WO2012007455A1 - Process for the preparation of organic salts - Google Patents

Process for the preparation of organic salts Download PDF

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Publication number
WO2012007455A1
WO2012007455A1 PCT/EP2011/061842 EP2011061842W WO2012007455A1 WO 2012007455 A1 WO2012007455 A1 WO 2012007455A1 EP 2011061842 W EP2011061842 W EP 2011061842W WO 2012007455 A1 WO2012007455 A1 WO 2012007455A1
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Prior art keywords
sitagliptin
orotate
process according
water
free base
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PCT/EP2011/061842
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French (fr)
Inventor
Gianpiero Ventimiglia
Domenico Magrone
Fabio Massimo Bravin
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Chemo Iberica, S.A.
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Priority to ES11743210.4T priority Critical patent/ES2525916T3/en
Priority to EP11743210.4A priority patent/EP2593459B1/en
Priority to JP2013519069A priority patent/JP2013533260A/en
Publication of WO2012007455A1 publication Critical patent/WO2012007455A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid

Definitions

  • the present invention relates to a novel process for the preparation of sitagliptin orotate in amorphous form.
  • Sitagliptin, 7-[(3i?)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3- ]pyrazine, is the compound of formula (I):
  • 03/004498 Al belongs to a class of beta-amino tetrahydrotriazolo-[4,3- ]pyrazines, which are potent second generation inhibitors of dipeptidyl-peptidase IV (DP-IV) useful for the treatment of Type-2 diabetes.
  • DP-IV dipeptidyl-peptidase IV
  • the preparation of the compound is also described in the paper "Highly Efficient Asymmetric Synthesis of Sitagliptin", Hansen et al: Journal of the American Chemical Society (2009), 131(25), 8798-8804; once obtained, the compound can be purified according to methods standard in the field, obtaining sitagliptin of purity suitable for pharmaceutical applications.
  • Sitagliptin is marketed as monophosphate salt and monohydrate adduct under the trade name Januvia ® (Trademark of Merck & Co.).
  • APIs active pharmaceutical ingredients
  • amorphous forms of APIs can provide new commercial opportunities for a pharmaceutical company.
  • use of eco-compatible chemicals and processes, suitable for large scale preparations, is desirable.
  • the amorphous salt is obtained by a precipitation mixing between sitagliptin free base and orotic acid in acetonitrile, thus giving rise to a sticky gel very difficult to stir, handle and filter;
  • An object of the present invention is to provide a novel process for the preparation of sitagliptin with orotic acid, herein below referred to as sitagliptin orotate.
  • polymorphism may also give rise to distinct spectroscopic properties that may be detectable by X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) analysis.
  • XRPD X-Ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • the present invention relates to a novel process for the preparation of amorphous salt of sitagliptin with orotic acid, characterized by the following improvements:
  • the invention provides a process for preparing sitagliptin orotate comprising the steps of:
  • the invention provides sitagliptin orotate in amorphous form.
  • Figure 1 provides a DSC thermogram of amorphous sitagliptin orotate
  • Figure 2 provides a XRPD pattern of amorphous sitagliptin orotate.
  • sitagliptin may be isolated as a novel salt with orotic acid by means of a new suitable, economic, efficient and eco-compatible process, particularly suited for large-scale preparation.
  • Orotic acid has the IUPAC name 1,2,3,6- tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid and formula (II):
  • orotic acid protonates the amino group of sitagliptin, giving rise to a salt formed by ionic attraction between the sitagliptin-derived cation and the orotate anion in stoichiometric ratio.
