Novel axitinib molecular associates

Abstract

The invention relates to a molecular association compound which is a novel axitinib polymorphic substance, and axitinib is physically combined.

Description

Technical Field

[0001] This invention relates to novel molecular complexes of axitinib. Background Technology

[0002] Axitinib is a tyrosine kinase inhibitor, a compound represented by Formula 1 having the structure 6-[2-(methylcarbamoyl)phenylthio]-3-E-[2-(pyridin-2-yl)vinyl]indazole, and is known to be manufactured by Pfizer. The main ingredient in it, the latter being a treatment for kidney cancer.

[0003] [Formula 1]

[0004]

[0005] Axitinib is known to exist in several polymorphs, but the known polymorphs have problems with thermodynamic instability or photochemical instability, so new polymorphs are being continuously investigated.

[0006] For example, Pfizer proposed in 2006 that form IV (US Patent Application Publication US2006 / 0094763A1) was the most thermodynamically stable polymorph of axitinib, but later introduced forms XXV and XLI (European Patent EP 2134702B2), claiming that forms XXV and XLI were more thermally stable than form IV in terms of density, heat of fusion, and solubility. Furthermore, forms XXV and XLI reportedly possess advantages such as improved light stability, more regular crystal form, no tendency to form aggregates, and bulk flowability that does not adhere to the probe in the container. These improved properties are claimed to make processing and tablet preparation easier, and the filtration process, which takes 26 hours when preparing form IV, is reduced to 4 hours when preparing forms XXV and XLI. Moreover, it is claimed that the use of ethanol in the preparation of forms XXV and XLI avoids the problems and toxicity issues caused by the lower flash point compared to the preparation method of form IV using n-heptane.

[0007] In this way, taking into account the preparation process and stability, novel polymorphs of axitinib are being continuously studied.

[0008] [Existing Technical Documents]

[0009] [Patent Literature]

[0010] (Patent Document 1) US2006 / 0094763A1

[0011] (Patent Document 2) EP 2134702B2 Summary of the Invention

[0012] [Technical Issues]

[0013] This invention introduces a molecularly associated compound in which axitinib is physically bound, which not only facilitates the preparation process but also exhibits excellent solubility and stability.

[0014] Therefore, the purpose of this invention is to provide a novel molecular complex of axitinib and its preparation method, wherein the molecular complex is easy to prepare and has excellent solubility and stability.

[0015] [Technical Solution]

[0016] To achieve the above objectives, the present invention provides a molecular conjugate in which axitinib is physically bound, wherein the X-ray powder diffraction pattern of the molecular conjugate has X-ray diffraction peaks at diffraction angles 2θ at 24.99°±0.1° and 26.32°±0.1°.

[0017] Furthermore, when measured at a heating rate of 10 °C / min, 99.999% N2, and differential scanning calorimetry (DSC) conditions ranging from 30 °C to 250 °C, the molecular associative compounds of the present invention can have a differential scanning calorimetry (DSC) spectrum characterized by a glass transition at a single endothermic temperature of 220.4 ± 2.0 °C.

[0018] Furthermore, the average particle size of the molecularly associated compounds of the present invention can be from 3 μm to 12 μm.

[0019] Furthermore, the molecular conjugates of the present invention may have the following solubility: a solubility concentration of 3.0 mg / mL or more at pH 1 and a solubility concentration of 0.1 mg / mL or more at pH 2.

[0020] [Beneficial Effects]

[0021] Compared to conventional axitinib, the novel molecular complex of axitinib according to the present invention has the advantages of superior solubility and stability.

[0022] Furthermore, pharmaceutical compositions comprising the molecular complex of axitinib of the present invention have the advantages of easy dissolution and absorption as well as excellent bioavailability. Attached Figure Description

[0023] Figure 1 The DSC of axitinib API as Comparative Example 1 is shown.

[0024] Figure 2 The DSC of axitinib SCAI form (SCAI-Form) as an embodiment 1 of the present invention is shown.

[0025] Figure 3The XRD of axitinib API is shown as Comparative Example 1.

[0026] Figure 4 The XRD pattern of axitinib SCAI form, as an example of Embodiment 1 of the present invention, is shown.

[0027] Figure 5 The SEM image of axitinib API, used as Comparative Example 1, is shown.

[0028] Figure 6 The image shown is a SEM image of axitinib SCAI as an embodiment 1 of the present invention. Detailed Implementation

[0029] the term

[0030] As used herein, the term "precursor" refers to a precursor substance used in the production of axitinib according to the present invention. That is, a precursor of axitinib according to the present invention refers to axitinib or a salt of axitinib without shear stress.

