Novel molecular aggregate of axitinib

Abstract

This invention relates to a molecular aggregate which is a novel axitinib polymorph to which axitinib is physically bound.

Description

Technical Field

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

Background Art

[0002] Axitinib is a compound having the structure of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole represented by Chemical Formula 1 below, and is well-known as the main component of Inlyta (registered trademark), a therapeutic agent for renal cancer of Pfizer, as a tyrosine kinase inhibitor.

[0003]

Chem.

[0004] Although it is known that axitinib has various polymorphs, the known polymorphs have problems of being thermodynamically unstable or photochemically unstable, and new polymorphs are continuously being studied.

[0005] For example, in 2006, Pfizer stated that Form IV (US Application Publication 2006-0094763) was the most thermally stable form of axitinib. Later, they introduced Forms XXV and XLI (EP 2134702 B2), stating that Forms XXV and XLI are more thermally stable than Form IV in terms of density, heat of fusion, and solubility. Furthermore, Forms XXV and XLI have improved photostability, a more regular crystalline structure, a tendency not to form aggregates, and possess bulk flow properties, which have the advantage of not adhering to probes in tanks. These improved properties make purification and manufacturing easier; the filtering process for Form IV took 26 hours, but for Forms XXV and XLI, the filtering time was reduced to 4 hours. Furthermore, the manufacturing process for Form XXV and XLI uses ethanol, and compared to the manufacturing process for Form IV, which uses n-heptane, it did not involve the problems associated with a lower flash point or toxicity issues.

[0006] Thus, new axitinib polymorphs that take into account the manufacturing process and stability are currently being continuously researched. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] US 2006-0094763 A1 [Patent Document 2] EP 2134702 B2 [Overview of the project] [Problems that the invention aims to solve]

[0008] This invention introduces a molecular aggregate in which axitinib is physically bound, which is not only easy to manufacture but also has excellent solubility and stability.

[0009] Therefore, the object of the present invention is to provide a novel axitinib molecular aggregate that is easy to manufacture and has excellent solubility and stability, as well as a manufacturing process for this aggregate. [Means for solving the problem]

[0010] In order to achieve the aforementioned objectives,

[0011] The present invention is a molecular aggregate to which axitinib is physically bound.

[0012] The X-ray powder diffraction spectrum of the molecular aggregate provides a molecular aggregate having X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1°.

[0013] Furthermore, when measured under differential scanning calorimetry (DSC) conditions of a heating rate of 10°C / min, 99.999% N2, and 30-250°C, the molecular aggregate of the present invention can have a DSC profile characterized by a glass transition at a single endothermic temperature of 220.4 ± 2.0°C.

[0014] Furthermore, the molecular aggregates of the present invention can have an average particle size of 3 to 12 μm.

[0015] Furthermore, the molecular aggregate of the present invention can have a solubility of 3.0 mg / mL or higher at pH 1 and 0.1 mg / mL or higher at pH 2. [Effects of the Invention]

[0016] The novel axitinib molecular aggregate according to the present invention has the advantage of having superior solubility and stability compared to conventional axitinib.

[0017] In addition, the pharmaceutical composition containing the molecular aggregate of axitinib of the present invention can be easily dissolved and absorbed, and has the advantage of excellent bioavailability.

Brief Description of Drawings

[0018] [Figure 1] DSC of Axitinib API of Comparative Example 1. [Figure 2] DSC of Axitinib SCAI-Form of Example 1 of the present invention. [Figure 3] XRD of Axitinib API of Comparative Example 1. [Figure 4] XRD of Axitinib SCAI-Form of Example 1 of the present invention. [Figure 5] SEM of Axitinib API of Comparative Example 1. [Figure 6] SEM of Axitinib SCAI-Form of Example 1 of the present invention.

Modes for Carrying Out the Invention

[0019] term The term "precursor" used in this specification means a precursor substance or a progenitor substance used to produce axitinib according to the present invention. That is, the precursor of axitinib according to the present invention means axitinib or a salt of axitinib to which shear stress has not been applied.

[0020] The term "molecular aggregate" used in this specification is a molecular aggregate in which axitinib is physically bonded. When the molecular aggregate is formed in a composition so as to be contained in water, the molecular aggregate in the composition can have an aggregated structure.

