Crystalline forms of pyrimidine-4-carboxamide compounds and oral pharmaceutical formulations comprising same

Abstract

The present invention relates to novel stable crystalline forms of the compound of Formula 1 and processes for obtaining such crystalline forms. Furthermore, the present invention relates to a pharmaceutical preparation, particularly an oral pharmaceutical preparation, which contains a compound of chemical formula 1 (preferably a compound of a crystal form according to the present invention) as an active ingredient and which has ensured stability, high dissolution rate, high bioavailability, and the like, and a method for preparing the same.

Description

Technical Field

[0001] This application claims the benefit of priority to Korean Patent Application No. 10-2022-0102292, filed on August 16, 2022, and all contents disclosed in the specification and drawings of the said application are incorporated herein by reference.

[0002] The present invention relates to a novel crystalline form of a pyrimidine-4-carboxamide compound having a specific structure and / or an oral (pharmaceutical) preparation comprising the crystalline solid form as an active ingredient. Background Art

[0003] 2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R,2s,3S,5S,7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide represented by the following Chemical Formula 1 is a compound included in the chemical formula disclosed in U.S. Pat. No. 9,096,571.

[0004] [Chemical formula 1]

[0005]

[0006] The compound of Chemical Formula 1 is effective in preventing or treating nonalcoholic steatohepatitis, and has particular characteristics of improving dyslipidemia, protecting liver cells, and exhibiting anti-fibrosis function (see Korean Patent No. 10-2177304).

[0007] The compound of Chemical Formula 1 above is a substance falling within the definition of "almost insoluble", has a water solubility of 1 μg / mL or less, and is classified into Category 2 according to the Biopharmaceutics classification system (BCS).

[0008] There are many difficulties in developing drugs using poorly soluble drug raw materials. For example, amorphous or partially crystalline raw materials can be used to improve water solubility, but amorphous or partially crystalline raw materials have the disadvantage of being unstable compared to crystalline raw materials. In addition, amorphous or partially crystalline raw materials may undergo crystal transition during storage or drug preparation, and it is difficult to control drug dissolution and blood concentration.

[0009] Meanwhile, the method of preparing amorphous solid dispersions using hydrophilic polymers and / or water-soluble carriers can effectively improve the solubility of drugs. However, there is a disadvantage that the amorphous active ingredient of the solid dispersion changes into a crystalline form depending on the storage conditions, resulting in changes in dissolution. In addition, amorphous solid dispersion preparations have a fundamental problem of lower thermodynamic stability compared to preparations using crystalline raw materials. Summary of the invention

[0010] Technical issues

[0011] The object sought to be solved by the present disclosure is to provide a new crystal form of the compound of the above Chemical Formula 1 having physicochemical properties useful as an effective ingredient for a drug, and a method for producing the crystal form.

[0012] Another object sought to be solved by the present disclosure is to provide a pharmaceutical preparation, preferably an oral preparation, and a method for producing the preparation, which contains the compound of the above Chemical Formula 1 as an active ingredient but has ensured stability and high bioavailability.

[0013] Technical Solution

[0014] In order to achieve the above object, one embodiment of the present invention provides a crystalline form of the compound of Chemical Formula 1 (2-((R)-4-(2-fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)-N-((1R, 2s, 3S, 5S, 7S)-5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide), which has a powder X-ray diffraction (PXRD) pattern comprising peaks at the following 2θ diffraction angles: 5.3±0.2°, 7.5±0.2°, 10.1±0.2°, 10. 6±0.2°, 11.5±0.2°, 14.3±0.2°, 14.7±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 16.3±0.2°, 16.5±0.2°, 19.1±0.2°, 19.3±0.2°, 19.7±0.2°, 20.3±0.2°, 20.6±0.2°, 21.4±0.2°, 21.8±0.2°, 22.6±0.2° and 27.5±0.2°.

[0015] [Chemical formula 1]

[0016]

[0017] In another embodiment of the present invention, the present invention provides a crystalline form of the compound of Chemical Formula 1 having Figure 1 X-ray diffraction pattern shown in .

[0018] In another embodiment of the present invention, the present invention provides a crystalline form which shows a 1100 cm -1 (Aromatic CF), 1518cm -1 (NH), 1579cm -1 (aromatic C=C), 1680cm -1 (C=O), 2911cm -1 (aliphatic CH) and 3445cm -1In another embodiment of the present invention, the present invention provides a crystalline form of the compound of Chemical Formula 1, which has the following characteristics in infrared absorbance analysis: Figure 2 The absorption spectrum shown in .

[0019] Even if the compounds have the same chemical formula, they exhibit different physicochemical properties depending on the crystal form. Differences according to the crystal form include, but are not limited to, stability (e.g., thermal stability or light stability), compressibility and density (important in formulation and production), and solubility (which can affect bioavailability). In particular, differences in stability can lead to changes in chemical reactivity (e.g., discoloration, water absorption) or mechanical properties (e.g., changes due to conversion to a thermodynamically more stable polymorph). In particular, humidity stability can vary according to the crystal form, the likelihood of forming a soluble compound can vary, and the ease of filtering or washing can also vary.

