WO2021157861A1 - Novel sacubitril calcium/valsartan co-crystal and co-amorphous form - Google Patents

Abstract

The objective of the present invention is to provide a novel sacubitril calcium/valsartan co-crystal and co-amorphous form which overcomes the low stability, water solubility, and ease of formulation of sacubitril/valsartan sodium 2.5 hydrate, which is currently used as a therapeutic agent for chronic heart failure.

Description

New sacubitril calcium/valsartan co-crystal and co-amorphous

The present invention is to provide a novel co-crystal and co-amorphous form of sacubitril calcium/valsartan that has improved stability, water solubility, and ease of formulation, which are problems of sacubitril/valsartan sodium 2.5 hydrate.

Cocrystals are rich in functional groups capable of forming hydrogen bonds such as O, OH, N, etc., or coformers with a difference of 3 or less in pKa, which combine in a regular ratio through hydrogen bonds to form a new crystal structure. means a crystalline solid with Since these co-crystals contain two or more molecules of the compound, they can be expressed in the form of a complex. Since the formation of such a co-crystal forms a crystal structure through new hydrogen bonds of two or more molecules, the solubility and dissolution rate of the drug can be increased. This can change the absorption rate of the drug in the human body, thereby changing the bioavailability. In order to overcome poor solubility, the co-molecules of the co-crystal must be water-friendly molecules that are well soluble in water. If the co-molecule is not water-friendly and has poor solubility, it does not overcome the poor solubility of the drug, but rather causes the solubility to decrease. Therefore, the selection of co-molecules is a very important requirement. And co-crystals include salt forms, amorphous forms, polymorphs, hydrates, solvates, and the like.

Since crystals generally preferentially precipitate metastable crystals during the crystallization process and then transition to a more stable crystal structure in a solvent medium and a solid state to maintain thermodynamic stability, in general, phase transition (phase) in a solvent Through transformation), the molecules are rearranged to form a more stable crystal structure. This creates polymorphism, which is called ostwald's rule of stage. Therefore, the physicochemical properties of the metastable crystal and the stable crystal are changed. Therefore, it causes a change in solubility, which represents the thermodynamic energy of the most important crystal as a drug. In addition, the crystal structure of the co-molecules of the co-crystal is changed through a phase transition phenomenon in which they are generally replaced with the solvent molecules in the solvent, or the existence of a crystal polymorph of the co-crystal itself can be confirmed. Therefore, the co-crystal may undergo a phase change as a hydrate in water, which may cause a phenomenon in which the solubility of the co-crystal is changed to that of the hydrate. The reason that the solubility is not improved even when the co-crystal is prepared from the poorly soluble hydrate crystalline form is because the co-crystal has undergone a phase change to the hydrate. Therefore, the selection of co-molecules is very important. Depending on which co-molecule is used, the phase transition can be inhibited or promoted (Crystal Growth & Design (2011) 11, 887-895, Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74, Drug Discovery Today ( 2008) 13, 440-446).

The formation of co-crystals is achieved through cocrystallization. The co-crystallization method is a solvent evaporation technique, an anti-solvent method, a solvent drop grinding method, a slurry technique, a solid state grinding method, etc. (Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74).

Amorphous refers to a solid state in which molecular interactions exist but do not form a crystal arrangement. Therefore, it has a higher energy level than that of the crystalline form, and thus the solubility is higher than that of the crystalline form. However, in general, due to the high energy level, thermodynamic stability is low, and there is a problem in that the phase transition to the crystalline form is very fast. However, unlike the general amorphous form, co-amorphous co-crystals in an amorphous form form an amorphous solid through new hydrogen bonds between two or more molecules, thereby inhibiting the phase transition to a crystalline form. It is a solid state that can overcome The reason why the phase transition of the amorphous co-crystal to the crystalline form can be suppressed is that the glass transition temperature of the amorphous form is higher than that of the amorphous drug itself (Advanced Drug Delivery Reviews (2016) 100, 116-125). In addition, in the formation of amorphous co-crystals, a crystallization method must be used to quickly reach a high degree of supersaturation by controlling the crystallization rate very quickly. Typically, a method of inducing a very extremely rapid crystallization rate such as vacuum evaporation crystallization, supercritical crystallization, liquid nitrogen crystallization, and freeze evaporation crystallization is used. However, in the formation of co-crystals, hydrogen bonding due to the interaction between drug molecules and co-molecules is very diverse, so even using this extreme crystallization method, it is very difficult to design and control the amorphous form (From Molecules to Crystallizers An Introduction to Crystallization 2000; pp. 2-14).