[0021] As used herein, the term "aspect ratio" refers to the value obtained by dividing the particle length by the particle thickness. "Particle length" refers to the longest 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 using this ratio.

[0022] If axitinib is a molecular aggregate to which molecules are physically bound, and the molecular aggregate is formed in a composition such that it is contained in water, then the molecular aggregate may have an aggregated structure within the composition.

[0023] Axitinib of the present invention The present invention provides a molecular aggregate in which axitinib, a compound of the following chemical formula 1, is physically bound.

[0024] [ka]

[0025] The molecular aggregate to which the axitinib is physically bound has X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1° in its X-ray powder diffraction spectrum.

[0026] Furthermore, when measured under differential scanning calorimetry (DSC) conditions of a heating rate of 10°C / min, 99.999% N2, and 30-250°C, the molecular aggregate to which axitinib is physically bound in the present invention can have a DSC profile that exhibits a glass transition at a single endothermic temperature of 220.4 ± 2.0°C. In other words, while conventional axitinib shows a glass transition at two endothermic temperatures of approximately 212.5°C and approximately 220.6°C relative to its DSC profile, the molecular aggregate to which axitinib is physically bound in the present invention has a DSC profile characterized by a glass transition at a single endothermic temperature of 220.4 ± 2.0°C.

[0027] Furthermore, the molecular aggregate to which the axitinib of the present invention is physically bound may have an average particle size of 2.0 to 15 μm, preferably 3.0 μm or more, 5.0 μm or more, and 13.0 μm or less, or 10.0 μm or less. If the average particle size of the molecular aggregate exceeds 15.0 μm, there is a problem that the dispersibility decreases and the transparency and transmittance decrease. Also, if the average particle size of the molecular aggregate is less than 2.0 μm, there is a problem that it is difficult to manufacture and the performance is not achieved.

[0028] Furthermore, the molecular aggregate to which axitinib is physically bound according to the present invention can have an aspect ratio of 0.3 to 1.0. In other words, conventional axitinib has an aspect ratio of less than 0.3 and has an elongated rod-like shape, as shown in Figure 5. In contrast, the molecular aggregate to which axitinib is physically bound according to the present invention has an aspect ratio of 0.3 or higher because it has a structure to which pure axitinib is physically bound, and specifically has a relatively round shape, as disclosed in Figure 6.

[0029] The molecular aggregate 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, or 0.9 or more, and may also have an aspect ratio of 1.0 or less, 0.9 or less, or 0.8 or less.

[0030] In the present invention, the aspect ratio of a particle can be determined by measuring the length and thickness of the particle using any suitable measurement technique, preferably using a dynamic image analysis method performed in accordance with the ISO 13322-2:2006 standard, and then calculating the aspect ratio from the measured dimensions of the particle as described above.

[0031] Furthermore, the molecular aggregate to which axitinib is physically bound according to the present invention can have a solubility of 3.0 mg / mL or higher at pH 1 and 0.1 mg / mL or higher at pH 2.

[0032] Specifically, the molecular aggregate to which axitinib of the present invention is physically bound may have a solubility concentration of 3.0 mg / mL or higher, 3.5 mg / mL or higher, 4.0 mg / mL or higher, or 4.3 mg / mL or higher at pH 1, and there is no particular upper limit, although it may be 10.0 mg / mL or lower.

[0033] Specifically, the molecular aggregate to which the axitinib of the present invention is physically bound may have a solubility concentration of 0.1 mg / mL or higher, 0.3 mg / mL or higher, 0.5 mg / mL or higher, 1.0 mg / mL or higher, 1.5 mg / mL or higher, or 1.7 mg / mL or higher at pH 2. There is no particular upper limit, but it may be 5.0 mg / mL or lower.

[0034] The axitinib of the present invention may have a solubility 1.5 times or more than 2 times higher than that of the original axitinib itself.

[0035] Method for producing axitinib according to the present invention Axitinib according to one embodiment of the present invention can be produced by applying shear stress to a solution containing axitinib or a salt of axitinib, which is a precursor of the structure.

[0036] The shear stress applied to the solution containing axitinib, a precursor of the aforementioned structure, may be either mechanical shear stress or ultrasonic application.