[0020] The inventors of the present invention have been able to obtain a stable crystalline form of the compound of Chemical Formula 1 according to the present invention through a lot of efforts, and the crystalline form according to the present invention exhibits the desired physicochemical and mechanical properties in the above-mentioned aspects. In particular, the crystalline form according to the present invention is very stable, so there is no need to worry about the physicochemical properties of the drug ingredient changing during the storage of raw materials, the production of the drug, the storage and distribution of the drug.

[0021] Another embodiment of the present invention also provides a method for preparing a crystalline form of the compound of Formula 1 according to the present invention, comprising the following steps: (S1) dissolving the compound of Formula 1 in ethyl acetate; (S2) adding tert-butyl methyl ether to the ethyl acetate solution of step S1 for crystallization; and (S3) filtering the suspension of step S2 to obtain a crystalline compound of Formula 1.

[0022] In addition, the present inventors attempted to use the compound of Chemical Formula 1, in particular the crystalline form according to the present invention, as a drug raw material to prepare an oral preparation. The compound of Chemical Formula 1 is a substance falling within the definition of "almost insoluble", having a water solubility of 1 μg / mL or less, and is a poorly soluble substance classified as Class 2 (high permeability, low solubility) according to the Biopharmaceutical Classification System (BCS).

[0023] In order to improve the bioavailability of poorly soluble substances, the inventors have made a variety of attempts. First, since the compound of Chemical Formula 1 does not have the feature of improving solubility according to pH, there is no room for controlling the drug dissolution rate by salification. In addition, when using amorphous raw materials or solid dispersion technology in which active ingredients exist in an amorphous state, it is not easy to achieve long-term stability. In addition, even by simply mixing hydrophilic components (e.g., hydrophilic polymers, surfactants), it is difficult to achieve the desired bioavailability level.

[0024] Under such circumstances, the present inventors have determined that when a pharmaceutical preparation is prepared by drying water in which the compound of Chemical Formula 1 is suspended and a hydrophilic polymer is dissolved, not only (long-term) stability can be achieved but also bioavailability can be significantly improved.

[0025] Therefore, another embodiment of the present invention also provides a pharmaceutical preparation, preferably an oral pharmaceutical preparation, comprising particles prepared by drying water in which the compound of the above Chemical Formula 1 (preferably, the compound having the crystalline form according to the present invention) is suspended and a hydrophilic polymer is dissolved.

[0026] In a preferred embodiment of the present invention, the hydrophilic polymer may be at least one selected from the group consisting of hypromellose, polyvinyl pyrrolidone, polyvinyl alcohol and hydroxypropyl cellulose, and among them, for the purpose of the present invention, hypromellose is more preferred.

[0027] In achieving the object of the present invention, the hydrophilic polymer is preferably contained in an amount of 30 to 80 wt % relative to the content of the compound of Chemical Formula 1, and more preferably contained in an amount of 40 to 70 wt % relative to the content of the compound of Chemical Formula 1.

[0028] Another embodiment of the present invention also provides a pharmaceutical preparation, preferably an oral pharmaceutical preparation, comprising particles prepared by drying water in which a micronized compound of Formula 1 (preferably a compound having a crystalline form according to the present invention) is suspended and a hydrophilic polymer is dissolved. The type and content of the hydrophilic polymer are the same as above.

[0029] Preferably, the micronized compound of Chemical Formula 1 has a d(50) of 5 μm or less, and more preferably, a d(50) of 2 μm or less.

[0030] Such micronization of the compound of Chemical Formula 1 may be performed using jet milling, high pressure particle size mill (Microfluidics), etc., but the present invention is not limited to such a specific micronization method.

[0031] The bioavailability of the compound of formula 1 can be significantly improved by a specific preparation method using a hydrophilic polymer, and in particular, the bioavailability can be further improved by using a micronized compound of formula 1 (preferably, a compound having a crystalline form according to the present invention). In the pharmaceutical preparation of the present invention, the hydrophilic polymer is believed to have multiple effects, such as stabilizing the micronized compound of formula 1 dispersed in the suspension phase so that it no longer aggregates and becomes larger, and by binding to the surface of the compound of formula 1 so that it can be fully wetted in an aqueous solution, thereby exhibiting a synergistic effect. However, the present invention is not limited to such theoretical predictions. In particular, the effect of the present invention is closely related to the preparation method, because it is difficult to achieve the desired bioavailability by simply mixing the relevant components.

[0032] In a preferred embodiment of the present invention, the process of micronizing the compound of Chemical Formula 1 can be carried out in water in which the compound of Chemical Formula 1 (preferably, the compound having the crystalline form according to the present invention) is suspended and the hydrophilic polymer is dissolved. In other words, in a preferred embodiment of the present invention, the process of micronizing the compound of Formula 1 is carried out after mixing with the hydrophilic polymer.