In order to confirm the improvement in stability in the co-amorphous form of the amorphous form, it is necessary to check whether the glass transition temperature (Tg) appears at a higher temperature than that of the amorphous drug of the existing drug through temperature differential scanning calorimetry (DSC) analysis. The reason is that the glass transition temperature indicates the temperature at which an amorphous form can exist (Advanced Drug Delivery Reviews 100 (2016) 116 -125).

International Patent Publication WO 2007/056546 and Korean Patent No. 10-1549318 disclose sacubitril/valsartan sodium 2.5 hydrate, which is an angiotensin receptor blocker and neutral endopeptidase inhibitor. This known co-crystal salt has the effect of reducing the risk factors due to cardiovascular disease and heart failure in chronic heart failure patients with reduced left ventricular systolic function, and is marketed under the trade name of Endressto.

There are reports that sacubitril/valsartan sodium 2.5 hydrate reported in International Patent Publication No. WO 2007/056546 and Korean Patent No. 10-1549318 has poor stability and water solubility, and the ease of formulation is very poor. there is.

Therefore, in the present invention, a new sacubitril calcium salt/valsartan co-crystal and co-amorphous form were developed that overcome the problems of sacubitril/valsartan sodium 2.5 hydrate.

Numerous papers and patent documents are referenced throughout this specification and their citations are indicated. The disclosure contents of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the level of the technical field to which the present invention pertains and the content of the present invention.

[Prior art literature]

[Patent Literature]

(Patent Document 1) International Patent Publication WO 2007/056546

(Patent Document 2) Domestic Registered Patent 10-1549318

In the present invention, a new sacubitril calcium salt/valsartan co-crystal and co-amorphous form were developed that overcome the problems of low stability, water solubility, and ease of formulation of sacubitril/valsartan sodium 2.5 hydrate.

It is an object of the present invention to provide a novel sacubitril calcium salt/valsartan co-crystal and co-amorphous form.

Another object of the present invention is to provide a method for preparing sacubitril calcium salt/valsartan co-crystal and co-amorphous form.

Other objects and advantages of the present invention may be more clearly supplemented by the following description, claims and drawings.

According to one aspect of the present invention, there is provided a co-crystal in which one molecule of sacubitril calcium salt and one molecule of valsartan are combined.

The present inventors have co-crystallized sacubitril calcium salt and valsartan instead of the known sacubitril/valsartan sodium 2.5 hydrate to prepare a new sacubitril calcium/valsartan co-crystal in which one molecule of sacubitril calcium salt and one molecule of valsartan are combined. prepared.

Furthermore, the present inventors prepared a co-crystal using sacubitril calcium salt and valsartan in order to overcome the low stability and water solubility of the known sacubitril/valsartan sodium 2.5 hydrate, and the ease of formulation, resulting in a 50-fold increase in water solubility. It was confirmed that the above increased, and the stability and ease of formulation were improved.

According to one embodiment of the present invention, the sacubitril calcium/valsartan co-crystal is a compound represented by the following formula (1):

[Formula 1]

In the sacubitril calcium/valsartan co-crystal of Formula 1, one molecule of sacubitril calcium and one molecule of valsartan form a co-crystal in a 1:1 ratio by hydrogen bonding.

The sacubitril calcium/valsartan co-crystal of the present invention is a novel co-crystal that has not been reported anywhere.

According to an embodiment of the present invention, the sacubitril calcium/valsartan co-crystal has 2θ diffraction angles of 7.592±0.2, 12.900±0.2, 18.760±0.2 when tested at 1°/min in X-ray diffraction (PXRD) analysis. , 19.639±0.2, 22.871±0.2 and 27.271±0.2, characterized in that it has a powder X-ray diffraction pattern showing characteristic peaks.

