Crystalline forms of ertugliflozin

Abstract

New forms of ertugliflozin were discovered that are more stable than ertugliflozin LPGA cocrystal in aqueous media.

Description

26107-US-PSPCRYSTALLINE FORMS OF ERTUGLIFLOZINTECHNICAL FIELD

[0001] The production and characterization of crystalline forms of organic compoundsBACKGROUND

[0002] Ertugliflozin (MK-8835) is a potent sodium glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is responsible for the reabsorption of filtered glucose from the kidney back to the blood stream. By its inhibitory mechanism, ertugliflozin can effectively promote glucose excretion in urine and thus prevent accumulation in blood stream.

[0003] US Patent No. 8,080,580 discloses ertugliflozin.

[0004] Stelglatro® tablets, which contain ertugliflozin L-pyroglutamic acid (ertugliflozin L- PGA) as an active ingredient, are approved and marked for lowering the blood glucose levels in human adults with type 2 diabetes mellitus. Kovacich et al. Pharmacy &Therapeutics, December 2018, Volume 43, No. 12, pp 736-742. Ertugliflozin sesquihydrate is not disclosed.

[0005] W02020026273A1 discloses crystalline forms of ertugliflozin (IS, 2S, 3S, 4R, 5S)-5- (4-chl oro-3 -(4-ethoxybenzyl) phenyl)-l -(hydroxymethy l)-6,8-di oxabicyclo [3.2.1] octane- 2,3,4-triol free base and process for the preparation thereof. Also disclosed are amorphous, solid dispersions of ertugliflozin L-PGA (IS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl) phenyl)- 1- (hydroxymethyl)-6,8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol L-pyroglutamic acid and process the preparation thereof. Ertugliflozin sesquihydrate is not disclosed.26107-US-PSP

[0006] There is a need for ertugliflozin crystals of superior stability.SUMMARY OF INVENTION

[0007] An embodiment of the invention is a crystalline form of ertugliflozin sesquihydrate having at least one of the following characteristics: an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.3, 8.6, 11.1, 11.5, 12.8, 13.0, 14.0, 14.5, 15.7, 16.9, 17.5, 18.1, 18.8, 20.0, 20.8, 21.3, 21.9, 22.2, 23.1, 24.4, 25.0, 25.4, 26.0, 18.2, 28.7, 29.5, 31.0, 31.8, 32.2, 32.8, 33.8, 34.5, 34.9, 36.5, 38.2 and 38.8; a carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum having at least one peak selected from the group consisting of 16.06, 18.13, 37.90, 60.76, 62.51, 68.30, 71.46, 77.29, 86.09, 108.9, 113.88, 129.44, 131.72, 135.05, 136.74 and 156.69 ppm; or a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 69 °C+ / -5°C.DESCRIPTION OF DRAWINGS

[0008] Figure l is a characteristic X-ray diffraction pattern of the ertugliflozin sesquihydrate crystalline form.

[0009] Figure 2 is the X-ray diffraction pattern of the ertugliflozin sesquihydrate crystalline form with peak labels.

[0010] Figure 3 is a characteristic DSC trace of the ertugliflozin sesquihydrate crystalline form.

[0011] Figure 4 is a characteristic TGA thermogram of the ertugliflozin sesquihydrate crystalline form.

[0012] Figure 5 is the13C CPMAS spectrum of the ertugliflozin sesquihydrate crystalline form.

[0013] Figure 6 is a characteristic X-Ray Powder Diffraction of ertugliflozin monohydrate (Form 2).

[0014] Figure 7 is a characteristic DSC trace of ertugliflozin monohydrate (Form 2).

[0015] Figure 8 is a characteristic TGA thermogram of ertugliflozin monohydrate (Form 2).

[0016] Figure 9 is a characteristic X-Ray Powder Diffraction of ertugliflozin (Form 3).

[0017] Figure 10 is a characteristic X-Ray Powder Diffraction of ertugliflozin (Form 4).26107-US-PSPDESCRIPTION OF EMBODIMENTS

[0018] New crystalline forms of ertugliflozin have been identified. These forms are more stable than ertugliflozin LPGA cocrystal in aqueous media.

