WO2024062310A1 - Co-crystals derived from empagliflozin and dapagliflozin with l-proline - Google Patents
Co-crystals derived from empagliflozin and dapagliflozin with l-proline Download PDFInfo
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- WO2024062310A1 WO2024062310A1 PCT/IB2023/058661 IB2023058661W WO2024062310A1 WO 2024062310 A1 WO2024062310 A1 WO 2024062310A1 IB 2023058661 W IB2023058661 W IB 2023058661W WO 2024062310 A1 WO2024062310 A1 WO 2024062310A1
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- Prior art keywords
- dapagliflozin
- proline
- empagliflozin
- crystal
- crystals
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- 239000013078 crystal Substances 0.000 title claims abstract description 50
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 29
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims abstract description 28
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 title claims abstract description 25
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 23
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 21
- 229960002429 proline Drugs 0.000 claims abstract description 26
- 229930182821 L-proline Natural products 0.000 claims abstract description 23
- 238000001228 spectrum Methods 0.000 claims description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 11
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000008186 active pharmaceutical agent Substances 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 101800000268 Leader protease Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000003836 solid-state method Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101100008681 Glycine max DHPS1 gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000004453 electron probe microanalysis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- UFZOPKFMKMAWLU-UHFFFAOYSA-N ethoxy(methyl)phosphinic acid Chemical compound CCOP(C)(O)=O UFZOPKFMKMAWLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000001304 sample melting Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- CO-CRYSTALS DERIVED FROM EMPAGLIFLOZIN AND DAPAGLIFLOZIN WITH L-PROLINE DESCRIPTION Field of the invention 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.
- 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.
- co-crystals have 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.
- co-former i.e., the co-crystallization agent.
- 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.
- 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]oxyphenyl]methyl]-phenyl]- 6-(hydroxymethyl)oxan-3,4,5-triol; and its molecular formula is shown below: .
- 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.
- 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.
- 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.
- 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.
- 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.
- Co-crystal TRQ02-LPRO 1-1 was prepared by a two-step experiment.
- 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.
- 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.
- 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.
- TGA confirmed decomposition of the Empagliflozin moiety above approx.360 °C.
- the co-crystal of the invention is polimorphically purer (melting range lower than 1 °C) than the prior art co-crystal.
- 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.
- 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.
- 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.
- 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.
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.
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]oxyphenyl]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.
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
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WO2008002824A1 (en) * | 2006-06-28 | 2008-01-03 | Bristol-Myers Squibb Company | Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes |
WO2016131431A1 (en) * | 2015-02-18 | 2016-08-25 | Zentiva, K.S. | Solid forms of empagliflozin |
CZ2015834A3 (en) * | 2015-11-26 | 2017-06-07 | Zentiva, K.S. | The solid form of dapagliflozin |
WO2017130217A1 (en) * | 2016-01-27 | 2017-08-03 | Msn Laboratories Private Limited | The present invention relates to process for the preparation of d-glucitol, 1,5- anhydro-1-c-[4-chloro-3-[[4-[[(3s)-tetrahydro-3-furanyl] oxy]phenyl] methyl]phenyl]-, (1s) and its crystalline forms thereof. |
WO2017203457A1 (en) * | 2016-05-26 | 2017-11-30 | Dr. Reddy's Laboratories Limited | Solid state forms of empagliflozin |
CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
WO2022124749A1 (en) * | 2020-12-08 | 2022-06-16 | Chong Kun Dang Pharmaceutical Corp. | Pharmaceutical composition comprising empagliflozin co-crystal |
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WO2008002824A1 (en) * | 2006-06-28 | 2008-01-03 | Bristol-Myers Squibb Company | Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes |
WO2016131431A1 (en) * | 2015-02-18 | 2016-08-25 | Zentiva, K.S. | Solid forms of empagliflozin |
CZ2015834A3 (en) * | 2015-11-26 | 2017-06-07 | Zentiva, K.S. | The solid form of dapagliflozin |
WO2017130217A1 (en) * | 2016-01-27 | 2017-08-03 | Msn Laboratories Private Limited | The present invention relates to process for the preparation of d-glucitol, 1,5- anhydro-1-c-[4-chloro-3-[[4-[[(3s)-tetrahydro-3-furanyl] oxy]phenyl] methyl]phenyl]-, (1s) and its crystalline forms thereof. |
WO2017203457A1 (en) * | 2016-05-26 | 2017-11-30 | Dr. Reddy's Laboratories Limited | Solid state forms of empagliflozin |
CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
WO2022124749A1 (en) * | 2020-12-08 | 2022-06-16 | Chong Kun Dang Pharmaceutical Corp. | Pharmaceutical composition comprising empagliflozin co-crystal |
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