KR102518204B1 - Novel edoxaban propylene glycol solvate - Google Patents

Abstract

The inventors of the present invention have improved crystallinity, moisture stability, ease of preparation, and crystallization methods unsuitable for mass production, which are problems of conventional edoxaban tosylate monohydrate and its crystalline form, and a novel edoxaban propylene glycol solvate and It is about its crystalline form.

Description

Novel edoxaban propylene glycol solvate {NOVEL EDOXABAN PROPYLENE GLYCOL SOLVATE}

The present invention relates to active ingredient drug substances of edoxaban products. An item refers to a finished drug product designed by mixing active ingredients and excipients.

[Edoxaban]

Edoxaban is an anticoagulant of the class of Xa inhibitors of the structural formula:

[Formula 1]

It is known as a preventive or therapeutic drug for thrombotic diseases, and its specific efficacy and effects are as follows.

1. Reduced risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation

2. Treatment of deep venous thrombosis and pulmonary embolism

3. Reduced risk of recurrence of deep venous thrombosis and pulmonary embolism

The list of major patents of Daiichi Sankyo, which developed Edoxaban, is as follows.

1. Republic of Korea Patent Registration No. 10-0863113 Edoxaban substance patent (active ingredient)

2. Republic of Korea Patent Registration No. 10-1424843 Edoxaban preparation patent (formulation)

3. Republic of Korea Patent Registration No. 10-1708528 Edoxaban p-toluenesulfonate crystal patent (main ingredient raw material)

[Edoxaban active ingredient]

Usually, when an original company develops an active ingredient before launching an item, research on the optimized raw material for the active ingredient is carried out from various angles for a fairly long period of time. Therefore, if you look at the original company's main ingredient patent, you can indirectly understand the raw material development situation of Edoxaban.

Korean Patent Registration No. 10-1708528 introduces the development of a new form II crystalline form of edoxaban p-toluenesulfonate, and discloses form I and form II crystal forms.

As such, the original company was obsessed with exploring the crystal form of a specific acid addition salt compound of edoxaban. Although there is no document that specifically mentions the reason for this, Korean Patent Registration No. 10-1424843 shows that edoxaban is soluble in neutral aqueous solution in the free base state. In light of the fact that it was significantly lacking, it is assumed that attention was paid to salt compounds to improve solubility.

In addition, Korean Patent Registration No. 10-1424843 discloses a hydrochloride salt compound of edoxaban.

Republic of Korea Patent Registration No. 10-0863113 Republic of Korea Patent Registration No. 10-1424843 Republic of Korea Patent Registration No. 10-1708528

However, conventional main ingredient raw materials have the following limitations.

The crystalline form of edoxaban tosylate monohydrate of Korean Patent Registration No. 10-1708528 has a problem in reproducibly obtained when prepared by a general crystallization method. Therefore, since it relies on vapor adsorption, freeze drying, and crystallization methods that combine various temperatures, and also uses solvents such as dioxane and dimethyl sulfoxide, which are special solvents, yield, efficiency, and mass production are not easy. problems are predicted.

In addition, even when crystallized using the method according to Korean Patent Registration No. 10-1708528, there is a report that the crystallinity of edoxaban tosylate monohydrate is very poor and the stability due to moisture absorption is weak.

And according to other literature, there is also a report that edoxaban tosylate raw material has hygroscopic properties, very low stability, and weak acid stability during storage and storage (Acta Scientific Pharmaceutical Sciences 3.1 (2019): 73- 81).

In an effort to overcome this problem, Korean Patent Registration Nos. 10-2090912, 10-2215625, and 10-2222784 have developed new crystalline forms and new salts of edoxaban.

However, the above new crystalline form and new salt also did not significantly improve the problems of stability by moisture and ease of preparation, and the stability by moisture and ease of preparation were equivalent to or slightly improved than edoxaban tosylate monohydrate. It seems that the problem of .

The present invention relates to a new active ingredient of edoxaban that overcomes the above limitations by approaching them from an advanced point of view.

The characteristic configuration of the present invention is as follows.

1. Edoxaban propylene glycol solvate.

2. Edoxaban propylene glycol solvate according to 1 above, having the following structural formula.

[Formula 2]

3. A crystalline form of the edoxaban propylene glycol solvate according to 1 or 2 above.

4. The crystalline form according to 3 above, characterized by having a characteristic peak at a 2θ diffraction angle of 17.255±0.2 in powder X-ray diffraction analysis.

5. In the above 3 or 4, the endothermic peak due to desolvation appears at 150 ° C to 185 ° C, the endothermic onset temperature appears at 299.21 ° C ± 3 ° C, and the endothermic temperature is 300.31 ° C ± 3 ° C in the temperature differential scanning calorimetry analysis A crystalline form characterized in that it appears in.

