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Title:
CO-CRYSTALS DERIVED FROM EMPAGLIFLOZIN AND DAPAGLIFLOZIN WITH L-PROLINE
Document Type and Number:
WIPO Patent Application WO/2024/062310
Kind Code:
A1
Abstract:
The present invention provides derivatives of (2S,3R,4R,5S,6R)-2-[4- chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]-phenyl]-6-(hydroxymethyl)- oxan-3,4,5-triol (empagliflozin) and (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)-tetrahydro-2H-piran-3,4,5-triol (dapagliflozin) to be used for preparing tablets for the treatment of type-2 diabetes. These derivatives are empagliflozin and dapagliflozin co-crystals with L-proline.

Inventors:
SAVOI GUILHERME (AR)
Application Number:
PCT/IB2023/058661
Publication Date:
March 28, 2024
Filing Date:
September 01, 2023
Export Citation:
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Assignee:
SAVOI GUILHERME (AR)
International Classes:
C07D407/12; C07D207/16; C07D309/10
Domestic Patent References:
WO2016131431A12016-08-25
WO2022124749A12022-06-16
WO2017203457A12017-11-30
WO2017130217A12017-08-03
WO2008002824A12008-01-03
Foreign References:
CN110922372A2020-03-27
CZ2015834A32017-06-07
Attorney, Agent or Firm:
GUERRA IP (BR)
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Claims:
CLAIMS 1. An empagliflozin derivative comprising an empagliflozin/L-proline co-crystal wherein empagliflozin and L-proline are present in 1:1 stoichiometric ratio. 2. The empagliflozin derivative according to claim 1, characterized in that its XRPD spectrum is shown in Figure 1. 3. The empagliflozin derivative according to claim 1, characterized in that its DSC profile is illustrated in Figure 2. 4. The empagliflozin derivative according to claim 1, characterized in that its TGA (ful line) and dTGA (dotted line) profiles are illustrated in Figure 3. 5. A dapagliflozin derivative comprising a dapagliflozin/L-proline co- crystal wherein dapagliflozin and L-proline are present in 1:2 stoichiometric ratio. 6. The dapagliflozin derivative according to claim 5, characterized in that its XRPD spectrum is shown in Figure 4. 7. The dapagliflozin derivative according to claim 5, characterized in that its DSC profile is illustrated in Figure 5. 8. The dapagliflozin derivative according to claim 5, characterized in that its TGA profile is illustrated in Figure 6. 1
Description:
CO-CRYSTALS DERIVED FROM EMPAGLIFLOZIN AND DAPAGLIFLOZIN WITH L-PROLINE DESCRIPTION Field of the invention The present application pertains to the field of solid pharmaceutical forms of empagliflozin and dapagliflozin; particularly, the pharmaceutical forms are empagliflozin and dapagliflozin co-crystals obtained with L-proline, a pharmaceutically acceptable amino acid used as a co-former. Background of the invention A co-crystal is a crystalline complex formed by two or more neutral species present in the same crystal lattice which stay attached by non-covalent interactions, mainly by hydrogen bonding. In particular, preparation of co-crystals has become greatly relevant in the pharmaceutical industry as an active pharmaceutical ingredient (API) may in many cases remarkably improve its pharmacological properties, such as bioavailability, dissolution, dissolution rate, etc., when converted to a co-crystal. The components coexist in a stoichiometric ratio between the API and the “co-former”, i.e., the co-crystallization agent. While liquids and gases can also be useful as co-crystal “co-formers”, the fact that all the components are solid has practical considerations: co-crystals may be prepared in solid state and tend to be more thermally stable than solvates or hydrates. While the latter are known to be usually the unexpected result of crystallization from a solution, pharmaceutical co-crystals represent a wide type of less explored compounds. In a crystalline salt, interactions are assisted by charges and the components are present in ionized states, whereas in co-crystals the molecules interact through non-ionic interactions and the components are present in neutral state. This means that they have the advantage of rendering solid forms of the API´s, even when they have non-ionizable moieties in their structure. In this manner, materials may be obtained having properties which differ from or improve with