[0019] A new sesquihydrate form of Ertugliflozin has been identified. A new monohydrate form of ertugliflozin has been identified. A new form of ertugliflozin has been identified.

[0020] The sesquihydrate of a compound is a hydrate form of the compound that contains three water molecules and two molecules of the compound.

[0021] In another embodiment, the crystalline form of ertugliflozin sesquihydrate has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

[0022] An embodiment of the invention is a crystalline form of ertugliflozin sesquihydrate having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °2 9 (±0.2) selected from the group consisting of 4.3, 8.6, 11.1, 11.5, 12.8, 13.0, 14.0, 14.5, 15.7, 16.9, 17.5, 18.1, 18.8, 20.0, 20.8, 21.3, 21.9, 22.2, 23.1, 24.4, 25.0, 25.4, 26.0, 18.2, 28.7, 29.5, 31.0, 31.8, 32.2, 32.8, 33.8, 34.5, 34.9, 36.5, 38.2 and 38.8.

[0023] An embodiment of the invention is a crystalline form of ertugliflozin sesquihydrate having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °2 9(±0.2) selected from the group consisting of 4.3, 8.6, 11.1, 13.0, 14.5, 17.5, 18.1, 18.2, 19.2, 20.0, 20.8 and 23.1.

[0024] An embodiment of the invention is a crystalline form of ertugliflozin sesquihydrate having a carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum having at least one peak selected from the group consisting of 16.06, 18.13, 37.90, 60.76, 62.51, 68.30, 71.46, 77.29, 86.09, 108.9, 113.88, 129.44, 131.72, 135.05, 136.74 and 156.69 ppm.

[0025] In another embodiment, the crystalline form of ertugliflozin sesquihydrate has a carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum substantially as shown in Figure 5.

[0026] An embodiment of the invention is a crystalline form of ertugliflozin sesquihydrate having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 69 °C+ / -5°C.

[0027] An embodiment of the invention is a crystalline form of ertugliflozin sesquihydrate having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 69 °C± / -10°C.26107-US-PSP

[0028] In another embodiment, the crystalline form of ertugliflozin sesquihydrate has a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2.

[0029] An embodiment of the invention is a crystalline form of ertugliflozin monohydrate (Form 2) having at least one of the following characteristics: an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.4, 8.9, 9.5, 10.3, 11.4, 12.8, 13.3, 14.5, 15.8,16.2, 17.0, 17.8, 18.0, 18.3, 19.0, 19.1, 19.8, 20.7, 21.0, 21.7, 22.2, 22.4, 23.0, 23.8, 24.2, 24.7,25.1, 25.3, 25.9, 26.3, 26.6, 26.9, 27.5, 28.1, 28.6, 28.9, 29.3, 29.6, 29.9, 31.1, 31.3, 31.9, 32.3,32.5, 32.9, 33.3, 34.5, 34.9, 35.2, 35.4, 36.2, 36.5, 36.6, 37.2, 37.8, 38.0, 38.8 and 39.5; or a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 87 °C+ / -5°C.

[0030] In another embodiment, the crystalline form of ertugliflozin monohydrate (Form 2) has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 87 °C+ / -10°C.

[0031] In another embodiment, the crystalline form of ertugliflozin monohydrate (Form 2) has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 6.

[0032] In another embodiment, the crystalline form of ertugliflozin monohydrate (Form 2) has an X-ray powder diffraction (XRPD) pattern has at least one peak in terms of °29(±0.2) selected from the group consisting of 4.4, 8.9, 10.3, 14.5, 16.2, 17.8, 18.3, 19.1, 19.8, 20.7, 23.0 and 25.3.

[0033] In another embodiment, the crystalline form of ertugliflozin monohydrate (Form 2) has a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 7.