For example, the intensity and peak position of powder X-ray diffraction of an embodiment of the sacubitril calcium/valsartan co-crystal according to the present invention may be as shown in Table 1 below.

[Table 1]

(Intensity and peak position of PXRD of sacubitril calcium/valsartan co-crystal)

For reference, when the sacubitril calcium/valsartan co-crystal was tested at 3°/min in X-ray diffraction (PXRD) analysis, the 2θ diffraction angles were 7.48±0.2, 12.795±0.2, 13.422±0.2, 14.948±0.2, 16.042± Characteristic peaks may appear in the peaks including 0.2, 16.831±0.2, 17.8±0.2, 18.75±0.2 and 19.633±0.2, and may be specifically shown in Table 2 below.

[Table 2]

The experiment at 1°/min and the experiment at 3°/min are results for the same crystal form, which can be interpreted as the same result considering the error range of ±0.2.

In addition, the present invention shows that when the temperature increase rate is 10 ° C in the temperature differential scanning calorimetry (DSC) analysis using a closed fan, the endothermic initiation temperature is 61.35 ° C ± 3 ° C, and the endothermic temperature is 67.95 ° C ± 3 ° C. Provided is a sacubitril calcium/valsartan co-crystal formed in a 1:1 ratio.

In addition, the sacubitril calcium/valsartan co-crystal shows a sacubitril calcium/valsartan co-crystal dihydrate in thermogravimetric analysis (TGA) with a mass deceleration of about 3.5% to 4.2% before 100°C.

^{In addition, 1} H-NMR spectrum in nuclear magnetic resonance spectroscopy (NMR) analysis provides a sacubitril calcium/valsartan co-crystal in which the ratio of one molecule of sacubitril calcium and one molecule of valsartan is clear to 1:1.

^{In addition, 13} C-NMR spectrum from solid-state nuclear magnetic resonance spectroscopy (NMR) analysis indicates that the co-crystal of sacubitril calcium/valsartan clearly forms a co-crystal.

According to another aspect of the present invention, the present invention provides a co-amorphous form in which one molecule of sacubitril calcium salt and one molecule of valsartan are bound.

The present inventors co-amorphous sacubitril calcium salt and valsartan, not the known sacubitril/valsartan sodium 2.5 hydrate, to create a new sacubitril calcium/valsartan co-amorphous form in which one molecule of sacubitril calcium salt and one molecule of valsartan are combined. was prepared.

The present inventors have prepared a co-amorphous form using sacubitril calcium salt and valsartan in order to overcome the low stability and water solubility and ease of formulation of the known sacubitril/valsartan sodium 2.5 hydrate, resulting in a 50-fold increase in water solubility. It was confirmed that the stability and ease of preparation were improved.

According to one embodiment of the present invention, the sacubitril calcium/valsartan co-amorphous compound is a compound represented by the following formula (1):

[Formula 1]

In the sacubitril calcium/valsartan co-amorphous form of Formula 1, one molecule of sacubitril calcium and one molecule of valsartan form a co-amorphous form in a 1:1 ratio by hydrogen bonding.

The sacubitril calcium/valsartan co-amorphous form of the present invention is a novel co-amorphous form that has not been reported anywhere.

According to an embodiment of the present invention, the sacubitril calcium/valsartan cavity amorphous is characterized in that it has a powder X-ray diffraction pattern having an amorphous form with a 2θ diffraction angle in X-ray diffraction (PXRD) analysis.

^{In addition, 1} H-NMR spectrum in nuclear magnetic resonance spectroscopy (NMR) analysis provides a sacubitril calcium/valsartan joint amorphous form in which the ratio of one molecule of sacubitril calcium and one molecule of valsartan is clear to 1:1.

^{In addition, 13} C-NMR spectrum from solid-state nuclear magnetic resonance spectroscopy (NMR) analysis indicates that the co-amorphous form of sacubitril calcium/valsartan clearly forms co-amorphous.

