KR100632697B1 - Processes for preparing amlodipine nicotinate crystalline dihydrate - Google Patents

Abstract

The present invention relates to a process for the preparation of amlodipine nicotinate crystalline dihydrate, the amlodipine nicotinate crystalline dihydrate of the present invention is far superior to commercially available amlodipine besylate, solubility in water, stability, It is excellent in non-hygroscopicity and processability into tablet form.

Amlodipine Nicotinate Crystalline Dihydrate

Description

Process for preparing amlodipine nicotinate crystalline dihydrate

Figure 1 is an H-NMR chart of amlodipine besylate above the chart before the harsh test, below is a chart after the harsh test,

Figure 2 is an H-NMR chart of amlodipine nicotinate in the upper before the harsh experiment, the lower after the harsh experiment,

Figure 3 is an H-NMR chart of amlodipine besylate above the light irradiation before, below the light irradiation chart,

4 is an H-NMR chart of amlodipine besylate, the upper is before the hygroscopic experiment, the middle is after the hygroscopic experiment and the lower is the H-NMR chart after drying under reduced pressure,

5 is an H-NMR chart of amlodipine nicotinate prepared in Example 1,

6 is an XRD chart of amlodipine nicotinate prepared in Example 1,

7 is peak list data of an XRD pattern of amlodipine nicotinate prepared in Example 1,

8 is a graph showing the effect of amlodipine besylate on systolic blood pressure in congenital hypertensive rats,

9 is a graph showing the effect of amlodipine nicotinate on systolic blood pressure in congenital hypertensive rats,

10 is a graph showing the dose-response curves of amlodipine besylate and amlodipine nicotinate for peak changes in systolic blood pressure in congenital hypertensive rats.

The present invention relates to a process for the preparation of amlodipine nicotinate crystalline dihydrate.

Amlodipine has the chemical name 3-methyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dica Reboxylates are calcium channel blockers that have the following structural formula and are potent and prolonged activity useful as ischemic and hypertensive agents.

EP-A 89167 describes various different forms of pharmaceutically acceptable salts of amlodipine. In particular, pharmaceutically acceptable acid addition salts are formed from acids forming non-toxic acid addition salts containing pharmaceutically acceptable anions, for example hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, male Ate, fumarate, lactate, tartrate, citrate and gluconate salts. Among these salts, maleates are described as particularly preferred. However, EP-A-244244 describes that benzene sulfonate salts have a number of advantages over maleate salts.

The present inventors have verified the merits of benzene sulfonate salts and found that the amlodipine benzene sulfonate salts are very weak to light, and that the pH at saturation is not close to the pH of blood, and is more stable to light and closer to the biological pH. In the search for several salts that are excellent for the manufacture of pharmaceutical formulations, and while studying several kinds of salts, it is surprising that amlodipine nicotinate is not only best suited to its goals, but also has a surprisingly superior efficacy. Completed.

It is therefore an object of the present invention to provide a method for preparing nicotinate crystalline dihydrate of amlodipine.

Amlodipine is useful in free base form, but in practice it is most suitably administered in salt form with a pharmaceutically acceptable acid. In order to meet this purpose, pharmaceutically acceptable salts include: (1) good solubility; (2) excellent stability; (3) non-hygroscopic; And (4) four physicochemical criteria such as processability into tablet formulations. Accordingly, the present invention compares the known benzene sulfonate salt of amlodipine (the besylate salt of amlodipine) with the nicotinate salt dihydrate of amlodipine of the present invention by comparing the above-mentioned four physicochemical criteria with nicotinate of amlodipine. The present invention has been completed by demonstrating that salt dihydrate is superior to the preparation of pharmaceutical formulations over the benzene sulfonate salt of amlodipine.

The benzenesulfonate salt of amlodipine and the nicotinate salt dihydrate of amlodipine are specifically evaluated by setting the four physicochemical criteria indicated above.