[0034] An embodiment of the invention is a crystalline form of ertugliflozin (Form 3) having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.2, 8.5, 9.9, 10.5, 11.6, 14.4, 16.0, 16.4, 17.0, 17.8, 17.9,18.5, 19.0, 19.4, 19.6, 20.4, 21.2, 21.5, 22.6, 23.3, 23.5, 23.9, 25.1, 25.5, 25.9, 26.8, 27.4, 28.2, 29.0, 31.8, 33.2, 33.5, 33.7, 34.0, 36.2, 36.8, 37.8 and 38.7.

[0035] In another embodiment, the crystalline form of of ertugliflozin (Form 3) has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 9.

[0036] In another embodiment, the crystalline form of of ertugliflozin (Form 3) has an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.2, 8.5, 9.9, 10.5, 14.4, 16.4, 17.9, 18.5, 19.4, 19.6, 20.4, 23.3 and 25.5.26107-US-PSP

[0037] An embodiment of the invention is a crystalline form of ertugliflozin (Form 4) having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 3.9, 4.8, 11.5, 14.5, 16.0, 16.5, 17.1, 17.9, 19.3, 21.6, 22.2, 23.1, 24.2, 25.5, 26.5, 27.7, 29.2, 31.8, 33.4, 33.9, 38.4 and 39.2.

[0038] In another embodiment, the crystalline form of ertugliflozin (Form 4) has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10.

[0039] In another embodiment, the crystalline form of ertugliflozin (Form 4) has having an X- ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.8,14.5, 16.0, 16.5, 17.1, 17.9, 19.3, 22.2 and 24.2.

[0040] An alternative embodiment is a pharmaceutical composition comprising a crystalline form of ertugliflozin and a pharmaceutical excipient.

[0041] In another embodiment, the crystalline form is substantially purified.

[0042] An alternative embodiment is a method of treating or preventing diabetis in a companion animal comprising administering an effective amount of the composition comprising of the crystalline sesquihydrate form of ertugliflozin.

[0043] In another embodiment, the companion animal is a cat or a dog.

[0044] An alternative embodiment is a method of producing the crystalline sesquihydrate form of ertugliflozin, comprising a) dissolving ertugliflozin L-pyroglutamic acid into a solution comprising poloxamer and water and b) holding the ertugliflozin L-pyroglutamic acid solution at ambient temperature until the crystalline form precipitates.

[0045] In another embodiment, the method of producing the crystalline form, comprises seeding an aqueous solution of ertugliflozin L-pyroglutamic acid with ertugliflozin sesquihydrate to precipitates the crystalline form.

[0046] The ertugliflozin composition can be administered once daily at 0.1 mL / Kg by use of an oral syringe for ease of dosing. The target dose is 0.3 mg / Kg (or 3 mg / mL). Alternatively, the target dose is 0.1 mg / Kg (1 mg / mL). In a further alternative, the target dose is between about 0.05 mg / Kg (mg / mL) to about 0.25 mg / Kg (mg / mL). In yet a further alternative, the target dose is between about 0.5 mg / Kg (mg / mL) to about 0.25 mg / Kg (mg / mL).

[0047] Ertugliflozin may be administered in doses of 0.01-5 mg / kg per day or 0.01-4 mg / kg or 0.01-3 mg / kg or 0.01-2 mg / kg or 0.01-1.5 mg / kg or 0.01-1 mg / kg or 0.01-0.75 mg / kg or 0.01-0.5 mg / kg or 0.01-0.4 mg / kg or 0.01-0.4 mg / kg per day; or 0.1 to 3.0 mg / kg per day, preferably from 0.2 to 2.0 mg / kg per day, more preferably from 0.1 to 1 mg / kg per day. In another preferred26107-US-PSP embodiment the dose is 0.02-0.5 mg / kg per day, more preferably 0.03-0.4 mg / kg per day, e.g., 0.03-0.3 mg / kg per day.

[0048] The dose of ertugliflozin is between about 0.01 and about 1.0 mg / Kg of animal body weight, or between about 0.05 to 0.5 mg / kg of animal body weight, or preferably about 0.1 to 0.3 mg / Kg of animal body weight.

[0049] The administration of the dose of ertugliflozin may be at frequency greater than once a day. For example, the ertugliflozin dose may be administered once every 3 days or once every 7 days or once every 10 days.

