KR20130088989A - Co-crystals of bicalutamide and nicotinamide - Google Patents

Abstract

PURPOSE: A co-crystals of bicalutamide and nicotinamide improves the solubility of bicalutamide medicine to increase bioavailability, so that the co-crystal is useful for cancer treatment, as an activity inhibitor of androgen. CONSTITUTION: A co-crystals of bicalutamide and nicotinamide has bicalutamide and nicotinamide. The molar ratio between bicalutamide and nicotinamide is at 0.5: 1-0.1: 1. A manufacturing method for the co-crystals of bicalutamide and nicotinamide comprises the steps of: dissolving bicalutamide and nicotinamide in an organic solvent to produce a mixture solution, forming co-crystals of bicalutamide consisting of bicalutamide and nicotinamide, and collecting the co-crystals of bicalutamide produce in the previous step.

Description

Co-crystals of bicalutamide and nicotinamide < RTI ID = 0.0 >

The present invention relates to a pharmaceutical composition comprising, as an active ingredient, a co-crystal of bicalutamide consisting of bicalutamide and nicotinamide, a co-crystal of said bicalutamide, and a pharmaceutical composition comprising said bicalutamide crystal And a manufacturing method thereof.

Bicalutamide is represented by the following formula (1), and its compound name is N- [4-cyano-3- (trifluoromethyl) phenyl] -3- [4- (fluorophenyl) -Hydroxy-2-methylpropanamide. ≪ / RTI >

[Formula 1]

Bicalutamide has an androgen-inhibiting activity and is currently marketed as a treatment for prostate cancer. Several patent documents relating to bicalutamide have been reported. [U.S. Patent No. 4,636,505 and International Patent Publication Nos. WO 01 / 034,563, WO 03 / 053,920, WO 05 / 037,777, WO 06 / 006,736]

Since the drug has to reach the target cell or must be easy to bind to the target receptor in order to pass through the cell membrane or to have affinity with the receptor, the molecular structure of the drug should have a certain hydrophobicity Only. As a result, candidate medicines with high physiological activity have often been referred to as 'poorly soluble drugs', which exhibit low solubility in water. Bicalutamide is also classified as a poorly soluble drug. The low solubility of the poorly soluble drug lowers the absorption rate of the drug and leads to a decrease in the physiological activity thereof, so that the solubility should be improved.

Therefore, in order for bicalutamide to exhibit a sufficient therapeutic effect as an androgenase inhibitor, there is a desperate need to develop new medicines with improved dissolution characteristics of bicalutamide.

The present invention aims to improve the solubility of bicalutamide to improve bioavailability.

In order to solve the above problems, the present invention is characterized by the co-crystals of bicalutamide consisting of bicalutamide and nicotinamide.

In addition, the present invention is characterized by a pharmaceutical composition wherein the co-crystal of bicalutamide is included as an active ingredient.

The present invention also provides a process for preparing a mixed solution by dissolving bicalutamide and nicotinamide in an organic solvent; A process for producing a co-crystal of bicalutamide consisting of bicalutamide and nicotinamide; And recovering the co-crystals of the resulting bicalutamide; Characterized in that the method comprises the steps of:

The bicalutamide crystals according to the present invention can be easily mass produced in a simple and easy manner.

The co-crystals of bicalutamide according to the present invention are excellent in solubility in water and improve the bioavailability.

The co-crystals of bicalutamide according to the present invention are useful as therapeutic agents for cancer diseases treatable by conventional bicalutamide drugs.

Figure 1 is a differential scanning calorimetry (DSC) analysis of bicalutamide.
Figure 2 is a powder X-ray diffraction diagram for bicalutamide.
Figure 3 is a differential scanning calorimetry (DSC) analysis of nicotinamide.
Figure 4 is a powder X-ray diffraction diagram for nicotinamide.
Figure 5 is a differential scanning calorimetry (DSC) analysis of co-crystals of bicalutamide and nicotinamide.
6 is a powder X-ray diffraction diagram for the co-crystallization of bicalutamide and nicotinamide.
FIG. 7 is a scanning electron microscope (SEM) photograph of pure bicalutamide, pure nicotinamide, and co-crystals of bicalutamide and nicotinamide, respectively.
Figure 8 is a solubility curve in methanol solvent for pure bicalutamide, pure nicotinamide, and co-crystals of bicalutamide and nicotinamide, respectively.
Figure 9 is a solubility curve for pure bicalutamide and water solubility for co-crystals of bicalutamide and nicotinamide, respectively.