1. In general, what is required for bioavailability with good aqueous solubility is known in the art. Higher solubility is required for formulating injection solutions, but usually at least 1 mg / ml at a pH of 1 to 7.5 is recommended. In addition, salts which provide a solution having a pH close to the pH of the blood (7.4) are preferred because they can be easily mixed in vivo and can be easily buffered to the required pH range without changing their solubility. to be.

As can be seen from the comparative data below, amlodipine nicotinate salt dihydrate exhibits better solubility and closer to pH of blood than amlodipine benzene sulfonate salt.

salt Solubility (mg / ml) PH at saturation Amlodipine Benzene Sulfonate (Besylate) 4.6 6.6 Amlodipine Nicotinate 6.8 7.2

* The maximum dissolved mg value was obtained at room temperature using 50 ml of distilled water and ultrasonic waves, and the pH was measured using Fischer Scientific Accument (PH meter 15).

* The following NMR measurement was performed using a 300MHz FT-NMR Spectrometer (JEOL JNM-LA300).

2. While good stability in the solid state is very important for tablets and capsules, good stability in solution is necessary for aqueous injections.

To select for chemical stability, each salt is mixed in a powder vehicle to form a tablet. The vehicle of the tablet consists of a combination of 50:50 microcrystalline cellulose and anhydrous dibasic calcium phosphate. They are then stored for three weeks at 50 ° C., 60% relative humidity in sealed vials. Agents and any degradation products are extracted with methanol: chloroform (50:50) and separated using various solvent systems on silica TLC plates. The Rf value of the resulting decomposition product was confirmed, and the peak of NMR was confirmed to confirm the superiority of stability. The results are shown in FIGS. 1 and 2. Here, Figure 1 is an H-NMR chart of amlodipine besylate above the harsh test before, below is a harsh test chart, Figure 2 is an H-NMR chart of amlodipine nicotinate above the harsh test, below is harsh The chart after the experiment.

* TLC phase separation:

Developing Solvent Conditions (CHCl ₃ : MeOH: HAC: H₂O = 40: 10: 5: 2)

Amlodipine Benzenesulfonate Decomposition Product Rf = 0.38

* Peak on NMR: Amlodipine benzene sulfonate->

               Before severe experiment; Peak present at 1.67 ppm (bs, -NH₂)

               After severe experiment; 1.67ppm peak disappearance, broad around 1.90ppm

                                   appearance of peaks and impurity peaks

On the other hand, as one of the stability tests of the raw material itself, incandescent lamps (220V, 100W) were installed at 30 cm high from the sample and maintained at 25-30 ° C., respectively. After irradiation in light (100 × 200 mm), the amlodipine benzene sulfonate discolored yellow after 14 days. Therefore, it was found that amlodipine nicotinate salt dihydrate was more stable in terms of light stability, and a tablet containing commercially available amlodipine benzene sulfonate (Novask tablet) was tested and tested under the same conditions. It was confirmed that the discoloration. The results are shown in FIG. 3, and in the H-NMR chart of the amlodipine besylate of FIG. 3, the upper part is before the light irradiation and the lower part is after the light irradiation.

* NMR phase change: amlodipine benzene sulfonate->

               Before light irradiation; Peak present at 1.67 ppm (bs, -NH₂)

               After 14 days of light irradiation; 1.67ppm peak disappearance, broad at 2.15ppm

                               peak appearance

The results confirmed that the nicotinate salt dihydrate of amlodipine is more stable than the benzene sulfonate salt of amlodipine.

3. It is desirable to make non-hygroscopic salts to produce stable formulations. In solid state with high drug content, water absorbed film can act as a factor for hydrolysis and chemical degradation. Hygroscopicity of the medicament or salt thereof contributes to free moisture, which is usually the cause of instability.

