KR102402501B1 - Fimasartan Tromethamine Salt and Pharmaceutical Composition Comprising the Same - Google Patents

Abstract

The present invention relates to fimasartan tromethamine salt and a pharmaceutical composition comprising the same. Fimasartan tromethamine salt according to the present invention can be effectively used in pharmaceutical compositions because it exhibits excellent stability to moisture and heat and high oxidation stability.

Description

Fimasartan Tromethamine Salt and Pharmaceutical Composition Comprising the Same

The present invention relates to a fimasartan tromethamine salt and a pharmaceutical composition comprising the same, and more particularly, to a fimasartan tromethamine salt that has excellent moisture and heat stability as well as high oxidative stability, and a pharmaceutical comprising the same as an active ingredient It relates to a medical composition.

Fimasartan is an angiotensin II receptor antagonist and is used as a drug for the treatment of hypertension. Fimasartan is a compound represented by the following Chemical Formula 2, and is commercially available under the trade name of Kanarb in the form of fimasartan potassium salt trihydrate.

[Formula 2]

As the salt of fimasartan, meglumine salt, ammonium salt, and arginine salt as amine salts are disclosed in Korean Patent Laid-Open No. 10-2017-0061616, and as organic acid salts in Korean Patent Laid-Open No. 10-2017-0061615 Methanesulfonate, benzenesulfonate, camphorsulfonate, toluenesulfonate, ethanedisulfonate and naphthalenedisulfonate are disclosed, and Korean Patent Laid-Open No. 10-2017-0061493 discloses a choline salt of fimasartan. .

However, the salts of fimasartan have insufficient stability to moisture and heat and difficult to secure oxidative stability.

Republic of Korea Patent Publication No. 10-2017-0061616 Republic of Korea Patent Publication No. 10-2017-0061615 Republic of Korea Patent Publication No. 10-2017-0061493

As a result of intensive research and review to overcome the problems of the conventional salts of fimasartan, the present inventors showed that fimasartan tromethamine salt has excellent moisture and heat stability as well as high oxidation stability, so it can be usefully used in pharmaceutical compositions. It was discovered that there is, and the present invention was completed.

Accordingly, it is an object of the present invention to provide fimasartan tromethamine salt having excellent stability against moisture and heat and exhibiting high oxidative stability.

Another object of the present invention is to provide a pharmaceutical composition comprising fimasartan tromethamine salt as an active ingredient.

The present invention relates to a fimasartan tromethamine salt represented by the following formula (1).

[Formula 1]

In one embodiment of the present invention, the fimasartan tromethamine salt is crystalline fimasartan tromethamine salt or a hydrate thereof, and in particular, the fimasartan tromethamine salt dihydrate is crystalline.

The crystalline fimasartan tromethamine salt dihydrate is a hydrate crystal obtained by combining one molecule of tromethamine and one molecule of fimasartan to fimasartan tromethamine salt produced from one molecule of fimasartan with two molecules of water, and its crystal form is Cu. Characterized by the characteristic 2theta (2theta, 2θ) diffraction angle peak in the X-ray powder diffraction spectrum irradiated with the -Kα light source, the relative peak intensity according to each diffraction angle, and the distance between crystal planes.

Specifically, in the crystalline fimasartan tromethamine salt dihydrate of the present invention, I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) in X-ray diffraction analysis was 10% The value of the diffraction angle (2θ) that is greater than or equal to 4.59±0.2, 9.15±0.2, 11.24±0.2, 12.13±0.2, 13.74±0.2, 14.51±0.2, 15.04±0.2, 16.07±0.2, 16.45±0.2, 16.61±0.2, 19.23 ±0.2, 20.73±0.2, 22.56±0.2, 23.59±0.2, 26.32±0.2 and 27.61±0.2 crystalline fimasartan tromethamine salt dihydrate (hereinafter referred to as 'crystal form I').