The present invention relates to the co-crystals of bicalutamide consisting of bicalutamide and nicotinamide.

Figures 1 to 4 show DSC thermograms and powder XRD patterns for bicalutamide or nicotinamide, respectively. The DSC thermal analysis chart and the powder XRD pattern for the co-crystallization of bicalutamide according to the present invention are shown in FIGS. 5 to 6. FIG.

The co-crystals of bicalutamide according to the present invention showed a maximum endothermic peak at 110 to 120 DEG C on a spectrum analyzed by DSC. Also, the co-crystals of the bicalutamide were 8.0, 16.0, 18.1, 20.1, 21.1, 22.8, 23.9, 24.2, 25.2, 25.8, 26.6, 28.7, 29.2, 31.1, 32.5, 33.4, 33.9, 35.5 and has a crystal structure characterized by showing the 36.7 and diffraction angles _{(2θ, I / I 0>} 10%) of 39.3 °.

The above DSC thermal analysis and powder XRD pattern are compared with each other to confirm that the co-crystal of bicalutamide according to the present invention is a novel substance having physicochemical properties completely different from bicalutamide.

In addition, the co-crystals of bicalutamide according to the present invention were confirmed to have excellent solubility in water by comparison with bicalutamide. [Experimental Example 5]

As described above, the co-crystal of bicalutamide according to the present invention is a novel compound exhibiting physicochemical properties different from bicalutamide, and is also excellent in dissolution characteristics to water required as an active ingredient of a pharmaceutical composition. Accordingly, the present invention provides a pharmaceutical composition comprising the above-mentioned co-crystal of bicalutamide as an active ingredient, and the pharmaceutical composition of the present invention can be used as a therapeutic agent for a cancer disease treatable by a bicalutamide drug.

The pharmaceutical composition according to the present invention may contain the co-crystals of bicalutamide as an active ingredient within the range of 0.1 to 99% by weight based on the total weight of the pharmaceutical composition.

The daily effective dose of the pharmaceutical composition of the present invention is 0.01 to 1000 mg / day on an adult basis. The dose may vary depending on the patient's age, body weight, sex, dosage form, health condition, Or may be administered once or several times a day at a predetermined time interval according to the judgment of a pharmacist.

The pharmaceutical composition of the present invention can be formulated into a formulation by a conventional formulation method by including a carrier, adjuvant or diluent commonly used as an excipient together with a co-crystal of bicalutamide as an active ingredient, and the composition can be administered orally or parenterally It can be used in the form of a general pharmaceutical preparation.

Examples of excipients which can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonizing agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers and fragrances. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like. It is also possible to use, as diluents, for example, powders of cellulose, microcrystalline cellulose, microcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts and other substituted and substituted A cellulose-derived material such as cellulose, which is not water-soluble; Starch; Pregelatinized starch; And other diluents commonly used in the field of pharmaceutical formulation, including inorganic diluents such as calcium carbonate and dibasic calcium phosphate. In addition, other suitable diluents include sugar alcohols such as waxes, sugars and mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin. The present invention further includes acacia gums, pregelatinized starches, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tabletting processes as further excipients and may be used with sodium starch glycolate, crospovidone, Low substituted hydroxypropylcellulose and others may be used. Also included are tabletting lubricants such as magnesium and calcium stearate and sodium stearyl fumarate as excipients; Condiment; sweetener; antiseptic; Pharmaceutically acceptable dyes and glidants such as silicon dioxide may be used.

The route of administration of the pharmaceutical composition may vary depending on the nature and severity of the condition to be treated and may vary depending on the type of solid preparation such as tablets, powders, granules, aggregates, capsules, suppositories, sachets, troches, As well as a solution, a syrup, a suspension, an excipient and the like, and may be administered orally or parenterally. The capsule may contain a solid composition in a capsule or other conventional encapsulating material which may be prepared with gelatin. Tablets and powders can be coated. Tablets and powders can also be coated with enteric coatings. The intestinally coated powder type may be prepared by dissolving or dispersing a mixture of phthalic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, And, if desired, they can be used with suitable plasticizers and / or extenders. Coated tablets may have a coating on the surface of the tablet or may be a tablet containing a powder or granules with enteric coating. When formulated for parenteral administration, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and sterilized aqueous solutions are included.

Meanwhile, the co-crystallization of bicalutamide according to the present invention can be easily performed by a solvent evaporation method, a cooling method, or a solvent crystallization method using a non-solvent as a crystallization solvent.