According to the present invention, co-crystals and co-amorphous forms of sacubitril calcium/valsartan can be prepared.

The sacubitril calcium/valsartan co-crystal according to the present invention has excellent solubility and stability, and has good particle flow, uniformity, and electrostatic force, so it is advantageous when formulated.

The sacubitril calcium/valsartan co-amorphous form according to the present invention has increased water solubility more than 50 times, improved stability, and good particle flow, uniformity, and electrostatic force than the known sacubitril/valsartan sodium 2.5 hydrate. There are advantages to doing

1 shows a powder X-ray diffraction (PXRD) pattern result of a sacubitril calcium/valsartan co-crystal prepared according to an embodiment of the present invention when tested at 1°/min.

2 shows the results of temperature differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of sacubitril calcium/valsartan co-crystals prepared according to Examples of the present invention.

^{3 shows the nuclear magnetic resonance (NMR) 1} H-NMR spectrum results of the sacubitril calcium/valsartan co-crystal co-crystal prepared according to an embodiment of the present invention, in which sacubitril calcium/valsarlan The peak is precisely integrated with a stoichiometric ratio of 1:1.

^{4 shows a solid-state carbon nuclear magnetic resonance spectroscopy (solid-state 13} C-NMR) spectrum of a sacubitril calcium/valsartan co-crystal prepared according to an embodiment of the present invention. Through this spectrum, it was confirmed that sacubitril calcium/valsartan co-crystals were properly formed.

5 is a result of a comparative test for aqueous solubility of sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate at a concentration of 2 mg/mL prepared according to an example of the present invention. At this time, all of the sacubitril calcium/valsartan co-crystals of the present invention were dissolved, but the sacubitril/valsartan sodium 2.5 hydrate was not dissolved due to low solubility.

6 is a comparison of the powder photos of sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate prepared according to an embodiment of the present invention. This was compared by putting it in a PE bag used as an actual packaging container. Sacubitril/valsartan sodium 2.5 hydrate has difficulty in subdivision due to static electricity, and it is sticky and agglomerated, whereas Sacubitril calcium/valsartan according to the present invention The valsartan co-crystal is not only free from static electricity but also has good flowability.

7 shows the powder X-ray diffraction (PXRD) pattern results of sacubitril calcium/valsartan co-crystals prepared according to an embodiment of the present invention when tested at 3°/min.

8 shows the powder X-ray diffraction (PXRD) pattern results of sacubitril calcium/valsartan co-amorphous prepared according to an embodiment of the present invention.

^{9 shows nuclear magnetic resonance spectroscopy (NMR) 1} H-NMR spectrum results of sacubitril calcium/valsartan cavity amorphous prepared according to an embodiment of the present invention, in which sacubitril calcium/valsarlan chemistry The peak is precisely integrated with a stoichiometric ratio of 1:1.

^{FIG. 10 shows a solid-state 13} C-NMR spectrum of sacubitril calcium/valsartan co-amorphous solid-state carbon prepared according to an embodiment of the present invention. Through this spectrum, it was confirmed that sacubitril calcium/valsartan co-amorphous was properly formed.

11 is a comparison test result of the aqueous solubility of sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate at a concentration of 2 mg/mL prepared according to an embodiment of the present invention. At this time, the sacubitril calcium/valsartan co-amorphous form of the present invention was all dissolved, but the sacubitril/valsartan sodium 2.5 hydrate was not dissolved due to low solubility.

12 is a comparison of the powder photos of sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate prepared according to an embodiment of the present invention. This was compared by putting it in a PE bag used as an actual packaging container. Sacubitril/valsartan sodium 2.5 hydrate has difficulty in subdivision due to static electricity, and it is sticky and agglomerate, whereas Sacubitril calcium/valsartan according to the present invention Valsartan co-amorphous form can confirm a homogeneous state with good flowability as well as no static electricity.