[0033] Another embodiment of the present invention also provides a pharmaceutical preparation, preferably an oral pharmaceutical preparation, comprising particles prepared by drying water in which a compound of Chemical Formula 1 (preferably a compound having a crystalline form according to the present invention and micronized) is suspended and a hydrophilic polymer and a surfactant are dissolved. The type and content of the hydrophilic polymer and the micronization-related technology are the same as above.

[0034] The surfactant is preferably at least one selected from the group consisting of lauryl sulfate, poloxamer, glyceryl monostearate, polyoxyethylene and docusate salt, and for the purpose of the present invention, sodium lauryl sulfate is particularly preferred.

[0035] Preferably, such a surfactant is contained in the pharmaceutical preparation in an amount of 0.2 wt% to 2 wt% relative to the total weight of the pharmaceutical preparation.

[0036] The granules prepared by drying water in which the compound of Chemical Formula 1 (preferably a compound having a crystalline form according to the present invention and micronized) is suspended and a hydrophilic polymer and optionally a surfactant are dissolved can be prepared into capsules by mixing with other carriers (e.g., diluents), lubricants, etc. and filling into empty capsules, or can be prepared into tablets by mixing with other carriers, lubricants, etc. and then compressing. In a preferred embodiment of the present invention, the pharmaceutical preparation is a tablet.

[0037] The granules may be prepared by spraying onto other carriers and then drying water in which the compound of Chemical Formula 1 (preferably a compound having a crystalline form according to the present invention and micronized) is suspended and a hydrophilic polymer and optionally a surfactant are dissolved.

[0038] The following carriers that can be used in the present invention can be used: for example, microcrystalline cellulose, lactose, lactose hydrate, anhydrous lactose, mannitol, starch, dihydrogenated calcium phosphate, anhydrous divalent calcium phosphate, etc. as diluents. In a preferred embodiment of the present invention, the carrier is microcrystalline cellulose, lactose hydrate, mannitol, or a mixture thereof. In a preferred embodiment of the present invention, the carrier is microcrystalline cellulose and lactose hydrate. In a preferred embodiment of the present invention, the carrier is microcrystalline cellulose, lactose hydrate and mannitol.

[0039] The pharmaceutical preparation of the present invention may further optionally comprise a disintegrant. The disintegrant may be, for example, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, maltodextrin, or a mixture thereof. In a preferred embodiment of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone.

[0040] The pharmaceutical preparation of the present invention may optionally further comprise a lubricant. Lubricants are used to ensure smooth flow during capsule filling, packaging, etc., or to prevent sticking, capping, etc. during tablet compression. Suitable lubricants include colloidal silicon dioxide, talc, magnesium stearate, or a mixture thereof. In a preferred embodiment of the present invention, the lubricant is magnesium stearate.

[0041] Beneficial effects

[0042] One embodiment of the present invention provides a stable new crystalline form of the compound of Chemical Formula 1 and a method for obtaining such a crystalline form. Another embodiment of the present invention also provides a pharmaceutical preparation, preferably an oral pharmaceutical preparation, and a method for preparing the same, the pharmaceutical preparation comprising the compound of Chemical Formula 1 as an active ingredient (preferably a crystalline compound according to the present invention) and ensuring stability, high dissolution rate, high bioavailability, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the result of powder X-ray diffraction (PXRD) evaluation of the crystalline compound prepared in Example 1.

[0044] Figure 2 It is the result of infrared spectrum (IR) absorbance measurement of the crystalline compound prepared in Example 1.

[0045] Figure 3: is a graph comparing blood concentrations obtained after orally administering the tablet prepared in Preparation Example 10, which is one embodiment of the present invention, and the tablet prepared in Comparative Example to beagle dogs. DETAILED DESCRIPTION

[0046] Hereinafter, in order to help understand the present invention, embodiments and the like will be described in detail. However, the embodiments according to the present invention can be modified in a variety of different forms, and the scope of the present invention should not be interpreted as being limited to the following embodiments. The embodiments of the present invention are provided to explain the present invention more completely to a person with general knowledge in the field to which the present invention belongs.

[0047] Example 1: Preparation of a crystalline solid (crystal form) of the compound of formula 1

[0048] 4.14 kg of the compound of Chemical Formula 1 in solid form was dissolved in 17 kg of ethyl acetate, stirred at room temperature, and 15.5 kg of tert-butyl methyl ether was gradually added. The resultant was stirred at 25° C. for 3 hours to obtain a uniform suspension, which was filtered and washed with 2.5 kg of tert-butyl methyl ether. The resultant was vacuum dried at 45° C. for 15 hours and 3.52 kg of a white crystalline solid was obtained. (yield 85%).