[0031] As used herein, the term "molecular association" refers to a molecular association in which axitinib is physically bound, and when formed as a composition containing the molecular association in water, the molecular association in the composition may have an aggregated structure.

[0032] As used herein, the term "aspect ratio" refers to the length of a particle divided by its thickness. "Particle length" refers to the largest diameter among the particle diameters measured in this invention. "Particle thickness" refers to the shortest diameter among the particle diameters measured in this invention. Therefore, the aspect ratio is calculated as their ratio.

[0033] Molecular associations refer to molecular associations in which axitinib is physically bound, and when formed as a composition containing molecular associations in water, the molecular associations in the composition can have an aggregated structure.

[0034] The axitinib of this invention

[0035] The present invention provides a molecularly associated compound wherein axitinib, as a compound of Formula 1, is physically bound.

[0036] [Formula 1]

[0037]

[0038] The X-ray powder diffraction pattern of the physically bound molecular association of axitinib showed X-ray diffraction peaks at diffraction angles of 2θ at 24.99°±0.1° and 26.32°±0.1°.

[0039] Furthermore, when measured under DSC conditions of a heating rate of 10 °C / min, 99.999% N2, and 30 °C to 250 °C, the molecularly associated axitinib physically bound according to the invention can have a differential scanning calorimetry (DSC) curve of glass transition at a single endothermic temperature of 220.4 ± 2.0 °C. That is, while conventional generic axitinib exhibits a glass transition at two endothermic temperatures of approximately 212.5 °C and approximately 220.6 °C based on DSC curves, the molecularly associated axitinib physically bound according to the invention differs in that it has a DSC curve characterized by a glass transition at a single endothermic temperature of 220.4 ± 2.0 °C.

[0040] Furthermore, the axitinib-bound molecularly associated complex according to the present invention can have an average particle size of 2.0 μm to 15 μm, and preferably, an average particle size of 3.0 μm or more and 5.0 μm or more, and an average particle size of 13.0 μm or less and 10.0 μm or less. When the average particle size of the molecularly associated complex exceeds 15.0 μm, there are problems with poor dispersibility, transparency, and permeability. Furthermore, when the average particle size of the molecularly associated complex is less than 2.0 μm, there are problems with difficulty in preparation and inability to achieve the desired performance.

[0041] Furthermore, the molecularly associated axitinib physically bound according to the present invention can have an aspect ratio of 0.3 to 1.0. That is, conventional generic axitinib has an aspect ratio of less than 0.3, and therefore has the following properties: Figure 5 The elongated rod shape shown. In contrast, the molecularly associated axitinib according to the invention has a purely axitinib-bound structure, and therefore differs in that it exhibits an aspect ratio of 0.3 or greater, and specifically as shown... Figure 6 The shape shown is relatively circular.

[0042] According to the present invention, the molecularly associated axitinib that 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, or 0.9 or more, and may have an aspect ratio of 1.0 or less, 0.9 or less, or 0.8 or less.

[0043] In this invention, the aspect ratio of the particles can be determined by measuring the length and thickness of the particles using any suitable measurement technique, preferably using a dynamic image analysis method according to ISO 13322-2:2006, and calculating the aspect ratio from the measured particle size as described above.

[0044] Furthermore, the axitinib-bound molecular complex according to the present invention may have the following solubility: a solubility concentration of ≥3.0 mg / mL at pH 1 and a solubility concentration of ≥0.1 mg / mL at pH 2.

[0045] Specifically, according to the present invention, the axitinib-bound molecular complex can have a solubility concentration 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 at pH 1, and the upper limit can be, but is not particularly limited to, less than 10.0 mg / mL.

[0046] Furthermore, specifically, according to the present invention, the axitinib-bound molecular conjugate may have a solubility concentration of more than 0.1 mg / mL, more than 0.3 mg / mL, more than 0.5 mg / mL, more than 1.0 mg / mL, more than 1.5 mg / mL, or more than 1.7 mg / mL at pH 2, and the upper limit may be, but is not particularly limited to, less than 5.0 mg / mL.

[0047] The solubility of axitinib of the present invention can be 1.5 or 2 times higher than that of the original axitinib itself.

[0048] The method for producing axitinib of the present invention

[0049] According to one embodiment of the present invention, axitinib can be prepared by applying shear stress to a solution containing axitinib or axitinib salt as a structural precursor.

[0050] The shear stress applied to a solution containing axitinib as a structural precursor can be mechanical shear stress or ultrasound.

[0051] Mechanical shear stress can be applied by passing the solution through a column or filter paper filled with silica. Mechanical shear stress will be described in detail below.

[0052] According to an embodiment of the present invention, mechanical shear stress can 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 as it passes through a physically narrow region.