The present invention will be described in more detail with reference to the following examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

[ Example 1 ]

After adding 10 g of sacubitril calcium and 100 mL of water, stir at room temperature for 20 minutes. Thereafter, 1.2 equivalents of valsartan was added and stirred for 1 hour. Thereafter, crystals were precipitated while stirring the temperature at 30°C for 3 hours. After that, 50 mL of ethyl acetate was added and stirred for 20 minutes. Then, the precipitated crystals were filtered under reduced pressure, washed with 10 ml of ethyl acetate, and vacuum dried at 45° C. for 16 hours or more to obtain a novel sacubitril/valsartan co-crystal in 85% yield.

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

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

[Experimental Example 2] Temperature differential scanning calorimetry (DSC)

Using DSC Q20 obtained from TA, DSC measurements (see FIG. 2 ) were performed in a closed pan at a scan rate of 10° C. from 20° C. to 300° C. under nitrogen purge.

[Experimental Example 3] Thermogravimetric analysis (TGA)

Using a TGA Q50 obtained from TA, DSC measurements (see FIG. 2 ) were performed in a closed pan at a scan rate of 10° C. from 20° C. to 400° C. under nitrogen purge.

[Experimental Example 4] Solubility evaluation of sacubitril calcium/valsartan co-crystal

Since sacubitril/valsartan sodium 2.5 hydrate is poorly soluble with a water solubility of 0.1 mg/ml, a new co-crystal was prepared accordingly to improve the aqueous solubility and gastrointestinal pH solubility of sacubitril/valsartan sodium 2.5 hydrate. The results are summarized in Table 3 below.

[Table 3]

(solubility of sacubitril calcium/valsartan co-crystal)

As shown in Table 3 above, the aqueous solubility and solubility of the sacubitril calcium/valsartan co-crystal of the present invention at pH 6.8 in the small intestine were increased by about 50 times compared to the known sacubitril/valsartan sodium 2.5 hydrate. Therefore, it was confirmed that the aqueous solubility of the sacubitril calcium/valsartan co-crystal of the present invention can be increased by about 50 times compared to the known sacubitril/valsartan sodium 2.5 hydrate. Therefore, the sacubitril calcium co-crystal of the present invention is a novel crystal form that can overcome the low water solubility, which is a problem of sacubitril/valsartan sodium 2.5 hydrate, and maximizes the medicinal effect of sacubitril/valsartan or formulation It was predicted that formulation could be successful without complicated formulation design for the purpose of improving solubility.

[Experimental Example 5] Accelerated and severe stability evaluation of sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate

In order to establish the storage method and period of use of the drug, the stability test of the drug determines the significant change based on the established test method after setting the appropriate specifications and sets the expiration date. is one of the most important factors in the commercialization of drugs.

In order to confirm the commercialization potential of the sacubitril calcium/valsartan co-crystal of the present invention, acceleration and severe stability were performed according to the ICH guidelines using sacubitril/valsartan sodium 2.5 hydrate as a control, and described in the US Pharmacopoeia (USP) After analysis using liquid chromatography (HPLC) analysis, the results are shown in Tables 4 and 5.

[Table 4]

{Accelerated stability results of sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate (40℃± 2℃RH 75%)}

[Table 5]

{Result of severe stability evaluation of sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate (60℃± 2℃RH 75%)}

Stability tests under accelerated and severe conditions were performed on the sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate prepared in Example. As a result, as shown in Tables 4 and 5, the sacubitril calcium/valsartan co-crystal was stably maintained without the effect of purity, but it was confirmed that the sacubitril/valsartan sodium 2.5 hydrate had poor stability as the purity decreased.

That is, it was confirmed that the stability of the sacubitril calcium/valsartan co-crystal under accelerated and severe conditions was improved compared to that of sacubitril/valsartan sodium 2.5 hydrate.

[Experimental Example 5] Comparative test of aqueous solubility of sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate

In order to increase absorption in the body, water solubility must be increased to some extent. Therefore, the aqueous solubility of the sacubitril calcium/valsartan co-crystal of the present invention and the known sacubitril/valsartan sodium 2.5 hydrate was comparatively evaluated at a concentration of 2 mg/mL. As a result, it was confirmed that sacubitril/valsartan sodium 2.5 hydrate did not dissolve and was present in a suspension state, while all of the sacubitril calcium/valsartan co-crystals of the present invention were dissolved, thereby increasing water solubility. Therefore, the sacubitril calcium/valsartan co-crystal of the present invention has improved water solubility, thereby proving the value as a new drug substance that can overcome the poor solubility of sacubitril/valsartan sodium 2.5 hydrate [Fig. 5].