  • the resulting salt can be represented by formula (III) below, in which the dotted line indicates the zone of attraction between the two ions:
  • the invention provides a process for the preparation of sitagliptin orotate comprising the steps of:
  • Orotic acid can be used either anhydrous or, preferably, as monohydrate adduct; preferably, orotic acid is in a ratio of about 0.9: 1 to about 0.95: 1 mole/mole with respect to sitagliptin;
  • step b) heating the solution obtained in step b) up to a temperature preferably comprised in the range of about 30 °C to about 40 °C in order to promote the reaction between orotic acid and sitagliptin free base;
  • the concentration of sitagliptin free base in water is preferably comprised in the range of 6% up to 20% weight/weight; operating with a concentration lower than 6% the yield of the process is too low, while operating with a concentration in excess of 20% gives rise to problems in product handling in step g) of the process.
  • the organic solvent immiscible with water for the extraction of step e) is selected from the following classes: aromatics (preferably toluene), chlorinated (preferably dichloromefhane), esters, linear or branched aliphatic esters (preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate), ethers, preferably dialkyl ethers, linear or branched, preferably acyclic (diethylether, methyl tert-buty ⁇ ether (MTBE), diisopropylether), alcohols (preferably 1-butanol, 2-butanol, terT-butanol), ketones, linear or branched aliphatic ketones (preferably methyl ethyl ketone, methyl isobutyl ketone).
  • the organic solvent is used in a ratio of about 1 :4 to about 1:6 volume/volume with respect to water.
  • the aqueous phase obtained through separation in step f) is filtered before submitting it to the subsequent lyophilizing step in order to carefully get rid of particles that could damage the lyophilization apparatus, as known to the experts in the field. Filtering can be carried out by any known methods, preferably through a celite pad or a 0.45 ⁇ filter.
  • Sitagliptin orotate obtained by the process of the present invention shows a residual water content comprised in a range of about 3.5% to about 5.5% by weight, as determined by means of Karl Fischer titration.
  • Sitagliptin free base having HPLC purity of 99.9% and with an enantiomeric excess of the 3/?-isomer higher than 99.9%, is prepared according to the Hansen et al. paper cited before.
  • 1.6 g (3.9 mmol) of the compound are suspended in water (20 ml) at 20 °C and orotic acid monohydrate (0.64 g, equivalent to 3.7 mmol of anhydrous orotic acid, Sigma-Aldrich) is added.
  • the solution is warmed up to 35-37 °C, kept at this temperature for ten minutes, and then allowed to cool down spontaneously to 24-25 °C.
  • amorphous sitagliptin orotate (2.1 g), having a water content of 4.7% by weight as determined by Karl Fischer titration.
  • DSC thermal analysis is performed on a Mettler Toledo STAR e 822 differential scanning calorimeter.
  • a sample of approximately 5 mg is placed in an aluminium crimped pan and heated from 30 to 170 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute.
  • the results of this test are reported in Figure 2.
  • the upper line of the graph is the "base line" of the test, namely, it represents the heat exchanged by an empty sample holder (equal to the one holding the sample under test), while the lower line represents the heat exchanged by the sample holder; the difference between these two lines represents the contribution to heat exchange of the sample, and the integral of the areas defined between the two lines is a measure of the heat exchanged by the sample.
  • the DSC thermogram evidences a broad endothermic feature with a maximum peak at about 83 °C due to the loss of water; additionally, it's noteworthy to observe a thermal phenomenon at about 144 °C, due to a glass transition or a similar phenomenon.