[0053] Silica can be spherical or polygonal, but its shape is not limited.

[0054] The size of the silica can be from 0.01 μm to 100 μm, preferably from 0.1 μm to 10 μm, and more preferably from 2.5 μm to 3.7 μm. When the size of the silica is less than 0.01 μm or greater than 100 μm, even if a solution containing axitinib passes through a column filled with silica, shear stress may not be applied, and the structure may not change.

[0055] A negative pressure of 0.1 bar to 1.0 bar or 0.2 bar to 0.9 bar can be applied to the bottom of the silica-filled column. When the negative pressure applied to the bottom of the silica-filled column is less than 0.1 bar, the time required for the axitinib-containing solution to pass through the column increases, potentially extending the production time of the axitinib according to the invention. Conversely, when the negative pressure applied to the bottom of the silica-filled column exceeds 1.0 bar, the time required for the axitinib-containing solution to pass through the column decreases, potentially shortening the production time of the axitinib according to the invention; however, this may increase production costs due to the need for additional pump equipment.

[0056] According to another embodiment of the invention, mechanical shear stress can be applied by passing a solution containing axitinib through one or more sheets of filter paper. When passing through one or more sheets of filter paper, axitinib undergoes very high shear stress as it passes through physically narrow areas.

[0057] Filter paper can be a single sheet or two or more sheets. When filter paper consists of two or more sheets, they can be stacked. When filter paper consists of two or more sheets, it can provide higher shear stress compared to a single sheet.

[0058] The pore size of the filter paper can be from 0.1 micrometers to 5.0 micrometers or from 0.3 micrometers to 4.5 micrometers. When the pore size of the filter paper is less than 0.1 micrometers, the amount of axitinib-containing solution passing through or filtering through the filter paper is too small, which may reduce the production rate of axitinib according to the present invention. And when the pore size of the filter paper is greater than 5.0 micrometers, the axitinib-containing solution simply passes through the filter paper, which may make it impossible to effectively apply shear stress.

[0059] Implementation

[0060] The invention will be described in more detail below through embodiments thereof. It will be understood that the invention is not limited to these embodiments.

[0061] [Example]

[0062] Example 1. Method for preparing novel axitinib polymorphs (SCAI form)

[0063] 16.0 g of axitinib (Shilpa, India) was dissolved in 16.0 kg of ethanol (94.5% ethanol, Samchun) to prepare a solution of axitinib with a concentration of about 0.1%.

[0064] 270 g of SYLOID 244FP (GRACE, USA) was moistened with 4.32 kg of ethanol (94.5% ethanol, Samchun), and a 1.0 μm paper filter was combined with a Nutsche filter with a diameter of 350 mm. A SYLOID 244FP column with a height of approximately 1.4 cm was prepared by pouring the ethanol-moistened SYLOID 244FP solution into the Nutsche filter.

[0065] To strengthen the SYLOID 244FP column, 1.08 kg of prepared 94.5% ethanol was added to the column under vacuum. A solution of the prepared axitinib was then added, and an additional 3.24 kg of 94.5% ethanol was passed through the column to recover residual axitinib in the SYLOID 244FP. In this case, the weight of the axitinib eluent was approximately 21.86 kg.

[0066] The axitinib eluent was filtered using a 0.45 μm PVDF membrane filter and concentrated to a concentrate concentration of 3.0 mg / g using a rotary vacuum concentrator. Once concentration was complete, the axitinib concentrate was filtered using a 0.2 μm PVDF membrane filter.

[0067] Add 53.0 kg of purified water to a 100 L reactor, then slowly add the prepared axitinib concentrate while rapidly stirring the purified water. After the addition is complete, stir for another 30 minutes. Filter the mixture using 1.0 μm filter paper.

[0068] The filter cake was vacuum-depressurized for 30 minutes and dried with nitrogen for 2 hours. It was then dried in a vacuum oven at 25°C for 38 hours to obtain 14.07 g (88% yield) of axitinib as a white powder.

[0069] Comparative Example 1. Axitinib API

[0070] It is a commercially available axitinib substance (Shilpa, India).

[0071] [Experimental Example]

[0072] Experimental Example 1. X-ray diffraction (XRD) of a novel axitinib polymorph (SCAI form)

[0073] The reagent is placed in the sample holder, pressed with a glass rod, and filled into the molded portion. When tested according to the X-ray powder diffraction method in the general test method of the Korean Pharmacopoeia, it shows a crystalline form.

[0074] Table 1 below shows the operating conditions.