The fimasartan tromethamine salt of the present invention, particularly the crystalline fimasartan tromethamine salt dihydrate, hardly absorbs water, so it can maintain the same state without being decomposed or changed to another hydrate state even during long-term storage. Accordingly, the fimasartan tromethamine salt of the present invention maintains the same state during storage, preparation, or even after preparation, so that the uniformity of content of the preparation can be stably maintained for a long period of time. In addition, the fimasartan tromethamine salt of the present invention is advantageous for mass production because it does not require strict storage conditions and formulation manufacturing processes to maintain stability. In addition, the fimasartan tromethamine salt of the present invention exhibits relatively high oxidative stability compared to the conventional fimasartan potassium salt trihydrate, which is more advantageous in long-term storage.

Fimasartan tromethamine salt represented by Formula 1 according to the present invention may be prepared by reacting fimasartan represented by Formula 2 with tromethamine.

[Formula 2]

Hereinafter, the method for preparing fimasartan tromethamine salt according to the present invention will be described in more detail.

The fimasartan tromethamine salt of the present invention is preferably prepared by dissolving fimasartan and tromethamine in an organic solvent and stirring. Specifically, it can be prepared by suspending fimasartan in an organic solvent and then adding tromethamine to dissolve and stirring, or by dissolving fimasartan and tromethamine together in an organic solvent and stirring. The amount of tromethamine used is preferably 0.98 to 1.05 equivalents relative to fimasartan.

The method for preparing fimasartan tromethamine salt according to the present invention comprises reacting fimasartan represented by Formula 2 with tromethamine in an organic solvent, followed by:

(i) filtering the solid obtained by stirring the reaction solution;

(ii) lowering the temperature of the reaction solution and stirring, and filtering the obtained solid;

(iii) adding a precipitating solvent to the reaction solution, stirring, and filtering the obtained solid;

(iv) concentrating the reaction solution under reduced pressure, adding a precipitating solvent to the obtained residue and stirring, and then filtering the obtained solid may be further included.

In one embodiment of the present invention, when preparing the hydrated fimasartan tromethamine salt, water may be additionally added to the reaction solution.

As the organic solvent, at least one selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile and acetone may be used.

Examples of the precipitation solvent include ethers such as tetrahydrofuran, dioxane, and diisopropyl ether, nitriles such as acetonitrile, ketones such as acetone and 2-butanone, hydrocarbons such as n-pentane and n-hexane, At least one selected from aromatic hydrocarbons such as benzene, toluene, and xylene and esters such as ethyl acetate and isopropyl acetate may be used.

The reaction time is preferably 1 to 5 hours, and the reaction temperature is preferably 60 to 100 °C.

The method for preparing the fimasartan tromethamine salt of the present invention may further include washing and drying the obtained solid after filtering.

On the other hand, the present invention provides a pharmaceutical composition comprising fimasartan tromethamine salt together with a pharmaceutically acceptable carrier, specifically, stroke, stroke, stroke, cerebral infarction, Alzheimer's, vascular dementia, Creutzfeldt-Jakob disease, diabetes, It relates to a pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation and renal failure, in particular hypertension.

The pharmaceutical composition of the present invention may include another physiologically active substance in addition to fimasartan tromethamine salt.

The pharmaceutical composition according to the present invention may be administered orally, and may be formulated in various forms such as tablets, capsules, granules, powders, emulsions, suspensions, syrups, and the like. The various types of pharmaceutical compositions include excipients, fillers, extenders, binders, disintegrators, lubricants, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweeteners, solubilizers, bases ), dispersing agents, wetting agents, suspending agents, stabilizing agents, coloring agents, fragrances, and the like, can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each formulation.

In the preparation of the medicament, the content of the fimasartan tromethamine salt of the present invention varies depending on the form of the medicament, but is preferably in a concentration of 10 to 90% by weight, more preferably in a concentration of 30 to 80% by weight.

The dosage of the pharmaceutical composition of the present invention is variously changed in a wide range depending on the type of mammal including the person to be treated, the route of administration, body weight, sex, age, the degree of disease, the judgment of a doctor, and the like. In general, in the case of oral administration, the dosage of the active ingredient may be about 1-240 mg, preferably 5-180 mg, more preferably 10-120 mg per day based on a general adult weighing about 60 kg. The above-mentioned daily dose may be used at one time or in divided doses depending on the severity of the disease, the judgment of the doctor, and the like.