[Experimental Example 5] Comparative evaluation of uniformity and electrostatic force between sacubitril calcium/valsartan co-crystal and sacubitril/valsartan sodium 2.5 hydrate

In the case of solid powder, mixability with excipients, flow rate of particles, uniformity of particles, etc. are very important during tableting. In general, it is known that tableting is easy when the particle distribution is symmetrical and very uniform on the particle size distribution diagram. In order to see the adhesion and uniformity of the sacubitril calcium/valsartan co-crystal of the present invention and the known sacubitril/valsartan sodium 2.5 hydrate solid, it was placed in a PE bag and evaluated for comparison. As a result, it was confirmed that sacubitril/valsartan sodium 2.5 hydrate adhered to the packaging material due to high electrostatic force and the particles were not uniform. However, it was confirmed that the sacubitril calcium/valsartan co-crystal of the present invention exhibited an even particle shape and did not adhere to the packaging material and thus had no electrostatic force [Fig. 6].

Therefore, through this evaluation, it was confirmed that the sacubitril calcium/valsartan co-crystal of the present invention is an easy solid in the preparation process.

[Example 2] Preparation of sacubitril calcium/valsartan co-amorphous

10 g of sacubitril calcium and 300 ml of methanol were added, and the mixture was dissolved by stirring at room temperature for 20 minutes. Thereafter, 1.2 equivalents of valsartan was added and dissolved while stirring for 30 minutes. Then, all methanol was evaporated using a concentrator until crystals were precipitated. Then, 50 mL of ethyl acetate was added, stirred for 20 minutes, filtered under reduced pressure, washed with 10 ml of ethyl acetate, and vacuum dried at 45° C. for 16 hours or more to obtain a novel sacubitril calcium/valsartan co-amorphous form in 83% yield.

[Experimental Example 6] Powder X-ray diffraction (PXRD)

PXRD analysis (see FIG. 8 ) was performed on an X-ray powder diffractometer (D8 Advance) using Cu Kα radiation. The instrument was tube-powered, and the amperage was set at 45 kV and 40 mA. The divergence and scattering slits were set at 1°, and the light receiving slits were set at 0.2 mm. A continuous θθ scan of 3°/min (0.4 sec/0.02° interval) from 5 to 35° 2θ was used.

[Experimental Example 7] Solubility evaluation of sacubitril calcium/valsartan co-amorphous

Since sacubitril/valsartan sodium 2.5 hydrate is poorly soluble with a water solubility of 0.1 mg/ml, a new co-amorphous form was prepared accordingly to improve the aqueous solubility and gastrointestinal pH solubility of sacubitril/valsartan sodium 2.5 hydrate. The results are summarized in Table 6 below.

[Table 6]

(Solubility of sacubitril calcium/valsartan co-amorphous) As shown in Table 1 above, the aqueous solubility of sacubitril calcium/valsartan co-amorphous and small intestine pH 6.8 of the present invention compared to known sacubitril/valsartan sodium 2.5 hydrate The solubility of was increased by about 50 times. Therefore, it was confirmed that the aqueous solubility of the sacubitril calcium/valsartan co-amorphous form of the present invention can be increased by about 80 times or more compared to the known sacubitril/valsartan sodium 2.5 hydrate. Therefore, the co-amorphous sacubitril calcium of the present invention is a novel crystalline form that can overcome the low water solubility, which is a problem of sacubitril/valsartan sodium 2.5 hydrate, and that it can maximize the medicinal effect of sacubitril/valsartan. It was predicted.