6. The crystalline form according to any one of 3 to 5 above, characterized by containing 6 to 8% by weight of propylene glycol according to thermogravimetric analysis.

The present invention has an effect of improving the problems of the conventional edoxaban tosylate monohydrate raw material in terms of crystallinity, stability by moisture and ease of preparation, and at the same time, unlike the conventional edoxaban tosylate monohydrate crystalline raw material, it is suitable for mass production. It has the effect that it can be obtained through an easy crystallization method.

1 shows a powder X-ray diffraction pattern of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention.
Figure 2 shows the results of thermogravimetric analysis (TGA) of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention. From this result, it can be seen that the edoxaban propylene glycol solvate contains about 6% to 8% of propylene glycol.
Figure 3 shows a differential scanning calorimetry (DSC) analysis calorimetry curve of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention.
4 shows a hydrogen nuclear magnetic resonance spectroscopy spectrum of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention. From this result, it can be seen that edoxaban and propylene glycol form an edoxaban propylene glycol solvate through an exact intermolecular bond at a ratio of 2:1.
5 is a result of comparing the adhesion and electrostatic force of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention and conventional edoxaban tosylate monohydrate. From these results, it can be seen that the edoxaban propylene glycol solvate has no adhesiveness and no electrostatic force, whereas the conventional edoxaban tosylate monohydrate has high adhesiveness and electrostatic force and sticks to the device when formulated, making it difficult to prepare. there is.
6 is a result of comparing crystal images of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention and conventional edoxaban tosylate monohydrate by optical microscope. From these results, conventional edoxaban tosylate monohydrate exhibited a dendritic form, but edoxaban propylene glycol solvate showed rectangular crystals. When comparing the dendritic and rectangular crystals, it can be confirmed that the edoxaban propylene glycol solvate has a better crystal form than the conventional edoxaban tosylate monohydrate.
7 is a comparison of particle size distributions of edoxaban propylene glycol solvate prepared according to an embodiment of the present invention and conventional edoxaban tosylate monohydrate. Edoxaban propylene glycol solvate exhibits a constant particle size distribution, whereas the conventional edoxaban tosylate monohydrate is not uniform and has an uneven size distribution, indicating poor ease of preparation.

The edoxaban propylene glycol solvate referred to herein refers to a novel compound in which edoxaban and propylene glycol are combined, and is not limited to a solid crystal having a specific crystal form. Therefore, it is clarified that the edoxaban propylene glycol solvate should not be construed as being limited to a specific crystal or crystalline form unless otherwise specified as a crystal or crystalline form.

The present invention relates to a novel compound of edoxaban propylene glycol solvate and a specific crystalline form thereof.

First, a novel compound is introduced.

[Edoxaban propylene glycol solvate]

As a result of research efforts to overcome the crystallinity, stability, and ease of preparation of edoxaban tosylate monohydrate, the present inventors have found that the solubility is equivalent to that of edoxaban tosylate monohydrate, while at the same time crystallinity, moisture developed an edoxaban propylene glycol solvate with improved stability and ease of preparation.

Edoxaban propylene glycol solvate according to the present invention has a structure as shown in the following structural formula.

[Formula 2]

For reference, a solvate refers to a compound in which solute molecules and solvent molecules are combined in a stoichiometrically regular ratio through intermolecular bonds. Solvates refer to crystalline solids which, when obtained as solids, form a crystal structure.

Such solvates can exhibit various physical properties like polymorphs. For example, melting point, crystallinity, color, density, hardness, stability, solubility, etc. of edoxaban may all be different depending on the type of solvate.

On the other hand, solvates cannot be prepared with any solvent. Solvents can exist in various forms in crystalline solids. In order for a solvate to form, it must be a solvent molecule that is involved in the crystal structure and forms a crystal lattice. (NEWS & INFORMATION FOR CHEMICAL ENGINEERS, Vol. 28, No. 1, 2010).

[Figure 1]

The figure above illustrates a form in which a solvent can be incorporated into a crystal structure (Polymorphism in the pharmaceutical industry” edited by Rolf HifikerWiley-VCH, 2006).

As a result of research efforts to develop an edoxaban solvate with improved crystalline form, stability by moisture and ease of preparation, the present inventors succeeded in preparing the edoxaban propylene glycol solvate according to the present invention, and hydrogen nuclear magnetic resonance spectroscopy Analysis (H-NMR) confirmed that the present invention was formed by intermolecular bonding at a ratio of edoxaban to propylene glycol of 2:1.

