Crystal Forms of Gemcitabine

Abstract

A novel crystalline form of gepotidacin and pharmaceutical compositions containing same are disclosed, as are methods for their preparation and use.

Description

Technical Field

[0001] Description of Research Funded by the Federal Government This invention was made with government support under Contract No. HDTRA1-07-9-0002, awarded by the Defense Threat Reduction Agency. The U.S. government has certain rights in this invention.

Background Art

[0002] (2R)-2-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (hereinafter “gepotidacin”) selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique mechanism, which is not exploited by currently approved human therapeutic agents.

[0003] International Patent Application Publication WO2008 / 128942 describes a series of compounds that can be used as antibacterial agents, including gepotidacin. The mono HCl salt of gepotidacin was prepared in Example 39 of WO2008 / 128942, which is hereby incorporated by reference in its entirety.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

[0005] This application relates to a novel crystalline form of gepotidacin. Gepotidacin has the structure of formula (I).

[0006]

Chemical Formula

[0007] The present invention provides crystalline forms of gepotidacin, such as gepotidacin mesylate anhydrate, gepotidacin mesylate monohydrate, gepotidacin mesylate dihydrate, gepotidacin anhydrate, or combinations thereof. The present invention also provides methods for making crystalline forms of gepotidacin, pharmaceutical compositions comprising crystalline forms of gepotidacin, and methods of using crystalline forms of gepotidacin to treat bacterial infections. BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

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Mode for Carrying Out the Invention

[0009] This application is directed to novel crystalline forms of gepotidacin. Gepotidacin mesylate has a strong tendency to form various hydrates and solvates, and most have been found to be unstable. In addition to the gepotidacin mesylate dihydrate form, six additional hydrates have been characterized. Four non-solvated forms and numerous solvates have been identified. A total of at least 39 forms of gepotidacin mesylate, including solvates (dimethylformamide, trifluoroethanol, chlorobenzene, nitromethane) and solvate / hydrates (acetonitrile, dichloromethane, chloroform, dioxane, 1-butanol, isopropyl alcohol), have been observed.

[0010] Crystalline gepotidacin mesylate dihydrate (Form 1) is the major form observed from screening and has been shown to be the most thermodynamically stable form at or near room temperature.

[0011] Gepotidacin mesylate dihydrate (Form 1) In some embodiments, the crystalline form of gepotidacin is gepotidacin mesylate dihydrate. Gepotidacin mesylate dihydrate can be represented by the following structure.

[0012]

Chemical formula

[0013] In one embodiment, gepotidacin mesylate dihydrate has an X-ray powder diffraction (XRPD) pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffraction angles selected from the group consisting of about 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7° 2θ when measured using Cu K α radiation. As used herein, when the term "about" precedes a list of numbers, the term applies to each of the enumerated numbers. In one embodiment, gepotidacin mesylate dihydrate has an X-ray powder diffraction (XRPD) pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffraction angles selected from the group consisting of about 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7° 2θ when measured using Cu K αCharacterized by an XRPD pattern comprising at least three diffraction angles selected from the group consisting of about 13.4, 15.5, 17.6, and 18.6° 2θ when measured using a line. In one embodiment, gepotidacin mesylate dihydrate is Cu K α Characterized by an XRPD pattern comprising four diffraction angles of about 13.4, 15.5, 17.6, and 18.6° 2θ when measured using a line. In one embodiment, gepotidacin mesylate dihydrate is Cu K α Characterized by an XRPD pattern comprising three diffraction angles of about 13.4, 17.6, and 18.6° 2θ when measured using a line.

[0014] In one embodiment, gepotidacin mesylate dihydrate is characterized by an XRPD pattern that substantially coincides with FIG. 1. In one embodiment, gepotidacin mesylate dihydrate is characterized by an XRPD pattern that substantially coincides with FIG. 20.

[0015] In one embodiment, gepotidacin mesylate dihydrate has at least three, at least four, at least five, at least six, or at least seven peaks at positions selected from the group consisting of peaks at about 1154, 1269, 1306, 1518, 1584, 1637, and 1676 cm -1 characterized by a Raman spectrum. In one embodiment, gepotidacin mesylate dihydrate is characterized by a Raman spectrum that substantially coincides with FIG. 2.

[0016] In a further embodiment, gepotidacin mesylate dihydrate is characterized by a differential scanning calorimetry trace that substantially coincides with FIG. 3 and / or a thermogravimetric analysis trace that substantially coincides with FIG. 4.

[0017] In another embodiment, gepotidacin mesylate dihydrate has the following unit cell parameters: a = 6.9255(5) Å, b = 15.4500(12) Å, c = 25.7918(19) Å, α = β = γ = 90°, V = 2759.7(4) Å 3, Z' = 1, Space group P2 1 2 1 2 1 , Molecules / unit cell 4, Density (calculated) 1.398 g / cm 3 , where Z' is the number of molecules per asymmetric unit, characterized by single crystal XRD that gives rise to

[0018] This application also provides a method for preparing gepotidacin mesylate dihydrate, which includes the step of crystallizing gepotidacin mesylate in a solvent mixture of water and an organic solvent. In one embodiment, the organic solvent is acetone. In one embodiment, the organic solvent is alcohol. In one embodiment, the organic solvent is C 1~3 alkanol. In one embodiment, the organic solvent is 2-propanol (i.e., isopropanol).

[0019] In one embodiment, this application provides a method for preparing gepotidacin mesylate dihydrate, which includes the step of crystallizing gepotidacin mesylate in 2-propanol containing about 5% v / v water (e.g., a mixture of 5 mL water and 95 mL 2-propanol) or about 5.5% v / v water (e.g., a mixture of 5.5 mL water and 94.5 mL 2-propanol). In some embodiments, the method for preparing gepotidacin mesylate dihydrate is carried out on a commercial scale (e.g., more than 1 kg, 5 kg, or 10 kg).

[0020] Gepotidacin mesylate anhydrate (Form 2) In some embodiments, the crystalline form of gepotidacin is gepotidacin mesylate anhydrate. In one embodiment, the gepotidacin mesylate anhydrate is Cu K αWhen measured using the line, it is characterized by an XRPD pattern including at least 3, at least 4, at least 5, at least 6, or at least 7 diffraction angles selected from the group consisting of about 7.1, 9.7, 12.1, 14.2, 15.2, 17.3, and 20.2. In one embodiment, gepotidacin mesylate anhydride is Cu K α When measured using the line, it is characterized by an XRPD pattern including at least 3 diffraction angles selected from the group consisting of about 7.1, 9.7, 15.2, and 17.3. In one embodiment, gepotidacin mesylate anhydride is Cu K α When measured using the line, it is characterized by an XRPD pattern including 4 diffraction angles of about 7.1, 9.7, 15.2, and 17.3. In one embodiment, gepotidacin mesylate anhydride is Cu K α When measured using the line, it is characterized by an XRPD pattern including 3 diffraction angles of about 9.7, 15.2, and 17.3.

[0021] In one embodiment, gepotidacin mesylate anhydride is characterized by an XRPD pattern that substantially coincides with FIG. 5. In one embodiment, gepotidacin mesylate anhydride is characterized by an XRPD pattern that substantially coincides with FIG. 21.

[0022] In one embodiment, gepotidacin mesylate anhydride has at least 3, at least 4, at least 5, or at least 6 peaks at positions selected from the group consisting of peaks at about 1105, 1260, 1280, 1297, 1517, and 1642 cm -1 and is characterized by a Raman spectrum including them. In one embodiment, gepotidacin mesylate anhydride is characterized by a Raman spectrum that substantially coincides with FIG. 6.

