KR20180029401A - Solid dispersions comprising Telmisartan and the preparation method thereof - Google Patents

Abstract

The solid dispersions comprising telmisartan and a manufacturing method thereof, according to the present invention, unlike conventional methods requiring a low yield, can manufacture telmisartan of a high yield through simple and short steps by using a relatively inexpensive raw material, can secure excellent quality through reduction of generation of decomposition products, and can manufacture the solid dispersions on a mass production basis to be commercially available. Therefore, the solid dispersions of novel crystalline polymorph of the telmisartan of the present invention has improved storage stability and solubility, and can be synthesized at a high yield, thereby being expected to be very useful in the manufacture of pharmaceuticals.

Description

TECHNICAL FIELD The present invention relates to a solid dispersion containing telmisartan and a preparation method thereof,

The present invention relates to a solid dispersion containing telmisartan and a process for producing the same.

In 2000, about 1 billion people were hypertensive, accounting for about 26% of the adult population of the world at the time, and hypertension was already a global disease. Even the worldwide hypertensive population is exploding and is expected to be over 1.5 billion by 2025.

On the other hand, most hypertensive patients require two or more medications for treatment, and for those whose systolic blood pressure exceeds 160 mmHg or diastolic blood pressure exceeds 100 mmHg, the American Heart Association recommends that thiazide diuretics Angiotensin converting enzyme inhibitor, an angiotensin receptor blocker or calcium channel blocker, or an angiotensin converting enzyme inhibitor or a calcium channel blocker should be prescribed in combination with the same drug. Angiotensin-converting enzyme (ACE) inhibitor is a hypertensive drug that lowers blood pressure by inhibiting angiotensin converting enzyme (ACE). Calcium Channel Blocker (CCB) selectively inhibits the entry of calcium into cells Is a drug that lowers blood pressure. Angiotensin receptor blockers (ARBs) inhibit the activation of angiotensin leading to hypertension.

These hypertension medications have the effect of expanding the blood vessels and lowering blood pressure, but for this reason side effects or complications of angina, myocardial infarction, sudden death, arrhythmia and heart failure occur.

However, telmisartan among hypertension treatment medications has been reported to reduce death or stroke due to cardiovascular disease in patients who are unable to receive standard therapy.

In particular, Telmisartan, developed by Boehringer Ingelheim of Germany, is a non - peptide angiotensin II receptor blocker and a selective agent for Type I angiotensin receptor. Telmisartan is absorbed very rapidly when absorbed orally, and binds mostly to serum proteins such as albumin or α-1 acid glycoprotein. About 99% of the absorbed telmisartan binds to the serum protein, resulting in a very important physiological activity. The half-life of telmisartan is about 24 hours, and it is easily distributed as a sufficient concentration in the cytoplasm. In addition, telmisartan is completely excreted by the liver in normal subjects, except patients with liver disease, and the daily dose is 40 to 80 mg.

Telmisartan is the only ARB-based antihypertensive drug that has indications for cardioprotective effects, and is emerging as a next-generation ARB drug, and the market for telmisartan is gradually expanding.

However, the known process for preparing telmisartan is a complicated process which involves several steps of synthesis. There is a problem in that by-products are produced in the synthesis process. Solubility of the insoluble drug in BCS class II is 0.078 mg / mL < / RTI > (Korean Patent No. 10-0658959).

Therefore, it is required to economically process the product by completely eliminating the low yield, the complicated process of multistage synthesis and the use of the expensive solvent, which have been required in the known processes, and by improving and shortening the production process, have. In addition, there is a need to develop a telmisartan solid dispersion preparation in which the storage stability of telmisartan is improved and the solubility and the absorbability are increased.

Disclosure of the Invention The present invention has been made to overcome the above problems, and the present inventors have made improvements in the process of producing telmisartan to improve telmisartan yield, and have succeeded in producing telmisartan having improved storage stability and solubility A solid dispersion preparation of a crystalline polymorph was prepared, and the present invention was completed based on this.

Accordingly, an object of the present invention is to provide a process for preparing a compound represented by the following general formula (1): (1) producing a compound represented by the following general formula (3) by performing a coupling reaction under the condition of an alcohol solvent containing an alkali metal; And 2) hydrolyzing a compound represented by the above formula (3) to produce telmisartan represented by the following formula (4).

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

Another object of the present invention is to provide telmisartan or a pharmacologically acceptable salt thereof represented by the following formula (4); Sodium hydroxide, and polyvinylpyrrolidone as an active ingredient.