Abstract

Process for the production of sitagliptin orotate (III) in amorphous form is described.

Description

PROCESS FOR THE PREPARATION OF SITAGLIPTIN OROTATE Field of the invention
The present invention relates to a novel process for the preparation of sitagliptin orotate in amorphous form.
Background of the invention
Sitagliptin, 7-[(3i?)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-l,2,4-triazolo[4,3- ]pyrazine, is the compound of formula (I):
Figure imgf000003_0001
(I)
Sitagliptin, disclosed in US Pat. No. 6,699,871 B2 and in international application WO
03/004498 Al, belongs to a class of beta-amino tetrahydrotriazolo-[4,3- ]pyrazines, which are potent second generation inhibitors of dipeptidyl-peptidase IV (DP-IV) useful for the treatment of Type-2 diabetes. The preparation of the compound is also described in the paper "Highly Efficient Asymmetric Synthesis of Sitagliptin", Hansen et al: Journal of the American Chemical Society (2009), 131(25), 8798-8804; once obtained, the compound can be purified according to methods standard in the field, obtaining sitagliptin of purity suitable for pharmaceutical applications.
Sitagliptin is marketed as monophosphate salt and monohydrate adduct under the trade name Januvia® (Trademark of Merck & Co.).
The discovery of novel pharmaceutically acceptable salts of active pharmaceutical ingredients (APIs) in their amorphous forms provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing a pharmaceutical dosage form, or a drug with a targeted release profile, or other desired physico-chemical characteristics, such as density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting, flowability and suitable rate of dissolution in aqueous fluid. Further, amorphous forms of APIs can provide new commercial opportunities for a pharmaceutical company. Finally, use of eco-compatible chemicals and processes, suitable for large scale preparations, is desirable.
Several polymorphic forms are reported for the salts of sitagliptin in patent literature; see, e.g., WO 2005/072530 Al and WO 2009/085990 A2.
Among them, the phosphoric acid salt of sitagliptin in amorphous form has already been disclosed in patent application WO 2006/033848 Al. However, regarding large scale preparations, disposal of phosphate containing wastes could be a problem for environmental purposes.
Moreover, amorphous form of salt of sitagliptin with orotic acid has been disclosed in patent application US 2010/0249140 Al. According to those skilled in the art, the process described in said application is affected by several drawbacks:
a) the amorphous salt is obtained by a precipitation mixing between sitagliptin free base and orotic acid in acetonitrile, thus giving rise to a sticky gel very difficult to stir, handle and filter;
b) a stoichiometric ratio between sitagliptin free base and orotic acid cannot be guaranteed under these conditions;
c) due to the poor filterability of the obtained product, it's not reasonable in a large scale preparation to distil the solvent under normal or reduced pressure to obtain the dry solid, both for quality or safety purposes;
d) a residual amount of acetonitrile, which is no compatible with regulatory purposes, is still present in the final product.
On the basis of these considerations, a novel process for the preparation of amorphous salt of sitagliptin with orotic acid is desirable.
An object of the present invention is to provide a novel process for the preparation of sitagliptin with orotic acid, herein below referred to as sitagliptin orotate.
Finally, the potential for polymorphism may also give rise to distinct spectroscopic properties that may be detectable by X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) analysis. Summary of the invention
The present invention relates to a novel process for the preparation of amorphous salt of sitagliptin with orotic acid, characterized by the following improvements:
a) a higher eco-compatibility process;
b) a stoichiometric ratio between sitagliptin and orotic acid is guaranteed (excess sitagliptin free base is removed by means of washing with an organic solvent);
c) a higher suitability for large-scale preparations.
In one embodiment, the invention provides a process for preparing sitagliptin orotate comprising the steps of:
a) suspending sitagliptin free base in water;
b) adding orotic acid in a ratio of about 0.9: 1 to about 0.95: 1 mole/mole with respect to sitagliptin;
c) heating the solution up to a temperature preferably comprised in the range of about 30 °C to about 40 °C in order to promote the reaction of orotic acid with sitagliptin free base;
d) cooling down or allowing to cool the solution to a temperature comprised in a range of about 15 °C to about 25 °C;
e) extracting residual sitagliptin free base by means of an organic solvent immiscible with water;
f) separating the aqueous phase and filtering it;
g) lyophilizing the aqueous solution.
In another embodiment, the invention provides sitagliptin orotate in amorphous form.
Brief description of the drawings and instrumental skills
Figure 1 provides a DSC thermogram of amorphous sitagliptin orotate;
Figure 2 provides a XRPD pattern of amorphous sitagliptin orotate.
Detailed description of the invention
All terms as used in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
The present inventors have now found that sitagliptin may be isolated as a novel salt with orotic acid by means of a new suitable, economic, efficient and eco-compatible process, particularly suited for large-scale preparation. Orotic acid has the IUPAC name 1,2,3,6- tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid and formula (II):
Figure imgf000006_0001
(Π)