[0023] In a further embodiment, gepotidacin mesylate anhydride is characterized by a differential scanning calorimetry trace that substantially coincides with FIG. 7 and / or a thermogravimetric analysis trace that substantially coincides with FIG. 8.

[0024] In another embodiment, gempotidacin mesylate anhydrate has the following unit cell parameters: a = 12.3921(7) Å, b = 7.0262(4) Å, c = 14.6536(9) Å, α = γ = 90°, β = 95.0077(13)°, V = 1271.01(13) Å 3 Z' = 1, space group P2 1 , molecules / unit cell 2, density (calculated) 1.423 g / cm 3 , where Z' is the number of molecules per asymmetric unit, characterized by single crystal XRD that gives rise to these.

[0025] Gempotidacin mesylate monohydrate (Form 3) In some embodiments, the crystalline form of gempotidacin is gempotidacin mesylate monohydrate. In one embodiment, gempotidacin mesylate monohydrate has an XRPD pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffraction angles selected from the group consisting of about 5.6, 7.1, 8.8, 11.2, 13.0, 13.7, 20.1, 21.6, and 23.3 when measured using Cu K α radiation. In one embodiment, gempotidacin mesylate monohydrate has an XRPD pattern comprising at least 3 diffraction angles selected from the group consisting of about 8.8, 11.2, 20.1, and 23.3 when measured using Cu K α radiation. In one embodiment, gempotidacin mesylate monohydrate has an XRPD pattern comprising 4 diffraction angles of about 8.8, 11.2, 20.1, and 23.3 when measured using Cu K α radiation. In one embodiment, gempotidacin mesylate monohydrate has an XRPD pattern comprising 3 diffraction angles of about 8.8, 11.2, and 20.1 when measured using Cu K α radiation.

[0026] In one embodiment, crystalline gepotidacin mesylate monohydrate is characterized by an XRPD pattern that substantially coincides with FIG. 9. In one embodiment, crystalline gepotidacin mesylate monohydrate is characterized by an XRPD pattern that substantially coincides with FIG. 22.

[0027] In one embodiment, gepotidacin mesylate monohydrate has a Raman spectrum comprising at least 3, at least 4, or at least 5 peaks at positions selected from the group consisting of peaks at about 1148, 1272, 1292, 1516, and 1649 cm -1 . In one embodiment, gepotidacin mesylate monohydrate is characterized by a Raman spectrum that substantially coincides with FIG. 10.

[0028] In a further embodiment, gepotidacin mesylate monohydrate is characterized by a differential scanning calorimetry trace that substantially coincides with FIG. 11 and / or a thermogravimetric analysis trace that substantially coincides with FIG. 12.

[0029] Gepotidacin anhydride In some embodiments, the crystalline form of gepotidacin is gepotidacin anhydride (i.e., the free base). In one embodiment, gepotidacin anhydride has an XRPD pattern comprising at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 diffraction angles selected from the group consisting of about 8.8, 10.8, 11.7, 12.8, 13.2, 14.4, 16.3, 19.9, 20.8, and 25.0 when measured using Cu K α α radiation. In one embodiment, gepotidacin anhydride has an XRPD pattern comprising at least 3 diffraction angles selected from the group consisting of about 8.8, 13.2, 14.4, and 20.8 when measured using Cu K α α radiation. In one embodiment, gepotidacin anhydride has an XRPD pattern comprising at least 3 diffraction angles selected from the group consisting of about 8.8, 13.2, 14.4, and 20.8 when measured using Cu K αCharacterized by an XRPD pattern comprising four diffraction angles of approximately 8.8, 13.2, 14.4, and 20.8 when measured using a line. In one embodiment, gepotidacin anhydrate is Cu K α Characterized by an XRPD pattern comprising three diffraction angles of approximately 8.8, 13.2, and 14.4 when measured using a line.

[0030] In one embodiment, gepotidacin anhydrate is characterized by an XRPD pattern that substantially coincides with FIG. 13. In one embodiment, gepotidacin anhydrate is characterized by an XRPD pattern that substantially coincides with FIG. 23.

[0031] In one embodiment, gepotidacin anhydrate has at least three, at least four, at least five, at least six, at least seven, or at least eight peaks at positions selected from the group consisting of peaks at approximately 1099, 1143, 1289, 1344, 1476, 1516, 1612, and 1687 cm -1 and is characterized by a Raman spectrum. In one embodiment, gepotidacin anhydrate is characterized by a Raman spectrum that substantially coincides with FIG. 14.

[0032] In a further embodiment, gepotidacin anhydrate is characterized by a differential scanning calorimetry trace that substantially coincides with FIG. 15 and / or a thermogravimetric analysis trace that substantially coincides with FIG. 16.

[0033] In another embodiment, gepotidacin anhydrate has the following unit cell parameters: a = 8.44022(16) Å, b = 6.42442(12) Å, c = 20.2774(5) Å, α = γ = 90°, β = 96.778(2)°, V = 1091.83(4) Å 3 Z' = 1, space group P2 1 , drug molecule / unit cell 2, density (calculated) 1.364 g / cm 3 , where Z' is the number of drug molecules per asymmetric unit, Characterized by single crystal XRD that results in

[0034] In yet further embodiments, as will be understood by those skilled in the art, specific gepotidacin polymorphs are characterized by any combination of two or more sets of the analytical data that characterize the foregoing embodiments. For example, in one embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern that substantially matches FIG. 1 or FIG. 20, a Raman spectrum that substantially matches FIG. 2, a differential scanning calorimetry trace that substantially matches FIG. 3, and a thermogravimetric analysis trace that substantially matches FIG. 4.

[0035] In another embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern that substantially matches FIG. 1 and a Raman spectrum that substantially matches FIG. 2. In another embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern that substantially matches FIG. 1 and a differential scanning calorimetry trace that substantially matches FIG. 3. In another embodiment, gepotidacin mesylate dihydrate is characterized by an X-ray powder diffraction (XRPD) pattern that substantially matches FIG. 1 and a thermogravimetric analysis trace that substantially matches FIG. 4.

[0036] In one embodiment, the present application provides crystalline forms of gepotidacin disclosed herein having a polymorph purity of at least 80%, at least 85%, at least 90%, or at least 95%. In one embodiment, the present application provides gepotidacin mesylate dihydrate having a polymorph purity of at least 80%, at least 85%, at least 90%, or at least 95%. In another embodiment, the present application provides gepotidacin anhydrate having a polymorph purity of at least 80%, at least 85%, at least 90%, or at least 95%. As used herein, the term "polymorph purity" refers to the weight percentage in a sample of a particular form, that form and other forms of gepotidacin. Polymorph purity is measurable by methods known in the art, such as XRPD.

[0037] When the XRPD pattern contains diffraction angles within ±0.2° 2θ of the specified value, the XRPD pattern should be understood to include the diffraction angle (expressed in ° 2θ) of the "about" value specified herein. Furthermore, it is well known and understood by those skilled in the art that the instruments, humidity, temperature, powder crystal orientation, and other parameters involved in obtaining the X-ray powder diffraction (XRPD) pattern can cause some variation in the appearance, intensity, and position of the lines in the diffraction pattern. The term "XRPD" is used interchangeably with the term "PXRD" herein.