respect to the properties of pure API´s, namely polymorphs and amorphous species, their solvates or salts. Co-formers are molecules containing functionalities that are complementary to the functionalities of the API, thus facilitating molecular recognition. The most common pharmaceutical co-crystal forming agents are carboxylic acids, amides, carbohydrates, alcohols and amino acids. Pharmaceutical co-crystals are mainly prepared by solution and solid- state methods. Solution methods consist in mixing the API and the co-former in certain ratios in an appropriate solvent so that co-crystals are obtained upon evaporation of the solvent. Solid-state methods consist in grinding the API and the co-former in certain ratios in a mortar or a mill. The present application refers to specific derivatives of the active ingredients empagliflozin and dapagliflozin. Empagliflozin and dapagliflozin are drugs belonging to the gliflozin family and are used in the treatment of type-2 diabetes as they are sodium/glucose type 2 (SGLT 2) co-transporter inhibitors. The empirical formula of empagliflozin is C23H27ClO7; its IUPAC name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphen yl]methyl]-phenyl]- 6-(hydroxymethyl)oxan-3,4,5-triol; and its molecular formula is shown below: . In turn, the empirical formula of dapagliflozin is C21H25ClO6; its IUPAC name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-etoxybenzyl)phenyl]-6- (hydroxymethyl)-tetrahydro-2H-piran-3,4,5-triol; and its molecular formula is shown below: L-proline is an amino acid that has been found to be useful as a co- former for preparing co-crystals of many substances having pharmacological activity. Its molecular formula is as follows: Prior art Applications US20170247356 A1 and US20190202814 A1 describe a co-crystal between empagliflozin and L-proline in a 1:2 ratio. Said co-crystal is mentioned in the specification, the examples and claims 6, 7, 8, 9, 10, and 18. Document WO2016131431 A1 describes a complex between empagliflozin and L-proline in molar ratios between 4:1 and 1:4, preferably 2:1 to 1:2, but ideally 1:1. The complex appears in several examples and in claims 1 to 18. The PCT Application published as WO2017141202 A1 describes in Examples 1, 2 and 3 the crystalline Form A of the empagliflozin/L-proline complex, which is consistent with the 1:2 co-crystal of the above-mentioned document US20170247356 A1. Also claims 1-6 are directed to this complex and claims 10-13 refer to a process for preparing same, but the stoichiometric ratio is never specified. As concerns dapagliflozin/L-proline co-crystals: PCT Application WO2008002824 A1 (granted as BR122017015106 B1) claims dapagliflozin/L-proline co-crystals. In the 56-clause claim set of the PCT case, claim 1 is broad and general whereas clause 2 claims co-crystals obtained with L-proline in the following ratios: 1:2, 1:1 and 1:1 hemihydrate. Documents KR20190115948, KR20200077674, WO2018097570, WO2018124468 and WO2018124497 refer to pharmaceutical compositions prepared with dapagliflozin/L-proline complexes. Other documents make reference to compositions comprising crystalline forms (polimorphs), but not co- crystals. Therefore, it is desirable to provide new empagliflozin and dapagliflozin derivatives having good water solubility, a definite chemical structure, and a no observed adverse effect level (NOAEL). The new derivatives of these anti- diabetic drugs should have good stability and compressibility, and be useful for preparing pharmaceutical compositions in the form of tablets. Brief Description of the Drawings The characteristics and advantages of certain embodiments of the present invention will be more easily demonstrated when considered along with the accompanying figures. The figures should not be construed as restrictive of any preferred embodiment. Figure 1 is the XRPD spectrum of co-crystal TRQ02-LPro 1-1. Figure 2 is the DSC profile of a sample of TRQ02-LPro 1-1. Figure 3 presents the TGA (full line) and the dTGA (dotted line) profiles of a sample of TRQ02-LPro 1-1. Figure 4 is the XRPD spectrum of co-crystal DAPA-LPro 1:2, lot DAPA03-65-5. Figure 5 is the DSC thermogram of co-crystal DAPA-LPro 1:2, lot DAPA03-65-5. Figure 6 shows the results of the TGA assays of co-crystal DAPA-LPro 1:2, lot DAPA03-65-5: mass vs. temperature, mass loss vs. time, and signal integration. Detailed Description of the Invention For the sake of clarity and comprehension of the description, the following table is included which comprises a glossary of terms used throughout the present application. Table 1. Glossary: Abbreviation list. The object of the present invention is to provide new empagliflozin and dapagliflozin co-crystals with L-proline as the co-former, having advantageous pharmaceutical properties. Preferred embodiments of the invention In a preferred embodiment of the invention, an empagliflozin co-crystal was prepared named TRQ02-LPRO 1-1 using L-proline as the co-former, in a 1:1 stoichiometric ratio of EMPA:LPro. In another preferred embodiment of the invention, a dapagliflozin co- crystal was prepared named TRIQUIM DAPA-LPro using L-proline as the co- former, in a 1:2 stoichiometric ratio of DAPA:LPro. Preparation and assessment of the preferred co-crystals of the invention Co-crystal TRQ02-LPRO 1-1 was prepared by a two-step experiment. In the first step, 5 g of Empagliflozin were reacted with 1.1 equivalents of L-Proline in 40 mL of ethanol in a 100 mL reactor vessel equipped with a stirrer. The stirring rate was set at 100 rpm, and the mixture was heated from 25 °C to 75 °C at 1 °C/min, kept at this temperature for 15 minutes, then cooled to 25 °C at 0.5 °C/min. A second heating/cooling cycle was applied, by heating the mixture from 25 °C to 70 °C at 0.5 °C/min, then stirring the mixture at this temperature for 30 minutes, followed by cooling to 25 °C at 0.5 °C/min. At the end of the cycle, the mixture was slurried at room temperature for approx.16 hours, then the formed solid was isolated by vacuum filtration, washed with 10 mL of solvent, and dried on the filter for 15 minutes. 5.052 g of compound were suspended in 32 mL of ethanol (concentration of TRQ02 = 125 mg/mL, calculated considering the solid as pure TRQ02-LPRO 1-1) and 0.25 equivalent of L-Proline (related to the amount of empagliflozina contained in the solid) was added. The mixture was heated to 75 °C at 1 °C/min, then kept at 75 °C for 15 minutes and finally cooled to 25 °C at 0.5 °C/min. After the cooling ramp, the mixture was slurried at room temperature for approx. 16 hours, then the solid was filtered, washed with 10 mL of fresh solvent, and dried on the filter for 15 minutes. The so isolated solid was then dried at 50 °C for 16 hours, and 4.467 g of product were isolated (yield = 71% over two steps). Figure 1 illustrates the XRPD spectrum of the co-crystal finally obtained. The main detected peaks of said spectrum are shown in Table 2: b) Characterization Isolated derivative TRQ02-LPRO 1-1 was completely characterized, as in addition to the above-mentioned XRPD spectrum, DSC and TGA analyses were conducted which are illustrated in Figures 2 and 3, respectively. The DSC profile (Figure 2) showed a sharp endothermic event ascribable to sample melting at 186.0 °C (Onset 185.2 °C), readily followed by a broad endothermic event at 232.4 °C (Onset 196.2 °C) due to sample degradation. TG-EG analysis confirmed the recovery of an anhydrous compound, since no weight loss was registered below sample degradation, which occurred at approx. 200 °C. A weight loss of 4.2% w/w was recorded starting from this temperature (Figure 3), in correspondence to the second event recorded by DSC. In addition, TGA confirmed decomposition of the Empagliflozin moiety above approx.360 °C. c) Comparison with prior art co-crystals Table 3: Differences in XRPD signals and differential scanning calorimetry signals are highlighted between a prior art co-crystal and the EMPA-LPRO co- crystal of the present invention: As indicated by the data of Table 3, some signals corresponding to the XRPD spectrum of free Empagliflozin and L-proline are present in the XRPD spectrum of the co-crystal of prior art document WO2016131431 A1 whereas they are absent in the XRPD spectrum of the co-crystal of the present invention. Furthermore, when the melting ranges obtained by DSC are compared, it is noted that the co-crystal of the invention is polimorphically purer (melting range lower than 1 °C) than the prior art co-crystal. These results suggest that the manufacturing method of the Empagliflozin/L-Proline co-crystal with stoichiometric ratio 1:1 allows obtaining a product of higher purity, devoid of free raw materials. 