[0075] [Table 1]

[0076]

[0077] Using copper radiation (CuKα, wavelength) on Rigaku Miniflex 600 X-ray powder diffraction patterns were generated for various polymorphic forms. 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 to 13.0 mm. Diffraction radiation was detected using a D / teX Ultra2. Continuous θ-2θ scans were performed from 3.0° to 60°2θ at 2.0° / min (1 sec / 0.03° step). Alumina standards were analyzed to confirm instrument calibration. Data were collected and analyzed using SmartLab Studio II.

[0078] Using copper radiation (CuKα, wavelength) on Rigaku Miniflex 600 X-ray powder diffraction patterns were measured. 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 to 13.0 mm. Diffraction radiation was detected using a D / teX Ultra2. Continuous θ-2θ scans were performed from 3.0° to 60°2θ at 2.0° / min (1 sec / 0.03°). Alumina standards were analyzed to confirm instrument calibration. Data were collected and analyzed using SmartLab Studio II.

[0079] Table 2 below shows the XRD results, namely the 2θ and relative intensities of axitinib, which is in both API and SCAI forms, the latter being a molecular conjugate of axitinib according to the present invention.

[0080] [Table 2]

[0081]

[0082] Experimental Example 2. Differential Scanning Calorimetry (DSC) of a Novel Axitinib Polymorph (SCAI Form)

[0083] Measurements were performed using a heating program in a differential scanning calorimeter apparatus (Table 3). In this case, a sample volume of less than 4.0 mg was recommended, and the apparatus was kept in a nitrogen atmosphere at a flow rate of 10 mL / min.

[0084] [Table 3]

[0085] rate Target Keep Record 20℃ / min 100 ℃ 20min 10℃ / min 30 ℃ 5min - 10℃ / min 250 ℃ 5min √

[0086] Table 4 below shows the peak temperature and ΔH of axitinib as an API and the molecular conjugate of axitinib according to the present invention in the form of SCAI.

[0087] [Table 4]

[0088]

[0089] Experimental Example 3. Scanning Electron Microscopy (SEM) of a Novel Axitinib Polymorph (SCAI Form)

[0090] Measurement conditions

[0091] The powder sample was placed on a carbon ribbon fixed to an aluminum short column. The sample was scanned in an FE-SEM using a Jeol JSM-IT800. Images were acquired using a secondary electron detector at an accelerating voltage of 1.00 kV.

[0092] The crystal structures of axitinib in API and SCAI forms were analyzed using the above measurement methods.

[0093] Axitinib API is shaped like a square strip resembling a tree branch (see...). Figure 5 ).

[0094] On the other hand, the novel axitinib polymorph (SCAI form) of the present invention has a non-sharp (rounded corner) polyhedral shape (see...). Figure 6 ).

[0095] In addition, such as Figure 5 As shown, it can be confirmed that the axitinib API has an aspect ratio much smaller than 0.3; while as Figure 6 As shown, it can be confirmed that its aspect ratio is close to 1.

[0096] exist Figure 6 In the images, the lower image is an enlarged version of the upper image, and the maximum diameter of the molecular associations according to the present invention can be measured as shown in Table 5 below.

[0097] [Table 5]

[0098] Classification Diameter (length, μm) average value 6.68 Minimum value 3.29 Maximum value 12.84

[0099] Experimental Example 4. Solubility of a novel axitinib polymorph (SCAI form)

[0100] Method for measuring solubility at pH 1: Stir at a concentration of 5 mg / mL for 15 minutes, then filter, dilute 10-fold with DW, and analyze (the results are described as values ​​calculated as [measured value × 10]).

[0101] Method for measuring solubility at pH 2: Stir at a concentration of 1 mg / mL for 15 minutes, then filter, analyze, and show in Table 6.

[0102] [Table 6]

[0103]

[0104] As can be seen from the above, the solubility of SCAI is about twice that of API.

Claims

1. A molecular association compound wherein axitinib is physically bound, in, The X-ray powder diffraction pattern of the molecular association has X-ray diffraction peaks at diffraction angles of 2θ at 24.99°±0.1° and 26.32°±0.1°.

2. The molecular associative compound according to claim 1, when measured under differential scanning calorimetry (DSC) conditions of a heating rate of 10 °C / min, 99.999% N2, and 30 °C to 250 °C, has a glass transition at a single endothermic temperature of 220.4 ± 2.0 °C.

3. The molecular association compound according to claim 1, characterized in that, The aspect ratio of the molecular pair is from 0.3 to 1.

0.

4. The molecular association compound according to claim 1, characterized in that, The average particle size of the molecularly associated compounds is 2 μm to 15 μm.

5. The molecular association compound according to claim 1, characterized in that, The molecular association has the following solubility: The solubility concentration at pH 1 is above 3.0 mg / mL, and The solubility concentration at pH 2 is above 0.1 mg / mL.

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