The method for preparing bicalutamide according to the present invention will now be described in more detail.

The first step is a step of dissolving bicalutamide and nicotinamide in an organic solvent to prepare a mixed solution.

The organic solvent used in the first step is a good solvent for dissolving bicalutamide and nicotinamide. Examples of the organic solvent include alcohols such as methanol, ethanol, propanol and isopropanol, methyl ethyl ketone (MEK), acetic acid, acetone, acetonitrile ACN), a single solvent of ethyl acetate, or a mixed solvent of two or more selected from these may be used. The amount of the organic solvent used may vary depending on the selected solvent or the dissolution temperature. The concentration of the bicalutamide can be appropriately adjusted within the range of 0.001 to 10 g / mL.

In order to prepare the mixed solution, the order of introduction of the bicalutamide and nicotinamide into the organic solvent is not particularly limited in the present invention. However, it is preferable that the molar ratio of bicalutamide and nicotinamide is kept in the range of 0.5: 1 to 0.1: 1. This is because crystals of bicalutamide and co-crystals of bicalutamide and nicotinamide coexist when they are out of the range. It is preferable to dissolve the bicalutamide and nicotinamide through sufficient stirring and, if necessary, heat the mixed solution completely to dissolve. At this time, the dissolution temperature is in the range of 20 캜 to the reflux temperature of the solvent, preferably in the range of 20 캜 to 70 캜, and if necessary, heated in the temperature range of 30 캜 to 70 캜 to obtain a completely dissolved transparent solution. The heating stirring time is about 10 minutes to 1 hour.

The second step is the process of producing a co-crystal of bicalutamide and nicotinamide.

The crystals can be produced by a 'solvent evaporation method' in which the solvent is evaporated while slowly stirring the mixed solution. The solvent evaporation should be maintained at a temperature in the range of 20 ° C to 70 ° C. If the evaporation temperature is kept too high, bicalutamide decomposes and the yield of the coarse crystals may be lowered. The solvent evaporation time is from 20 minutes to 50 hours. If it is too early, the purity of the co-crystals may be lowered. Therefore, it is preferable to evaporate while maintaining the proper evaporation rate.

Or a 'cooling method' in which the mixed solution is rapidly or slowly cooled to a temperature of -30 ° C to 20 ° C to induce a supersaturated state. The cooling rate is preferably maintained at 0.01 to 20 ° C / min. When the cooling rate is low, the co-crystal formation time is long and the productivity is low. When the cooling rate is high, It can be difficult.

Or a 'solvent crystallization method' in which a non-solvent is added to the mixed solution as a crystallization solvent. The crystallization solvent used herein is a non-solvent having a low solubility in bicalutamide. Examples of the solvent include alcohols such as methanol, ethanol and 2-propanol, and organic solvents such as methyl ethyl ketone (MEK), acetone, ethyl acetate (EA), acetonitrile (ACN) or a mixed solvent of two or more selected from these may be used.

In addition, crystalline seeds may be added to the mixed solution to promote the formation of co-crystals.

The third step is a process of recovering the co-crystals of the produced bicalutamide.

The method for recovering the co-crystals suitably uses a conventional method. For example, the co-crystals are recovered from the reaction mixture by filtration by gravity or suction, centrifugation, or the like. The recovered co-crystals may be further purified by cleansing using the non-coalescer described above.

The present invention as described above is explained in more detail based on the following examples. However, this is for the purpose of helping to understand the constitution and operation of the present invention, and the scope of the present invention is not limited by the following examples.

[Example]

Example 1. Co-crystal preparation of bicalutamide and nicotinamide

After 0.5 mmol of bicalutamide and 1 mmol of nicotinamide were mixed, 10 mL of methanol was added and the mixture was heated and dissolved at a temperature of 40 ° C for 5 minutes. The molten solution was stirred for 10 minutes, then cooled and evaporated at 25 ° C for 40 hours, and then slowly evaporated at room temperature to form a co-crystal. The resulting co-crystals were obtained by filtration (85% yield). The obtained crystals were analyzed by DSC and XRD, and HPLC analysis confirmed that bicalutamide and nicotinamide had a molar ratio of 0.5: 1.

