CN113544127A - Novel co-crystals of engagliflozin - Google Patents
Novel co-crystals of engagliflozin Download PDFInfo
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Abstract
The present inventors have attempted to improve the low stability and water solubility that are problems of empagliflozin, and as a result, developed an empagliflozin co-crystal having increased stability and water solubility by more than 120 times. The crystalline solid of engagliflozin of the present invention is a novel solid form in which the stability and water solubility of the known crystalline form of engagliflozin are overcome, and is very useful as an optimal raw material pharmaceutical substance that can maximize pharmaceutical applications.
Description
Technical Field
The present invention provides novel eutectic crystals of empagliflozin with improved stability and water solubility, which have been problems of empagliflozin.
Background
Cocrystals (crystallines) refer to crystalline solids having a new crystal structure by hydrogen bonding at a regular ratio to a eutectic former (coformer) rich in functional groups capable of forming hydrogen bonds such as O, OH, N, etc., or having a pKa difference of 3 or less.
Such a cocrystal contains 2 or more molecules of a compound and thus can be expressed in the form of a complex.
In the formation of such a cocrystal, a crystal structure is formed by a new hydrogen bond of 2 or more molecules, and thus the solubility and dissolution rate of the drug can be increased. Bioavailability can therefore be altered by altering the absorption rate of the drug in the human body.
As a eutectic former for overcoming a poorly soluble cocrystal, a molecule having affinity for water, which is easily dissolved in water, should be selected. If a cocrystal former which is not compatible with water and has poor solubility is selected, the problem of poor solubility of the drug, which is a phenomenon of poor solubility, cannot be overcome. Therefore, the selection of the eutectic formation is an especially important requirement.
Also, the co-crystal includes amorphous polymorph, hydrate, solvate, and the like.
Crystals (crystals) have a characteristic of maintaining stability by being transferred to a more stable crystal structure in a solvent medium and a solid state after a metastable crystal is preferentially precipitated substantially during crystallization, and thus molecules are rearranged substantially in a solvent by phase transition to form a more stable crystal structure.
Thus, a polymorphic form is produced, which is called the steady state law stage (rule of stage) of ostwald.
As a result, the physicochemical properties of the metastable crystals and the stable crystals change. Therefore, a change in solubility is caused which indicates the thermodynamic property of the crystal which is most important as a drug.
Further, the eutectic formation of the cocrystal is substantially in the solvent, and the change in crystal structure or the existence of a polymorphic form of the cocrystal itself can be confirmed by a phase transition phenomenon in which the solvent molecules are substituted.
Therefore, the eutectic becomes a hydrate in water and may change phase, and thus, a phenomenon may occur in which the solubility of the eutectic becomes the solubility of the hydrate.
In the poorly soluble hydrate crystal form, the reason why the solubility cannot be improved even if the cocrystal is prepared is that the cocrystal is transformed into a hydrate.
Therefore, the selection of the eutectic formation is particularly important. Depending on which eutectic former is used, phase transformation may be inhibited or promoted (Crystal Growth & Design (2011)11,887-895, recrystallization in Material Processing Intech: Vienna, Austria, 2015; pp.173-74, Drug Discovery Today (2008)13, 440-446).
The co-crystals are formed by co-crystallization (cocrystallization).
Examples of the co-crystallization method include a solvent evaporation method (solvent evaporation technique), an anti-solvent method (anti-solvent method), a solvent drop mill method (solvent drop mill), a slurry method (slurry technique), and a solid phase mill method (solid state mill fining) (crystallization in Materials Processing Intech: Vienna, Austria, 2015; pp.173-74).
Amorphous (amorpous) refers to a solid state that cannot form crystalline arrangements despite molecular interactions. Therefore, it has a higher energy level than the crystalline form, and thus its solubility is higher than that of the crystalline form. However, since the thermodynamic stability is low due to the high energy level, there is a problem that the phase is rapidly changed to a crystalline form.
The amorphous cocrystal (co-amophorus) forms an amorphous solid by a new hydrogen bond between two or more molecules, thereby exhibiting an effect of suppressing a phenomenon of phase transition to a crystalline form, and is in a solid state in which a poor solubility can be overcome by a high solubility.
The reason why the phenomenon of phase transition to a crystalline form can be suppressed is that the glass transition temperature of the amorphous form of the co-crystal is higher than the glass transition temperature of the amorphous form of the Drug itself (Advanced Drug Delivery Reviews (2016)100, 116-125).
Further, in the formation of an amorphous cocrystal, a crystallization method is required in which the crystallization rate is controlled very rapidly to rapidly achieve a high supersaturation degree. Typically, a method of extremely accelerating the crystallization rate such as reduced pressure evaporation crystallization, supercritical crystallization, liquid nitrogen crystallization, freeze evaporation crystallization, or the like is used.
However, since hydrogen bonds based on the interaction between drug Molecules and the co-crystal former are very diverse during the formation of co-crystals, it is difficult to design and control the amorphous form even using this extreme Crystallization method (From Molecules to crystals An Introduction to Crystallization 2000; pp.2-14).
