilpa, India].

[0076]

[0077] [Experimental Example]

[0078] Experimental Example 1. X-ray diffraction analysis (XRD) of a novel axitinib polymorph (SCAI-Form)

[0079] When the reagent is placed in the specimen holder, pressed with a glass rod to form a charge in the charging section and tested according to the powder X-ray diffraction measurement method in the general test methods of the Korean Pharmacopoeia, it exhibits a crystalline form.

[0080] Table 1 below shows the operating conditions.

[0081] ConditionsActual measurement conditionsConditionsActual measurement conditions

[0082] Powder X-ray diffraction patterns of various polymorphic forms were performed on a Rigaku Miniflex600 using copper radiation (CuKα, wavelength: 1.5406 Å). The tube voltage and current were set to 40 kV and 15 mA, respectively. The divergence and scatter slits were set to 8.0 mm, and the receiving slit was set to 13.0 mm. The diffracted radiation was detected with a D / teX Ultra2. A theta-2 theta continuous scan at 2.0 degrees / min (1 s / 0.03 degree step) was used from 3.0 to 60 degrees 2θ. An alumina standard was analyzed to verify instrument alignment. The data were collected and analyzed using SmartLab Studio Ⅱ.

[0083] Powder X-ray diffraction patterns were measured on a Rigaku Miniflex 600 using copper radiation (CuKα, wavelength: 1.54056 Å). The tube voltage and current were set to 40 kV and 15 mA, respectively. The divergence and scattering slits were set to 8.0 mm, and the receiving slit was set to 13.0 mm. The diffracted radiation was detected with a D / teX Ultra2. A theta-2 theta continuous scan at 2.0 degrees / min (1 s / 0.03 degrees) was used over a 2θ range of 3.0 to 60 degrees. An alumina standard was analyzed to verify instrument alignment. Data collection and analysis were performed using SmartLab Studio Ⅱ.

[0084] Table 2 below shows the 2 theta and relative intensity XRD results of axitinib, the API of the present invention, and SCAI-Form, a molecular complex of axitinib.

[0085] APISCAI-Form(AXTEN03A)Anglerelativeintensity(%)Anglerelativeintensity(%)8.19102.708. 8453.211.924.2311.99133.114.743.9314.602615.3420.1315.2451.915.5643.4115.7076.617.45 57.1917.7127.619.394.7219.3358.120.698.4120.6558.821.409.2121.7085.123.2944.4623.2353.424.0155.3924.193825.9610024.99(25.0)10026.243.7526.32(26.3)38.827.788.1327.5911.9

[0086] Experimental Example 2. Differential scanning calorimetry (DSC) of a novel axitinib polymorph (SCAI-Form)

[0087] Measurements were made using the temperature increase program [Table 3] in the differential scanning calorimeter device. At this time, the sample amount is recommended to be 4.0 mg or less, the environment inside the device is maintained as nitrogen, and the nitrogen flow rate is 10 mL / min.

[0088] RateTargetHoldRecord20 ℃ / min100 ℃20 min10 ℃ / min30 ℃5 min-10 ℃ / min250 ℃5 min√

[0089] Table 4 below shows the peak temperature and ΔH of axitinib, the API of the present invention, and SCAI-Form, a molecular complex of axitinib.

[0090] APISCAI-Form(AXTEN03A)peak temp.(℃)212.5220.4220.6H(J / g)129.1131.7

[0091] Experimental Example 3. Scanning Electron Microscope (SEM) of the Novel Axitinib Polymorph (SCAI-Form)

[0092] Measurement conditions

[0093] Powder samples were placed on carbon tape fixed to an aluminum stub. The samples were scanned in a FE-SEM using a JSM-IT800, Jeol. Images were acquired at an accelerating voltage of 1.00 kV using a secondary electron detector.

[0094]

[0095] The crystal structures of Axitinib API and SCAI-Form were analyzed using the above measurement method.

[0096] Axitinib API has a wooden-like shape (see Figure 5).

[0097] In contrast, the novel axitinib polymorph (SCAI-Form) of the present invention has a non-sharp (rounded) polyhedral shape. (See Fig. 6)

[0098] Additionally, as shown in Fig. 5, it can be confirmed that the Axitinib API has an aspect ratio much smaller than 0.3, and as shown in Fig. 6, it can be confirmed that it has an aspect ratio close to 1.

[0099] The lower figure in the figure of Fig. 6 is an enlarged version of the upper figure, and the maximum diameter of the powder assembly according to the present invention could be measured as shown in Table 5 below.

[0100] Distinctive diameter (length μm) average value 6.68 minimum value 3.29 maximum value 12.84

[0101] Experimental Example 4. Solubility of the novel axitinib polymorph (SCAI-Form)

[0102] pH 1 Solubility Measurement Method: Stir for 15 minutes at a concentration of 5 mg / mL, filter, dilute 10 times with DW, and conduct analysis. (The value calculated as [measured value x 10] is reported in the results.)

[0103] pH 2 Solubility Measurement Method: After stirring for 15 minutes at a concentration of 1 mg / mL, filter and analyze, which are shown in Table 6.

[0104] Distinction Batch No. pH 1 Dissolution Concentration (mg / mL) pH 2 Dissolution Concentration (mg / mL) API Axitinib API (Shilpa) 2.6610.073 SCAI-Form AXTEN03A4.3630.171

[0105] As above, it can be seen that the solubility of SCAI-Form is about twice as high as that of API.

Claims

1. As a molecular complex in which axitinib is physically bound, The X-ray powder diffraction spectrum of the above molecular complex has X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1°. Molecular assembly.

2. In paragraph 1, The above molecular assembly is characterized in that it has a DSC profile having a glass transition at a single endothermic temperature of 220.4±2.0°C when measured under differential scanning calorimetry (DSC) conditions of 30-250°C, 99.999% N2, and a heating rate of 10°C / min. Molecular assembly.

3. In paragraph 1, The above molecular aggregate is characterized in that it has an aspect ratio value of 0.3 to 1.

0. Molecular assembly.

4. In paragraph 1, The above molecular aggregate is characterized by having an average particle diameter of 2 to 15 μm. Molecular assembly.

5. In paragraph 1, The above molecular assembly is The solubility concentration at pH 1 is 3.0 mg / mL or more, Characterized in that it has a solubility of 0.1 mg / mL or more at pH 2. Molecular assembly.

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