[0038] An X-ray powder diffraction pattern "substantially consistent with" the X-ray powder diffraction patterns of Figures 1, 5, 9, 13, 20, 21, 22, or 23 provided herein is an XRPD pattern that those skilled in the art would consider to represent a compound having the same crystal form as the compound that gave rise to the XRPD pattern of Figures 1, 5, 9, 13, 20, 21, 22, or 23. That is, the XRPD pattern may be identical to the XRPD pattern of Figures 1, 5, 9, 13, 20, 21, 22, or 23, or may be somewhat different therefrom. Such an XRPD pattern need not necessarily show each of the lines of any one of the diffraction patterns presented herein, and / or may show slight changes in the appearance, intensity, or position shift of said lines resulting from differences in the conditions involved in obtaining the data. Those skilled in the art can determine whether a sample of a crystalline compound has the same form or a different form as the forms disclosed herein by comparing their XRPD patterns. For example, those skilled in the art can overlay the XRPD pattern of a sample containing gepotidacin with Figure 1 and, using the expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially consistent with the XRPD pattern of gepotidacin mesylate dihydrate (Form 1). If the XRPD pattern is substantially consistent with Figure 1, the sample form can be readily and accurately identified as having the same form as Form 1.

[0039] The Raman spectrum is within ±5.0 cm of the specified value -1If it contains peaks within, the Raman spectrum should be understood to include peaks at the "about" values specified herein (cm -1 as represented). Further, it is well known and understood by those skilled in the art that the instruments used, humidity, temperature, orientation of the powder crystals as a solid or in suspension, and other parameters involved in obtaining the Raman spectrum can cause some variation in the appearance, intensity, and position of the peaks in the spectrum. A Raman spectrum that is "substantially identical" to the Raman spectrum of FIGS. 2, 6, 10, or 14 provided herein is a Raman spectrum that those skilled in the art would consider to represent a compound having the same crystal form as the compound that gave rise to the Raman spectrum of FIGS. 2, 6, 10, or 14. That is, the Raman spectrum may be identical to the Raman spectrum of FIGS. 2, 6, 10, or 14, or may be somewhat different therefrom. Such a Raman spectrum need not necessarily show each of the peaks of any one of the spectra presented herein, and / or may show slight changes in the appearance, intensity, or position shift of said peaks resulting from differences in the conditions involved in obtaining the data. Those skilled in the art can determine whether a sample of a crystalline compound has the same form or a different form as the form disclosed herein by comparing their Raman spectra. For example, those skilled in the art can overlay the Raman spectrum of a sample of gepotidacin mesylate with FIG. 2 and, using the expertise and knowledge in the art, easily determine whether the Raman spectrum of the sample substantially coincides with the Raman spectrum of gepotidacin mesylate dihydrate (Form 1). If the Raman spectrum substantially coincides with FIG. 2, the sample form can be easily and accurately identified as having the same form as Form 1.

[0040] The "compound of the present invention" means its novel crystalline forms including (2R)-2-({4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (i.e., gepotidacin), as well as gepotidacin mesylate anhydride, gepotidacin mesylate monohydrate, gepotidacin mesylate dihydrate, gepotidacin anhydride, and combinations thereof.

[0041] Use, treatment methods, and pharmaceutical compositions The present invention includes a method of treating a bacterial infection in a human in need thereof, the method comprising administering to the human an effective amount of the compound of the present invention, or a composition comprising an effective amount of the compound of the present invention and any pharmaceutically acceptable carrier. The bacterial infection can be caused by a wide range of organisms including both Gram-negative and Gram-positive organisms, and the infections include, but are not limited to, upper and / or lower respiratory tract infections, skin and soft tissue infections, urinary tract infections, and gonorrhea. In some embodiments, the infection is a urinary tract infection. In some embodiments, the infection is gonorrhea. The methods of treating bacterial infections by using gepotidacin are disclosed in WO2008 / 128942 and WO2016 / 027249, which are hereby incorporated by reference in their entireties.

[0042] In some embodiments, the infection is a urinary tract infection caused by Escherichia coli (E. coli), Staphylococcus saprophyticus, Citrobacter koseri, or Klebsiella pneumoniae (K. pneumoniae). In some embodiments, the infection is a urinary tract infection caused by E. coli.

[0043] In another embodiment, the infection is gonorrhea caused by Neisseria gonorrhoeae.

[0044] As used herein, the term "treatment" refers to alleviating a specified condition, removing or reducing one or more symptoms of a condition, slowing or arresting the progression of a condition, and preventing or delaying the recurrence of a condition in a patient or subject previously afflicted with or diagnosed with the condition.

[0045] As used herein, the term "effective amount" means the amount of a drug or agent that elicits a biological or medical response in a tissue, system, animal, or human, as desired by, for example, a researcher or clinician. Unless otherwise specified, the amount of the drug or agent refers to the amount of the free base compound and not to the amount of the corresponding pharmaceutically acceptable salt.

[0046] The present invention also relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The present invention further relates to a method for preparing a pharmaceutical composition, which comprises mixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0047] "Pharmaceutically acceptable carrier" means any one or more compounds and / or compositions of sufficient purity and quality for use in the formulation of a compound of the present invention that, when suitably administered to humans, do not cause adverse reactions and are used as a vehicle for the active ingredient (i.e., the compound of the present invention). The carrier may include excipients, diluents, granulating and / or dispersing agents, surfactants and / or emulsifying agents, binders, preservatives, buffering agents, lubricants, and natural oils.

[0048] The present invention further includes a method for preparing a pharmaceutical composition, which includes mixing a compound of the present invention and one or more pharmaceutically acceptable carriers, and includes the composition resulting from such a method, and such a method includes conventional pharmaceutical formulation techniques. For example, the compound of the present invention may be micronized before formulation. The compound of the present invention may be prepared by grinding, micronizing or other particle size reduction methods known in the art. The pharmaceutical composition of the present invention may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company), the entire teachings of which are incorporated herein by reference.

[0049] In particular, the compound of the present invention, or the corresponding pharmaceutical composition or formulation used in the present invention, may be formulated for administration in any convenient manner for use in human or veterinary medicine by analogy from other antibacterial / anti-tuberculosis compounds.

[0050] The pharmaceutical composition used in the present invention may be formulated for administration by any route, including forms suitable for oral, topical or parenteral use, and may be used in mammals including humans.

[0051] The composition may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

[0052] In one embodiment, the compound of the present invention is in tablet or capsule form. In one embodiment, this is in tablet form. In one embodiment, the tablet is a 750 mg tablet.

[0053] The formulation may also contain suitable conventional carriers, such as cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may be present as about 1% to up to about 98% of the formulation. More generally, these form up to about 80% of the formulation.

[0054] The tablets and capsules for oral administration in the present invention may be in the form of unit dosage presentations and may contain conventional excipients such as binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate, talc, polyethylene glycol or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as dry products for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hardened edible fats, emulsifying agents such as lecithin, sorbitan monooleate, or gum arabic; non-aqueous media (which may include edible oils) such as almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

[0055] Suppositories contain conventional suppository bases such as cocoa butter or other glycerides.

[0056] For parenteral administration, the compound, and water utilize a preferred sterile medium to prepare a fluid unit dosage form. The compound may be suspended or dissolved in the medium depending on the medium and concentration used. In the preparation of solutions, the compound is dissolved in water for injection, filtered and sterilized, and then may be filled and sealed in suitable vials or ampoules.

[0057] Advantageously, agents such as local anesthetics, preservatives, and buffers may be dissolved in the medium. To enhance stability, the composition may be frozen after filling into the vial and water removed under vacuum. The dried lyophilized powder is then sealed in the vial and a vial of the accompanying water for injection may be provided for reconstituting the liquid prior to use. The parenteral suspension is prepared substantially in the same manner except that the compound is suspended in the medium instead of being dissolved and sterilization cannot be achieved by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in the sterile medium. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

[0058] Furthermore, the amount of the compound or pharmaceutical composition used in the present invention may vary depending on the patient and the mode of administration and may be any effective amount.