[Chemical Formula 4]

Still another object of the present invention is to provide a method for preparing a medicament for the treatment of inflammation, comprising the steps of: 1) dissolving telmisartan or a pharmaceutically acceptable salt thereof represented by the following formula 4 in an aqueous solution of sodium hydroxide; 2) preparing a mixed solution by adding polyvinylpyrrolidone to an aqueous solution of sodium hydroxide in which telmisartan is dissolved in step 1); 3) drying the solvent of the mixed solution to obtain a mixture; And 4) pulverizing the mixture. The present invention also provides a method for producing the solid dispersion.

[Chemical Formula 4]

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to accomplish the above object of the present invention, the present invention provides a process for preparing a compound represented by the following formula (3): (1) reacting a compound represented by the following formula (1) and a compound represented by the following formula (2) under an alcohol solvent containing an alkali metal, Producing a compound; And 2) hydrolyzing a compound represented by the above formula (3) to produce telmisartan represented by the following formula (4).

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In one embodiment of the present invention, in step 1), the alkali metal may be sodium (Na).

In another embodiment of the present invention, in step 1), the alcohol may be methyl alcohol.

In another embodiment of the present invention, the step 1) may be carried out at 10 to 80 캜.

In another embodiment of the present invention, the step 2) may be carried out under a mixed solvent of an aqueous solution of sodium hydroxide and tetrahydrofuran (THF) at a concentration of 0.1 to 10N.

In another embodiment of the present invention, the step 2) may be carried out at 70 to 120 ° C.

In another embodiment of the present invention, the preparation method can be carried out in a single reaction vessel ( in-situ ).

In another embodiment of the present invention, the compound represented by Formula 1 may be purified by recrystallization at room temperature in a mixed solvent of hexane and dichlolomethane.

In another embodiment of the present invention, the compound represented by Formula 2 may be purified by recrystallization at a room temperature in a dichloromethane solvent.

Another object of the present invention is to provide telmisartan or a pharmacologically acceptable salt thereof represented by the following formula (4); Sodium hydroxide and polyvinylpyrrolidone as an active ingredient, wherein the sodium hydroxide is mixed in an amount of 1 to 20% by weight based on the total weight of the telmisartan and the polyvinylpyrrolidone, The present invention provides a solid dispersion which is characterized in that the molar ratio of the at least one compound is in the range of 0.5: 1 to 9: 1 based on the telmisartan.

[Chemical Formula 4]

In one embodiment of the present invention, the solid dispersion exhibits an endothermic maximum point at 168 占 1 占 by differential scanning calorimetry (DSC).

The present invention also relates to a method for preparing a medicament for the prevention and treatment of cancer, comprising the steps of: 1) dissolving telmisartan or a pharmaceutically acceptable salt thereof represented by the following formula 4 in an aqueous solution of sodium hydroxide; 2) preparing a mixed solution by adding polyvinylpyrrolidone to an aqueous solution of sodium hydroxide in which telmisartan is dissolved in step 1); 3) drying the solvent of the mixed solution to obtain a mixture; And 4) pulverizing the mixture, wherein the sodium hydroxide is mixed in an amount of 1 to 20% by weight based on the total weight of the telmisartan and the polyvinylpyrrolidone Are mixed in a molar ratio of 0.5: 1 to 9: 1 based on the telmisartan.

[Chemical Formula 4]

It is still another object of the present invention to provide a pharmaceutical composition for treating hypertension comprising the telmisartan solid dispersion of the present invention as an active ingredient.

Further, the present invention provides a method for treating hypertension comprising the step of administering the pharmaceutical composition to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for preventing or treating hypertension.

The telmisartan solid dispersion of the present invention and its preparation method are different from the conventional methods which require a low yield, a complicated process of multi-step synthesis and use of expensive raw materials, It is possible to produce telmisartan with a high yield and to secure excellent quality through reduction of generation of decomposition products, and it is possible to mass-produce it, thus being commercially available. Therefore, the solid dispersion of the novel crystalline polymorph of telmisartan of the present invention has improved storage stability and solubility, and can be synthesized with high yield, and can be very usefully applied in the manufacture of pharmaceuticals.

FIG. 1 shows the result of confirming the structure of Telmisartan obtained by using the production method of the present invention using a nuclear magnetic resonance spectrometer (NMR).
FIG. 2 shows the results of confirming the purity of Telmisartan obtained by using the production method of the present invention using High Performance Liquid Chromatography (HPLC).
Fig. 3 shows the result of showing Telmisartan obtained by using the production method of the present invention.
4 shows the results of analysis of the thermal behavior of the telmisartan solid dispersion of the present invention using differential scanning calorimetry (DSC).
FIG. 5 is a result of analyzing the spectroscopic structure of the telmisartan solid dispersion of the present invention by using an infrared spectrometer (FT-IR).
FIG. 6 is a result of spectroscopic qualitative analysis and quantitative analysis of Telmisartan solid dispersion of the present invention using High Performance Liquid Chromatography (HPLC).
Figure 7 shows the results of the telmisartan solid dispersion granules of the present invention.