In order to confirm the improvement of stability in the amorphous form of the cocrystal, it is necessary to confirm whether or not the glass transition temperature (Tg) occurs at a higher temperature than the amorphous form of the conventional drug by temperature Differential Scanning Calorimetry (DSC) analysis. This is because the temperature at which amorphous morphology can exist is the glass transition temperature (Advanced Drug Delivery Reviews 100(2016) 116-125).
SGLT-2 (sodium/glucose co-transporter 2) is a transporter in the kidney responsible for excessive glucose reabsorption with SGLT-1 (sodium/glucose co-transporter 1) instruments, and SGLT-2 plays a major role. Therefore, if the SGLT-2 inhibitor inhibits SGLT-2 transporter, the blood sugar discharged by urination increases, eventually leading to a decrease in blood sugar, and further discharging calories possessed by blood sugar, resulting in an effect of reducing body weight.
One of the drugs developed as SGLT-2 inhibitors which are useful as a type ii diabetes therapeutic agent with such an effect is engelizin (Empagliflozin), which is developed by the company brigling hagen and is currently marketed worldwide under the trade name of western european medicines.
Engeletin is represented by the following structural formula (chemical formula 1) and disclosed in international patent publication No. WO 2005/092877.
[ chemical formula 1]
International patent publication No. WO 2006/117359 discloses an englezin crystalline form, and international patent publication No. WO 2011/039107 discloses a crystallization method for producing the englezin crystalline form.
However, it is reported that the crystalline form of empagliflozin disclosed in International patent publication No. WO 2006/117359 has a water solubility of only 0.11mg/mL and a low stability.
Further, since the stability of empagliflozin used as a raw material pharmaceutical product is low, it is difficult to maintain a predetermined quality, and therefore, it has a drawback that empagliflozin cannot be used in pharmaceutical preparations.
International patent publication No. WO 2011/039107 discloses a method for producing an engelazin crystalline form, but the method has a problem of complexity in the crystallization method using centrifugal separation and a cooling lamp.
Accordingly, the present invention has developed an engagliflozin cocrystal by a crystallization method which is easier to handle and which is easy to improve production efficiency, in order to overcome the low water solubility of engagliflozin and the stability that cannot maintain a constant quality.
Throughout this specification, reference is made to a number of papers and patent documents, the contents of which are incorporated herein by reference. The disclosures of the cited articles and patent documents are incorporated herein by reference in their entirety, to more clearly describe the state of the art to which the present invention pertains and the contents of the present invention.
[ Prior art documents ]
[ patent document ]
(patent document 1) International patent publication No. WO 2005/092877
(patent document 2) International patent publication No. WO 2006/117359
(patent document 3) International patent publication No. WO 2011/039107
Disclosure of Invention
Technical problem
As a result of an effort to improve the low water solubility and stability, which are problems of empagliflozin, the present inventors developed empagliflozin/fumaric acid cocrystals, empagliflozin/citric acid amorphous cocrystals, and empagliflozin/L-pyroglutamic acid cocrystals.
Accordingly, it is an object of the present invention to provide novel eutectic crystals of engagliflozin/fumaric acid, engagliflozin/citric acid, and engagliflozin/L-pyroglutamic acid.
Another object of the present invention is to provide a method for producing the novel crystalline eutectic of engagliflozin/fumaric acid, engagliflozin/citric acid, and engagliflozin/L-pyroglutamic acid of the present invention.
Other objects and advantages of the present invention will become more apparent from the following summary, claims and drawings.
Means for solving the problems
According to one embodiment of the present invention, there is provided a cocrystal in which one molecule of empagliflozin and one molecule of fumaric acid are combined.
According to one embodiment of the present invention, there is provided an amorphous cocrystal in which one molecule of empagliflozin and one molecule of citric acid are combined.
According to one embodiment of the present invention, there is provided a cocrystal in which one molecule of empagliflozin and one molecule of L-pyroglutamic acid are bound.
The present inventors prepared empagliflozin/fumaric acid cocrystals, empagliflozin/citric acid amorphous form cocrystals, and empagliflozin/L-pyroglutamic acid cocrystals using fumaric acid, citric acid, and L-pyroglutamic acid as amino acids or organic acids without using basic inorganic salts.
Therefore, in order to overcome the low stability and water solubility of the engagliflozin, the inventor selects L-proline, L-arginine, L-lysine, fumaric acid, oxalic acid, L-pyroglutamic acid and citric acid which have very high water solubility and are rich in NH, N, O and OH, and tries to design and prepare the co-crystal.
As a result, an empagliflozin/fumaric acid cocrystal, an empagliflozin/citric acid amorphous form cocrystal, and an empagliflozin/L-pyroglutamic acid cocrystal were developed.
Therefore, a method for reproducibly producing the crystalline forms of engagliflozin/fumaric acid, the crystalline forms of engagliflozin/citric acid and the crystalline forms of engagliflozin/L-pyroglutamic acid has been established through experimental optimization, and the crystalline forms of engagliflozin/fumaric acid, the crystalline forms of engagliflozin/citric acid and the crystalline forms of engagliflozin/L-pyroglutamic acid thus produced have a solubility in water and a solubility in small intestine pH increased by about 120 times as compared with the conventional crystalline forms of engagliflozin, and can be sufficiently dissolved in 250ml of water to be administered when an oral preparation is taken, so that the oral absorption can be improved and the hygroscopicity and stability can be improved.