[0059] The composition may contain from 0.1% to, preferably, from 10% to 60% by weight of the active substance, depending on the method of administration. When the composition contains dosage units, each unit preferably contains from 50 to 1000 mg of the active ingredient.

[0060] The dosage utilized in the treatment of adults in the present invention is preferably in the range of 100 to 6000 mg per day, for example 1500 mg per day, depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to about 80 mg / kg per day. Preferably, the dosage is 5 to 80 mg / kg per day. In one embodiment, the dosage is 1500 mg twice a day (i.e., 3000 mg per day). In one embodiment, the dosage is 3000 mg twice a day (i.e., 6000 mg per day). In one embodiment, the two doses in a day are administered 6 to 12 hours apart.

[0061] Thus, in one embodiment, the present invention is a method for treating urinary tract infection (UTI), comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a human subject in need thereof, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered twice a day at 1500 mg, 6 to 12 hours apart.

[0062] In particular, the compositions of the present invention are presented as unit doses and are preferably administered 1 to 5 times a day, for example once or twice a day to achieve the desired effect. In one embodiment, gepotidacin or a pharmaceutically acceptable salt thereof is administered for any continuous period of 3, 4, 5, 6 or 7 days. In one embodiment, in any aspect of the present invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered for 5 consecutive days.

[0063] In another embodiment, the present invention is a method for treating an infection caused by Neisseria gonorrhoeae, comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a human subject in need thereof, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered twice at 3000 mg each, 6 to 12 hours apart. In another embodiment, the present invention is a method for treating an infection caused by Neisseria gonorrhoeae, comprising the step of administering gepotidacin or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a human subject in need thereof, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered twice at 3000 mg each, 10 to 12 hours apart.

[0064] Conventional methods of administration may be suitable for use in the present invention.

[0065] Depending on the treatment being performed, the compounds and / or compositions of the present invention may be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Preferably, the composition is suitable for oral administration.

[0066] The gepotidacin or pharmaceutically acceptable salt used in the present invention may be the only therapeutic agent in the composition of the present invention or may be in combination with other antibacterial agents. When the other antibacterial agent is a β-lactam, a β-lactamase inhibitor may also be utilized.

[0067] In certain embodiments, the present invention relates to a pharmaceutical composition comprising gepotidacin mesylate anhydrate, gepotidacin mesylate monohydrate, gepotidacin mesylate dihydrate, gepotidacin anhydrate, or a combination thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising gepotidacin, wherein at least 10% by weight of the gepotidacin is present as gepotidacin mesylate dihydrate. In another embodiment, the present invention relates to a pharmaceutical composition comprising gepotidacin, wherein at least 20% by weight, or at least 30% by weight, or at least 40% by weight, or at least 50% by weight, or at least 60% by weight, or at least 70% by weight, or at least 80% by weight, or at least 90% by weight of the gepotidacin is present as gepotidacin mesylate dihydrate. In another embodiment, the present invention relates to a pharmaceutical composition comprising gepotidacin, wherein at least 95% by weight, or at least 96% by weight, or at least 97% by weight, or at least 98% by weight, or at least 99% by weight of the gepotidacin is present as gepotidacin mesylate dihydrate.

[0068] In another embodiment, the present invention relates to a pharmaceutical composition comprising gepotidacin, wherein at least 10% by weight of the gepotidacin is present as gepotidacin anhydride. In another embodiment, the present invention relates to a pharmaceutical composition comprising gepotidacin, wherein at least 20% by weight, or at least 30% by weight, or at least 40% by weight, or at least 50% by weight, or at least 60% by weight, or at least 70% by weight, or at least 80% by weight, or at least 90% by weight of the gepotidacin is present as gepotidacin anhydride. In another embodiment, the present invention relates to a pharmaceutical composition comprising gepotidacin, wherein at least 95% by weight, or at least 96% by weight, or at least 97% by weight, or at least 98% by weight, or at least 99% by weight of the gepotidacin is present as gepotidacin anhydride.

[0069] In another embodiment, the present invention relates to a pharmaceutical composition comprising a mixture selected from the group consisting of gepotidacin mesylate anhydride, gepotidacin mesylate monohydrate, gepotidacin mesylate dihydrate, and gepotidacin anhydride. In one embodiment, the pharmaceutical composition comprises a mixture of gepotidacin mesylate dihydrate, gepotidacin mesylate anhydride, and gepotidacin mesylate monohydrate. In one embodiment, the pharmaceutical composition comprises a mixture of gepotidacin mesylate dihydrate and gepotidacin mesylate anhydride. In one embodiment, the pharmaceutical composition comprises a mixture of gepotidacin mesylate dihydrate and gepotidacin anhydride.

[0070] In some embodiments, the present application relates to a pharmaceutical composition comprising gepotidacin mesylate dihydrate that is substantially free of gepotidacin mesylate anhydride. In some embodiments, the present application relates to a pharmaceutical composition comprising gepotidacin mesylate dihydrate that is substantially free of gepotidacin mesylate anhydride and gepotidacin mesylate monohydrate. As used herein, the term "substantially free of" means less than about 10% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, or less than about 1% by weight compared to the total weight of the gepotidacin form.

[0071] The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention in any way.

Example

[0072] Experiment The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but rather are intended to provide guidance to those skilled in the art for preparing and using the compounds, compositions, and methods of the present invention. Specific embodiments of the present invention are described, but those skilled in the art will understand that various changes and modifications may be made without departing from the spirit and scope of the present invention. Unless otherwise specified, reagents are commercially available or prepared according to procedures in the literature.

[0073] [Example 1] Gepotidacin mesylate dihydrate (Form 1) [Example 1a] - Preparation Method 1 Acetone (5 ml) was added to gepotidacin (294.14 mg). Methanesulfonic acid (3 M aqueous solution, 1 equivalent) was added to the slurry over a period of 60 minutes. The slurry was heated to 50 °C for 3 hours, slowly cooled to 20 °C, stirred at 20 °C for 5 hours, and further cooled to 5 °C. The slurry was stirred at 5 °C overnight. The crystalline solid was filtered under vacuum, washed with acetone, and dried in a vacuum oven at 60 °C to obtain crystalline gepotidacin mesylate dihydrate (Form 1) in 72.9% yield.

[0074] [Example 1b] - Preparation Method 2 Gepotidacin (32.00 kg) and methanesulfonic acid (7.00 kg, 1.02 eq) were heated to 74 - 80 °C in 304 L of 2 - propanol and 16.1 kg of water. The solution was filtered and placed in a crystallization vessel and cooled to 59 - 63 °C. Form 1 dihydrate (0.318 kg) suspended in 5% v / v aqueous 2 - propanol (1.194 kg of 2 - propanol and 0.080 L of water) was added and the mixture was aged at 58 - 64 °C for 2 hours. The mixture was cooled to 15 - 25 °C and the resulting slurry was wet - milled. The slurry was heated to 55 - 61 °C and cooled to 15 - 25 °C. Gepotidacin mesylate dihydrate was isolated by filtration, washed twice with 5% v / v aqueous 2 - propanol (2 × 106 L of 2 - propanol and 2 × 5.6 kg of water), and dried under vacuum at about 40 °C to obtain gepotidacin mesylate dihydrate (Form 1) (38.505 kg) as a crystalline solid.