[0050] When longer durations between the administration of the doses of ertugliflozin are used, the doses may be 1-10 mg / kg.

[0051] Clinical signs of diabetes mellitus observed with feline animals include polydipsia, polyuria, weight loss, and / or polyphagia. Pathognomonic for diabetes mellitus in cats is a plantigrade stance (weakness in hind legs, hocks touch the ground when the cat walks). This is caused by a diabetic neuropathy. Further particularly relevant clinical signs of diabetes mellitus in feline animals within the context of the present invention are hyperglycemia and glucosuria. Hyperglycemia in a feline animal (e.g., a cat) is defined as plasma glucose values above normal values (3.9 - 8.3 mmol / 1 or 70 - 150 mg / dl), e.g., 8 mmol / 1 or more or 150 mg / dl or more plasma glucose. Glucosuria in a feline animal (e.g., a cat) is defined as glucose levels in urine above normal values (0 - 2 mmol / L, or 36 mg / dl). The renal threshold is reached with blood glucose concentrations of approximately 11 - 17 mmol / 1 or 200 to 300 mg / dl. The diagnosis of diabetes mellitus in feline animals may alternatively be based on three criteria, e.g., as follows: (l)Fasting blood glucose concentration measurements> 250 mg / dl; (2) Glucosuria as defined above; and (3) One or more of the following: polyuria, polydipsia, polyphagia, weight loss despite good appetite, or ketonuria (without signs of severe ketoacidosis). See W02015091313, page 21, lines 8-27.

[0052] A companion animal is a domesticated animal or a pet. Examples are feline animals and canine or canidae animals.

[0053] A feline animal is a member of the Felidae family (i.e., a felid). It may thus belong either to the subfamily felinae or the subfamily pantherinae. The term feline animal encompasses the term cat, e.g., a domestic cat. The term domestic cat encompasses the terms Felis catus and Felis silvestris catus.

[0054] A canine or canidae animal is a cosmopolitan family of carnivorous mammals that includes the wolves, jackals, foxes, coyote, and the domestic dog.

[0055] In another embodiment of the invention, the animal is a feline.26107-US-PSP

[0056] In another embodiment of the invention, the animal is a companion animal.

[0057] In another embodiment of the invention, the animal is a dog.

[0058] In another embodiment is a pharmaceutical composition comprising the anyone of crystalline form and a pharmaceutical excipient.

[0059] In another embodiment, the crystalline form is substantially purified in the pharmaceutical composition.

[0060] A pharmaceutical excipient is a substance in addition to the active ingredient that is incorporated into a pharmaceutical composition. A general discussion regarding formulation of drugs and various excipients may be found in, for example, Gennaro, A.R., et al., eds., Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins, 20th Ed., 2000). Another general discussion regarding formulation of drugs and various excipients may be found in, for example, Liberman, H. A., et al., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980). These references are incorporated by reference herein.EXAMPLESExample 1 - Preparation of ertugliflozin sesquihydrate

[0061] The crystalline ertugliflozin sesquihydrate was manufactured at 300L scale. 300g of methylparaben and 30g of propylparaben were dissolved into 150L of purified water at 60°C. After dissolution of methylparaben and propylparaben, 720g of sucralose, 150g of vanillin, 780g of citric acid monohydrate, and 660g of sodium citrate were added to the solution and dissolved at 60°C. 3kg of poloxamer 188 and 120L of purified water then added to the solution and mixed until dissolved and homogeneous. The solution was then cooled to less than 40°C. After cooling, 394.0g of Ertugliflozin L-pyroglutamic acid was added to the solution and dissolved. Finally, the solution was q.s. with purified water to 300L.

[0062] 100L of the resulting 300L batch was transferred through a 10pm stainless steel filter into a holding vessel after manufacture. The solution was then held at ambient conditions for approximately 30 days. After 30 days, crystalline material was identified at the bottom of the vessel. The vessel was drained of liquid and the resulting crystals were isolated with a spatula. Crystalline material was then dried by blowing overlayed nitrogen on the crystals at ambient temperature for approximately 24 hours. The crystals were then further rinsed with water to remove any excipients remaining in the process and dried for further characterization.