The fimasartan tromethamine salt of the present invention exhibits excellent stability against moisture and heat and high oxidation stability, so that the content uniformity of the formulation can be stably maintained for a long period of time. In addition, the fimasartan tromethamine salt of the present invention is advantageous for mass production because it does not require strict storage conditions and formulation manufacturing processes to maintain stability.

1 is a diagram showing an X-ray diffraction spectrum of crystalline fimasartan tromethamine salt dihydrate (crystal form I) obtained in Example 1. FIG.
FIG. 2 is a diagram showing the results of a Thermal Gravimetric Analysis (TGA) of the crystalline fimasartan tromethamine salt dihydrate (crystalline Form I) obtained in Example 1. FIG.
3 is a diagram showing a Differential Scanning Calorimeter Thermogram of crystalline fimasartan tromethamine salt dihydrate (crystalline Form I) obtained in Example 1. FIG.

Hereinafter, the present invention will be described in more detail by way of Examples and Comparative Examples. These Examples and Comparative Examples are only for illustrating the present invention, and it is apparent to those skilled in the art that the scope of the present invention is not limited thereto.

Example One: fimasartan tromethamine salt Preparation of dihydrate

250 g of fimasartan, 60.4 g of tromethamine, and 1,600 g of isopropanol were placed in a reactor and dissolved by heating under reflux. The reaction solution was cooled to 20 to 30° C., and 160 g of purified water was added to the reaction solution. The reaction solution was cooled to 0 to 5° C. and stirred for 2 hours, then the resulting solid was filtered and vacuum dried to obtain 299 g of fimasartan tromethamine dihydrate. The yield was 91%. In addition, the moisture content measured with a Karl-Fisher moisture meter was 5.60%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.50(m, 1H), 7.33(m, 3H), 7.02(d, 2H), 6.94(d,2H), 5.21(br, 2H), 3.75( s, 3H), 3.41 (m, 12H), 2.58 (m, 2H), 2.47 (m, 3H), 2.13 (s, 3H), 1.53 (m, 2H), 1.24 (m, 2H), 0.78 (t) , 3H)

¹³ C NMR (400 MHz, DMSO-d ₆ ): 199.6, 162.3, 160.9, 159.6, 159.0, 141.0, 140.4, 134.8, 132.0, 130.9, 130.5, 12907, 128.2, 127.3, 125.9, 119.5, 61.4, 59.7, 45.8, 44.7, 41.9, 38.6, 33.8, 28.7, 22.2, 22.1, 14.2

Example 2: fimasartan tromethamine salt Preparation of dihydrate

250 g of fimasartan, 60.4 g of tromethamine, and 2,000 g of ethanol were placed in a reactor and dissolved by heating and refluxing. The reaction solution was cooled to 20 to 30° C., and 200 g of purified water was added to the reaction solution. The reaction solution was cooled to 0 to 5° C. and stirred for 2 hours, then the resulting solid was filtered and dried to obtain 259 g of fimasartan tromethamine salt dihydrate. The yield was 79%. In addition, the moisture content measured with a Karl-Fisher moisture meter was 5.47%.

Example 3: fimasartan tromethamine salt Preparation of dihydrate

250 g of fimasartan, 60.4 g of tromethamine, and 8 kg of acetone were added to the reactor and dissolved by heating under reflux. The reaction solution was cooled to 20 to 30° C., and 800 g of purified water was added to the reaction solution. The reaction solution was cooled to 0 to 5° C. and stirred for 2 hours, then the resulting solid was filtered and vacuum dried to obtain 286 g of fimasartan tromethamine dihydrate. The yield was 87%. In addition, the moisture content measured with a Karl-Fisher moisture meter was 5.59%.

comparative example One: fimasartan potassium salt trihydrate Produce

50.0 g of fimasartan and 400 g of isopropanol were added to the reactor and dissolved by heating. An aqueous solution of potassium hydroxide in which 6.71 g of potassium hydroxide was dissolved in 45 g of purified water was slowly introduced into the reactor and stirred under reflux. The reaction solution was cooled to room temperature and the resulting solid was filtered to obtain fimasartan potassium salt. Fimasartan potassium salt was added to a 1:10 mixed solution of water and tetrahydrofuran, dissolved under reflux, and then cooled to 20 to 30° C. to form crystals. The resulting crystals were filtered and dried to obtain 41.5 g of fimasartan potassium salt trihydrate. The moisture content measured with a Karl-Fisher moisture meter was 9.10%.

test example One: fimasartan tromethamine salt X-ray of dihydrate Diffraction analysis

X-ray diffraction analysis of the fimasartan tromethamine salt dihydrate obtained in Example 1 was performed, and the results are shown in FIG. 1 . X-ray diffraction analysis was performed using a PANalytical, X'pert-Pro equipped with a solid state detector.