Therefore, when the empagliflozin/fumaric acid cocrystal, the empagliflozin/citric acid amorphous form cocrystal, and the empagliflozin/L-pyroglutamic acid cocrystal of the present invention are used, they can be suitably used as a novel drug for improving the stability and water solubility of empagliflozin.
According to an embodiment of the present invention, the aforementioned engeletin/fumaric acid cocrystal is a compound represented by the following chemical formula 2:
[ chemical formula 2]
For the engeletin/fumaric acid cocrystal of chemical formula 2, a cocrystal is formed from one molecule of engeletin and one molecule of fumaric acid in a 1:1 ratio through a hydrogen bond.
Fumaric acid having such high water solubility forms a co-crystal with engagliflozin through hydrogen bonds, and due to interaction with fumaric acid, when fumaric acid is dissolved, engagliflozin is also dissolved in water together, and thus the water solubility and the small intestine pH 6.8 solubility are increased.
The present invention of the engeletin/fumaric acid cocrystals is a novel solid form that has not been reported in any literature.
According to an example of the present invention, there is provided an engletin/fumaric acid co-crystal represented by the following chemical formula 2, characterized in that the aforementioned engletin/fumaric acid co-crystal has a powder X-ray diffraction pattern having characteristic peaks at 2 θ diffraction angles of 14.703 ± 0.2, 15.747 ± 0.2, 17.958 ± 0.2, 18.859 ± 0.2, 19.192 ± 0.2, 19.518 ± 0.2, 20.367 ± 0.2, 25.23 ± 0.2 and 28.794 ± 0.2 in a powder X-ray diffraction (PXRD) analysis.
For example, the intensity and peak position of the powder X-ray diffraction of an example of the engelettin/fumaric acid cocrystal of the present invention can be as shown in [ table 1] below.
[ Table 1]
(PXRD Strength and Peak position of Empagliflozin/fumaric acid cocrystal)
Also, the present invention provides an engeletin/fumaric acid cocrystal in which an endothermic onset temperature is 145.78 ℃. + -. 3 ℃ and an endothermic temperature is 148.10 ℃. + -. 3 ℃ and a molecular ratio is 1:1 when a temperature rise rate of 10 ℃/min is employed in a temperature Differential Scanning Calorimetry (DSC) analysis using a sealing disk.
The present invention also provides an empagliflozin/fumaric acid cocrystal which, in nuclear magnetic resonance spectroscopy (NMR) analysis,1the H-NMR spectrum is clearly defined as one molecule of empagliflozin and one molecule of fumaric acid, the ratio of the molecules being formed in the range of 1: 1.
According to an embodiment of the present invention, the aforementioned amorphous form of the empagliflozin/citric acid cocrystal is a compound represented by the following chemical formula 3:
[ chemical formula 3]
For the amorphous form of engagliflozin/citric acid co-crystal of chemical formula 3, the co-crystal is formed from one molecule of engagliflozin and one molecule of citric acid in a 1:1 ratio by hydrogen bonding. Citric acid having such high water solubility forms an amorphous form with engagliflozin through hydrogen bonds, and due to interaction with citric acid, engagliflozin is also dissolved in water together when citric acid is dissolved, and thus the water solubility and the small intestine pH 6.8 solubility are increased.
The amorphous form of the empagliflozin/citric acid cocrystal of the invention is a novel solid form which has not been reported in any literature.
According to an embodiment of the present invention, the aforementioned amorphous form of the crystalline eutectic or complexing agent for empagliflozin/citric acid is an amorphous form of the co-crystalline or complexing agent having a ratio of molecules of 1:1, which exhibits an amorphous form at a 2 θ diffraction angle in powder X-ray diffraction (PXRD) analysis and an amorphous form at a thermal profile in temperature Differential Scanning Calorimetry (DSC) analysis.
The present invention also provides an amorphous form of the empagliflozin/citric acid cocrystal, which is characterized in that, in nuclear magnetic resonance spectroscopy (NMR) analysis,1the H-NMR spectrum is clearly defined as one molecule of empagliflozin and one molecule of citric acid, the ratio of which molecules is formed at 1: 1.
According to an embodiment of the present invention, the aforementioned eutectic crystal of engelettin/L-pyroglutamic acid is a compound represented by the following chemical formula 4:
[ chemical formula 4]
For the engeletin/L-pyroglutamic acid cocrystal of chemical formula 4, a cocrystal is formed of one molecule of engeletin and one molecule of L-pyroglutamic acid in a ratio of 1:1 by a hydrogen bond. L-pyroglutamic acid having such high water solubility forms a co-crystal with Empagliflozin through a hydrogen bond, and due to the interaction with L-pyroglutamic acid, when L-pyroglutamic acid is dissolved, Empagliflozin is also dissolved together in water, and thus the water solubility and the solubility of small intestine pH 6.8 are increased.
The empagliflozin/L-pyroglutamic acid cocrystals of the present invention are novel solid forms that have not been reported in any literature.