[0063] Further crystalline material has been generated by utilizing these seeds to precipitate out aqueous solutions of ertugliflozin L-pyroglutamic acid. This indicates the superior stability of the26107-US-PSP ertugliflozin sesquihydrate crystals when compared to the ertugliflozin L-pyroglutamic acid cocrystals.Example 2 - characterization of ertugliflozin sesquihydrate X-ray powder diffraction (XRPD)

[0064] X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism. The X-ray powder diffraction pattern of was generated on Bruker AXS D8 Advance with a LYNXEYE XE-T detector in reflection mode. The instrument was configured in the Bragg-Brentano configuration and equipped with a Cu radiation source with monochromatization to Ka achieved using a Nickel filter. A fixed slit optical configuration was employed for data acquisition. Data were acquired between 2 and 40° 29. Samples were prepared by gently pressing powdered sample onto a shallow cavity zero background silicon holder.

[0065] Figure 1 shows the X-ray powder diffraction pattern of ertugliflozin sesquihydrate. Figure 2 shows the X-ray powder diffraction patten of ertugliflozin sesquihydrate with peaks labeled with 2 theta values. The ertugliflozin sesquihydrate exhibited characteristic diffraction peaks corresponding to d-spacings of Angstroms. The ertugliflozin sesquihydrate was further characterized by the d-spacings of Angstroms.Table 1. Characteristic Peak Position and Corresponding d-Spacing for ertugliflozin sesquihydrate26107-US-PSPThermogravimetric Analysis (TGA)

[0066] Thermogravimetric analysis was carried out on a TA Q50 Thermogravimetric Analyzer (TA Instrument). Samples (2-15 mg) in open pans were heated from 25 to 300°C at 10°C / min, with a nitrogen purge of 100 mL / min. When the run was complete, the data were analyzed using26107-US-PSP the TGA analysis program in the system software. The observed weight loss up to a specific temperature was reported.Differential Scanning Calorimetry (DSC)

[0067] DSC data was acquired using TA Instruments DSC Q2000 or equivalent instrumentation. A sample with a weight between 1 and 6 mg was weighed into a open pan. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed, and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C / min to a temperature of approximately 275 °C. When the run was completed, the data were analyzed using the DSC analysis program in the system software. The observed endo- and exotherms were integrated between baseline temperature points that were above and below the temperature range over which the endotherm or exotherm was observed. The data reported are the onset temperature, peak temperature and enthalpy.

[0068] Figure 3 is a typical DSC curve of the ertugliflozin sesquihydrate. The DSC curve was characterized by a dehydration endotherm with an extrapolated onset temperature of 62°C, a peak temperature of 69°C and enthalpy of 152 J / g.

[0069] Figure 4 is a typical TGA thermogram of the ertugliflozin sesquihydrate. The TGA thermogram was characterized by a weight loss of 5.8% up to 200°C.Solid State NMR

[0070] In addition to the X-ray powder diffraction pattern described above, the ertugliflozine sesquihydrate was characterized by carbon 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) Experiment. The ertugliflozin sesquihydrate sample was packed into a Zirconia 4-mm solid-state NMR rotor to capacity and the rotor was sealed with a Kel-F® drive tip.13C CPMAS spectrum of the sample was collected on a Bruker Avance III 500 NMR spectrometer operating at aJH Larmor frequency of 500.150 MHz using a Bruker 4 mm HXY triple resonance MAS probe. An MAS rate of 14 kHz and a pulse delay of 5 s were utilized. During CP, a 100 kHz 'H n / 2 excitation pulse was applied, followed by a 'H lock pulse for which the power was linearly increased from 41.7 kHz to 83.3 kHz (50% to 100%) over 1.5 ms. The pulse power for the corresponding13C square pulse was matched to the respective1H ramp to produce the maximum signal. High-power SPINAL64 'H decoupling at 100 kHz was applied during data acquisition while collecting 4,000 scans for signal averaging.26107-US-PSP

[0071] A Gaussian line broadening of 10 Hz, zero filling to 32k data points, and standard baseline-correction methods were applied during processing. Throughout the CP experiment, the sample temperature was controlled with a Bruker VT control unit at 280 K. The13C CP spectrum was externally referenced using the sample adamantane to 37.8 ppm. Chemical shifts and the corresponding relative peak intensities were measured with standard peak-picking routines as part of the instrument software and listed in the table below.