The present invention relates to a solid dispersion containing telmisartan as an active ingredient and a method for producing the same, and it relates to a process for improving telmisartan by improving the yield of telmisartan and improving telmisartan To obtain a solid dispersion preparation of telmisartan novel crystalline polymorph with improved storage stability and solubility, and on the basis of which the present invention was completed.

Hereinafter, the present invention will be described in detail.

The present invention provides a process for preparing telmisartan. More specifically, the present invention provides a process for preparing a compound represented by the following formula (3): (1) coupling a compound represented by the following formula (1) or (2) under the condition of an alcohol solvent containing an alkali metal; And 2) hydrolyzing a compound represented by the above formula (3) to produce telmisartan represented by the following formula (4).

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

Also, in step 1), the alkali metal may be sodium (Na), and the alcohol may be methyl alcohol, and the step 1) may be carried out at 10 to 80 ° C. Preferably, the step 1) may be performed at room temperature or 70 ° C, but is not limited thereto.

In addition, the step 2) may be carried out under a mixed solvent of an aqueous sodium hydroxide solution and tetrahydrofuran (THF) at a concentration of 0.1 to 10 N, most preferably in an aqueous sodium hydroxide solution at a concentration of 3 N, It is not.

In addition, the step 2) may be carried out at 70 to 120 ° C and most preferably at 100 ° C, but is not limited thereto.

Further, the above-mentioned method for preparing telmisartan can be carried out in a two-step reaction and also in a single reaction vessel ( in-situ ).

The compound represented by the formula (1) can be purified by recrystallization in a mixed solvent of hexane and dichlolomethane at room temperature. The compound represented by the formula (2) can be obtained by reacting dichlolomethane It can be purified by recrystallization in a solvent. At this time, the normal temperature means a temperature range of 10 to 30 ° C.

Terms of this invention "telmisartan (2- (4 - {[4 -methyl-6- (1-methyl-1 H -1,3-benzodiazol-2-yl) -2-propyl-1 H -1, 3-benzodiazol-1-yl] methyl} phenyl) benzoic acid "is a non-peptide angiotensin II receptor blocker and selectively acts on Type I angiotensin receptor. Telmisartan is an ARB-based antihypertensive drug that is rapidly absorbed when absorbed orally, and binds mostly to serum proteins such as albumin or α-1 acid glycoprotein. About 99% of the absorbed telmisartan binds to the serum protein, resulting in a very important physiological activity. The half-life of telmisartan is about 24 hours, and it is easily distributed as a sufficient concentration in the cytoplasm. In addition, telmisartan is completely excreted by the liver in normal subjects, except patients with liver disease, and the daily dose is 40 to 80 mg.

Telmisartan is a crystalline material. Crystalline telmisartan exists as two polymorphs having different melting points. It is affected by heat and humidity and has a low melting point (183 +/- 2 DEG C) and polymorph B Form B) is irreversibly deformed to polymorph A (Form A) with a high melting point (269 ± 2 ° C). When a particular compound forms two or more crystalline states, these different crystalline states are referred to as crystalline. It is generally known that the stability varies depending on the crystal form of each crystalline polymorph.

Telmisartan, on the other hand, is an insoluble drug belonging to the BCS class II and has a very low solubility in water of 0.078 mg / mL. As a method for solubilizing such poorly soluble drugs, there is a solid dispersion method. The solid dispersion is obtained by mixing a poorly soluble drug with a water-soluble polymer such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), cellulose derivatives, etc., followed by heating and melting. If the drug dissolves in the water-soluble polymer as a carrier in a molten state, the drug in the carrier is dispersed in a molecular state, and after solidifying, the drug is pulverized to obtain a solid dispersion. When the obtained solid dispersion powder is added to water, the water-soluble carrier rapidly dissolves and the soluble drug molecules are surrounded by water, thereby forming a solution in which the poorly soluble drug is dissolved.

In the solid dispersion method, a poorly soluble drug and a water-soluble polymer are dissolved in the same solvent, and then the solvent is removed by drying to obtain a homogeneous mixture. Through this process, the crystallinity of the drug decreases and the particle size also decreases, . Also, through the formation of a solid dispersion, the crystalline drug particles may be transformed into an amorphous state with decreasing crystallinity to increase solubility through the formation of new particles because the amorphous state is in a crystalline state Are known to be thermodynamically high energy levels.