From FIG. 1, it was confirmed that the crystalline fimasartan tromethamine salt dihydrate (crystal form I) prepared in Example 1 had a characteristic crystal form by powder X-ray diffraction analysis. The characteristic peaks shown in the powder X-ray diffraction spectrum of FIG. 1 are shown in Table 1 below, where '2θ' is the diffraction angle, 'd' is the distance between crystal planes, and 'I/I ₀ ' is the relative intensity of the peak.

2θ d I/I ₀ 2θ d I/I ₀ 4.59 19.27 100 16.45 5.39 15.5 9.15 9.66 59.8 16.61 5.34 10.5 11.24 7.87 13.5 19.23 4.61 19.0 12.13 7.29 11.3 20.73 4.28 40.0 13.74 6.44 45.4 22.56 3.94 11.2 14.51 6.11 23.6 23.59 3.77 40.8 15.04 5.89 26.2 26.32 3.38 30.8 16.07 5.51 11.1 27.61 3.23 10.3

test example 2: fimasartan tromethamine salt Moisture content of dihydrate

The water content of the fimasartan tromethamine salt dihydrate obtained in Example 1 was measured by thermogravimetric analysis (TGA), and the results are shown in FIG. 2 .

Thermogravimetric analysis (TGA) is a method of measuring the change in sample weight as a function of temperature. The TGA result of FIG. 2 was obtained using a DSC 823e manufactured by Mettler Toledo. The sample size was about 5 mg. Samples were analyzed while heating from 30°C to 700°C at a heating rate of 10°C/min. The oven was purged with nitrogen gas at a flow rate of 50 mL/min. The TGA results in FIG. 2 show that the total weight loss is 5.07% (w/w). This value corresponds to the theoretical value of 5.47% of the water content contained in fimasartan tromethamine salt dihydrate. In addition, this value corresponds to the water content of 5.60% measured by a Karl-Fisher moisture meter in Example 1 above.

test example 3: fimasartan tromethamine salt Differential scanning calorimetry analysis of dihydrate

Differential scanning calorimetry (DSC) was performed on the fimasartan tromethamine salt dihydrate obtained in Example 1.

Differential scanning calorimetry was performed using a differential scanning calorimeter manufactured by Mettler Toledo at a heating rate of about 10°C/min in the range of -10°C to 250°C with a sample weight of about 3 mg. The oven was constantly purged with nitrogen gas at a flow rate of 50 mL/min. The results of differential scanning calorimetry are shown in FIG. 3 .

The differential scanning calorimetry analysis result of FIG. 3 showed a characteristic having two endothermic peaks at 65.73°C and 125.15°C.

test example 4: Purity change under severe conditions

Purity changes were compared by measuring the purity of the fimasartan tromethamine salt dihydrate obtained in Example 1 before and after leaving it exposed or sealed at 60° C. and 75% relative humidity for 4 weeks. The results are shown in Table 2 below.

division water(%) before neglect After leaving at 60℃ and 75% relative humidity exposure state sealed Example 1 99.95 99.95 99.95

From Table 2, it can be seen that the purity of the fimasartan tromethamine salt dihydrate prepared in Example 1 is maintained almost unchanged under severe conditions (60° C., 75% relative humidity). From this, it can be seen that the fimasartan tromethamine salt dihydrate according to the present invention has excellent stability and thus can be easily applied to mass production, and can be stably maintained without a change in purity for a long period of time during manufacture and storage.

test example 5: Hygroscopicity test

The fimasartan tromethamine salt dihydrate obtained in Example 1 was left at a temperature of 40° C. and a relative humidity of 75% for 14 days, and on the 1st, 3rd, 7th and 14th days, Karl-Fisher, respectively. Moisture content was measured with a moisture meter. The results are shown in Table 3 below.