[0049] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=4.8Hz,1H),8.20(d,J=7.8Hz,1H),7.68(dd,J=2.2,12.4Hz,1H),7.65(dd,J=2.2,8. 5Hz,1H),7.25(t,J=8.5Hz,1H),7.16(d,J=4.8Hz,1H),4.93-4.88(m,1H),4.56-4.52(m,1H),4.49(s,1H),3.96-3.93(m ,1H),3.67-3.63(m,1H),3.59-3.56(m,1H),3.41-3.37(m,1H),3.20(s,3H),3.14-3.11(m,1H),3.01-2.98(m,1H),2.10 -2.05(m,3H),1.78-1.72(m,4H),1.68-1.63(m,4H),1.49-1.44(m,2H),1.29(d,J=6.7Hz,3H); MS(FAB)m / z:544[M+H]+.

[0050] In order to obtain a suitable crystalline form, in addition to the combination conditions of ethyl acetate / tert-butyl methyl ether in Example 1, various other combinations were tried (for example, using diethyl ether, isobutyl acetate, isopropyl acetate, methyl isobutyl ketone, n-butyl acetate, n-heptane, n-pentane, n-hexane, cyclohexane, methylcyclohexane, tetrahydrofuran, acetone, etc. instead of tert-butyl methyl ether), but no crystalline form with satisfactory stability was obtained.

[0051] Meanwhile, tert-butyl methyl ether was fixed, and solvents such as acetonitrile, dichloromethane, 1,2-dichloroethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, 1,4-dimethoxyethane, In the present invention, ethyl acetate was replaced by alkane, methanol, ethanol, ethylene glycol, 1-butanol, 2-butanol, 1-propanol, 2-propanol and propyl acetate. However, a sufficiently stable crystalline form as a pharmaceutical raw material was not obtained.

[0052] In addition, the above-mentioned combination of ethyl acetate / tert-butyl methyl ether was changed, and various combinations of solubilizing solvents and antisolvents were tried to prepare the crystal form, but the target crystal form could not be obtained.

[0053] When preparing the crystalline form of the drug raw material, it is very important to select a suitable single solvent or mixed solvent. The resulting crystalline solid must have excellent stability and desired physical properties, and after the crystalline solid is dried, it must meet the residual solvent tolerance standards of the ICH guideline (GUIDELINE FOR RESIDUAL SOLVENTS Q3C) (R8). For this reason, solvates, except hydrates, are generally not used as drug raw materials, even if they actually have excellent crystallinity.

[0054] The present inventors attempted to dissolve the compound of Chemical Formula 1 using a single solvent as a solubilizing solvent and then precipitate the solid using a solvent evaporation method, but the crystalline form obtained in this way has the following problems: it is a solvate, or even after a long period of reduced pressure drying, the residual solvent is not sufficiently removed, so it greatly exceeds the ICH standard. In the method of inducing solid precipitation using a variety of solubilizing solvents and antisolvents, the results obtained are mainly amorphous, solvated or other crystalline forms, which cannot be used as raw materials for drugs because the residual solvent is not easy to remove. Even so, the yield is low or discoloration occurs during the preparation process.

[0055] In other words, the present inventors have determined that the combination of ethyl acetate / tert-butyl methyl ether as a mixed solvent is suitable for the purpose of the present invention, and the combination is used to prepare the crystalline form of the above Chemical Formula 1 having suitable properties as a raw material for a drug. The crystalline solid thus obtained not only has excellent stability and physical properties, but is also an anhydrous crystalline form, and the residual solvent analysis result does not exceed the residual limit allowed by the ICH guidelines for each of the above solvents, so it is sufficient to be used as a raw material for a drug.

[0056] Experimental Example 1: Powder X-ray Diffraction (PXRD) Analysis of the Crystalline Form of Example 1

[0057] The powder X-ray diffraction pattern is a unique characteristic of a crystalline form and is widely used to distinguish polymorphs and hydrates.

[0058] Crystallinity analysis of the crystalline compound produced in Example 1 was performed on an X-ray powder diffractometer using Cu-Kα radiation. The measuring equipment was equipped with reactive power, and the current was set to 45 kV and 40 mA. The divergence and scattering slits were set to 1 °, and the receiving slit was set to 0.2 mm. A θ-2θ continuous scan of 3 ° / min (0.4 sec / 0.02 ° step) was used from 5 ° to 35 ° 2θ.

[0059] The experimental results are Figure 1 In the display. Figure 1 As disclosed in , the crystalline compound prepared according to Example 1 has a powder X-ray diffraction (PXRD) pattern comprising peaks at the following 2θ diffraction angles: 5.3±0.2°, 7.5±0.2°, 10.1±0.2°, 10.6±0.2°, 11.5±0.2°, 14.3±0.2°, 14.7±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 16.3±0.2°, 16.5±0.2°, 19.1±0.2°, 19.3±0.2°, 19.7±0.2°, 20.3±0.2°, 20.6±0.2°, 21.4±0.2°, 21.8±0.2°, 22.6±0.2° and 27.5±0.2°.