[0072] Figure 5 is the13C CPMAS spectrum of the ertugliflozin sesquihydrate crystalline form sample. Spinning sidebands are indicated by the asterisks. Table 226107-US-PSPExample 3 - Preparation of ertugliflozin monohydrate (Form 2)Example 3 A

[0073] 53.05 mg of ertugliflozin sesquihydrate was added to a 4 ml vial followed by the addition of 400 pl of cumene. Mixture was aged at 50 °C for at least 7 days. Solids were isolated to provide Form 2.Example 3B

[0074] 50.72 mg of ertugliflozin sesquihydrate was added to a 4 ml vial followed by the addition of 400 pl of MTBE-Heptane (1 : 1, v / v). Mixture was aged at 50 °C for at least 7 days. Solids were isolated to provide Form 2.Example 3C

[0075] 769.72 mg of ertugliflozin sesquihydrate was added to a 4 ml vial followed by the addition of 2.5 ml of cumene. Mixture was stirred and aged at 50 °C for at least 3 days. Solids were isolated to provide Form 2.Example 4 - Characterization of ertugliflozin monohydrate (Form 2)

[0076] Figure 6 shows the X-ray powder diffraction pattern of ertugliflozin monohydrate (Form 2).Table 3. Characteristic Peak Position and Corresponding d-Spacing for ertugliflozin monohydrate (Form 2). Characteristic 2-0, d-Spacings and Relative Intensity26107-US-PSP26107-US-PSP

[0077] Figure 7 is a typical DSC curve of the ertugliflozin monohydrate (Form 2). The DSC curve was characterized by a dehydration endotherm with an onset temperature of 66°C, a peak temperature of 87°C and enthalpy of 77 J / g.

[0078] Figure 8 is a typical TGA thermogram of the ertugliflozin monohydrate (Form 2). The TGA thermogram was characterized by a weight loss of 2.1% up to 175°C.Example 5 - Preparation of ertugliflozin (Form 3)

[0079] Approximately -700 g of ertugliflozin monohydrate (Form 2) were dried in vacuum oven at 50 °C under reduced pressure for -19 hours. The sample was further dried in the vacuum oven under reduced pressure at 80 °C for -21 hours. Solids isolated to obtain ertugliflozin (Form 3).

[0080] Alternatively, Form 1 (5.18 mg) was heated to 100 °C at 1 °C / min in a DSC to yield Form 3.Example 6 - Characterization of ertugliflozin (Form 3)

[0081] Figure 9 shows the X-ray powder diffraction pattern of ertugliflozin (Form 3).Table 4. Characteristic Peak Position and Corresponding d-Spacing for ertugliflozin (Form 3).Characteristic 2-0, d-Spacings and Relative Intensity26107-US-PSPExample 7 - Preparation of ertugliflozin (Form 4)

[0082] 51.20 mg of ertugliflozin (Form 3) was added to a 4 ml vial, followed by the addition of 400 pl of diethyl ether and molecular sieves. The mixture was aged at ambient temperature in a shaker (500 rpm) for at least 20 hours. An additional 200 pl of diethyl ether was added. After 3 days of aging at ambient conditions, gummy solids observed. The mixture was vortexed and sonicated followed by additional sonication after three more days of aging. Afterwards, the mixture was further aged at ambient conditions for three more days. Solids were isolated to provide ertugliflozin (Form 4).Example 8 - Characterization of ertugliflozin (Form 4)26107-US-PSP

[0083] Figure 10 shows the X-ray powder diffraction pattern of ertugliflozin (Form 4).Table 5. Characteristic Peak Position and Corresponding d-Spacing for ertugliflozin monohydrate (Form 2). Characteristic 2-0, d-Spacings and Relative Intensity