In the conditions of the process of the invention, orotic acid protonates the amino group of sitagliptin, giving rise to a salt formed by ionic attraction between the sitagliptin-derived cation and the orotate anion in stoichiometric ratio. The resulting salt can be represented by formula (III) below, in which the dotted line indicates the zone of attraction between the two ions:
Figure imgf000006_0002
In one embodiment, the invention provides a process for the preparation of sitagliptin orotate comprising the steps of:
a) suspending sitagliptin free base in water at a suitable temperature, comprised in the range of about 10 °C to about 30 °C; preferably, the temperature is comprised in the range of about 15 °C to about 25 °C;
b) adding orotic acid. Orotic acid can be used either anhydrous or, preferably, as monohydrate adduct; preferably, orotic acid is in a ratio of about 0.9: 1 to about 0.95: 1 mole/mole with respect to sitagliptin;
c) heating the solution obtained in step b) up to a temperature preferably comprised in the range of about 30 °C to about 40 °C in order to promote the reaction between orotic acid and sitagliptin free base;
d) cooling down the solution with suitable means, or allowing the solution to freely cool down, to a temperature comprised in the range of about 15 °C to about 25 °C;
e) extracting residual sitagliptin free base by means of an organic solvent immiscible with water;
f) separating the aqueous phase by means of methods well known to those skilled in the art and filtering it;
g) lyophilizing the aqueous solution thus obtained by means of methods well known to those skilled in the art, at temperature preferably comprised in the range of about 15 °C to about 25 °C.
In step a), the concentration of sitagliptin free base in water is preferably comprised in the range of 6% up to 20% weight/weight; operating with a concentration lower than 6% the yield of the process is too low, while operating with a concentration in excess of 20% gives rise to problems in product handling in step g) of the process.
The organic solvent immiscible with water for the extraction of step e) is selected from the following classes: aromatics (preferably toluene), chlorinated (preferably dichloromefhane), esters, linear or branched aliphatic esters (preferably ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate), ethers, preferably dialkyl ethers, linear or branched, preferably acyclic (diethylether, methyl tert-buty\ ether (MTBE), diisopropylether), alcohols (preferably 1-butanol, 2-butanol, terT-butanol), ketones, linear or branched aliphatic ketones (preferably methyl ethyl ketone, methyl isobutyl ketone). Preferably, the organic solvent is used in a ratio of about 1 :4 to about 1:6 volume/volume with respect to water.
The aqueous phase obtained through separation in step f) is filtered before submitting it to the subsequent lyophilizing step in order to carefully get rid of particles that could damage the lyophilization apparatus, as known to the experts in the field. Filtering can be carried out by any known methods, preferably through a celite pad or a 0.45 μπι filter.
Sitagliptin orotate obtained by the process of the present invention shows a residual water content comprised in a range of about 3.5% to about 5.5% by weight, as determined by means of Karl Fischer titration.
The invention is further illustrated by means of one example, which is not construed to be viewed as limiting the scope of the invention.
Example 1
Sitagliptin free base, having HPLC purity of 99.9% and with an enantiomeric excess of the 3/?-isomer higher than 99.9%, is prepared according to the Hansen et al. paper cited before. 1.6 g (3.9 mmol) of the compound are suspended in water (20 ml) at 20 °C and orotic acid monohydrate (0.64 g, equivalent to 3.7 mmol of anhydrous orotic acid, Sigma-Aldrich) is added. The solution is warmed up to 35-37 °C, kept at this temperature for ten minutes, and then allowed to cool down spontaneously to 24-25 °C. The system is then extracted twice with dichloromethane (5 ml), and the resulting aqueous phase is separated, filtered through a celite pad and lyophilized at 25 °C, thus affording amorphous sitagliptin orotate (2.1 g), having a water content of 4.7% by weight as determined by Karl Fischer titration.
On the thus obtained product, XRPD analysis and DSC thermal analysis are carried out. XRPD analysis is performed on a APD 2000 Ital Structures diffractometer at room temperature, using a CuKa tube (40 kV, 30 mA, λ = 1.5406 A) as the X-ray source. Data collection is made in 2Θ step scan mode, at a scan speed of 0.04°/s in the range of 3° to 40° in 2Θ, using as sample approximately 100 mg of product accurately ground and placed on an aluminium sampler. The results of this test are reported in Figure 1, which shows the typical pattern of an amorphous material.
DSC thermal analysis is performed on a Mettler Toledo STARe 822 differential scanning calorimeter. A sample of approximately 5 mg is placed in an aluminium crimped pan and heated from 30 to 170 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/minute. The results of this test are reported in Figure 2. In the figure, the upper line of the graph is the "base line" of the test, namely, it represents the heat exchanged by an empty sample holder (equal to the one holding the sample under test), while the lower line represents the heat exchanged by the sample holder; the difference between these two lines represents the contribution to heat exchange of the sample, and the integral of the areas defined between the two lines is a measure of the heat exchanged by the sample. The DSC thermogram evidences a broad endothermic feature with a maximum peak at about 83 °C due to the loss of water; additionally, it's noteworthy to observe a thermal phenomenon at about 144 °C, due to a glass transition or a similar phenomenon.