[0060] Experimental Example 2: Infrared Spectroscopy (IR) Analysis of the Crystalline Form of Example 1

[0061] The vibrational energy between atoms of the molecules that make up a substance in a crystalline solid varies depending on the crystal structure, which means that different crystal forms exhibit different infrared absorbances. Therefore, it can be considered that the infrared absorbance of a particular crystalline material reflects the unique characteristics of the crystal form.

[0062] The infrared absorbance of the crystal prepared in Example 1 was analyzed using Perkin Elmer FT-IR (Fourier transform infrared spectroscopy), and the results were Figure 2 As shown in Figure 2 As disclosed in -1 (Aromatic CF), 1518cm -1 (NH), 1579cm -1 (aromatic C=C), 1680cm -1 (C=O), 2911cm -1 (aliphatic CH) and 3445cm -1 Absorption spectrum at (OH).

[0063] Experimental Example 3: Stability Evaluation of the Crystalline Form of Example 1

[0064] The compound of Chemical Formula 1 is a raw material for pharmaceutical purposes, and appropriate specifications and stability must be ensured to set the storage method and shelf life of the drug. In other words, the stability of the pharmaceutical raw material is one of the most important factors in maintaining the quality of the final product.

[0065] The stability of the crystalline solid of the compound of Chemical Formula 1 prepared by Example 1 was evaluated. According to the ICH guidelines, the stability test was carried out under long-term storage (25 ± 2 ° C, 60 ± 5% RH) and accelerated (40 ± 2 ° C, 75 ± 5% RH) conditions. HPLC was used for analysis to evaluate the change in content and the appearance of impurities, and the results are shown in Table 1 below.

[0066] Results of stability evaluation of the crystallized compound of Chemical Formula 1 (HPLC, %)

[0067] [Table 1]

[0068]

[0069] As can be seen from the results in Table 1 above, the crystalline solid compound of Chemical Formula 1 of the present invention has excellent stability when stored under long-term and accelerated storage conditions, with almost no change in content and no increase in impurities for up to 12 months and 6 months, respectively.

[0070] In addition, the crystal form of the samples stored for 3, 6 and 12 months (in the case of long-term storage test) in the stability test was measured in the same manner as in Experimental Example 1, and it was determined that the crystal form did not change. For substances of BCS category 2, such as the compound of Chemical Formula 1, it is very important that the crystal form remains stable under storage conditions. The more insoluble the substance, the greater the impact of the change in crystallinity on the quality of the final product. Changes in crystal form lead to changes in hygroscopicity, stability, solubility, etc. Sometimes, the quality of the final product can be significantly reduced, even for partial crystallization transformations (where only a portion of the drug raw material changes instead of all). The crystal form of the present invention is suitable for use as a raw material for drugs because it does not undergo polymorphic transformation over time.

[0071] Preparation Examples 1 to 3 of Final Products: Preparation of Formulations of Compounds of Formula 1 with Different Particle Sizes

[0072] Preparation Examples 1 to 3, which are compositions containing the crystal form of Example 1, were prepared according to the following Table 2. In the case of Preparation Examples 2 and 3, the compositions were all exactly the same, and only the preparation methods were different to prepare preparations having different particle sizes.

[0073] [Table 2]

[0074]

[0075] First, in the composition of Table 2, Preparation Example 1 does not apply any treatment to the compound of Chemical Formula 1 as the main component.

[0076] In Preparation Example 2, the adhesive solution Those ingredients used in are mixed, and then homogenized using a homogenizer to prepare a binding solution containing particles of the compound of Chemical Formula 1.

[0077] In Preparation Example 3, those ingredients used in the binding solution were mixed and then pulverized under high-energy grinding conditions using a high-pressure particle size grinder (Microfluidics) to prepare a binding solution containing micronized particles of the compound of Chemical Formula 1.

[0078] The particle size of the compound of Chemical Formula 1 in Preparation Examples 2 and 3 was measured in the state of a binder solution, that is, in a state where SLS and HPMC were mixed. Since the binder solution is in a suspended state, SLS and HPMC are dissolved in purified water, and only the main component is suspended in a solid state, the particle size of the main component can be measured. The particle size of the compound of Chemical Formula 1 was measured using a laser scattering particle size analyzer (Mastersizer 2000, manufacturer: Malvern Instruments). The particles of the compound of Chemical Formula 1 prepared according to Preparation Examples 1 to 3 and the solvent (purified water) were added to a beaker (1,000 ml), stirred at 1,500 rpm, and the particles in the uniformly suspended dispersed phase were measured. The results are shown in Table 3.