[0037] The aforementioned mechanical shear stress may be applied by passing the solution through a silica-filled column or filter paper. The mechanical shear stress will be described in detail below.

[0038] According to one embodiment of the present invention, the mechanical shear stress may be applied by passing a solution containing axitinib through a silica-packed column. When the axitinib-containing solution passes through a silica-packed column, the axitinib is subjected to a very high shear stress by passing through a physically narrow region.

[0039] The silica may be spherical or angular, but its form is not limited.

[0040] The size of the silica particles may be 0.01 to 100 μm, preferably 0.1 to 10 μm, and more preferably 2.5 to 3.7 μm. If the size of the silica particles is less than 0.01 μm or greater than 100 μm, even if the solution containing axitinib passes through the silica-packed column, no shear stress is applied, and therefore there may be no change in the structure.

[0041] 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-packed column. If the negative pressure applied to the bottom of the silica-packed column is less than 0.1 bar, the time it takes for the axitinib-containing solution to pass through the column increases, which may delay the production time of axitinib according to the present invention. If the negative pressure applied to the bottom of the silica-packed column exceeds 1.0 bar, the time it takes for the axitinib-containing solution to pass through the column decreases, which may shorten the production time of axitinib according to the present invention, but this may increase production costs because an additional pumping device is required.

[0042] 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. When the axitinib passes through the one or more filter papers, it is subjected to a very high shear stress by passing through a physically narrow area.

[0043] 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 can be stacked and arranged. If the filter paper is two or more filter papers, it can provide higher shear stress than a single filter paper.

[0044] The pore size of the filter paper may be 0.1 to 5.0 microns or 0.3 to 4.5 microns. If the pore size of the filter paper is less than 0.1 microns, the amount of solution containing axitinib that passes through or is filtered through the filter paper may be too small, potentially reducing the rate of axitinib production according to the present invention. If the pore size of the filter paper exceeds 5.0 microns, the solution containing axitinib may simply pass through the filter paper, and shear stress may not be effectively applied.

[0045] The present invention will be described in more detail below through examples of the present invention. It goes without saying that the present invention is not limited to these examples. [Examples]

[0046] Example 1. Method for producing a novel axitinib polymorph (SCAI-Form) 16.0 g of axitinib [Shilpa, India] was dissolved in 16.0 kg of ethanol (94.5% Ethanol, SAMCHUN, South Korea) to prepare an axitinib solution with a concentration of approximately 0.1%.

[0047] 270g of SYLOID 244FP (GRACE, USA) was wetted with 4.32kg of ethanol (94.5% Ethanol, SAMCHUN, South Korea), and a 1.0μm filter paper was attached to a 350mm diameter Nutche filter to prepare the column. The ethanol-moistened SYLOID 244FP solution was poured into the Nutche filter to prepare a SYLOID 244FP column approximately 1.4cm high.

[0048] Using a vacuum, 1.08 kg of 94.5% ethanol prepared on the column was added to stiffen the SYLOID 244FP column. The prepared axitinib solution was then added, and another 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.

[0049] 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 concentrator. After concentration was complete, the axitinib concentrate was filtered using a 0.2 μm PVDF membrane filter.

[0050] 53.0 kg of purified water was added to a 100 L reactor, and while rapidly stirring the purified water, the prepared axitinib concentrate was gradually added. After the addition was complete, stirring was continued for an additional 30 minutes. The mixture was filtered using 1.0 μm filter paper.

[0051] The filtered cake was reduced in vacuum for 30 minutes and dried using nitrogen for 2 hours. It was then dried in a vacuum oven at 25°C for 38 hours to obtain 14.07 g (88%) of axitinib as a white powder.

[0052] Comparison example 1. Axitinib API This is Axitinib, a commercially available substance [Shilpa, India].

[0053] [Example of experiment] Experimental Example 1. X-ray diffraction analysis (X-ray Diffractometer, XRD) of a novel axitinib polymorph (SCAI-Form) The reagent is placed in a sample holder, pressed with a glass rod to fill and mold it into the packing area, and then tested using powder X-ray diffraction, one of the general test methods in the Korean Pharmacopoeia, to reveal its crystalline form. Table 1 below shows the operating conditions.