Example 2. Co-crystal preparation of bicalutamide and nicotinamide

After 0.4 mmol of bicalutamide and 1 mmol of nicotinamide were mixed, 7 mL of methyl ethyl ketone (MEK) was added and the mixture was dissolved by heating at 70 ° C for 5 minutes. The molten solution was stirred for 10 minutes, then cooled and evaporated at 25 ° C for 20 hours, and slowly evaporated at room temperature to form a co-crystal. The resulting co-crystals were obtained by filtration (yield 82%). The obtained crystals were analyzed by DSC and XRD, and HPLC analysis confirmed that bicalutamide and nicotinamide had a molar ratio of 0.5: 1.

Example 3. Co-crystal preparation of bicalutamide and nicotinamide

0.3 mmol of bicalutamide and 1 mmol of nicotinamide were mixed, 10 mL of ethyl acetate was added, and the mixture was heated and dissolved at 70 DEG C for 5 minutes. The molten solution was stirred for 10 minutes, then cooled and evaporated at 25 ° C for 20 hours, and slowly evaporated at room temperature to form a co-crystal. The resulting co-crystals were obtained by filtration (yield 90%). The obtained crystals were analyzed by DSC and XRD, and HPLC analysis confirmed that bicalutamide and nicotinamide had a molar ratio of 0.5: 1.

Example 4. Co-crystal preparation of bicalutamide and nicotinamide

0.2 mmol of bicalutamide and 1 mmol of nicotinamide were mixed, and then 8 mL of acetonitrile was added and the mixture was dissolved by heating at 70 DEG C for 5 minutes. The molten solution was stirred for 10 minutes, then cooled and evaporated at 25 ° C for 20 hours, and slowly evaporated at room temperature to form a co-crystal. The resulting co-crystals were obtained by filtration (yield 92%). The obtained crystals were analyzed by DSC and XRD, and HPLC analysis confirmed that bicalutamide and nicotinamide had a molar ratio of 0.5: 1.

[Experimental Example]

Experimental Example 1. Differential scanning calorimetry (DSC) analysis

For DSC analysis, DSC 2010 instrument from TA Instrument was used. A sample of 5 mg was heated at a constant heating rate of 10 캜 / min from 30 캜 to 400 캜 and purge gas (40 mL / min) using nitrogen was used. The results of differential scanning calorimetry (DSC) analysis of the bicalutamide and nicotinamide co-crystals prepared in Example 1 are shown in FIG.

The bicalutamide and nicotinamide co-crystals prepared in Example 1 had a melt initiation temperature of 114.91 ° C and showed broad endotherm after melting due to decomposition of bicalutamide.

In addition, the melting points (Tm) and calories of the pure bicalutamide, nicotinamide, and bicalutamide and the co-crystals of nicotinamide (Example 3) are shown in Table 1 below.

division Tm (占 폚) Hm (KJmol- ¹ ) ? H ^* m (Jg- ¹ ) Bicalutamide (BI) 194.740 44.910 104.352 Nicotinamide (NCT) 130.220 19.113 156.500 BI-NCT co-decision 114.910 19.113 241.91

Considering that the melting initiation temperature and the maximum endothermic temperature by DSC analysis may be different depending on the machine, the measuring method or the sample, the results shown in the above Table 1 should not be considered to be absolute values . Although the melting point (Tm) of pure bicalutamide is 194.7 ° C, the co-crystals of bicalutamide and nicotinamide characterized by the present invention have a maximum endothermic peak observed at 110 ° C to 120 ° C Noteworthy.

Experimental Example 2. X-ray powder diffraction (XRD) analysis

X-ray powder diffraction (XRD) Analysis was performed using a Rigaku's D / MAX-2500H instrument. The tube was made of copper (Cu), and the tube current was 100 mA and the tube voltage was 40 kV. The sampling width was 0.02 deg., And the measurement diffraction angle (2 [theta]) range was 3 to 40 deg. The differential scanning calorimetry (DSC) analysis of the bicalutamide and nicotinamide cocrystals prepared in Example 1 is shown in FIG. 6.

The main X-ray powder diffraction angles (2?) Of I / I ₀ > 10% were 8.0, 16.0, 18.1, 20.1, 21.1, 22.8, 23.9, 24.2, 25.2, 25.8, 26.6, 28.7, 29.2, 31.1, 32.5, 33.4, 33.9, 35.5, 36.7, and 39.3. The detailed diffraction peak values are shown in Table 2 below.