[0075] [Example 1c] - XRPD The X - ray powder diffraction (XRPD) pattern of gepotidacin mesylate dihydrate (Form 1) is shown in Figure 1, and a summary of the diffraction angle and d - spacing is shown in Table 1 below. The XRPD analysis was performed on a PANalytical X'Pert Pro diffractometer on a Si zero - background wafer. The acquisition conditions included Cu K α line, generator voltage 45 kV, generator current: 40 mA, and step size 0.03° 2θ.

[0076] [Table 1] TIFF0007682923000004.tif91159

[0077] The XRPD pattern of another sample of gepotidacin mesylate dihydrate (Form 1) is shown in Figure 20 (see Table 2). The XRPD analysis was performed on a PANalytical Empyrean diffractometer on a Si zero - background wafer. The acquisition conditions included Cu K α line, generator voltage 45 kV, generator current: 40 mA, and step size 0.03° 2θ.

[0078]

Table 2

[0079] [Example 1d] - Raman Spectrum The Raman spectrum of gepotidacin mesylate dihydrate (Form 1) was recorded at a resolution of 4 cm−1 by excitation from an Nd:YVO4 laser (λ = 1064 nm) on a Nicolet NXR9650 or Thermo Electron NXR 960 spectrometer. The Raman spectrum of gepotidacin mesylate dihydrate (Form 1) is shown in Figure 2, and the major peaks are observed at 455, 492, 558, 525, 590, 628, 667, 752, 775, 823, 940, 993, 1037, 1109, 1154, 1216, 1269, 1306, 1346, 1392, 1424, 1472, 1518, 1584, 1637, 1676, 2929, 3005 and 3046 cm−1. -1 -1

[0080] [Example 1e] - DSC The DSC of gepotidacin mesylate dihydrate (Form 1) was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a cooling system with a refrigeration function under a purge of 40 mL / min N2. In a crimped Al pan, a DSC thermogram of the sample was obtained at 15 °C / min. The DSC thermogram of Form 1 exhibits a broad endotherm, followed by a sharp endotherm at an onset temperature of about 129 °C, and then an endotherm at an onset temperature of about 195 °C (Figure 3). Those skilled in the art will recognize that the onset temperature of the endotherm may vary depending on the experimental conditions. 2

[0081] [Example 1f] - TGA The thermogravimetric analysis (TGA) thermogram of gepotidacin mesylate dihydrate (Form 1) was obtained using a TA Instruments Q50 thermogravimetric analyzer under a purge of 60 mL / min N2. 2 ​​​It was recorded at a flow-down and heating rate of 10 °C / min. The TGA thermogram of gepotidacin mesylate dihydrate (Form 1) exhibits a loss of approximately 6% (2.0 eq) at 30 - 130 °C (Figure 4).

[0082] [Example 1g] - Single Crystal Structure Single crystals of gepotidacin mesylate dihydrate were prepared by slow cooling from an aqueous / 2-propanol solution of gepotidacin mesylate.

[0083] Single crystal data were collected on a Bruker D8 Venture system using an Incoatec microfocus 3.0 CuKα Source. Data collection and unit cell indexing were carried out with the APEX3 v2017.3-0 suite (Bruker AXS Inc., 2017), and the processing of the measured intensity data was performed using the SAINT V8.38A software package (Bruker AXS Inc., 2017). The structure was solved by the direct method using the SHELXT-2018 / 2 software package (Sheldrick, 2018). The derived atomic parameters (coordinates and temperature factors) were refined by full-matrix least-squares methods with SHELXL-2018 / 3 (Sheldrick, 2018). Hydrogen atoms were introduced at idealized positions refined freely, except for the positions at heteroatoms.

[0084] Single crystal X-ray data were measured at low temperature (-123 °C). The single crystal has the following unit cell parameters: a = 6.9255(5) Å, b = 15.4500(12) Å, c = 25.7918(19) Å, α = β = γ = 90°, V = 2759.7(4) Å 3 , Z' = 1, space group P2 1 2 1 2 1 , molecules / unit cell 4, density (calculated) 1.398 g / cm 3 , where Z' is the number of molecules per asymmetric unit, and was confirmed as a mesylate dihydrate structure having.

[0085] Figure 17 compares the calculated and experimental XRPD patterns for gepotidacin mesylate dihydrate and shows good agreement at the peak 2θ values.

[0086] [Example 1h] - Solubility The solubility of gepotidacin mesylate dihydrate (Form 1) was determined at ambient room temperature (20 - 25 °C) in simulated gastric fluid pH 1.6 (SGF), fasted-state simulated intestinal fluid pH 6.5 (FaSSIF), and fed-state simulated intestinal fluid pH 6.5 (FeSSIF). See Table 3 below.

[0087] [Table 3]

[0088] [Example 2] Gepotidacin mesylate anhydrate (Form 2) [Example 2a] - Preparation Gepotidacin mesylate dihydrate (Form 1) (894 mg) was suspended in isopropyl alcohol (IPA) (5.4 ml) and heated to 61 °C. The resulting solid was analyzed in-situ by Raman and as a wet slurry by XRPD.

[0089] In another preparation, one spatula tip (<20 mg) of gepotidacin mesylate dihydrate (Form) 1 was suspended in IPA (<1.5 ml). The suspension was heated using a heat gun to dissolve most of the solid and then left to cool slowly to room temperature. The resulting crystals were filtered and analyzed by DSC, TGA, and XRPD. Note that this form is unstable under ambient conditions and thus the analysis obtained may not be for a phase-pure anhydrate sample.

[0090] [Example 2b] - XRPD It is wet with the solvent, and the X-ray powder diffraction (XRPD) pattern of gepotidacin mesylate anhydrate (Form 2) is shown in Figure 5, and a summary of the diffraction angle and d-spacing is shown in Table 4 below. The XRPD analysis was performed on a PANalytical Empyrean diffractometer on a Si zero-background wafer. The acquisition conditions included Cu K α line, generator voltage 45 kV, generator current: 40 mA, and step size 0.03° 2θ.

[0091]

Table 4

[0092] The XRPD pattern of another sample of gepotidacin mesylate anhydrate (Form 2) is shown in Figure 21 (see Table 5). The XRPD analysis was performed on a PANalytical X'Pert Pro diffractometer on a Si zero-background wafer. The acquisition conditions included Cu K α line, generator voltage 45 kV, generator current: 40 mA, and step size 0.02° 2θ.

[0093]

Table 5

[0094] [Example 2c] - Raman Spectrum The Raman spectrum of gepotidacin mesylate anhydrate (Form 2) was collected in-situ in an IPA suspension using a Kaiser Raman RXN-4 equipped with an IO1 / 4 inch S-NIR probe with a 15-second exposure time and 1 accumulation. The excitation was from a λ = 785 nm laser. The Raman spectrum of the authentic substance suspended in IPA is shown in Figure 6, and the main peaks are 418, 463, 587, 631, 670, 753, 819, 953, 1042, 1105, 1150, 1260, 1280, 1297, 1345, 1453, 1517, 1578, 1603, 1642 cm-1 is observed.

[0095] [Example 2d] - DSC The DSC of gepotidacin mesylate anhydride (Form 2) was carried out using a TA Instruments Q200 differential scanning calorimeter equipped with an autosampler and a cooling system with a refrigerator function under a purge of 50 mL / min N. 2 In a crimped Al pan, a DSC thermogram of the sample was obtained at 10 °C / min. The DSC thermogram of Form 2 exhibits an endotherm at an onset temperature of approximately 201 °C (Figure 7). Those skilled in the art will recognize that the onset temperature of the endotherm can vary depending on the experimental conditions.