[0079] <Conditions for measuring particle size>

[0080] Device: Malvern Mastersizer 2000 / Hydro 2000MU

[0081] Sample size: 0.5g

[0082] Sample refractive index: 1.520

[0083] Annotation Mode: General Purpose

[0084] Sensitivity: Normal

[0085] Sample measurement time: 10 seconds

[0086] Annotation range: 0.020 to 2000.0 μm

[0087] [Table 3]

[0088]

[0089] In the case of Preparation Examples 2 to 3, granules were prepared using a fluidized bed granulator. The binding solution was sprayed onto microcrystalline cellulose and lactose hydrate used as carriers, and granules were prepared under the following conditions: an injection temperature of 70°C to 85°C, an internal temperature of 35°C to 45°C, and an injection rate of 6 to 30 g / min. The main components or granules prepared in Preparation Examples 1 to 3 were filled into capsules.

[0090] Experimental Example 4: Effect of particle size on dissolution rate

[0091] The preparations of Preparation Examples 1 to 3 were tested using the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test. Dissolution was carried out using purified water, a paddle speed of 50 rpm, and at 37°C, and quantification was carried out using HPLC (manufacturer: Agilent) under the following conditions. The results are shown in Table 4.

[0092] [HPLC measurement conditions]

[0093] Detector: UV spectrophotometer (measurement wavelength: 254 nm)

[0094] Column: Inertsil ODS-4C18 (4.6 × 150 mm, 5 μm)

[0095] Flow rate: 1.0 mL / min

[0096] Column temperature: 35°C

[0097] Mobile phase: pH 3.0 phosphoric acid solution: acetonitrile = 4:6 (v / v%)

[0098] Injection volume: 20 μL

[0099] [Table 4]

[0100]

[0101] As can be seen from Table 4 above, the dissolution rate and dissolution velocity are affected by particle size, and it was evaluated that the dissolution rate increases as the particle size decreases. It is speculated that this is because the surface area increases as the particle size decreases, but the present invention is not limited to this theoretical mechanism. In terms of the dissolution rate at 45 minutes, the dissolution rate of Preparation Examples 2 to 3 with reduced particle size increased by about two times compared to Preparation Example 1. In addition, it was determined that the additional use of a hydrophilic polymer is necessary to increase the dissolution rate, and therefore an evaluation was performed.

[0102] Preparation Examples 4 to 6: Dissolution changes according to the content of hydrophilic polymer

[0103] In order to compare and evaluate the dissolution effect according to the content of the hydrophilic polymer, tablets of Preparation Examples 4 to 6 were prepared with the compositions shown in the following Table 5. Preparation Example 4 used the hydrophilic polymer only in the binding solution 1, while Preparation Examples 5 to 6 additionally used the binding solution 2 in which the hydrophilic polymer was dissolved.

[0104] [Table 5]

[0105]

[0106] Preparation Example 4 was prepared as follows: granules were prepared using the method of Preparation Example 3, and then the granules were fully mixed with mannitol, crospovidone and magnesium stearate, and then compressed into tablets.

[0107] Preparation Examples 5 to 6 were prepared as follows: a binding solution 1 was prepared using the method of Preparation Example 3, and a binding solution 2 was prepared by mixing hypromellose with purified water. Then, the binding solution 1 and the binding solution 2 were mixed to prepare a final binding solution. Then, using microcrystalline cellulose and lactose hydrate as carriers, granules were prepared according to the method of Preparation Example 3. The prepared granules were fully mixed with mannitol, crospovidone, and magnesium stearate, and then compressed into tablets.

[0108] The particle sizes of the compounds of Chemical Formula 1 prepared according to Preparation Examples 4 to 6 were measured using a laser scattering particle size analyzer (Mastersizer 2000, manufacturer: Malvern Instruments). The results are shown in Table 6 below.

[0109] [Table 6]

[0110]

[0111]

[0112] Experimental Example 5: Dissolution changes according to the content of hydrophilic polymer

[0113] Similar to Experimental Example 4, the tablets of Preparation Examples 4 to 6 were tested by the second dissolution test method (paddle method) of the Korean Pharmacopoeia. The dissolution solution was purified water, the paddle speed was 50 rpm, and the dissolution test was performed at 37°C. Under the same conditions as Experimental Example 4, quantification was performed by HPLC (manufacturer: Agilent). The results are shown in Table 7.

[0114] [Table 7]

[0115]

[0116] As shown in Table 7, the dissolution rate of Preparation Example 4 in which the amount of the hydrophilic polymer (hydroxypropyl methylcellulose) was 15 mg per tablet (15 parts by weight relative to 100 parts by weight of the compound of Chemical Formula 1) was not improved much. However, in Preparation Examples 5 to 6 in which the amount of the hydrophilic polymer was 50 to 60 mg per tablet (50 to 60 parts by weight relative to 100 parts by weight of the compound of Chemical Formula 1), the dissolution rate was improved by about 5 to 6 times compared with Preparation Example 4.

[0117] Preparation Examples 7 to 10: Dissolution changes according to the amount of surfactant

[0118] The effect on dissolution according to the amount of surfactant was compared and evaluated. Tablets of Preparation Examples 7 to 10 were prepared with the compositions shown in Table 8 below.