Edoxaban propylene glycol solvate, a novel compound of the present invention, is not bound to a specific crystal form when obtained in a solid state, and has improved stability by moisture compared to conventional edoxaban tosylate monohydrate, so it is suitable for storage and storage of raw materials. There is an advantage, and in obtaining a crystal having a specific crystal form introduced below, there is also an advantage that it can be obtained reproducibly by a general crystallization method rather than a complicated crystallization method.

In addition, compared to the conventional edoxaban tosylate monohydrate, the edoxaban propylene glycol solvate according to the present invention has no adhesiveness and no electrostatic force during the formulation process, so it can be used as a raw material with improved ease of preparation. For reference, raw materials with adhesiveness and electrostatic force are problematic because they stick to the device during the formulation process.

In addition, the edoxaban propylene glycol solvate according to the present invention has the same solubility as the conventional edoxaban tosylate. If only the stability and ease of formulation are improved, but the solubility is lowered, it has no value as a raw material. However, stability and solubility are often two sides of the same coin. That is, raw materials with improved stability tend to have low solubility, and conversely, raw materials with improved solubility tend to have low stability.

However, the present invention is a raw material having a surprising effect because it has the same solubility as conventional edoxaban tosylate monohydrate and at the same time has improved stability and improved ease of preparation, and thus has a very high value as a raw material.

The characteristics of the novel compound according to the present invention were examined above. Hereinafter, a specific crystalline form of the novel compound according to the present invention is introduced.

[Specific crystalline form of edoxaban propylene glycol solvate]

In one embodiment, the novel compound according to the present invention can be obtained as a solid crystal having a characteristic peak at a 2θ diffraction angle of 17.255±0.2 in powder X-ray diffraction (PXRD) analysis. This is also referred to as the crystalline form according to the present invention hereinafter.

The crystalline form according to the present invention has the strongest peak at 17.255±0.2. Although peaks are observed at 6.589±0.2, 10.692±0.2, 11.274±0.2, 12.311±0.2, 13.834±0.2 or 20.780±0.2, the representative value representing the crystalline form according to the present invention is whether or not it has a peak of 17.255±0.2. .

One data value of intensity and peak position of powder X-ray diffraction of the crystalline form according to the present invention may be as follows.

(PXRD intensity and peak position of the crystalline form according to the present invention)

In addition, according to the data values of the crystalline form according to the present invention, in temperature differential scanning calorimetry (DSC), the endothermic peak due to desolvation appears at 150 ° C to 185 ° C, the endothermic onset temperature appears at 299.21 ° C ± 3 ° C, and the endothermic temperature appears at 300.31℃±3℃.

In addition, the crystalline form according to the present invention shows a mass loss of propylene glycol in the range of 6% to 8% in thermogravimetric analysis (TGA).

Meanwhile, the crystalline form according to the present invention can be obtained reproducibly by a relatively simple method.

For example, Korean Patent Registration No. 10-1708528 prepares a specific crystalline form of edoxaban tosylate monohydrate by combining vapor adsorption, lyophilization, and various temperatures. In addition, at this time, special solvents such as dioxane and dimethyl sulfoxide are used, and the yield is only about 70%. This is a yield that is not easy for mass production, and is a very weak crystallization method in terms of efficiency.

However, the crystalline form according to the present invention can be obtained reproducibly by a crystallization method that is more efficient, easy to mass-produce, and has a yield of 90% or more.

The characteristics of the crystallization method can be summarized as follows.

1. Obtaining solid crystals by simple vacuum evaporation crystallization using general solvents without using special temperatures and special solvents.

2. Filtration of solid crystals obtained by simple slurry method without special method and equipment at room temperature.

In addition, additional effects of the crystalline form according to the present invention are as follows.

The conventional crystal form of edoxaban tosylate monohydrate has lower crystallinity as a dendrite, whereas the crystal form according to the present invention has a rectangular shape and high crystallinity. Therefore, the crystalline form according to the present invention is a raw material with improved ease of preparation.

In addition, since the crystalline form according to the present invention has an even particle size distribution compared to the conventional edoxaban tosylate monohydrate crystalline form, it is a raw material with improved ease of preparation due to a high flow rate of the formulation.

In addition, the crystalline form according to the present invention is a raw material with improved ease of preparation as compared to the conventional edoxaban tosylate monohydrate crystalline form without adhesiveness and electrostatic force during the formulation process.

In addition, the crystalline form according to the present invention hardly absorbs moisture compared to the conventional crystalline form of edoxaban tosylate monohydrate. An increase in moisture adversely affects stability during storage and storage of raw materials, and in particular, salts such as edoxaban tosylate may cause stability degradation due to hydrolysis. However, the present invention has a better advantage during storage and storage due to less stability change due to moisture absorption.