[0054] [Table 1]

[0055] Powder X-ray diffraction patterns of various polymorphic forms were obtained using copper radiation (CuKα, wavelength: 1.5406 Å) with a Rigaku Miniflex600. 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 with a D / teX Ultra2. A theta-2 theta continuous scan was used from 3.0 degrees to 60 degrees 2θ at 2.0 degrees / min (1 second / 0.03 degree interval). Alumina standards were analyzed to verify instrument alignment. Data were collected and analyzed using SmartLab Studio II.

[0056] Powder X-ray diffraction patterns were measured using copper radiation (CuKα, wavelength: 1.54056 Å) with a Rigaku Miniflex 600. 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 with a D / teX Ultra2. A theta-2 theta continuous scan was used at 3.0–60 degrees 2θ at 2.0 degrees / min (1 second / 0.03 degrees). Alumina standards were analyzed to confirm instrument alignment. Data acquisition and analysis were performed using SmartLab Studio II.

[0057] Table 2 below shows the 2-theta and relative intensity XRD results for axitinib, the API of the present invention, and SCAI-Form, a molecular aggregate of axitinib.

[0058] [Table 2]

[0059] Experimental Example 2. Differential scanning calorimetry (DSC) of a novel axitinib polymorph (SCAI-Form)

[0060] Measurements were taken using the temperature rise program [Table 3] within the differential scanning calorimetry analyzer. A sample volume of 4.0 mg or less is recommended, the environment inside the analyzer should be maintained with nitrogen, and the nitrogen flow rate should be 10 mL / min.

[0061] [Table 3]

[0062] Table 4 below shows the peak temperature and ΔH of axitinib, the API of the present invention, and SCAI-Form, a molecular aggregate of axitinib.

[0063] [Table 4]

[0064] Experimental Example 3. Scanning Electron Microscope (SEM) of Novel Axitinib Polymorphs (SCAI-Forms) Measurement conditions The powder sample was placed on carbon tape fixed to an aluminum stub. The sample was scanned using a FE-SEM with a JSM-IT800, Jeol. Images were acquired using a secondary electron detector at an accelerating voltage of 1.00kV.

[0065] The crystal structures of Axitinib API and SCAI-Form were analyzed using the measurement method described above. The Axitinib API has a morphological form resembling a piece of wood or a rectangular block. (See Figure 5) On the other hand, the novel axitinib polymorph (SCAI-Form) of the present invention has a non-sharp (rounded) polygonal shape. (See Figure 6)

[0066] Furthermore, as shown in Figure 5, we were able to confirm that the Axitinib API has an aspect ratio much smaller than 0.3, and as shown in Figure 6, we were able to confirm that it has an aspect ratio close to 1.

[0067] In Figure 6, the lower figure is an enlarged view of the upper figure, and the maximum diameter of the molecular aggregate according to the present invention could be measured as shown in Table 5 below.

[0068] [Table 5]

[0069] Experimental Example 4. Solubility of Novel Axitinib Polymorph (SCAI-Form) Method for measuring pH1 solubility: After stirring at a concentration of 5 mg / mL for 15 minutes, the solution was filtered and analyzed after a 10-fold dilution by DW. (The result is recorded as [measured value × 10].)

[0070] Method for measuring pH2 solubility: After stirring at a concentration of 1 mg / mL for 15 minutes, the solution was filtered and analyzed, and the results are shown in Table 6.

[0071] [Table 6]

[0072] As mentioned above, it can be seen that SCAI-Form has about twice the solubility of API.

Claims

1. Axitinib is a molecular aggregate to which axitinib is physically bound. The X-ray powder diffraction spectrum of the molecular aggregate has X-ray diffraction peaks at diffraction angles 2θ of 24.99°±0.1° and 26.32°±0.1°. Molecular association.

2. The molecular aggregate is characterized by having a DSC profile that exhibits 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. The molecular aggregate according to claim 1.

3. The molecular aggregate is characterized by having an aspect ratio value of 0.3 to 1.

0. The molecular aggregate according to claim 1.

4. The molecular aggregate is characterized by having an average particle size of 2 to 15 μm. The molecular aggregate according to claim 1.

5. The aforementioned molecular aggregate is The solubility at pH 1 is 3.0 mg / mL or higher. It is characterized by having a solubility of 0.1 mg / mL or more at pH 2. The molecular aggregate according to claim 1.

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