The degree of hygroscopicity of amlodipine nicotinate salt dihydrate and amlodipine benzene sulfonate for 14 days at 50 ° C. and 60% relative humidity showed that the amlodipine nicotinate salt dihydrate remained the dihydrate. Was kept as it is. However, in the case of amlodipine benzene sulfonate, H-NMR was measured before and after the harsh test, and the position of -NH₂ peak was changed from 1.67ppm to 2.25ppm and the size was smaller. When -NMR was measured, it was observed in the vicinity of 1.67 ppm, which is the position before the harsh experiment. Thus, it has been shown that amlodipine benzene sulfonate may have other problems in stability regardless of hygroscopicity. The results are shown in Figure 4, in the H-NMR chart of the amlodipine besylate of Figure 4, the upper is before the hygroscopic experiment, the middle is after the hygroscopic experiment and the lower is the H-NMR chart after drying under reduced pressure.

4. The final properties of the acceptable salts are considered processability, ie compression properties and the ability to adhere or not adhere to the tablet maker. For high dose formulations, good compressibility is very important in the manufacture of square tablets. In low dose tablets, the need for good compressibility can be somewhat reduced by using an appropriate diluent excipient, called compression aid. Microcrystalline cellulose is a commonly used compression aid. However, at any dose the sticking of the drug in the punch of the tablet maker should be prevented. When the medicament is loaded onto the punch surface, it leaves marks on the tablet surface, making it undesirable for use. In addition, drug adhesion in this manner requires high desorption when the tablet is separated from the machine. In practice, the tack can be reduced by total wetting treatment, careful selection of excipients and the use of large amounts of anti-sticking agents such as magnesium stearate. However, the above-mentioned stickiness problem can be reduced by selecting a salt having excellent anti-sticking properties.

To compare the tackiness of amlodipine nicotinate salt dihydrate and amlodipine benzene sulfonate, the following process is carried out using a conventional tablet maker: calcium sulfate dihydrate, microcrystalline cellulose and amlodipine nicotinate salt dihydrate ( 50 tablets containing 47.5: 47.5: 5) are prepared and the material adhering to the tablet punch is extracted using methanol and the amount is measured by spectrometer. The process is repeated with 100, 150, 220, 250 and 300 purifications. After each run, the material adhering to the tablet punch is extracted with methanol and the amount is measured. Plot the value and calculate the mean value from the slope of the line created therefrom. The process as described above is repeated for amlodipine benzene sulfonate. The amount of amlodipine determined to be tacky to the tablet punch is shown in Table 2 in a ratio relative to amlodipine benzene sulfonate.

salt Sticky Amlodipine (μg) per tablet cm 2 Relative Ratios for Benzene Sulfonate Nicotinate 0.44 36.7% Benzene Sulfonate 1.20 100.0%

* Note: Korean Patent No. 1995-0006710-> Benzene Sulfonate: 1.17㎍

           (Within ± 3% of error range)

Clearly nicotinate has superior anti-sticking properties compared to benzene sulfonate. Thus, nicotinate salt dihydrate is a salt of good solubility, good stability, non-hygroscopicity and good processability, which is more suitable for the preparation of pharmaceutical formulations than benzene sulfonate.

In order to more easily understand the present invention, the present invention is illustrated with reference to the following examples, but the present invention is not limited thereto.

Example 1 Method for Preparing Amlodipine Nicotinate Salt and Its Hydrate

Amlodipine (10.0 g, 24.45 mmole) is dissolved completely in 95% industrial methylated alcohol (40.0 ml) and then added to nicotinic acid (3.0 g, 24.37 mmol) slurried in 95% industrial methylated alcohol (10.0 ml). The solution was slowly warmed to react at reflux for 3 hours, and then cooled to 5 ° C. or lower to form amlodipine nicotinate salt hydrate, which was filtered and washed with industrial isopropanol (20.0 ml).