2? (?) Relative strength (%) 2? (?) Relative strength (%) 8.04 18503 26.60 3950 16.04 12893 28.70 2379 18.12 57609 29.16 1000 20.12 1305 31.12 643 21.10 2226 32.46 6791 22.78 5275 33.36 939 23.88 1334 33.90 1484 24.16 1669 35.54 1197 25.24 530 36.66 6948 25.84 630 39.30 653

As will be appreciated by those skilled in the art, the exact position of a peak may vary from machine to machine, from sample to sample, or from slight variations in accordance with the measurement conditions used. Therefore, as the X-ray powder diffraction pattern for the co-crystals of bicalutamide and nicotinamide characterized by the present invention, the X-ray powder diffraction angle (2?) Illustrated in Table 6 and Table 2 is regarded as an absolute value No. The co-crystals of bicalutamide of the present invention have substantially the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern shown in FIG. 6 and have substantially the most significant diffraction angle (2 &thetas; . One skilled in the art of X-ray powder diffraction can determine the substantial identity of the X-ray powder diffraction pattern. For additional information on this, see Jenkins, R & Snyder, RL 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons, 1996.

Experimental Example 3. Scanning Electron Microscope (SEM) Analysis

The co-crystals of the bicalutamide and nicotinamide obtained by the production methods of Examples 1 to 3, the pure bicalutamide and the pure nikctinamide were observed with a scanning electron microscope (SEM).

The SEM image shown in FIG. 7 shows that the co-crystallization of bicalutamide and nicotinamide changed the physical properties compared to that of pure bicalutamide.

Experimental Example 4. Measurement of solubility in methanol solvent

The following experiments were carried out to investigate the solubilities of bicalutamide and nicotinamide in co-crystals, pure bicalutamide, and pure niktinamide in methanol solvent. Solubility was measured as the amount of solute dissolved in 1 mL of methanol at temperatures of 30 DEG C, 40 DEG C, and 60 DEG C. The result is shown in FIG.

According to FIG. 8, the co-crystal of bicalutamide and nicotinamide shows an increase in solubility by about 1.5 times as compared to that of pure bicalutamide.

Experimental Example 5. Measurement of Solubility in Water Solvent

The following experiments were carried out in order to examine the solubilities of bicalutamide and nicotinamide in co-crystals, pure bicalutamide and pure nikntinamide in water solvent. The solubility was measured by dissolving 5 mL of the solute in 1,000 mL of water, observing the solubility in 1 hour period, dissolving the solute until it was no longer dissolved, and measuring the solubility. The results are shown in Fig.

According to Fig. 9, pure bicalutamide dissolves 5 mg in 1,000 mL of solvent at 37 占 폚. In contrast, co-crystals of bicalutamide and nicotinamide are dissolved at 37 ° C in 19.0 g in 1,000 mL of solvent. That is, the co-crystal of bicalutamide and nicotinamide shows a 3800-fold increase in solubility in water as compared to pure bicalutamide.

As described above, the bicalutamide and nicotinamide co-crystals characterized by the present invention is a novel substance which has not been reported to date, and by improving the solubility of the bicalutamide drug, ultimately the bioactive substance of the bicalutamide drug It is useful as a new cancer treatment agent.

Claims (7)

A cocrystal of bicalutamide, comprising bicalutamide and nicotinamide.
The method of claim 1,
A co-crystal of bicalutamide, wherein bicalutamide and nicotinamide have a molar ratio of 0.5: 1 to 0.1: 1.
The method of claim 1,
Characterized in that the maximum endothermic peak on the spectrum analyzed by differential scanning calorimetry (DSC) is observed at 110 to 120 < 0 > C.
The method of claim 1,
The diffraction angles (2θ) on the powder XRD spectrum are 8.0, 16.0, 18.1, 20.1, 21.1, 22.8, 23.9, 24.2, 25.2, 25.8, 26.6, 28.7, 29.2, 31.1, 32.5, 33.4, 33.9, 35.5, 36.7, and 39.3 ° A cocrystal of bicalutamide, characterized in that.
A pharmaceutical composition for treating cancer, characterized in that the cocrystal of the bicalutamide of any one of claims 1 to 4 is included as an active ingredient.
Preparing a mixed solution by dissolving bicalutamide and nicotinamide in an organic solvent;
A process for producing a co-crystal of bicalutamide consisting of bicalutamide and nicotinamide; And
Recovering the co-crystals of the produced bicalutamide;
Method for producing a bicalutamide cocrystal, characterized in that it comprises a.
The method according to claim 6,
The organic solvent is characterized by using a single solvent of methanol, ethanol, propanol, isopropanol, methyl ethyl ketone (MEK), acetic acid, acetone, acetonitrile (ACN), ethyl acetate or two or more mixed solvents selected therefrom. A method for producing a bicalutamide cocrystal.

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