Therefore, it is important to maintain the morphology stably even when the drug is stored for a long period of time, and it is also important to develop a technique for industrially easily and reproducibly producing the morphology.

Thus, in one embodiment of the present invention, telmisartan was produced in a simple and short step using a relatively inexpensive raw material (see Example 1). The structure was confirmed by NMR and HPLC analysis. Residual solvents of telmisartan were also evaluated (see Example 2).

Further, as another aspect of the present invention, the present invention provides a solid dispersion comprising telmisartan or a pharmaceutically acceptable salt thereof. More specifically, the solid dispersion of the present invention comprises telmisartan or a pharmaceutically acceptable salt thereof represented by the following formula (4): Sodium hydroxide and polyvinylpyrrolidone as active ingredients.

[Chemical Formula 4]

At this time, the sodium hydroxide is preferably mixed with 1 to 20 wt%, and most preferably 10 wt%, based on the total weight of the telmisartan. In addition, the polyvinylpyrrolidone may be mixed in a molar ratio of 0.5: 1 to 9: 1 based on the telmisartan.

Further, the solid dispersion of the present invention shows the maximum endotherm at 168 占 1 占 by differential scanning calorimetry (DSC). More specifically, when the solid dispersion containing telmisartan of the present invention as an active ingredient was prepared with polyvinylpyrrolidone in a molar ratio of 1: 9 and 1: 0.5, the results of differential scanning calorimetry were 167.6 < The maximum endothermic peak was found at 168.1 ℃, and the maximum endothermic peak of Telmisartan Form A, which was previously known, appeared at about 267.8 ℃. All crystalline polymorphs including amorphous compounds exhibit characteristic absorption patterns in infrared (IR) spectroscopic analysis, respectively, or exhibit different melting points, in which case they can be analyzed by differential scanning calorimetry (DSC).

Accordingly, it was confirmed that the crystalline state of the telmisartan solid dispersion of the present invention disappeared from the crystalline form of the existing telmisartan polymorph A and the polymorph B, and it was confirmed that it was a novel crystalline polymorph having properties different from the existing crystalline polymorph . Further, this crystal form is kept for a long time under ordinary storage conditions and is chemically stable.

Further, in another aspect of the present invention, the present invention provides a method for producing a solid dispersion comprising telmisartan or a pharmaceutically acceptable salt thereof. 1) dissolving telmisartan or a pharmaceutically acceptable salt thereof represented by the following formula (4) in an aqueous solution of sodium hydroxide; 2) preparing a mixed solution by adding polyvinylpyrrolidone to an aqueous solution of sodium hydroxide in which telmisartan is dissolved in step 1); 3) drying the solvent of the mixed solution to obtain a mixture; And 4) pulverizing the mixture.

[Chemical Formula 4]

At this time, the sodium hydroxide is preferably mixed with 1 to 20 wt%, and most preferably 10 wt%, based on the total weight of the telmisartan. In addition, the polyvinylpyrrolidone may be mixed in a molar ratio of 0.5: 1 to 9: 1 based on the telmisartan.

In addition, the solid dispersion containing telmisartan as an active ingredient may be a pharmaceutical composition.

Therefore, the solid dispersion of telmisartan of the present invention is not limited to a pharmaceutical composition for preventing, ameliorating or treating a specific disease, but may be used as an additional active ingredient in a drug to obtain an effect of blocking the angiotensin II receptor have.

In one embodiment of the present invention, a solid dispersion of a new crystalline polymorph of telmisartan was prepared (see Example 3), and the structure of the solid dispersion containing telmisartan was analyzed (see Example 4) , Confirming the intrinsic functional groups of telmisartan and confirming that telmisartan and the solid dispersion containing it are the same substance.

In another embodiment of the present invention, the quantitative and qualitative analysis of the telmisartan novel crystalline polymorphic solid dispersion (see Example 5) was carried out, and the telmisartan contained in the standard solution and the sample solution and the solid dispersion containing the same were the same substance , And the content of the obtained solid dispersion was confirmed.

In another embodiment of the present invention, tablets of the telmisartan novel crystalline polymorphic solid dispersion were prepared (see Example 6), from which the physical properties of the telmisartan solid dispersion tablets were evaluated (see Example 7) As a result, it was confirmed that the recognition angle, the density, the true density, the compressibility and the fluidity were all good.

In another embodiment of the present invention, the formulation evaluation of tablets of the new crystalline polymorph of telmisartan polymorph (see Example 8) was carried out and it was confirmed that there was no problem in formulation.