According to an example of the present invention, there is provided an engrel/L-pyroglutamic acid cocrystal represented by chemical formula 4, which is characterized in that the aforementioned engrel/L-pyroglutamic acid cocrystal has a powder X-ray diffraction pattern having characteristic peaks at 2 θ diffraction angles of 14.738 ± 0.2, 18.001 ± 0.2, 18.892 ± 0.2, 20.418 ± 0.2, 22.226 ± 0.2, 23.041 ± 0.2, 24.878 ± 0.2, 25.712 ± 0.2 and 27.306 ± 0.2 in a powder X-ray diffraction (PXRD) analysis.
For example, the intensity and peak position of powder X-ray diffraction of an example of the present engelettin/L-pyroglutamic acid cocrystal can be shown as follows [ table 2 ].
[ Table 2]
(PXRD Strength and Peak position of Empagliflozin/L-Pyroglutamic acid cocrystal)
Also, the present invention provides an engeletin/L-pyroglutamic acid cocrystal in which an endothermic onset temperature is 122.98 ℃. + -. 3 ℃ and an endothermic temperature is 127.09 ℃. + -. 3 ℃ and a molecular ratio is formed at 1:1, using a temperature Differential Scanning Calorimetry (DSC) analysis using a sealing disk at a temperature rise rate of 10 ℃/min.
Also disclosed is an empagliflozin/L-pyroglutamic acid cocrystal which, in nuclear magnetic resonance spectroscopy (NMR) analysis,1the H-NMR spectrum was clearly defined as one molecule of empagliflozin and one molecule of L-pyroglutamic acid, the ratio of the molecules being formed in 1: 1.
According to another embodiment of the present invention, there is provided a method for preparing a co-crystal of empagliflozin comprising the following steps.
Mixing empagliflozin and an organic solvent, wherein organic acid is added respectively; a step (b) of heating the resultant obtained in the step (a) and stirring the heated resultant under reflux; a step (c) of cooling and stirring the resultant obtained in the step (b); a step (d) of evaporating 1/2 the solvent of the step (c); and (e) drying the result of the step (d) in vacuum to obtain the eutectic crystal of the empagliflozin.
The present inventors established a method for preparing a novel pharmaceutically useful cocrystal of engagliflozin and capable of preparing a novel very pure cocrystal in high yield without adding an additional step of adding or removing a salt during the preparation process. This method is called a solvent evaporation method in the co-crystallization.
Since the method of the present invention is used for the preparation of the aforementioned empagliflozin/fumaric acid cocrystal, empagliflozin/citric acid amorphous form cocrystal, and empagliflozin/L-pyroglutamic acid cocrystal of the present invention, the common contents between these descriptions are omitted in order to avoid excessive complexity of the specification due to duplicate descriptions.
The process of the invention for the preparation of the crystalline empagliflozin/fumaric acid cocrystal, the crystalline empagliflozin/citric acid amorphous form cocrystal, the crystalline empagliflozin/L-pyroglutamic acid cocrystal is described in detail below, in different steps, as follows:
(a) mixing of engagliflozin and organic solvent and adding of organic acid
First, the method of the present invention includes a step of mixing solid powders of empagliflozin and an organic solvent, wherein the organic acids are added separately.
According to an embodiment of the present invention, the exenatide of step (a) above is added in an amount of 1-30 (w/v)%, more preferably 6-25 (w/v)%, and even more preferably 10-20 (w/v)%, relative to the volume of the organic solvent.
In the preparation of the aforementioned engletin cocrystal, it is proved that the organic solvent which is a solvent for efficiently removing the organic acid used in excess, while producing the engletin cocrystal in high yield, is preferably at least 1 selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dimethylacetamide, dimethyl sulfoxide, dimethylformamide, chloroform, methyl ethyl ketone, ethyl acetate, dichloromethane, and acetonitrile, i.e., a single solvent or a mixed solvent thereof is selected, more preferably methanol, ethanol, isopropanol, or acetone, and most preferably methanol.
According to another embodiment of the present invention, the organic acid of step (a) above is added in a molar ratio of 1 to 1.5 equivalents with respect to engeletin.
Preferably, the organic acid is added in a molar ratio of 1 to 1.5 equivalents, respectively, with respect to the engagliflozin. The novel amorphous form of engagliflozin cocrystal or complex thus obtained becomes an amorphous form of engagliflozin/organic acid cocrystal or complex in combination with engagliflozin.
According to another embodiment of the present invention, the organic acid of step (a) is added in an amount of 1/3 to the above-mentioned combined empagliflozin and organic solvent.
This is because, in the case of preparing the aforementioned engelet/organic acid cocrystal or composite, when mixing solid powders of engelet and organic acid, it is important that the mixing ratio of the organic acid and the engelet is 1: 1.
In contrast, when 1/3, which is the entire mixing equivalent, is mixed in portions, the most effective amount is formed compared to when the organic acid mixed with solid powder of engagliflozin is added at one time.
More preferably, the organic acid of the step (a) is added to the mixed engeletin and organic solvent in an amount of 1/3 every 20 minutes.
(b) Heating and reflux stirring the above-mentioned fruits
Next, the method of the present invention includes a step of heating the resultant of the step (a) and refluxing the resultant.
The temperature rise time of the result of the step (a) requires 1 hour or more, and in this case, the temperature must be adjusted to the reflux temperature, and the stirring time at the reflux temperature should not exceed three hours.