The present invention will be described in more detail through the following examples. However, these examples are merely examples for explaining the present invention in more detail, and the scope of the present invention is not limited to these examples.

In addition, in the examples, the manufacturing process of edoxaban propylene glycol solvate and the manufacturing process of its crystalline form are integrated and introduced as a series of processes without dividing them separately. However, it is added that this introduction is not intended to limit the scope of the present invention to only a specific crystalline form of edoxaban propylene glycol solvate.

[Example 1] Preparation of edoxaban propylene glycol solvate and its crystal

10 g of edoxaban free base was dissolved in 150 mL of methylene chloride. Then, after adding 1 equivalent of propylene glycol, the mixture was stirred for 30 minutes. After that, it was concentrated under reduced pressure in a water bath at 50 degrees. Upon completion of the concentration, a solid is precipitated. After adding 50 mL of cyclohexane to the precipitated solid, the mixture was stirred for 10 minutes. Thereafter, the mixture was filtered under reduced pressure and vacuum dried at 30 degrees for 16 hours to obtain 10.3 g of edoxaban propylene glycol solvate crystals.

[Example 2] Preparation of edoxaban propylene glycol solvate and its crystal

10 g of edoxaban free base was dissolved in 150 mL of methylene chloride. Then, after adding 1 equivalent of propylene glycol, the mixture was stirred for 30 minutes. Thereafter, the solid was precipitated by concentrating under reduced pressure in a water bath at 50 degrees. The precipitated solid was obtained and vacuum dried at 30 degrees for 16 hours to obtain 11.2 g of edoxaban propylene glycol solvate crystals.

[Experimental Example 1] Powder X-ray diffraction (PXRD)

PXRD analysis (see Figure 1) was performed on a (D8 Advance) X-ray powder diffractometer using Cu Kα radiation. The instrument was equipped with tube power, and the amount of current was set to 45 kV and 40 mA. The divergence and scattering slits were set to 1°, and the light-receiving slits were set to 0.2 mm. A θ-2θ continuous scan was used from 5 to 35° 2θ at 3°/min (0.4 sec/0.02° interval).

[Experimental Example 2] Thermogravimetric analysis (TGA)

Using a TGA Q50 obtained from TA, measurements were performed using a TGA fan (see Fig. 2) at a scan rate of 10 °C/min from 20 °C to 400 °C under nitrogen purge.

[Experimental Example 3] Temperature Differential Scanning Calorimetry (DSC)

Using a DSC Q50 obtained from TA, DSC measurements (see Fig. 3) were performed in an airtight pan from 20 °C to 350 °C at a scan rate of 10 °C/min under nitrogen purge.

[Experimental Example 4] Evaluation of hygroscopicity

Edoxaban propylene glycol solvate crystals of the present invention prepared in Example 1 or 2, conventional Edoxaban tosylate monohydrate crystals, and Edoxa of Korean Patent Registration Nos. 10-2222784 and 10-2215625 In order to compare and evaluate the hygroscopicity of semi-new salt crystals, the inorganic salt saturated solution in Table 2 was used and the hygroscopicity evaluation was attempted for a total of 10 days using the method shown in Figure 2.

The analysis was confirmed by water Karl Fischer analysis.

The results are shown in Table 3.

P ₂ O ₅ MgCl ₂ Mg(NO ₃ ) ₂ NaNO ₂ NaCl KNO ₃ relative humidity 11% 33% 52% 64% 75% 93%

(Inorganic salts used for hygroscopic evaluation)

[Figure 2]

(relative humidity evaluation method)

RH 11% RH 33% RH 52% RH 64% RH 75% RH 93% Edoxaban
propylene glycol
solvate crystals 0.52% 0.49% 0.43% 0.62% 0.61% 0.58% Edoxaban
tosylate
monohydrate crystals 2.78% 2.94% 3.24% 4.58% 5.26% 6.38% registered patent
10-2222784
new salt determination 2.34% 2.82% 4.42% 6.24% 8.45% 9.54% registered patent
10-2215625
new salt determination 0.68% 0.84% 2.85% 4.58% 9.62% 10.24%

(Evaluation of hygroscopicity of edoxaban propylene glycol solvate)

As shown in Table 3, the present invention hardly absorbs moisture compared to conventional edoxaban tosylate monohydrate crystals and new salt crystals disclosed in Korean Patent Registration Nos. 10-2222784 and 10-2215625.