[0096] [Example 2e] - TGA The thermogravimetric analysis (TGA) thermogram of gepotidacin mesylate anhydride (Form 2) was recorded with a TA Instruments Q5000 thermogravimetric analyzer at a flow rate of 25 mL / min N 2 and a heating rate of 10 °C / min. The TGA thermogram of the anhydride exhibits a weight loss of approximately 2% between 25 and 200 °C (Figure 8).

[0097] Gepotidacin mesylate anhydride (Form 2) was shown to convert to gepotidacin mesylate dihydrate (Form 1) after 1 hour at ambient conditions. The DVS of gepotidacin mesylate anhydride shows a decisive RH step in the first adsorption cycle at 60% RH with a water uptake of 4.8%, indicating conversion to gepotidacin mesylate dihydrate (Form 1).

[0098] [Example 2f] - Single Crystal Structure Single crystals of gepotidacin mesylate anhydride were prepared by slow cooling from a 2-propanol solution.

[0099] Single-crystal data were collected on a Bruker D8 Venture system using an Incoatec microfocus 3.0 CuKα Source. Data collection and unit cell indexing were carried out with the APEX3 v2017.3-0 suite (Bruker AXS Inc., 2017), and the processing of the measured intensity data was performed using the SAINT V8.38A (Bruker AXS Inc., 2017) software package. The structure was solved by direct methods using the SHELXT-2018 / 2 (Sheldrick, 2018) software package. The derived atomic parameters (coordinates and temperature factors) were refined by full-matrix least-squares methods with SHELXL-2018 / 3 (Sheldrick, 2018). Hydrogen atoms were introduced at idealized positions refined freely, except for the positions of heteroatoms.

[0100] Single-crystal X-ray data were measured at low temperature (-123 °C). The single crystal had the following unit cell parameters: a = 12.3921(7) Å, b = 7.0262(4) Å, c = 14.6536(9) Å, α = γ = 90°, β = 95.0077(13)°, V = 1271.01(13) Å 3 , Z' = 1, space group P2 1 , drug molecule / unit cell 2, density (calculated) 1.423 g / cm 3 , where Z' is the number of drug molecules per asymmetric unit, and was confirmed as the mesylate anhydrate structure having

[0101] Figure 18 compares the calculated and experimental XRPD patterns for gepotidacin mesylate anhydrate and shows good agreement at the peak 2θ values.

[0102] [Example 3] Gepotidacin mesylate monohydrate (Form 3) [Example 3a] - Preparation Gepotidacin mesylate dihydrate (Form 1) (900 mg) was suspended in IPA (5.4 ml) and heated to 61 °C. Water (0.17 ml) was added. The resulting solid was slurried overnight and then analyzed in-situ by Raman. The suspension was filtered and the crystalline solid was analyzed by XRPD, DSC and TGA.

[0103] [Example 3b] - XPRD The X-ray powder diffraction (XRPD) pattern of gepotidacin mesylate monohydrate is shown in Figure 9, and a summary of the diffraction angle and d-spacing is shown in Table 6 below. The XRPD analysis was performed on a PANalytical Empyrean diffractometer on a Si zero-background wafer. The acquisition conditions included Cu Kα radiation, generator voltage 45 kV, generator current: 40 mA, and step size 0.03° 2θ.

[0104] [Table 6]

[0105] The XRPD pattern of another sample of gepotidacin mesylate monohydrate is shown in Figure 22 (see Table 7). The XRPD analysis was performed on a PANalytical X'Pert Pro diffractometer on a Si zero-background wafer. The acquisition conditions included Cu K α radiation, generator voltage 45 kV, generator current: 40 mA, and step size 0.02° 2θ.

[0106] [Table 7] TIFF0007682923000014.tif182160

[0107] [Example 3c] - Raman Spectrum The Raman spectrum of gepotidacin mesylate monohydrate was recorded in-situ in an IPA / water suspension using a Kaiser Raman RXN-4 equipped with an IO1 / 4 inch S-NIR probe, with a 15-second exposure time and 1 accumulation. The excitation was from a λ=785 nm laser. The Raman spectrum of the authentic substance suspended in IPA is shown in Figure 10, and the major peaks were observed at 418, 449, 586, 627, 668, 753, 778, 819, 953, 1044, 1109, 1148, 1211, 1272, 1292, 1346, 1386, 1453, 1516, 1576, 1602, 1649 and 1686 cm -1 -1.

[0108] [Example 3d] - DSC The DSC of gepotidacin mesylate monohydrate was performed using a TA Instruments Q200 differential scanning calorimeter equipped with an autosampler and a cooling system with refrigeration function under a purge of 50 mL / min N 2 In a crimped Al pan, a DSC thermogram of the sample was obtained at a rate of 10 °C / min. The DSC thermogram of gepotidacin mesylate monohydrate exhibits a broad endotherm from about 50 to 130 °C, followed by an endotherm with an onset temperature of about 202 °C (Figure 11). Those skilled in the art will recognize that the onset temperature of the endotherm may vary depending on the experimental conditions.

[0109] [Example 3e] - TGA The thermogravimetric analysis (TGA) thermogram of gepotidacin mesylate monohydrate was recorded using a TA Instruments Q5000 thermogravimetric analyzer under a flow of 25 mL / min N 2 and a heating rate of 10 °C / min. The TGA thermogram of gepotidacin mesylate monohydrate exhibits a loss of about 3.1% (1.0 eq) at 55 - 80 °C (Figure 12).

[0110] [Example 4] Gepotidacin anhydride [Example 4a] - Preparation Method 1 Gepotidacin (52 g) and 1-propanol (440 mL) were heated to 90 °C. 40 mL of 1-propanol was added to the clear solution, and the combined contents were reheated to 90 °C. The clear solution was cooled to 76 °C and stirred for 1 hour. The slurry was cooled to 0 °C and stirred overnight. The slurry was filtered, washed with cooled 1-propanol, and dried under vacuum at 50 °C for approximately 6 hours to obtain gepotidacin anhydrate as a crystalline solid (47.8 g).

[0111] [Example 4b] - Preparation Method 2 The preparation of gepotidacin anhydrate was carried out on a scale according to the following steps: n-Propanol (12 volumes) was added to gepotidacin (1.0 equivalent), and the mixture was heated to 95 ± 3 °C to achieve complete dissolution. The mass was filtered at 95 ± 3 °C, and the filter was washed with n-propanol (0.1 volume). The filtrate was collected and reheated to 95 ± 3 °C to ensure complete dissolution. The mass was cooled to 77 ± 2 °C. A seed slurry (1.0% w / w suspended in 2.5 volumes of n-propanol) was added, and the mixture was stirred at 77 ± 2 °C for at least 1 hour. The mass of the slurry was further cooled to 0 ± 2 °C and stirred for 1 hour. The substance was filtered, and the cake was washed with n-propanol (2 volumes). The substance was dried under vacuum at 50 ± 2 °C.

[0112] [Example 4c] - XRPD The X-ray powder diffraction (XRPD) pattern of gepotidacin anhydrate is shown in Figure 13, and a summary of the diffraction angle and d-spacing is shown in Table 8 below. The XRPD analysis was performed on a PANalytical X'Pert Pro diffractometer on a Si zero-background wafer. The acquisition conditions included Cu K α line, generator voltage 45 kV, generator current: 40 mA, and step size 0.02° 2θ.