In another embodiment of the present invention, the stability of the new crystalline polymorph of telmisartan polymorph was evaluated (see Example 9), and as a result, it was confirmed that the solid dispersion tablets having improved stability were produced.

By using the above-mentioned telmisartan solid dispersion and its production method, telmisartan with high yield can be produced in a simple and short step, and excellent quality can be secured by reducing decomposition products, .

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

< Example >

Example 1. Preparation of Telmisartan

1-1. Purification of compounds

High performance liquid chromatography (HPLC) analysis was carried out in order to purify compounds represented by the following formulas (1) and (2), which are commercially available, in high purity. To purchase commercially available compound represented by the formula 1 a purity measured with HPLC analysis of (1,7'-dimethyl-2'-propyl -1 H, 3 'H -2,5'-bibenzo [d] imidazole) The results were confirmed to include a purity level of 85%. In order to obtain a high purity compound (a), first column chromatography was performed under the condition of hexane: ethyl acetate = 5: 1 at a solvent ratio, followed by primary purification, thin layer chromatography (TLC) However, it was confirmed that a considerable amount of impurities were not removed. Thus, recrystallization of the compound a obtained from the first column chromatography purification was attempted. Various solvents _{(methanol, ethyl acetate, CH 2} Cl 2, hexane / ethyl acetate, hexane / CH 2 Cl 2, hexane / diethyl ether) after the condition search, hexane / CH ₂ Cl ₂ After recrystallization at room temperature conditions, the compound a (&Gt; 99% purity).

Likewise, the purity of the compound b ( tert- butyl 4 '- (bromomethyl) - [1,1'-biphenyl] -2-carboxylate) Purity. &Lt; / RTI &gt; In order to obtain a high purity compound b, TLC and HPLC analysis were carried out after performing primary column chromatography under the condition of solvent ratio hexane: ethyl acetate = 6: 1, followed by primary purification, but still a considerable amount of impurities were not removed Respectively. Thus, recrystallization of the compound b obtained from the first column chromatography purification was attempted. After recrystallization from various solvents (methanol, ethyl acetate, hexane / ethyl acetate, CH ₂ Cl ₂ , diethyl ether) and recrystallization at room temperature under CH ₂ Cl ₂ alone, compound b was obtained in high purity (> 99% .

[Chemical Formula 1]

(2)

1-2. Telmisartan  synthesis

Compound c was synthesized using Compound a and Compound b purified in Example 1-1. Lithium tert- butoxide was reacted in an inexpensive t- BuOH ( tert- butyl alcohol) solvent to obtain compound c in a yield of 54%. Thus, pyridine, DMAP, Et ₃ N, K ₂ CO _3, KOAc, NaOEt, NaH, Na / Comparison of the different basic conditions of MeOH, etc., Na / MeOH at room temperature conditions, 66%, in the 70 ℃ conditions 71% yield To give compound c. A reaction of 1 g scale was also performed to synthesize compound c in the final 70% yield. Then, in order to hydrolyze the obtained compound c, hydrolysis optimum reaction conditions were searched under various acid or base conditions. The reaction was searched in acid hydrolysis conditions, HCl / CH ₂ Cl ₂ or H ₂ SO ₄ / H ₂ O, but the yield was not improved, and the hydrolysis reaction was carried out using the base conditions. The reaction was optimized using sodium hydroxide (NaOH), THF, DMSO, toluene or H ₂ O solvent, and 3N NaOH / THF at 100 ℃ was selected. As a result, telmisartan, a compound represented by the following formula (4), was obtained in a yield of 93%.

(3)

[Chemical Formula 4]

1-3. Telmisartan in-situ  synthesis

In order to carry out the in-situ synthesis of telmisartan, the reaction conditions of the two-step production method described in Example 1-2 above were used. Using the conditions of the coupling reaction, Na / MeOH, 70 ° C., 20 h, and the second step of hydrolysis, 3N NaOH / THF, 100 ° C. and 20 h, a b was synthesized result, telmisartan in 55% yield by performing the in-situ coupling reaction using as a starting material. NMR and HPLC analysis of the obtained telmisartan compound was also carried out.

As a result, as shown in Figs. 1 to 3, the structure and purity (> 99.0% or more) of telmisartan were confirmed.

Example 2. Evaluation of residual solvents of telmisartan

The results of evaluating the residual solvents of telmisartan prepared in Example 1 are shown in Table 1 below.