division Moisture content (%) Example 1 Early 1 day 3 days 7 days 14 days 5.60 5.62 5.68 5.70 5.6

From Table 3, it can be seen that the fimasartan tromethamine salt dihydrate prepared in Example 1 maintains a moisture content within 0.1% at a temperature of 40° C. and a relative humidity of 75% and hardly absorbs moisture. From this, the fimasartan tromethamine salt dihydrate according to the present invention can be exposed to air for a long period of time or can stably maintain the hydrate state during the formulation process, and the same hydrate state for a long period of time without maintaining a difficult storage environment during storage It can be seen that the .

test example 6: Determination of solubility

The solubility of the active ingredient of the pharmaceutical composition in the aqueous solution affects the dissolution rate of the composition, which greatly affects the bioavailability of the drug. The solubility of fimasartan tromethamine salt dihydrate obtained in Example 1 was compared with that of fimasartan potassium salt trihydrate obtained in Comparative Example 1, a known material. The solubility of the active ingredient is dependent on the in vivo pH range required for bioabsorption, i.e., the pH in the stomach (1.2), the pH in the gastrointestinal tract (4.0), and the pH in the intestine (6.8) at 25±5° C. temperature condition. was carried out with

Specifically, each salt was dissolved in an aqueous phosphoric acid solution having a pH of 1.2, an aqueous phosphoric acid solution having a pH of 4.0, and an aqueous phosphoric acid solution having a pH of 6.8, and then the insoluble solutes were filtered to collect the filtrate and diluted. The diluted filtrate was analyzed by ultraviolet absorption spectroscopy at a wavelength of 261 nm using liquid chromatography (HPLC) to measure solubility (unit: mg/mL).

division pH 1.2 pH 4.0 pH 6.8 Example 1 0.0153 0.0015 0.299 Comparative Example 1 0.0142 0.0016 0.301

From Table 4, it can be seen that the fimasartan tromethamine salt dihydrate of Example 1 according to the present invention exhibits similar solubility to the fimasartan potassium salt trihydrate of Comparative Example 1 at pH 1.2, 4.0 and 6.8.

test example 7: Purity change under severe oxidizing conditions

Fimasartan tromethamine salt dihydrate obtained in Example 1 and fimasartan potassium salt trihydrate obtained in Comparative Example 1 were left under severe oxidizing conditions (0.3% hydrogen peroxide/room temperature/1 hour), and then liquid chromatography (HPLC ) was analyzed at a wavelength of 261 nm by UV absorption spectroscopy to measure related substances.

division Related Substances (%) by Relative Retention Time (RRT) Total related substances (%) 0.13 0.32 0.42 Example 1 0.015 5.502 2.083 12.073 Comparative Example 1 0.048 12.954 8.410 21.591

From Table 5, it can be seen that the fimasartan tromethamine salt dihydrate of Example 1 according to the present invention exhibits higher oxidative stability than the fimasartan potassium salt trihydrate of Comparative Example 1. From this, it can be seen that the fimasartan tromethamine salt dihydrate according to the present invention can be stably maintained without a change in purity in the long term during the preparation and storage period of the formulation.

Claims (6)

In X-ray diffraction analysis, the values of the diffraction angle (2θ) with I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) of 10% or more were 4.59±0.2, 9.15±0.2 , 11.24±0.2, 12.13±0.2, 13.74±0.2, 14.51±0.2, 15.04±0.2, 16.07±0.2, 16.45±0.2, 16.61±0.2, 19.23±0.2, 20.73±0.2, 22.56±0.2, 23.59±0.2, 26.32 Determination of fimasartan tromethamine salt dihydrate with ±0.2 and 27.61 ±0.2. delete delete delete Stroke, stroke, cerebral hemorrhage, cerebral infarction, Alzheimer's, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery comprising the crystal of fimasartan tromethamine salt according to claim 1 together with a pharmaceutically acceptable carrier A pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of diseases, angina, myocardial infarction, hypertension, heart failure, inflammation and renal failure. The pharmaceutical composition according to claim 5, for preventing or treating hypertension.

Images