According to another example of the present invention, the temperature increase of the above step (b) is performed for 1 to 3 hours.
According to another example of the present invention, the reflux stirring of the above step (b) is performed for 1 to 3 hours, more preferably for 30 minutes to 2 hours, and further preferably for 30 minutes to 1 hour.
(c) Cooling and stirring the above-mentioned resultant
Next, the method of the present invention includes a step of cooling and stirring the refluxed reaction solution which is the result of the step (b).
According to another example of the present invention, the cooling of step (c) above is performed at 15-40 ℃, more preferably at a temperature of 15-30 ℃, most preferably at 15-20 ℃.
According to another example of the present invention, the stirring of the above step (c) is performed for 1 to 12 hours, more preferably for 1 to 8 hours, and further preferably for 3 to 5 hours.
(d) Evaporating and stirring the above-mentioned resultant
Next, the method of the present invention includes a step of evaporating 1/2 of the solvent of the cooled reaction solution, which is the product of the step (c), and stirring the same.
According to another example of the present invention, the evaporation of step (d) above is performed at 30-60 ℃, more preferably at a temperature of 30-50 ℃, even more preferably at 30-40 ℃.
According to another example of the present invention, the stirring of the above step (d) is performed for 1 to 12 hours, more preferably for 1 to 8 hours, and further preferably for 3 to 5 hours.
According to another embodiment of the present invention, the method further comprises a step (d-1) of filtering the product of the step (d) under reduced pressure and washing the product with an organic solvent.
According to another embodiment of the present invention, the organic solvent of the above step (d-1) is selected from 1 or more organic solvents consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dimethylacetamide, dimethylsulfoxide, dimethylformamide, chloroform, methyl ethyl ketone, ethyl acetate, dichloromethane, and acetonitrile, i.e., a single selected solvent or a mixed solvent thereof, more preferably methanol, ethanol, isopropanol, or acetone, and most preferably acetone.
According to another embodiment of the present invention, the organic solvent of the above step (c-1) is added in an amount of 1 to 30 (v/v)%, more preferably 1 to 10 (v/v)%, and further preferably 2 to 5 (v/v)%, relative to the volume of the organic solvent of the above step (a).
(e) Vacuum drying of the above-mentioned results and obtaining of eutectic of empagliflozin
Finally, the process of the invention goes through a step of vacuum drying the result of step (e) above and obtaining the eutectic of empagliflozin.
According to another embodiment of the present invention, the vacuum drying of the above step (e) is performed at a temperature of 30-65 ℃ for 8 hours to 12 hours.
More preferably, the above vacuum drying is performed at a temperature of 40-55 deg.C, more preferably at a temperature of 45-50 deg.C.
The amorphous eutectic of empagliflozin obtained by vacuum drying at the above temperature and time has a moisture content of 1% or less and a purity of 99.5% or more by high performance liquid chromatography HPLC.
By this method, a cocrystal of engagliflozin, which is a SGLT-2 inhibitor inhibiting reabsorption of blood glucose in the kidney and excreting blood glucose through urine, combined from 1 equivalent of engagliflozin and 1 equivalent of an organic acid, can be prepared, and thus can be used as a type II diabetes therapeutic agent for regulating blood glucose.
ADVANTAGEOUS EFFECTS OF INVENTION
The features and advantages of the present invention are summarized as follows:
(a) the present invention provides an engagliflozin/fumaric acid cocrystal, an engagliflozin/citric acid amorphous form cocrystal, an engagliflozin/L-pyroglutamic acid cocrystal, and a method for producing the same, each of which is formed by combining one molecule of engagliflozin and one molecule of organic acid.
(b) The engelet/fumaric acid cocrystal, the engelet/citric acid amorphous cocrystal, and the engelet/L-pyroglutamic acid cocrystal of the present invention can obtain a novel cocrystal with an optimum ratio in excellent purity and yield by adjusting the equivalent weight of an organic acid, the evaporation amount of a stirring solvent, and the evaporation temperature and time of the solvent in a special solvent environment for cocrystallization in the preparation process.
(c) The present invention provides an engagliflozin/fumaric acid cocrystal, an engagliflozin/citric acid amorphous cocrystal, and an engagliflozin/L-pyroglutamic acid cocrystal, which can be used as a pharmaceutical product as a raw material for engagliflozin by increasing the stability and water solubility of the engagliflozin having a very low value to 120 times the water solubility and the solubility at pH 6.8 in the small intestine and by improving the stability.
Drawings
Fig. 1 shows powder X-ray diffraction (PXRD) pattern results of an engelet/fumaric acid cocrystal prepared according to an example of the present invention.
Fig. 2 shows powder X-ray diffraction (PXRD) pattern results for amorphous form of the engelet/citric acid cocrystal prepared according to an embodiment of the present invention.
Fig. 3 shows powder X-ray diffraction (PXRD) pattern results of engelet/L-pyroglutamic acid cocrystals prepared according to an embodiment of the present invention.
Fig. 4 shows the powder X-ray diffraction (PXRD) pattern results of the crystalline form of engelazin prepared according to the example of international laid-open patent publication No. WO 2006/117359.
Fig. 5 shows temperature Differential Scanning Calorimetry (DSC) thermograms of the engeletin/fumaric acid co-crystals prepared according to an example of the present invention.