Residual solvent Criteria (ppm or less) Results (ppm) Methanol 3000 100 ppm or less 1,2-dimethoxyethane
(1,2-dimethoxyethane) 100 Below detection limit Ethanol (ethanol) 5000 100 ppm or less Acetic acid 5000 Below detection limit

Example 3: Preparation of solid dispersion containing telmisartan

The aqueous sodium hydroxide solution containing sodium hydroxide in a proportion of 10% w / w (% by weight) based on the total weight of the telmisartan and telmisartan was prepared to dissolve telmisartan, and then polyvinylpyrrolidone ) Were mixed with a molar ratio (telmisartan: polyvinyl pyrrolidone) of at least 1: 0.5 and 1: 9 at maximum to prepare a telmisartan solid dispersion. The telmisartan solid dispersion was obtained in a high yield of about 80% or more. The physical properties of the prepared solid dispersion were constant regardless of the amount of polyvinylpyrrolidone, and the yield was quantitatively increased in proportion to the amount of polyvinylpyrrolidone. Thermal behavior of the telmisartan solid dispersion was also analyzed by differential scanning calorimetry (DSC) thermal analysis.

As a result, as shown in Fig. 4, the maximum endothermic peak of Telmisartan Form A was found at about 267.8 DEG C, and the ratio of telmisartan prepared at a molar ratio of 1: 9 and 1: 0.5 The solid dispersions showed maximum endothermic peaks at 167.6 캜 and 168.1 캜, respectively. In addition, the melting enthalpy (H) used to form the solid dispersion was -109 J / g for a molar ratio of 1: 9 to -110 J / g for a molar ratio of 1: 0.5.

Example 4. Structural analysis of a solid dispersion containing telmisartan

To confirm whether the solid dispersion prepared in Example 3 was the same as telmisartan, the spectroscopic structure analysis of each functional group of telmisartan molecules was performed by FT-IR measurement. FT-IR analysis was performed by KBr disc analysis at 400-4000 cm ^-1 .

As a result, as shown in Fig. 5, the stretching vibration at around 1697 cm ^-1 (C = O stretching), 1457 cm ^-1 (CH bending) and 1265 cm ^-1 (CO stretching) And bending vibration were confirmed to confirm that telmisartan and the solid dispersion containing it were the same material.

Example 5. Qualitative and Quantitative Analysis of Solid Dispersion Containing Telmisartan

5-1. Prepare standard solution

In order to carry out HPLC analysis of the solid dispersion prepared in Example 3, a standard solution was prepared by the following method. 80 mg of telmisartan standard form is precisely weighed and placed in a 100 mL volumetric flask. Dilution solution (0.2 g of sodium hydroxide dissolved in 10 mL of water, adjusted to room temperature, methanol is added to make a total volume of 1000 mL) 70 mL was added and sonicated. Thereafter, the solution was cooled to room temperature and diluted to make a volume of 100 mL accurately. 10 mL of the prepared liquid was precisely taken, and a mobile phase prepared by the method described in Table 2 below was added to accurately make a volume of 100 mL. Respectively.

5-2. Preparation of test liquid

The amount of 800 mg of telmisartan solid dispersion prepared in Example 3 was taken into a 1000-mL volumetric flask, and 50 mL of water was added thereto for ultrasonication. Add 700 mL of the diluted solution and ultrasonicate for 30 minutes while shaking. After cooling to room temperature, add the diluted solution to make exactly 1000 mL, and shake well and filter. 5 mL of the first filtrate is discarded, and 10 mL of the filtrate is precisely taken and 100 mL of the mobile phase is used as the sample solution.

5-3. HPLC analysis

In order to carry out qualitative analysis and quantitative analysis of the solid dispersion containing the telmisartan crystalline polymorph using the standard solution and the sample solution prepared in Examples 5-1 and 5-2, HPLC was carried out under the conditions shown in Table 2 Respectively.

Detector Ultraviolet absorption spectrophotometer (237 nm) column A stainless steel tube having an internal diameter of 4.6 mm and a length of 150 mm was packed with a column of 5 袖 m octadecylsilylated silica gel for liquid chromatography or a similar column Mobile phase A solution of 2.0 g of ammonium dihydrogenphosphate dissolved in 1000 mL of water and adjusted to pH 2.8 ± 0.1 with phosphoric acid and 450 mL of methanol and 550 mL of methanol Flow rate 2.0 mL / min Column temperature Constant temperature around 40 ° C Dose 10 μL

As a result, as shown in FIG. 6, the retention time of the telmisartan contained in the standard solution and the sample solution was about 10.1 minutes, confirming that telmisartan contained in the standard solution and the sample solution was the same substance , And the content of the obtained solid dispersion was about 100.39%, which was within the standard range.