[0113]

Table 8

[0114] The XRPD pattern of another sample of gepotidacin anhydride is shown in Figure 23. The XRPD analysis was performed on a Si zero-background wafer in a PANalytical X'Pert Pro diffractometer. The acquisition conditions included Cu K α line, generator voltage 45 kV, generator current: 40 mA, and step size 0.02° 2θ.

[0115] [Table 9] TIFF0007682923000017.tif115159

[0116] [Example 4d] - Raman Spectrum The Raman spectrum of gepotidacin anhydride was recorded at a resolution of 4 cm with excitation from a Nd:YVO4 laser (λ = 1064 nm) in a Nicolet NXR9650 or Thermo Electron NXR 960 spectrometer. The Raman spectrum of this substance is shown in Figure 14, and the main peaks are observed at 453, 471, 586, 630, 656, 748, 825, 985, 1099, 1143, 1289, 1344, 1391, 1429, 1476, 1516, 1572, 1612, 1647, 1687, 2927, and 3051 cm -1 -1

[0117] [Example 4e] - DSC The DSC of gepotidacin anhydride was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a cooling system with a refrigeration function under a purge of 40 mL / min N 2 The DSC thermogram of the sample was obtained at 10 °C / min in a crimped Al pan. The DSC thermogram of gepotidacin anhydride exhibits a single endotherm with an onset temperature of approximately 196 °C (Figure 15). Those skilled in the art will recognize that the onset temperature of the endotherm may vary depending on the experimental conditions.

[0118] [Example 4f] - TGA ​​The thermogravimetric analysis (TGA) thermogram of gepotidacin anhydride was recorded with a TA Instruments Q50 thermogravimetric analyzer under a nitrogen flow of 25 mL / min and a heating rate of 10 °C / min. The TGA thermogram of the anhydride exhibits a loss of approximately 0.25% from 25 to 200 °C (Figure 16). 2 The TGA thermogram of the anhydride exhibits a loss of approximately 0.25% from 25 to 200 °C (Figure 16).

[0119] [Example 4g] - Single Crystal Structure Single crystals of gepotidacin anhydride were prepared by slow cooling from a 1-propanol solution with seeding.

[0120] Single crystal data were collected on an Oxford Diffraction Xcalibur A Nova system using a Nova X-ray CuKα Source. Data collection and unit cell indexing were carried out with the CrysAlisPro 1.171.37.34i suite (Agilent Technologies, 2014), and the processing of the measured intensity data was also performed using the CrysAlisPro 1.171.37.34i (Agilent Technologies, 2014) software package. The structure was elucidated by the direct method using the SHELXT-2018 / 2 (Sheldrick, 2018) software package. The derived atomic parameters (coordinates and temperature factors) were refined by full-matrix least-squares methods with SHELXL-2018 / 3 (Sheldrick, 2018). Hydrogen atoms were introduced at idealized positions refined freely, except for the positions at heteroatoms.

[0121] Single crystal X-ray data were measured at low temperature (-123 °C). The single crystal has the following unit cell parameters: a = 8.44022(16) Å, b = 6.42442(12) Å, c = 20.2774(5) Å, α = γ = 90°, β = 96.778(2)°, V = 1091.83(4) Å 3 , Z' = 1, space group P2 1 , drug molecules / unit cell 2, density (calculated) 1.364 g / cm 3 , Here, Z' is the number of drug molecules per asymmetric unit. was confirmed as the free base anhydrate structure having

[0122] Figure 19 compares the calculated and experimental XRPD patterns for gepotidacin anhydrate and shows good agreement in the peak 2θ values.

[0123] Gepotidacin anhydrate exhibits low to moderate solubility (<20 mg / mL) in common solvents and water, except for dichloromethane and trifluoroethanol (>100 mg / mL).

[0124] Crystal form screening of gepotidacin free base also resulted in hydrates and other solvates. The relative thermodynamic stabilities of crystalline anhydrous gepotidacin and other forms were studied. At 40 °C, gepotidacin anhydrate is more stable than the hydrate up to at least a w = 0.5. At 23 °C, gepotidacin anhydrate is more stable at a w of 0 to 0.8.

[0125] [Example 5] Preparation of Gepotidacin Mesylate Monoisopropyl Alcohol Solvate Dihydrate Gepotidacin mesylate monoisopropyl alcohol solvate dihydrate can be prepared by dissolving Form 1 in 3% Aq v / v IPA using a heat gun and then placing the saturated solution directly in a cardice bath. Gepotidacin mesylate monoisopropyl alcohol solvate dihydrate gradually converts to Form 1 in suspension and upon isolation. Gepotidacin mesylate monoisopropyl alcohol solvate dihydrate can be formed by this method in 5% aqueous IPA but converts to Form 1 within 3 hours at 20 °C.

[0126] [Example 6] Others [Example 6a] - Polymorphs and Water Activity Forms 1, 2, 3, and the mesylate IPA solvate dihydrate can be formed in a water / IPA mixture by varying the order of addition of the aqueous composition and / or solvent, e.g., by adding water to the compound in IPA or adding as a mixture. Various forms were observed within the following water content boundaries (quoted, w / w water content in IPA) estimated using solubility and KF data (see also Figures 24A and 24B): 20 - 25 °C: Form 2 <1.147%> IPA / water solvate <2.169%> Form 1, 61 °C: Form 2 <2.694%> Form 3 <4.643%> Form 1.

[0127] At room temperature, the solubility of Form 1 is lower than that of the other polymorphs throughout the wide range of water contents, suggesting that this is the more stable form.

[0128] At 61 °C, it was observed that Form 3 converts to Form 1 at a water content of 5.2% w / w, but not at 4.2% w / w water content (no seed crystal added). The estimated phase boundary is 4.6% w / w water content, based on the trend line (log scale) generated from the water content vs. concentration data.

[0129] The crystallization method to produce Form 1 is in 5% v / v aqueous IPA, which is equivalent to 6.25% w / w water. Thus, this method is carried out at a composition favorable for the thermodynamic stability of Form 1.

[0130] [Example 6b] - Amorphous Solid Amorphous gepotidacin mesylate can be produced by lyophilization. Form 1 (150 mg) was dissolved in MeCN / water (80 / 20 v / v, 1 mL). Clear filtration was carried out and the filtrate was added to a 20 mL vial. The solution was frozen under liquid nitrogen and lyophilized for 4 hours. The substance was determined to be amorphous by PXRD but began to convert to Form 1 unless stored in a sealed vial with a desiccant.

[0131] The amorphous substance was also prepared by freeze-drying an aqueous solution of t-BuOH, exhibited a glass transition temperature of 63.9 °C, and was physically stable for at least 3 days under ambient conditions.

[0132] [Example 6c] - Comparison of mesylate and HCl salt Gepotidacin HCl salt was prepared as shown in Example 39 of WO2008 / 128942. Gepotidacin mesylate dihydrate exhibits advantages in handling compared to gepotidacin HCl. The water adsorption / desorption isotherms of gepotidacin mesylate dihydrate and gepotidacin HCl were obtained over a range of relative humidity from 5 to 90%. The gepotidacin mesylate dihydrate sample incorporated less than 2% water, while the gepotidacin HCl sample incorporated approximately 10% water.

[0133] It should be understood that the present invention is not limited to the embodiments or forms exemplified above, and that rights are reserved with respect to all modifications within the scope of the exemplified embodiments and the following claims.