[0119] [Table 8]

[0120]

[0121] Preparation Examples 7 to 10 were prepared according to the method of Preparation Example 6. The amount of the surfactant was 1.5 to 8 mg, and the difference according to the amount of the surfactant and the preparation method was evaluated by using each of the binding solution 1 and the binding solution 2.

[0122] The particle sizes of the compounds of Chemical Formula 1 prepared according to Preparation Examples 7 to 10 were measured using a laser scattering particle size analyzer (Mastersizer 2000, manufacturer: Malvern Instruments). The results are shown in Table 9 below.

[0123] [Table 9]

[0124]

[0125] Experimental Example 6: Dissolution changes according to surfactant content

[0126] The tablets of Preparation Examples 7 to 10 were tested by the second dissolution test method (paddle method) of the Korean Pharmacopoeia. The dissolution solution was purified water (added with 0.3 wt% sodium lauryl sulfate (SLS)), the paddle speed was 50 rpm, and the dissolution test was carried out at 37 °C. Quantification was performed by HPLC (manufacturer: Agilent) under the same conditions as the previous method. The results are shown in Table 10 below.

[0127] [Table 10]

[0128]

[0129] As shown in Table 10 above, regardless of the amount of surfactant in each tablet varying from 1.5 mg to 8 mg, the final dissolution rate achieved within 60 minutes was similar.

[0130] Experimental Example 7: Stability Test of Formulation

[0131] For Preparation Example 10, the content and impurities were evaluated after storage under accelerated conditions (40 ± 2 °C, 75% RH ± 5%) and long-term conditions (25 ± 2 °C, 60% RH ± 5%). The results are shown in Tables 12 to 13. The unit is %.

[0132] <HPLC Measurement Conditions_Content>

[0133] Detector: UV spectrophotometer (measurement wavelength: 254 nm)

[0134] Column: Inertsil ODS-4C18 (4.6 × 150 mm, 5 μm)

[0135] Flow rate: 1.0 mL / min

[0136] Column temperature: 35 °C

[0137] Mobile phase: pH 3.0 phosphoric acid solution: acetonitrile = 4:6 (v / v%)

[0138] Injection volume: 20 μL

[0139] Measurement range: 7 minutes

[0140] <HPLC Measurement Conditions_Purity>

[0141] Detector: UV spectrophotometer (measurement wavelength: 254 nm)

[0142] Column: YMC Hydrosphere C18 5 μm, 4.6 × 250 mm

[0143] Flow rate: 1.0 mL / min

[0144] Column temperature: 35 °C

[0145] Mobile phase A: 0.68 g of potassium dihydrogen phosphate was dissolved in water to make up to 1000 mL, and the pH was adjusted to 3.0 with phosphoric acid.

[0146] Mobile phase B: acetonitrile and methanol in a ratio of 95:5.

[0147] Measuring range: 60 minutes

[0148] Gradient elution conditions:

[0149] [Table 11]

[0150] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 80 20 20 30 70 40 20 80 45 20 80 50 80 20 60 80 20

[0151] [Table 12]

[0152]

[0153] [Table 13]

[0154] content(%) Accelerated conditions 1 month Accelerated conditions 3 months Accelerated conditions 6 months Preparation Example 10 100.65 98.21 98.17 purity(%) Accelerated conditions 1 month Accelerated conditions 3 months Accelerated conditions 6 months Preparation Example 10 0.23 0.23 0.24

[0155] As shown in Tables 12 and 13 above, during the time period of the stability test, as a result of the content evaluation and purity test, it was determined that the formulation of the present invention was stable without significant changes.

[0156] Experimental Example 8: Comparative Pharmacokinetic Testing of Formulations

[0157] Tablets containing 25, 50 and 100 mg of the crystalline solid of Chemical Formula 1 as a drug raw material were prepared by applying the conditions of Preparation Example 10. An experiment was conducted to analyze the pharmacokinetic characteristics of the prepared tablets after oral administration to beagle dogs.

[0158] The compound of Chemical Formula 1 was administered orally as a single dose of 25, 50 and 100 mg tablets / head, orally as a single dose of 25 mg liquid / head, and intravenously as a single dose of 2 mg / kg to beagle dogs. Blood samples were collected before (0) and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 16 hours and 24 hours after the administration of the test substance to measure the blood concentration of the compound of Chemical Formula 1.

[0159] A preparation for single oral administration in liquid / head was prepared by uniformly suspending 275 mg of the compound of Chemical Formula 1 in 220 ml of a previously prepared 2.5% HP-βCD (sterile aqueous solution) to obtain 1.25 mg / ml. In addition, a preparation for single intravenous administration was prepared by dissolving 300 mg of the compound of Chemical Formula 1 in 150 ml of a previously prepared 10% HP-βCD (sterile aqueous solution) to obtain 2 mg / ml.