2) TRIQUIM DAPA-LPRO 1-2 a) Synthesis 10.00 g (1 eq.) Dapagliflozin Propanodiol Monohydrate was loaded in a 250-mL round bottomed flask together with 60.2 mL (6.2 vol.) of methylene chloride and 100.0 mL (10 vol.) of purified water for extraction. The mixture was stirred for 20 minutes at room temperature to obtain a white emulsion which formed two phases. The organic phase was extracted by means of a separatory funnel and the aqueous phase was discarded. Then the organic phase was dried with 4.94 g (1.8 eq) of anhydrous sodium sulfate at room temperature for 30 minutes and vacuum filtered using a Buchner funnel in order to remove the salts. Methylene chloride was removed by vacuum distillation until a yellowish oil was obtained. The oil was dissolved in 39.8 mL (3.9 vol.) of isopropyl acetate and the solvent was removed by vacuum distillation until a yellowish oil was obtained. Then the oil was re-dissolved in 81.3 mL (8.1 vol.) of isopropyl acetate and stirred for 10 minutes at room temperature to obtain a slightly turbid or translucent solution. 6.2 mL (0.6 vol.) of purified water was added followed by 6.87 g (3 eq.) of L-Proline and 100 mL of cyclohexane at room temperature. The mixture was strongly stirred overnight (18-24 hs.) at room temperature. A viscous white suspension was formed. The suspension was vacuum filtered using a Buchner funnel and the resulting cake was washed with 20.3 mL (2 vol.) of isopropyl acetate at room temperature. Then the crude filtered product was dried in a stove at 50°C for 24 hours. 11.44 g of crude (1:2) Dapagliflozin-L- Proline Co-crystal were obtained (90.0% yield). 11.44 g of crude (1:2) Dapagliflozin-L-Proline were loaded in a 250-mL round bottomed flask together with 34.4 mL (3 vol.) of methanol. The suspension was heated to 60°C until dissolution. Once complete dissolution was confirmed, 286 mL (25 vol.) of isopropyl acetate was added to the solution in a 10-minute period of time, while keeping the internal temperature at 60°C. The mixture was cooled to room temperature in order to precipitate the co- crystal. The suspension was stirred at about 20°C for 48 hours. The suspension was vacuum filtered using a Buchner funnel and the cake was washed with 45.8 mL (4 vol.) of methanol at room temperature. Then the filtered product was dried in a stove at 40°C for 72 hours to afford 10.54 g of purified 1:2 Dapagliflozin-L-Proline Co-crystal (92.2% yield). b) Characterization i) Using samples of co-crystal 1-2 DAPA-LPRO, the XRPD spectrum was run which may be viewed in Figure 4. The main detected peaks of said spectrum are shown in Table 4: ii) Differential scanning calorimetry (DSC) As shown in Figure 5, in the scanned temperature range, the thermogram corresponding to the analyzed sample presents two endothermic peaks. The first one, sharp and of medium intensity, appears centered at 185 ºC; the second one, which is broader, of medium intensity and slightly overlapped to the first one, spans from 210 to 260 ºC. iii) Thermogravimetric analysis Along the studied temperature range, the thermogram of the analyzed sample (shown in Figure 6) presents two significant mass losses, the first one between 215 and 252 ºC corresponding to 36% (1.47 mg), and the second one between 357 and 395 ºC corresponding to 56% (2.28 mg). PCT Application WO2008002824 A1 (granted as BR122017015106 B1) teaches that synthesis of dapagliflozin/L-proline co-crystals is carried out starting from appropriate raw materials which after several synthetic steps render Dapagliflozin base (drug), which is either directly used without prior isolation of Dapaglifozin base or isolating Dapaglifozin base as an amorphous solid. In contrast, the present invention features a process for preparing a Dapagliflozin/L-proline co-crystal in a 1:2 stoichiometric ratio starting from Dapagliflozin 1,2-propanodiol monohydrate, with which use of the amorphous material (which may have hygroscopicity and stability issues) is avoided. Moreover, Dapagliflozin 1,2-propanodiol monohydrate is commercially available, which provides the possibility of conducting a short process instead of manufacturing the co-crystal starting from the raw materials.