Claims

26107-US-PSPCLAIMS1. A crystalline form of ertugliflozin sesquihydrate having at least one of the following characteristics: an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.3, 8.6, 11.1, 11.5, 12.8, 13.0, 14.0, 14.5, 15.7, 16.9, 17.5, 18.1, 18.8, 20.0, 20.8, 21.3, 21.9, 22.2, 23.1, 24.4, 25.0, 25.4, 26.0, 18.2, 28.7, 29.5, 31.0, 31.8, 32.2, 32.8, 33.8, 34.5, 34.9, 36.5, 38.2 and 38.8; a carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum having at least one peak selected from the group consisting of 16.06, 18.13, 37.90, 60.76, 62.51, 68.30, 71.46, 77.29, 86.09, 108.9, 113.88, 129.44, 131.72, 135.05, 136.74 and 156.69 ppm; or a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 69 °C+ / -5°C.

2. The crystalline form of claim 1, having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

3. The crystalline form of claim 1, having a carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum substantially as shown in Figure 5.

4. The crystalline form of claim 1, having a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2.

5. A crystalline form of ertugliflozin monohydrate (Form 2) having at least one of the following characteristics: an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.4, 8.9, 9.5, 10.3, 11.4, 12.8, 13.3, 14.5, 15.8, 16.2, 17.0, 17.8, 18.0, 18.3, 19.0, 19.1, 19.8, 20.7, 21.0, 21.7, 22.2, 22.4, 23.0, 23.8, 24.2, 24.7, 25.1, 25.3, 25.9, 26.3, 26.6, 26.9, 27.5, 28.1, 28.6, 28.9, 29.3, 29.6, 29.9, 31.1, 31.3, 31.9, 32.3, 32.5, 32.9, 33.3, 34.5, 34.9, 35.2, 35.4, 36.2, 36.5, 36.6, 37.2, 37.8, 38.0, 38.8 and 39.5;26107-US-PSP or a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 87 °C+ / -5°C.

6. The crystalline form of claim 5, having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 6.

7. The crystalline form of claim 5, having a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 7.

8. A crystalline form of ertugliflozin (Form 3) having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 4.2, 8.5, 9.9, 10.5, 11.6, 14.4, 16.0, 16.4, 17.0, 17.8, 17.9, 18.5, 19.0, 19.4, 19.6, 20.4, 21.2, 21.5, 22.6, 23.3, 23.5, 23.9, 25.1, 25.5, 25.9, 26.8, 27.4, 28.2, 29.0, 31.8, 33.2, 33.5, 33.7, 34.0, 36.2,36.8, 37.8 and 38.7.

9. The crystalline form of claim 8, having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 9.

10. A crystalline form of ertugliflozin (Form 4) having an X-ray powder diffraction (XRPD) pattern having at least one peak in terms of °29(±0.2) selected from the group consisting of 3.9,4.8, 11.5, 14.5, 16.0, 16.5, 17.1, 17.9, 19.3, 21.6, 22.2, 23.1, 24.2, 25.5, 26.5, 27.7, 29.2, 31.8, 33.4, 33.9, 38.4 and 39.2.

11. The crystalline form of claim 10, having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10.

12. A pharmaceutical composition comprising the crystalline form of anyone of claims 1-11 and a pharmaceutical excipient.

13. The pharmaceutical composition of claim 12, wherein the crystalline form is substantially purified.26107-US-PSP14. A method of treating or preventing diabetes in a companion animal comprising administering an effective amount of the composition of any of claims 12-13.

15. The method of claim 14, wherein the companion animal is a cat or a dog.

16. A method of producing the crystalline form of anyone of claims 1-6, comprising a) dissolving ertugliflozin L-pyroglutamic acid into a solution comprising poloxamer and water and b) holding the ertugliflozin L-pyroglutamic acid solution at ambient temperature until the crystalline form precipitates.

17. A method of producing the crystalline form of anyone of claims 1-6, comprising seeding an aqueous solution of ertugliflozin L-pyroglutamic acid with ertugliflozin sesquihydrate to precipitates the crystalline form.

Images