FIG. 6 shows the results of thermal curve of temperature Differential Scanning Calorimetry (DSC) of crystalline form of Engelliflozin prepared according to examples of International publication No. WO 2006/117359.
Fig. 7 shows temperature Differential Scanning Calorimetry (DSC) thermograms of amorphous forms of empagliflozin/citric acid co-crystals prepared according to an embodiment of the present invention.
Figure 8 shows temperature Differential Scanning Calorimetry (DSC) thermograms of amorphous form of empagliflozin/citric acid cocrystals, citric acid, empagliflozin crystalline forms prepared according to an embodiment of the present invention.
Fig. 9 shows temperature Differential Scanning Calorimetry (DSC) thermograms of empagliflozin/L-pyroglutamic acid cocrystals prepared according to an example of the present invention.
Fig. 10 shows the results of temperature Differential Scanning Calorimetry (DSC) thermograms of crystalline forms of empagliflozin/L-pyroglutamic acid, empagliflozin prepared according to an example of the present invention.
FIG. 11 shows nuclear magnetic resonance spectroscopy (NMR) of an empagliflozin/fumaric acid cocrystal prepared according to an example of the invention1H-NMR spectroscopic results in which the stoichiometric ratio of empagliflozin/fumaric acid was exactly 1:1 and the peaks thereof were integrated.
FIG. 12 shows nuclear magnetic resonance spectroscopy (NMR) of amorphous forms of empagliflozin/citric acid cocrystals prepared in accordance with an embodiment of the invention1H-NMR spectroscopic results in which the stoichiometric ratio of empagliflozin/fumaric acid was exactly 1:1 and the peaks thereof were integrated.
FIG. 13 shows nuclear magnetic resonance spectroscopy (NMR) of the crystalline eutectic of empagliflozin/L-pyroglutamic acid prepared in accordance with an embodiment of the present invention1H-NMR spectroscopic results in which the stoichiometric ratio of empagliflozin/fumaric acid was exactly 1:1 and the peaks thereof were integrated.
FIG. 14 shows nuclear magnetic resonance spectroscopy (NMR) of an crystalline form of Empagliflozin produced in accordance with an example of International patent publication No. WO 2006/1173591H-NMR spectrum results.
Fig. 15 is a result of comparative tests for water solubility at a concentration of 1mg/mL for the empagliflozin/fumaric acid co-crystal, the empagliflozin/citric acid amorphous form co-crystal, the empagliflozin/L-pyroglutamic acid co-crystal, and the empagliflozin crystalline form prepared according to the examples of the present invention. At this time, although the engletin cocrystals of the present invention are all dissolved, the engletin crystalline form has low solubility and is not dissolved.
Detailed Description
The present invention will be described in more detail below with reference to examples. It will be apparent to those skilled in the art that these examples are merely for illustrating the present invention in more detail, and the scope of the present invention is not limited to these examples according to the gist of the present invention.
EXAMPLE 1 preparation of empagliflozin/fumaric acid cocrystals
After 10g of engletin and 100ml of methanol were charged, the mixture was stirred at room temperature for 20 minutes. Then, 1.2 equivalents of fumaric acid were each charged into 1/3, the temperature was slowly raised for 1 hour until the reflux temperature was reached, and then further stirred for 30 minutes. After slowly cooling to 15-20 ℃, stirring for 3 hours. Then, the mixture was stirred at 30 ℃ to 40 ℃ for 3 hours to evaporate 70ml of methanol and precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10ml of acetone, and vacuum-dried at 45 ℃ for 16 hours or more, whereby a novel engeletin/fumaric acid cocrystal was obtained in a yield of 90%.
EXAMPLE 2 preparation of empagliflozin/citric acid cocrystals
After 10g of engletin and 100mL of methanol were added, the mixture was stirred at room temperature for 20 minutes. Then, 1.2 equivalents of citric acid was added thereto, followed by stirring for 1 hour. Then, the mixture was stirred at 30 ℃ to 40 ℃ for 3 hours to evaporate 80mL of methanol and precipitate crystals. Then, 50mL of ethyl acetate was added thereto, and the mixture was stirred for 20 minutes. The precipitated crystals were filtered under reduced pressure, washed with 10ml of ethyl acetate, and vacuum-dried at 45 ℃ for 16 hours or more, whereby a novel engeletin/citric acid cocrystal was obtained in a yield of 85%.
EXAMPLE 3 preparation of empagliflozin/L-pyroglutamic acid cocrystal
After 10g of engletin and 100ml of methanol were charged, the mixture was stirred at room temperature for 20 minutes. Then, 1.2 equivalents of each of L-pyroglutamic acid was charged into 1/3, the temperature was gradually raised for 1 hour until the reflux temperature was reached, and then further stirred for 30 minutes. After slowly cooling to 15-20 ℃, stirring for 3 hours. Then, the mixture was stirred at 30 ℃ to 40 ℃ for 3 hours to evaporate 60ml of methanol and precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10ml of ethyl acetate, and vacuum-dried at 45 ℃ for 16 hours or more, whereby a novel engeletin/L-pyroglutamic acid cocrystal was obtained in a yield of 82%.