[Experimental Example 8] Accelerated and severe stability evaluation of sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate

In order to confirm the commercialization potential of sacubitril calcium/valsartan joint amorphous product of the present invention, acceleration and severe stability were performed according to the ICH guidelines using sacubitril/valsartan sodium 2.5 hydrate as a control, and described in the US Pharmacopoeia (USP) After analysis using a liquid chromatography (HPLC) analysis method, the results are shown in Tables 7 and 8.

[Table 7]

{Results of accelerated stability of sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate (40℃±2℃RH 75%)}

[Table 8]

{Results of severe stability evaluation of sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate (60°C±2°CRH 75%)} Sacubitril calcium/valsartan co-amorphous and Saku Vitryl/valsartan sodium 2.5 hydrate was tested for stability under accelerated and severe conditions. As a result, as shown in Tables 7 and 8, the sacubitril calcium/valsartan co-amorphous form was stably maintained without the effect of purity, but it was confirmed that the sacubitril/valsartan sodium 2.5 hydrate had poor stability as the purity decreased.

Therefore, it was confirmed that the stability of sacubitril calcium/valsartan co-amorphous accelerated and severe conditions was improved compared to that of sacubitril/valsartan sodium 2.5 hydrate.

[Experimental Example 9] Comparative test of aqueous solubility of sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate

The aqueous solubility of sacubitril calcium/valsartan co-amorphous and known sacubitril/valsartan sodium 2.5 hydrate of the present invention was comparatively evaluated at a concentration of 2 mg/mL. As a result, it was confirmed that sacubitril/valsartan sodium 2.5 hydrate did not dissolve and existed in a suspension state, whereas the sacubitril calcium/valsartan co-amorphous form of the present invention was all dissolved and the water solubility was increased. Therefore, the co-amorphous sacubitril calcium/valsartan of the present invention has improved water solubility, thereby proving its value as a new drug substance that can overcome the poor solubility of sacubitril/valsartan sodium 2.5 hydrate [Fig. 11].

[Experimental Example 10] Comparative evaluation of uniformity and electrostatic force between sacubitril calcium/valsartan co-amorphous and sacubitril/valsartan sodium 2.5 hydrate

In order to see the adhesion and uniformity of the sacubitril calcium/valsartan co-amorphous form of the present invention and the known sacubitril/valsartan sodium 2.5 hydrate solid, it was placed in a PE bag and evaluated for comparison. As a result, it was confirmed that sacubitril/valsartan sodium 2.5 hydrate adhered to the packaging material due to high electrostatic force and the particles were not uniform. However, it was confirmed that the sacubitril calcium/valsartan co-amorphous form of the present invention exhibits an even particle shape, and does not adhere to the packaging material and thus does not have an electrostatic force [Fig. 12].

Therefore, through this evaluation, it was confirmed that the sacubitril calcium/valsartan co-amorphous form of the present invention is an easy solid in the preparation process.

As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (4)

1. It is a sacubitril calcium/valsartan co-crystal in which sacubitril calcium salt and valsartan are combined. In X-ray diffraction (PXRD) analysis, 2θ diffraction angles are 7.592±0.2, 12.900±0.2, 14.987±0.2, 18.760±0.2, 19.639± Sacubitril calcium/valsartan co-crystal, characterized in that it has a powder X-ray diffraction pattern having characteristic peaks at 0.2, 22.871±0.2 and 27.271±0.2.
2. The thermogravimetric analysis of claim 1, wherein the sacubitril calcium/valsartan co-crystal has an endothermic onset temperature of 61.35°C±3°C in temperature differential scanning calorimetry (DSC) analysis, and an endothermic temperature of 67.95°C±3°C. Sacubitril calcium/valsartan co-crystal, characterized in that it is in the form of a dihydrate containing 3.5% to 4.5% moisture in (TGA).
3. In the sacubitril calcium/valsartan co-amorphous form in which sacubitril calcium salt and valsartan are combined, the sacubitril calcium/valsartan co-amorphous form is a compound represented by the following formula (1): Sacubitril calcium/valsartan cavity Amorphous:

   [Formula 1]

   
4. The sacubitril calcium/valsartan co-amorphous form according to claim 3, wherein the sacubitril calcium/valsartan co-amorphous form exhibits an amorphous form.

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