Claims

1. Process for the preparation of sitagliptin orotate in amorphous form, comprising the steps of:
a) suspending sitagliptin free base in water;
b) adding orotic acid in a ratio of about 0.9: 1 to about 0.95: 1 mole/mole with respect to sitagliptin;
c) heating the solution up to a temperature preferably comprised in the range of about 30 °C to about 40 °C in order to promote the reaction of orotic acid with sitagliptin free base;
d) cooling down or allowing to cool the solution to a temperature comprised in a range of about 15 °C to about 25 °C;
e) extracting residual sitagliptin free base by means of an organic solvent immiscible with water;
f) separating the aqueous phase and filtering it;
g) lyophilizing the aqueous solution.
2. Process according to claim 1, wherein in step a) the concentration of sitagliptin free base in water is preferably comprised in the range of 6% up to 20% weight/weight.
3. Process according to any one of the preceding claims, wherein the organic solvent used in step e) is selected from the following classes: aromatic compounds, chlorinated compounds, esters, ethers, alcohols and ketones.
4. Process according to claim 3, wherein said solvent is chosen among linear or branched aliphatic esters, linear or branched dialkyl ethers and linear or branched aliphatic ketones.
5. Process according to claim 4, wherein said solvent is chosen among toluene, dichloromethane, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethylether, methyl tert-buty\ ether (MTBE), diisopropylether, 1-butanol, 2-butanol, teri-butanol, methyl ethyl ketone and methyl isobutyl ketone.
6. Process according to any one of the preceding claims, wherein the organic solvent is used in a ratio of about 1:4 to about 1:6 volume/volume with respect to water.
7. Process according to any one of the preceding claims, wherein filtering of step f) is carried out by means of a celite pad or a 0.45 μπι filter.
8. Process according to any one of the preceding claims, wherein the lyophilization of step g) is carried out at a temperature in the range of about 15 °C to about 25 °C.
9. Sitagliptin orotate in amorphous form.
10. Sitagliptin orotate according to claim 9, comprising about 3.5% to about 5.5% by weight of water.
11. Sitagliptin orotate according to any one of claims 9 or 10, characterized by having the XRPD pattern of Figure 1.
12. Sitagliptin orotate according to any one of claims 9 or 10, characterized by having the DSC thermogram of Figure 2.
13. Pharmaceutical composition comprising a therapeutically effective amount of sitagliptin orotate in amorphous form and a pharmaceutically acceptable vehicle.
14. Amorphous form of sitagliptin orotate for use as a medicament, in particular for prevention or treatment of Type-2 diabetes.
PCT/EP2011/061842 2010-07-13 2011-07-12 Process for the preparation of organic salts WO2012007455A1 (en)

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ES11743210.4T ES2525916T3 (en) 2010-07-13 2011-07-12 Process for the preparation of sitagliptin orotate
EP11743210.4A EP2593459B1 (en) 2010-07-13 2011-07-12 Process for the preparation of sitagliptin orotate
JP2013519069A JP2013533260A (en) 2010-07-13 2011-07-12 Preparation method of organic salt

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WO2012147092A2 (en) 2011-03-03 2012-11-01 Cadila Healthcare Limited Novel salts of dpp-iv inhibitor
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WO2016112880A1 (en) 2015-01-13 2016-07-21 Zentiva, K.S Crystalline modification 3 of (3r)-3-amino-l-[3-(trifluoromethyl)-6,8-dihydro-5h- [l1,2,4]triazolol[4,3-]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one l-tartrate
WO2016112879A1 (en) 2015-01-13 2016-07-21 Zentiva, K.S. CRYSTALLINE MODIFICATION 2 OF (3/R)-3-AMINO-1-[3-(TRIFLUOROMETHYL)-6,8-DIHYDRO-5H-[1,2,4]TRIAZOLO[4,3-α]PYRAZIN-7-YL]-4-(2,4,5-TRIFLUOROPHENYL)BUTAN-1-ONE L-TARTRATE
KR20170036288A (en) 2015-09-24 2017-04-03 주식회사 종근당 Novel Salts of Sitagliptin and Preparation Method thereof

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