EXAMPLE 4 preparation of empagliflozin/fumaric acid cocrystals
After 10g of engletin and 300ml of methanol were charged, the mixture was stirred at room temperature for 20 minutes to dissolve. Then, 1.2 equivalents of fumaric acid was added, followed by stirring for 30 minutes to dissolve the fumaric acid. Then, the methanol is completely evaporated by using a concentrator until crystals are precipitated. Then, 50mL of ethyl acetate was added thereto, and after stirring for 20 minutes, the mixture was filtered under reduced pressure, washed with 10mL of ethyl acetate, and vacuum-dried at 45 ℃ for 16 hours or more, whereby a novel engeletin/fumaric acid cocrystal was obtained in a yield of 88%.
[ example 5] preparation of empagliflozin/L-pyroglutamic acid cocrystal
After 10g of engletin and 300ml of methanol were charged, the mixture was stirred at room temperature for 20 minutes to dissolve. Then, 1.2 equivalents of L-pyroglutamic acid was added, followed by stirring for 30 minutes to dissolve it. Then, the methanol is completely evaporated by using a concentrator until crystals are precipitated. Then, 50mL of ethyl acetate was added thereto, and after stirring for 20 minutes, the mixture was filtered under reduced pressure, washed with 10mL of ethyl acetate, and vacuum-dried at 45 ℃ for 16 hours or more, whereby a novel engeletin/L-pyroglutamic acid cocrystal was obtained in 83% yield.
[ Experimental example 1] powder X-ray diffraction (PXRD)
PXRD analysis was performed on a (D8 Advance) X-ray powder diffractometer using Cu ka radiation (see fig. 1 to 4). A tube power device is arranged on the instrument, and the current amount is set to be 45kV and 40 mA. The emission and scattering slit was set to 1 °, and the light receiving slit was set to 0.2 mm. The 2 theta is measured to 5 to 35 DEG, and the theta-2 theta continuous scanning is performed at a moving speed of 3 DEG/min (0.4 sec/0.02 DEG interval).
[ Experimental example 2] temperature Differential Scanning Calorimetry (DSC)
DSC measurement was performed in a sealing disk at a scanning speed of 10 ℃/min at 20 ℃ to 300 ℃ under nitrogen purge using DSC Q20 obtained from TA corporation (see fig. 5 to 10).
[ Experimental example 3] evaluation of solubility of eutectic body of Engelliflozin
Since engagliflozin is poorly soluble with a water solubility of 0.111mg/ml, a novel cocrystal is prepared in combination with fumaric acid, citric acid, and L-pyroglutamic acid, which have high water solubility, thereby improving the water solubility of engagliflozin and the pH solubility of the gastrointestinal tract. The results are shown in Table 3 below.
[ Table 3]
| H2O | pH6.8 | |
| Crystalline form of engagliflozin | 0.101mg/mL | 0.108mg/mL |
| Empagliflozin/fumaric acid | 1.85mg/mL | 1.78mg/mL |
| Empagliflozin/citric acid | 12.2mg/mL | 11.8mg/mL |
| Empagliflozin/L-pyroglutamic acid | 2.45mg/mL | 2.36mg/mL |
(solubility of crystalline forms of Empagliflozin and Empagliflozin)
As shown in table 3, it was confirmed that the water solubility and the solubility at small intestine pH 6.8 of the crystalline empagliflozin/fumaric acid cocrystal of the present invention were increased by about 18 times, the water solubility and the solubility at small intestine pH 6.8 of the amorphous empagliflozin/citric acid cocrystal were increased by about 120 times or more, and the water solubility and the solubility at small intestine pH 6.8 of the empagliflozin/L-pyroglutamic acid cocrystal were increased by about 24 times, as compared with the known crystalline empagliflozin.
Therefore, it was confirmed that the crystalline eutectic of empagliflozin of the present invention can increase the water solubility by about 120 times as compared with the known crystalline form of empagliflozin.
Therefore, the present invention is expected to maximize the drug efficacy of engagliflozin, because the engagliflozin cocrystal is a novel crystal form with low water solubility that can overcome the problem of the crystalline form of engagliflozin.
[ Experimental example 4] comparative evaluation of accelerated and severe stability of crystalline forms of empagliflozin and empagliflozin
The stability test of a pharmaceutical is a process of setting a shelf life by determining a significant change according to a predetermined test method after setting appropriate specifications for setting a storage method and a life of the pharmaceutical or the like, and thus securing appropriate stability of the pharmaceutical is one of factors important for the commercialization of the pharmaceutical.
Therefore, in order to confirm the possibility of producing the crystalline empagliflozin/fumaric acid cocrystal, the amorphous empagliflozin/citric acid cocrystal, and the amorphous empagliflozin/L-pyroglutamic acid cocrystal of the present invention, accelerated and severe stability tests were performed according to the ICH guidelines using the empagliflozin crystalline form known in international publication No. WO 2006/117359 as a control group, and the results were analyzed by a High Performance Liquid Chromatography (HPLC) analysis method described in the United States Pharmacopeia (USP), and the results are shown in tables 4 and 5.