[0160] As a result of observing general symptoms after administration, no abnormal symptoms due to administration of the test substance were observed during the entire experimental period.

[0161] The analytical method validation results in canine plasma confirmed that there was no influence of interfering substances, and it showed good linearity in the concentration range of 5 to 5000 ng / mL (plasma), as well as consistent results of intra- and inter-assay accuracy and precision. It showed sufficient selectivity, linearity, accuracy and precision and could be applied to sample analysis.

[0162] The drug concentration-time curves analyzed in plasma obtained by administering the tablet and liquid compound of Chemical Formula 1 and the pharmacokinetic parameters calculated using BA Calc 2007 program show as follows: Figure 3 and the spectra shown in Table 14.

[0163] [Table 14]

[0164]

[0165] As shown in Table 14 above, in the case of tablets, drug absorption (AUC 最终 ) tends to increase with increasing doses. The maximum drug concentration absorption time (T 最大 ) showed a range of 1 to 2 hours at each dose, and the mean half-life (t 1 / 2 ) were 4.42 hours, 5.29 hours, and 6.89 hours, indicating a pattern in which the excretion rate slowed down with increasing administered doses.

[0166] When comparing the 25 mg / head tablet administration group and the liquid administration group, the average absorption (AUC 最终 ) reached the average absorption (AUC) of the liquid administration group 最终 ), demonstrating that the oral formulation of the poorly soluble drug compound of Chemical Formula 1 is optimized in terms of solubility and in vivo absorption.

[0167] In conclusion, the present inventors obtained a stable new crystalline solid of the compound of Chemical Formula 1, and used it to obtain an oral preparation having excellent stability and oral absorption rate.

Claims

1. A crystalline form of the compound of Chemical Formula 1, having a powder X-ray diffraction (PXRD) pattern comprising peaks at the following 2θ diffraction angles: 5.3±0.2°, 7.5±0.2°, 10.1±0.2°, 10.6±0.2°, 11.5±0.2°, 14.3±0.2°, 14.7±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 16.3±0.2°, 16.5±0.2°, 19.1±0.2°, 19.3±0.2°, 19.7±0.2°, 20.3±0.2°, 20.6±0.2°, 21.4±0.2°, 21.8±0.2°, 22.6±0.2° and 27.5±0.2°. [Chemical formula 1] 2. A method for preparing a crystalline form of the compound of Chemical Formula 1 according to claim 1, comprising: (S1) a step of dissolving the compound of Chemical Formula 1 in ethyl acetate; [Chemical formula 1] (S2) adding tert-butyl methyl ether to the ethyl acetate solution of step S1 to perform crystallization; and (S3) A step of filtering the suspension obtained in step S2 to obtain a crystalline compound of Chemical Formula 1.

3. A pharmaceutical preparation comprising particles prepared by drying water in which the compound of Chemical Formula 1 is suspended and a hydrophilic polymer is dissolved. [Chemical formula 1] 4. The pharmaceutical preparation according to claim 3, wherein the hydrophilic polymer is at least one selected from the group consisting of hypromellose, polyvinyl pyrrolidone, polyvinyl alcohol and hydroxypropyl cellulose.

5. The pharmaceutical formulation according to claim 4, wherein the hydrophilic polymer is hypromellose. 6 . The pharmaceutical preparation according to claim 3 , wherein the content of the hydrophilic polymer relative to the compound of Chemical Formula 1 is 30 wt % to 80 wt %. 7 . The pharmaceutical preparation according to claim 6 , wherein the content of the hydrophilic polymer relative to the compound of Chemical Formula 1 is 40 wt % to 70 wt %.

8. The pharmaceutical preparation according to claim 3, wherein the compound of Chemical Formula 1 is micronized.

9. The pharmaceutical preparation according to claim 8, wherein the d(50) of the micronized compound of Chemical Formula 1 is 5 μm or less.

10. The pharmaceutical preparation according to claim 9, wherein the micronized compound of Chemical Formula 1 has d(50) of 2 μm or less.

11. The pharmaceutical preparation according to claim 3, wherein a surfactant is dissolved in the water.

12. The pharmaceutical preparation according to claim 11, wherein the surfactant is at least one selected from the group consisting of lauryl sulfate, poloxamer, glyceryl monostearate, polyoxyethylene, and docusate.

13. The pharmaceutical formulation according to claim 12, wherein the surfactant is sodium lauryl sulfate. 14 . The pharmaceutical preparation according to claim 11 , wherein the surfactant is contained in an amount of 0.2 wt % to 2 wt % based on the total weight of the pharmaceutical preparation. 15 . The pharmaceutical preparation according to any one of claims 3 to 14 , wherein the compound of Chemical Formula 1 has the crystal form according to claim 1 .

16. The pharmaceutical formulation according to any one of claims 3 to 14, wherein the pharmaceutical formulation is for oral use.

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