Example 6. Purification of solid dispersion containing telmisartan

Tablets containing the telmisartan solid dispersion were prepared according to the formulation ratios shown in Table 3 below in order to examine the possibility of application of the solid dispersion prepared in Example 3 above.

Ingredients mg / tablet Telmisartan 80 (corresponding amount) Mannitol 159 Crospovidone 16 Microcrystalline cellulose (MCC) 38 Low-substituted hydroxypropylcellulose (L-HPC) 54 Fibrin calcium carbonate (CMC Ca) 36 Sodium Hydroxide 8 Hydroxypropyl methylcellulose 2910 (HPMC 2910) 2 Aerosil 200 &lt; / RTI &gt; 30 Sodium stearyl fumarate (Sodium stearyl fumarate) 12 Ethanol (EtOH) qs Purified water qs

Telmisartan tablets were prepared according to the preparation methods shown in the following Table 4 as the raw materials and amounts. The method for preparing telmisartan tablets was carried out in accordance with the method for producing tablets in the General Regulations of the Korean Pharmacopoeia.

step Manufacturing method Stage 1 Telmisartan, HPMC2910 and Sodium Hydroxide dissolved in purified water and ethanol Step 2 Mannitol, Crospovidone, MCC and CMC Ca were mixed with the solution and mixed Step 3 dry Step 4 Screening (1.5 mm mesh screen) Step 5 Aerosil 200 and Sodium stearyl fumarate after final mixing compaction Step 6 Dedusting

As a result, as shown in Fig. 7, granules were obtained through the process from step 2 to step 4 of Table 4.

Example 7. Evaluation of Physical Properties of Solid Dispersion Tablets Containing Telmisartan

The physical properties of the telmisartan solid dispersion granules prepared in Example 6 above were evaluated to examine the fluidity to be considered in the manufacture of solid formulations. Among the physical properties of solid powders, flowability is recognized as one of the important factors in successful manufacturing process operation, and is measured using angle of repose, fluidity, compressibility and the like.

Angle of repose is the maximum inclination angle between the maximum slope and the horizontal plane of sedimentary layer formed by freely falling powder. As the powder flows down to the side of the sedimentary layer, the mutual friction of the particles becomes equal to gravity while forming the angle of angle θ, and tan of the angle of repose is equal to the coefficient of friction between particles. Therefore, as the surface of the particles is rough and irregular, the angle of repose becomes large. The angle of repose is a so-called dynamic angle, which is preferred as a factor for predicting the flow of powder during the manufacturing process. Generally, when the angle of repose is less than 35 °, it is known that the fluidity is excellent. The measurement method is such that a predetermined amount of each granule produced according to the raw material medicine and the amount is taken out and the powder is drained and deposited using an angle-of-inclination measuring device, and then the radius r and the height h of the accumulated powder are measured, 1. &Lt; tb &gt; &lt; TABLE &gt;

[Equation 1]

Angle of repose = tan? -1 (h / r)

Bulk density is one of the characteristic values of the fluidity, filling property, compressibility, etc. of the powder and is obtained by loosely filling the powder in the container. Tapped density is the density obtained by mechanically tapping a powdered measuring vessel. The density and true density of each sample were measured by the constant mass method in the Korean Pharmacopoeial Density Measurement Method and calculated using the equations shown in the following Equation 2 and Equation 3.

&Quot; (2) &quot;

The density (rho B) = M / V0

ρB: Density (g / mL) by the normal mass method

M: mass of powder (g)

V0: Apparent volume of powder (mL)

&Quot; (3) &quot;

True density (rho T) = M / Vf

ρT: Tap density (g / mL) by the normal mass method

M: mass of powder (g)

Vf: final apparent volume of powder (mL)

The density measurement described in Equations (2) and (3) is used as a criterion for quantitatively determining the flowability as a physical property of the powder.

Further, the Hausner Ratio and the Carr's Index were calculated by the following Equations (4) and (5) derived from the density and true density described above. Generally, when the fluidity value is 1.25 or more, the fluidity is low when the compressibility value is 23 or more.

&Quot; (4) &quot;

Hausner Ratio = Tapped density / Bulk density

&Quot; (5) &quot;

Carr's Index (%) = (true density-is density) x 100 / true density

The physical properties of the telmisartan solid dispersion granules prepared in Example 6 were measured. As shown in Table 5, the average angle of repose was 17.73 °, the compressibility was 7.73% and the fluidity was 1.08. Respectively.