[0134] All various references to academic journals, patents, and other publications cited herein are incorporated by reference into this specification as if fully set forth, and include the prior art. The following is one of the embodiments of the present invention. (1) A crystalline form of gepotidacin selected from the group consisting of gepotidacin mesylate anhydrate, gepotidacin mesylate monohydrate, gepotidacin mesylate dihydrate, and gepotidacin anhydrate. (2) The crystalline form according to (1), which is gepotidacin mesylate dihydrate. (3) When measured using Cu K α A crystalline form of gepotidacin mesylate dihydrate characterized by an X-ray powder diffraction (XRPD) pattern including at least three or at least four diffraction angles selected from the group consisting of about 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7° 2θ, according to (1). (4) The crystalline form according to (1), which is gepotidacin mesylate dihydrate characterized by an X-ray powder diffraction (XRPD) pattern substantially identical to FIG. 1. (5) The following unit cell parameters: a = 6.9255(5) Å, b = 15.4500(12) Å, c = 25.7918(19) Å, α = β = γ = 90°, V = 2759.7(4) Å 3 、Z'=1、 Space group P2 1 2 1 2 1 、 Molecules / unit cell 4, Density (calculated) 1.398 g / cm3 、 Here, Z' is the number of molecules per asymmetric unit, A crystalline form of gepotidacin mesylate dihydrate characterized by, according to (1). (6) The crystalline form according to (1), which is gepotidacin mesylate anhydrate. (7) When measured using Cu K α A crystalline form of gepotidacin mesylate anhydrate characterized by an X-ray powder diffraction (XRPD) pattern including at least three or at least four diffraction angles selected from the group consisting of about 7.1, 9.7, 12.1, 14.2, 15.2, 17.3, and 20.2° 2θ, according to (1). (8) The crystalline form according to (1), which is gepotidacin mesylate anhydrate characterized by an X-ray powder diffraction (XRPD) pattern substantially identical to FIG. 2. (9) The following unit cell parameters: a = 12.3921(7) Å, b = 7.0262(4) Å, c = 14.6536(9) Å, α = γ = 90°, β = 95.0077(13)°, V = 1271.01(13) Å 3 、Z'=1 Space group P2 1 、 Molecules / unit cell 2, Density (calculated value): 1.423 g / cm 3 、 where Z' is the number of molecules per asymmetric unit, The crystalline form according to (1), which is gepotidacin mesylate anhydrate characterized by (10) The crystalline form according to (1), which is gepotidacin mesylate monohydrate. (11) Cu K α The crystalline form according to (1), which is gepotidacin mesylate monohydrate characterized by an X-ray powder diffraction (XRPD) pattern including at least 3 or at least 4 diffraction angles selected from the group consisting of about 5.6, 7.1, 8.8, 11.2, 13.0, 13.7, 20.1, 21.6, and 23.3° 2θ when measured using the line. (12) The crystalline form according to (1), which is gepotidacin mesylate monohydrate characterized by an X-ray powder diffraction (XRPD) pattern substantially consistent with Figure 3. (13) Cu K α The crystalline form according to (1), which is gepotidacin anhydrate characterized by an X-ray powder diffraction (XRPD) pattern including at least 3 or at least 4 diffraction angles selected from the group consisting of about 8.8, 10.8, 11.7, 12.8, 13.2, 14.4, 16.3, 19.9, 20.8, and 25.0° 2θ when measured using the line. (14) The crystalline form according to (1), which is gepotidacin anhydrate. (15) The crystalline form according to (1), which is gepotidacin anhydrate characterized by an X-ray powder diffraction (XRPD) pattern substantially consistent with Figure 4. (16) The following unit cell parameters: a = 8.44022(16) Å, b = 6.42442(12) Å, c = 20.2774(5) Å, α = γ = 90°, β = 96.778(2)°, V = 1091.83(4) Å 3 、Z'=1 Space group P2 1 、 Molecules / unit cell 2, Density (calculated value): 1.364 g / cm 3 、 where Z' is the number of molecules per asymmetric unit, The crystalline form according to (1), which is gepotidacin anhydrate characterized by (17) The crystalline form according to any one of (1) to (16), having a polymorph purity of at least 80%, at least 85%, at least 90%, or at least 95%. (18) A pharmaceutical composition comprising the crystalline form according to any one of (1) to (17) and a pharmaceutically acceptable carrier. (19) The pharmaceutical composition according to (18), which is for oral administration. (20) The pharmaceutical composition according to (19), which is a tablet or a capsule. (21) A method for preparing a pharmaceutical composition comprising gepotidacin, the method comprising the step of mixing a crystalline form according to any one of (1) to (17) and a pharmaceutically acceptable carrier. (22) A method for treating a bacterial infection in a human in need thereof, the method comprising the step of administering to the human an effective amount of a crystalline form according to any one of (1) to (17). (23) The method according to (22), wherein the bacterial infection is a simple urinary tract infection or an infection caused by Neisseria gonorrhoeae. (24) A crystalline form according to any one of (1) to (17) for use in therapy. (25) A crystalline form according to any one of (1) to (17) for use in the treatment of a simple urinary tract infection or an infection caused by Neisseria gonorrhoeae. (26) A method for preparing mesylate gepotidacin dihydrate, the method comprising the step of crystallizing mesylate gepotidacin in a solvent mixture of water and an organic solvent. (27) The method according to (26), wherein the organic solvent is 2-propanol. (28) Use of a crystalline form according to any one of (1) to (17) in the manufacture of a medicament for the treatment of a simple urinary tract infection or an infection caused by Neisseria gonorrhoeae.

Claims

1. A crystalline form of gepotidacin mesylate, which is gepotidacin mesylate dihydrate, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three or at least four diffraction angles selected from the group consisting of 9.0, 11.5, 13.4, 14.3, 14.9, 15.5, 17.6, 18.6, and 20.7° 2θ ± 0.2° 2θ when measured using Cu Kα radiation.

2. The crystalline form according to claim 1, which is gepotidacin mesylate dihydrate, characterized by an X-ray powder diffraction (XRPD) pattern that substantially coincides with the following Figure 1:

3. The crystalline form according to claim 1, which is gepotidacin mesylate dihydrate, characterized by the following unit cell parameters:

4. The following unit cell parameters: a = 6.9255(5) Å, b = 15.4500(12) Å, c = 25.7918(19) Å, α = β = γ = 90°, V = 2759.7(4) Å 3 , Z' = 1, Space group P2 1 2 1 2 1 , 4 molecules / unit cell, Density (calculated value) 1.398 g / cm 3 , where Z' is the number of molecules per asymmetric unit,

5. The crystalline form according to claim 1, which is gepotidacin mesylate dihydrate, characterized by the following unit cell parameters:

6. The crystalline form according to any one of claims 1 to 3, having a polymorph purity of at least 80%, at least 85%, at least 90%, or at least 95%.

7. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 5, which is for oral administration.

9. The pharmaceutical composition according to claim 6, which is in the form of tablets or capsules.

10. A method for preparing a pharmaceutical composition comprising gepotidacin, the method comprising the step of mixing the crystalline form according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition for use in the treatment of bacterial infections, the composition comprising an effective amount of the crystalline form according to any one of claims 1 to 4.

12. The pharmaceutical composition according to claim 11, wherein the bacterial infection is a simple urinary tract infection or an infection caused by Neisseria gonorrhoeae.

13. A pharmaceutical composition for use in therapy, the composition comprising the crystalline form according to any one of claims 1 to 4.

14. A method for preparing gepotidacin mesylate dihydrate, the method comprising the step of crystallizing gepotidacin mesylate in a solvent mixture of water and an organic solvent.

15. The method according to claim 14, wherein the organic solvent is 2-propanol.

16. Use of the crystalline form according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of uncomplicated urinary tract infections or infections caused by Neisseria gonorrhoeae.

15. Use of the crystalline form according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of bacterial infections.

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