The obtained salt was dissolved in 95% methanol: isopropanol (1: 9) or water: isopropanol (5:95) solution (40.0 ml) and dissolved completely. The mixture was slowly stirred at room temperature, cooled to 0 ° C, and the resulting crystals were filtered. Washed with isopropanol (20.0 ml) and dried at 80 ° C. for 5 hours under reduced pressure.

11.0-11.3 g of dihydrate salts having the following analytical values were obtained. The results are shown in the H-NMR chart of FIG.

Yield: 79.3 ~ 81.4%

Melting Point: 174-176 ℃

H-NMR (CDCl₃): 9.17 (s, 1H), 8.60 (d, 1H), 8.19 (d, 1H), 7.91 (s, 1H), 6.99 ~ 7.30 (m, 5H), 5.31 (s, 1H) , 4.69 (gq, 2H), 4.00 (m, 2H), 3.76 (bs, 2H), 3.55 (s, 3H), 3.18 (bs, 2H), 2.21 (s, 3H), 1.15 (t, 3H)

6 is an XRD chart of amlodipine nicotinite prepared in Example 1. FIG.

7 is peak list data of an XRD pattern of amlodipine nicotinite prepared in Example 1. FIG.

Peak list data of XRD pattern of amlodipine nicotinate crystalline hydrate 2-Theta Intensity 8.280 329.4 12.080 1826.6 12.640 971.0 13.100 1375.3 14.120 338.7 16.300 489.3 19.920 618.6 22.940 506.2 24.720 721.6 26.680 528.1

* XRD model name; Rigaku Rotaflex 12Kw XRD-2000

LOD (Dry Loss Test): Take 200mg of the salt precisely, dry for 5 hours under reduced pressure below 120 ℃ and 5mmHg, and then confirm that it is a dihydrate by weight difference.

Example 2 Preparation of Amlodipine Nicotinate Salt Anhydride

The amlodipine nicotinate salt hydrate obtained in Example 1 was dried at 115 ° C to 125 ° C for 5 hours under reduced pressure to obtain amlodipine nicotinate salt anhydride.

Melting Point: 176-177 ℃

Calculated (%): C; 58.70 H; 5.68 N; 7.90

Found (%): C; 58.62 H; 5.65 N; 7.94

Experimental Example 1.Comparison of efficacy of amlodipine besylate and amlodipine nicotinate

Introduction

This experiment was performed to measure / compare the cardiovascular pharmacological effects on two test substances, Amlodipine besylate and Amlodipine nicotinate of the present invention. As an experimental item, an in vivo activity assay for measuring antihypertensive activity in congenital hypertensive rats was used.

2. Experimental method

(1) reagent

Amlodipine besylate (M.W. 567.05) and amlodipine nicotinate (M.W. 531.0) were dissolved in distilled water and administered. All drugs and reagents used in the experiment were prepared just before use.

(2) experimental animals

Congenital hypertensive rats (SHR, male, 13-14 weeks old) were purchased from Charles River, Japan, and were automatically contrasted at constant temperature (22.5 ± 1 ° C), humidity (55 ± 5%), and 12 hour intervals. It was used in experiments after stabilization in a controlled clean animal kennel.

(3) Antihypertensive Action in Congenital Hypertensive Rats (SHR)

SHR was used only for systolic blood pressure of 170 mmHg or more and 6-8 animals per group. Blood pressure was measured by the multi-channel 8000 (TSE, Germany) using the tail-cuff method, which is a method of measuring blood pressure from the tail of the experimental animal. In order to measure blood pressure smoothly, the experimental animals were warmed for about 10 minutes in a constant temperature box at 37 ℃. Test substance 1, 3 and 10 mg / kg doses were dissolved in distilled water (0.5 ml / 100g rat) and administered orally. Blood pressure measurements were taken before drug administration 2, 4, 6, 8, 10, 24 hours after drug administration.

(4) statistics

All experimental results were mean ± S.E.M. Statistical analysis of the experimental results was performed by unpaired t-test and one-way analysis of variance (ANOVA) using the Sigma Stat program of Jandel Co., USA. The secondary test was Dunnett. Multiple comparisons test was used.