[ Table 4]
| |
3 |
7 days | |
| Empagliflozin/fumaric acid | 99.84％ | 99.82％ | 99.83％ |
| Empagliflozin/citric acid | 99.82％ | 99.83％ | 99.82％ |
| Empagliflozin/L-pyroglutamic acid | 99.84％ | 99.83％ | 99.83％ |
| Crystalline form of engagliflozin | 99.8％ | 99.32％ | 99.02％ |
(accelerated stability results for the crystalline forms of Empagliflozin Co-crystals and Empagliflozin Co-crystals, 40 ℃. + -. 2 ℃ and RH 75%)
[ Table 5]
| |
3 |
7 days | |
| Empagliflozin/fumaric acid | 99.84％ | 99.81％ | 99.82％ |
| Empagliflozin/citric acid | 99.82％ | 99.82％ | 99.82％ |
| Empagliflozin/L-pyroglutamic acid | 99.84％ | 99.84％ | 99.83％ |
| Crystalline form of engagliflozin | 99.8％ | 99.02％ | 98.07％ |
(results of evaluation of rigorous stability of the eutectic of engagliflozin and engagliflozin at 60 ℃. + -. 2 ℃ and RH 75%)
Accelerated, harsh-condition stability tests of the crystalline forms of empagliflozin and the cocrystals of empagliflozin prepared according to the examples were carried out. As a result, as shown in tables 4 and 5, it was confirmed that the crystalline form of engletam had a decreased purity and poor stability, although the engletam cocrystal remained stable without being affected by the purity.
Therefore, it was confirmed that the stability under accelerated and severe conditions of the crystalline eutectic of empagliflozin was improved more than that of the crystalline form of empagliflozin.
[ Experimental example 5] comparative test for water solubility of crystalline forms of empagliflozin and empagliflozin
To increase the in vivo absorption rate, the water solubility should be increased somewhat. Therefore, the water solubility of the crystalline form of empagliflozin of the present invention and the known crystalline form of empagliflozin were comparatively evaluated at a concentration of 1 mg/mL.
As a result, it was confirmed that the crystalline form of engagliflozin was not dissolved but existed in a suspension state, whereas the eutectic of engagliflozin of the present invention was dissolved, and the water solubility was increased. Thus, it was demonstrated that the cocrystal of the present invention can overcome the poor solubility of empagliflozin by improving the water solubility, and is a novel pharmaceutical raw material value [ fig. 15 ].
Therefore, the present invention is expected to overcome the problems of engelet, and to provide a novel pharmaceutical raw material having low stability and water solubility.
It will be apparent to those skilled in the art that while certain aspects of the present invention have been described in detail, these specific details are merely illustrative of preferred embodiments and the scope of the invention is not limited thereto. Accordingly, the substantial scope of the present invention should be defined in accordance with the appended claims and their equivalents.
Claims (7)
1. An engletin/fumaric acid cocrystal characterized by having a powder X-ray diffraction pattern with characteristic peaks at 2 theta diffraction angles of 14.703 + -0.2, 15.747 + -0.2, 17.958 + -0.2, 18.859 + -0.2, 19.192 + -0.2, 19.518 + -0.2, 20.367 + -0.2, 25.23 + -0.2 and 28.794 + -0.2 in powder X-ray diffraction (PXRD) analysis, and having an endothermic onset temperature of 145.78 deg.C + -3 deg.C and an endothermic temperature of 148.10 deg.C + -3 deg.C in temperature Differential Scanning Calorimetry (DSC) analysis.
2. The empagliflozin/fumaric acid co-crystal of claim 1, wherein 1 equivalent of fumaric acid is combined in 1 equivalent of empagliflozin to form the empagliflozin/fumaric acid co-crystal.
3. An engeletine/citric acid cocrystal characterized by a powder X-ray diffraction (PXRD) pattern exhibiting an amorphous morphology.
4. The engagliflozin/citric acid co-crystal of claim 3, wherein 1 equivalent of citric acid is combined in 1 equivalent of engagliflozin to form the engagliflozin/citric acid co-crystal in an amorphous form.
5. An engletin/L-pyroglutamic acid cocrystal characterized by having characteristic peaks at 2 theta diffraction angles of 14.738 + -0.2, 18.001 + -0.2, 18.892 + -0.2, 20.418 + -0.2, 22.226 + -0.2, 23.041 + -0.2, 24.878 + -0.2, 25.712 + -0.2 and 27.306 + -0.2 in powder X-ray diffraction (PXRD) analysis, and having an endothermic onset temperature of 122.98 deg.C + -3 deg.C and an endothermic temperature of 127.09 deg.C + -3 deg.C in temperature Differential Scanning Calorimetry (DSC) analysis.
6. The empagliflozin/L-pyroglutamic acid cocrystal according to claim 5, wherein 1 equivalent of L-pyroglutamic acid is incorporated in 1 equivalent of empagliflozin to form said empagliflozin/L-pyroglutamic acid cocrystal.
7. A pharmaceutical composition for treating or preventing diabetes, comprising the co-crystal according to any one of claims 1 to 6, which regulates blood glucose by inhibiting SGLT-2.
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| WO2022065895A1 (en) * | 2020-09-24 | 2022-03-31 | 동아에스티 주식회사 | Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt |
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| UA91546C2 (en) | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | Crystalline form of 1-chloro-4-(я-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
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