Specifically, the conventional edoxaban tosylate monohydrate crystal showed a change in moisture up to 6% as the relative humidity increased, and the conventional new salt crystal increased the moisture up to 10% or more, but the present invention did not. .

An increase in moisture adversely affects stability during storage and storage of raw materials, and in particular, salts such as edoxaban tosylate may cause stability degradation due to hydrolysis.

However, the present invention has a better advantage during storage and storage due to less stability change due to moisture absorption.

[Experimental Example 5] Severe stability evaluation

The stability test of pharmaceuticals refers to tests for setting the storage method and shelf life of pharmaceuticals, etc. Since the expiration date is set by determining a significant change based on the established test method after setting appropriate specifications according to the relevant laws, securing appropriate stability of the drug is one of the very important factors in commercialization.

In order to confirm the possibility of commercialization of the present invention, the conventional edoxaban tosylate monohydrate crystals were used as a control and subjected to severe stability according to the ICH guidelines, and liquid chromatography (HPLC) analysis described in the United States Pharmacopoeia (USP) was used. After analysis using it, the results are shown in Table 5.

(HPLC analysis method for evaluating edoxaban propylene glycol solvate stability)

Early 3 days 7 days Edoxaban
tosylate
monohydrate crystals 99.76% 98.5% 98.06% Edoxaban
propylene glycol
solvate crystals 99.68% 99.58% 99.62%

(Severe stability results of edoxaban propylene glycol solvate and edoxaban tosylate monohydrate (60℃±2℃, RH 75%))

As a result of a stability test under severe conditions of the present invention and the conventional edoxaban tosylate monohydrate crystals prepared in Example 1 or 2, as shown in Table 5, the present invention was stably maintained without affecting the purity, but Edoxa It was confirmed that the stability of the half tosylate monohydrate was poor as the purity decreased.

This result suggests the possibility of a new edoxaban raw material with improved stability in the case of the present invention.

[Experimental Example 6] Ease of formulation evaluation

Figure 5 is an image comparing and evaluating the adhesiveness of the present invention and the formulation of edoxaban tosylate monohydrate crystals and the ease of formulation by electrostatic force. As shown in FIG. 5, the present invention neither adheres nor spreads to the plastic bag. That is, it can be seen that the adhesiveness and electrostatic force are remarkably low. In contrast, it can be seen that the conventional edoxaban tosylate monohydrate crystals stick to the plastic bag a lot and spread widely. This indicates that the tackiness and electrostatic force may be high.

From this, it can be confirmed that the present invention is a raw material that is easier to formulate than conventional edoxaban tosylate monohydrate crystals.

6 is an image confirming the crystal shape using an optical microscope in order to compare the crystallinity of the crystals of the present invention and the conventional edoxaban tosylate monohydrate.

Here, the crystal shape of the present invention is shown as a rectangle, but the edoxaban tosylate monohydrate crystal has a dendritic form, showing a strong cohesiveness and a high electrostatic force.

Predictably, the reason for the high cohesiveness and high electrostatic force of edoxaban tosylate monohydrate crystals appears to be the result of these dendritic crystal shapes.

In the case of solid powder, mixability with excipients, flowability of particles, uniformity of particles, etc. are very important during tableting. In general, it is known that a symmetrical particle distribution on a particle size distribution map and a very uniform shape are easy to tablet.

Figure 7 is a result of comparing the change in particle size distribution between the present invention and the conventional edoxaban tosylate monohydrate crystals.

From these results, the particle size distribution of the present invention was uniform, whereas the edoxaban tosylate monohydrate crystals showed an uneven particle size distribution. This affects the flowability of the particles in the formulation process, and also affects the adhesion and electrostatic force of FIG. 5, which means that the ease of final formulation will be affected.

Through the abnormal crystal shape, adhesiveness, electrostatic force, and particle size distribution results, it was confirmed that the present invention is a new crystalline solid that overcomes the ease of preparation, which is a problem of conventional edoxaban tosylate monohydrate crystals.

Claims (4)

Edoxaban propylene glycol solvate represented by Formula 2:
[Formula 2]

The edoxaban propylene glycol solvate according to claim 1, characterized in that it contains 6 to 8% by weight of propylene glycol. In powder X-ray diffraction (PXRD) analysis, it has a characteristic peak at the 2θ diffraction angle of 17.255 ± 0.2 °, and in temperature differential scanning calorimetry (DSC), the endothermic peak due to desolvation appears at 150 to 185 ° C, and the endothermic onset temperature is A crystalline form of edoxaban propylene glycol solvate according to claim 1, characterized in that it appears at 299.21 ± 3 ° C and has an endothermic temperature at 300.31 ± 3 ° C. delete

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