3. Experimental Results

Experimental results of measuring the antihypertensive effect of the test substance amlodipine besylate and amlodipine nicotinate in congenital hypertensive rats are shown in FIGS. 8 to 10 and Tables 4 and 5. Amlodipine besylate (FIG. 8, Table 4) and amlodipine nicotinate (FIG. 9 and Table 4) all lowered blood pressure in a dose-dependent manner, with the blood pressure drop pattern being similar in all dose groups. Significant antihypertensive effects began to appear after 2 hours of test substance administration, with maximum effects between 2 and 6 hours of administration. These antihypertensive effects lasted for more than 10 hours, especially at high doses of 10 mg / kg, which persisted even after 24 hours of administration. Only the maximum antihypertensive effect for each dose is shown separately in FIG. 10, wherein the maximum antihypertensive effects of amlodipine besylate and amlodipine nicotinate at 1 mg / kg dose were -7.0 ± 1.66 and -10.20 ± 2.71%, respectively. (p <0.05 vs. Amlodipine besylate) and -25.0 ± 1.98 and -26.8 ± 3.22% at the 3 mg / kg dose, respectively, and -38.7 ± 2.18 and -40.9 ± 2.08% at the high dose of 10 mg / kg, respectively. In the 1 mg / kg dose, there was significant significance. On the other hand, the ED ₂₀ level (dose 20% inhibition, 95% confidence interval) was found to be amlodipine besylate and amlodipine nicotinate 2.48 ± 0.46, 2.19 ± 0.57 mg / kg (Table 5).

Maximum antihypertensive effect at each dose Sample Name Dosage 1mg / kg Drop in blood pressure 3mg / kg Drop in blood pressure 10mg / kg Drop in blood pressure Amlodipine besylate  -7.0 ± 1.66  1.00  -25.0 ± 1.98  1.00  -38.7 ± 2.18  1.00 Amlodipine nicotinate  -10.20 ± 2.71  1.46  -26.8 ± 3.22  1.07  -40.9 ± 2.08  1.06

ED ₂₀ values Sample Name Capacity (mg) About effective strength  Amlodipine besylate  2.48 ± 0.46  1.00  Amlodipine nicotinate  2.19 ± 0.57  1.13

4. Conclusion

The antihypertensive effects of amlodipine besylate and amlodipine nicotinate in congenital hypertensive rats were measured. At concentrations (p <0.05 vs. Amlodipine besylate), 1.46 times better efficacy than amlodipine besylate was confirmed. On the other hand, comparing the ED ₂₀ level for antihypertensive action, amlodipine nicotinate was 1.13 times stronger than amlodipine besylate.

As demonstrated above, the novel amlodipine nicotinate and its hydrate of the present invention not only have superior efficacy compared to commercially available amlodipine besylate, but also have excellent solubility in water, stability, non-hygroscopicity, and processability into formulation formulations. Do.

Claims (2)

A method for producing amlodipine nicotinate crystalline dihydrate having the following XRD pattern by reacting amlodipine with nicotinic acid in a water-containing industrial methylated spirit. 2-Theta Intensity   8.280 329.4 12.080 1826.6 12.640 971.0 13.100 1375.3 14.120 338.7 16.300 489.3 19.920 618.6 22.940 506.2 24.720 721.6 26.680 528.1 The amlodipine nicotinate crystalline dihydrate having the following XRD pattern is prepared by reacting amlodipine with nicotinic acid in a water-containing industrial methylated alcohol, followed by recrystallization with a 95% methanol-isopropanol or water-isopropanol mixed solvent. How to. 2-Theta Intensity   8.280 329.4 12.080 1826.6 12.640 971.0 13.100 1375.3 14.120 338.7 16.300 489.3 19.920 618.6 22.940 506.2 24.720 721.6 26.680 528.1

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