Recognition angle
(degree) Density
(g / mL) True density
(g / mL) Compressibility
(%) liquidity 16.56 + - 0.49 0.56 ± 0.01 0.64 ± 0.01 11.56 1.13 15.84 + - 0.63 0.57 ± 0.01 0.61 ± 0.01 6.83 1.07 16.82 ± 0.52 0.60 ± 0.01 0.63 + - 0.01 5.12 1.05 19.28 ± 2.09 0.56 + 0.03 0.60 ± 0.01 7.09 1.08 20.13 + 1.49 0.54 + 0.02 0.59 + 0.03 8.05 1.09

Example 8. Formulation evaluation of solid dispersion tablets containing telmisartan

Table 6 shows the results of investigating the applicability of the tablets of telmisartan prepared in Example 6 above.

Measurement parameter result Disintegration 15-16 minutes Hardness 13 ~ 15kp Massono 0.21%

As a result, it was confirmed that disintegration, hardness, and degree of abrasion were similar to those of usual pharmaceutical parameters, so that formulation was not problematic.

Example 9. Evaluation of stability of tablets of solid dispersion containing telmisartan

The results of the stability evaluation (acceleration conditions: 45 ° C / 75% RH) of the tablets prepared according to the raw materials, amounts and manufacturing methods described in Example 6 are shown in Table 7 below.

Item standard Initial 3 months 6 months Appearance White or more white tablets fitness fitness fitness Confirmation test Main peak maintenance times of standard solution and standard solution are the same. Same Same Same Content test 90.0 ~ 110.0% 95.2% 96.1% 99.3% Dissolution test More than 80% 92.1% 94.3% 91.5% Purity test 0.2% or less of individual degradation products Not Detected Not Detected Up to 0.11% Hardness 8kp or more About 13kp About 13kp Approximately 11kp Disintegration Within 20 minutes About 15 minutes About 16 minutes About 13 minutes

As a result, it was confirmed that the solid dispersion tablets having improved stability were produced.

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (12)

1) coupling a compound represented by the following general formula (1) or (2) under an alcohol solvent condition containing an alkali metal to produce a compound represented by the following general formula (3); And
2) A method for producing telmisartan, comprising the step of hydrolyzing a compound represented by Formula 3 to produce telmisartan represented by Formula 4 below.
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

The method according to claim 1,
The method for producing telmisartan according to claim 1, wherein in step 1), the alkali metal is sodium (Na).
The method according to claim 1,
The method for producing telmisartan according to claim 1, wherein in step (1), the alcohol is methyl alcohol.
The method according to claim 1,
Wherein the step 1) is carried out at 10 to 80 캜.
The method according to claim 1,
Wherein the step 2) is carried out under a mixed solvent of an aqueous solution of sodium hydroxide and tetrahydrofuran (THF) at a concentration of 0.1 to 10 N. The method for producing telmisartan according to claim 1,
The method according to claim 1,
Wherein the step 2) is carried out at 70 to 120 캜.
The method according to claim 1,
Characterized in that the process is carried out in a single reaction vessel ( in-situ ).
The method according to claim 1,
Wherein the compound represented by Formula 1 is purified by recrystallization at room temperature in a mixed solvent of hexane and dichlolomethane.
The method according to claim 1,
Wherein the compound represented by Formula 2 is purified by recrystallization at a room temperature in a dichloromethane solvent.
Claims [I] A telmisartan represented by the following formula (4): or a pharmaceutically acceptable salt thereof; A solid dispersion containing sodium hydroxide and polyvinylpyrrolidone as an active ingredient,
The sodium hydroxide is mixed in an amount of 1 to 20% by weight based on the total weight of the telmisartan, and the polyvinylpyrrolidone is mixed in a molar ratio of 0.5: 1 to 9: 1 based on the telmisartan By weight of the solid dispersion.
[Chemical Formula 4]

11. The method of claim 10,
Wherein the solid dispersion exhibits an endothermic maximum point at 168 占 1 占 by differential scanning calorimetry (DSC).
1) dissolving telmisartan or a pharmaceutically acceptable salt thereof represented by the following formula (4) in an aqueous solution of sodium hydroxide;
2) preparing a mixed solution by adding polyvinylpyrrolidone to an aqueous solution of sodium hydroxide in which telmisartan is dissolved in step 1);
3) drying the solvent of the mixed solution to obtain a mixture; And
4) pulverizing the mixture, the method comprising the steps of:
The sodium hydroxide is mixed in an amount of 1 to 20% by weight based on the total weight of the telmisartan, and the polyvinylpyrrolidone is mixed in a molar ratio of 0.5: 1 to 9: 1 based on the telmisartan By weight based on the total weight of the solid dispersion.
[Chemical Formula 4]

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