WO2020161284A1 - Crystalline form of iclaprim mesylate - Google Patents

Crystalline form of iclaprim mesylate Download PDF

Info

Publication number
WO2020161284A1
WO2020161284A1 PCT/EP2020/053094 EP2020053094W WO2020161284A1 WO 2020161284 A1 WO2020161284 A1 WO 2020161284A1 EP 2020053094 W EP2020053094 W EP 2020053094W WO 2020161284 A1 WO2020161284 A1 WO 2020161284A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
iclaprim
mesylate
range
present
Prior art date
Application number
PCT/EP2020/053094
Other languages
French (fr)
Inventor
Sven Nerdinger
Marijan STEFINOVIC
Sandro NEUNER
Josef Spreitz
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2020161284A1 publication Critical patent/WO2020161284A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a crystalline form of iclaprim mesylate and a process for its preparation.
  • the invention also relates to a pharmaceutical composition comprising the crystalline form of iclaprim mesylate of the present invention, preferably in a predetermined and/or effective amount and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prophylaxis of bacterial infections caused by Gram positive bacteria.
  • Iclaprim is an antibiotic belonging to the class of diaminopyrimidines. It acts as a selective and potent inhibitor of bacterial dihydrofolate reductase (DHFR), a key enzyme in the bacterial folate synthesis pathway. Iclaprim is active against the clinically most relevant Gram-positive bacteria including resistant strains such as multidrug-resistant Staphylococcus aureus (MRSA). It is being studied for the treatment of various infections caused by Gram-positive bacteria including multidrug-resistant bacteria comprising skin and skin structure infections and nosocomial pneumonia.
  • MRSA multidrug-resistant Staphylococcus aureus
  • iclaprim can be designated as 5-[(2ft)-2-cyclopropyl-7,8- dimethoxy-2iT-chromen-5-ylmethyl]pyrimidine-2, 4-diamine or 5-[[(2//k)-2-cyclopropyl-7,8- dimethoxy-2iT-l-benzopyran-5-yl]methyl]pyrimidine-2, 4-diamine and is represented by the following chemical structure according to Formula (I)
  • Iclaprim is a racemate, and both enantiomers have been shown to be equipotent against various bacterial DHFR enzymes and to exhibit similar antimicrobial activity against a broad range of bacteria.
  • the (//(-enantiomer is represented by the chemical structure according to Formula (la) and the (//(-enantiomer is represented by the chemical structure according to Formula (lb) Formula (la) Formula (lb).
  • WO 1997/020839 Al describes in example 5 the preparation of iclaprim free base, which was obtained as white crystals after recrystallization from ethanol.
  • iclaprim mesylate having general properties such as a melting point range of 200-204 °C.
  • the application does not provide a concrete procedure for the production of iclaprim mesylate but refers to the synthesis described in US5,773,446, which is the US equivalent of above mentioned WO 1997/020839 Al .
  • a compound intended to be used for pharmaceutical purpose requires particular physicochemical properties, which ensure safe production and storage of the drug substance and the finished dosage form containing the drug substance. These properties are mainly determined by the crystal structure of the active pharmaceutical ingredient.
  • crystal structure of the active pharmaceutical ingredient For example, for the preparation of an oral solid dosage form it is important that a stable solid-state form of the drug substance is used, in order to ensure reliable safety and efficacy of the drug product over the whole shelf-life.
  • a crystalline form of the active pharmaceutical ingredient having a high melting point, high chemical stability and high thermodynamic stability is desirable.
  • iclaprim mesylate having general properties including i.a. a melting point in the range of 200-204 °C indicating that only one crystalline form iclaprim mesylate exists.
  • the present inventors now surprisingly found that iclaprim mesylate exists in more than one crystalline form i.e. exhibits polymorphism.
  • room temperature refers to a temperature in the range of from 20 to
  • the term“measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions.
  • standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature.
  • Standard conditions can mean a temperature of about 22°C.
  • standard conditions can additionally mean a measurement under 20-80% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% relative humidity.
  • the term“reflection” with regard to powder X-ray diffraction as used herein means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order.
  • Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material which lacks long-range order and only displays short-range order, thus resulting in broad scattering.
  • long-range order e.g.
  • the term“essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account.
  • a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably in the range of ⁇ 0.1° 2-Theta.
  • a reflection that usually appears at 4.0° 2-Theta for example can appear between 3.8° and 4.2° 2-Theta, preferably between 3.9 and 4.1° 2-Theta on most X-ray diffractometers under standard conditions.
  • relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
  • a typical precision of the wavenumber values is in the range of ⁇ 4 cm 1 , preferably in the range of ⁇ 2 cm 1 .
  • a peak at 1638 cm 1 for example can appear between 1634 and 1642 cm 1 , preferably between 1636 and 1640 cm 1 on most infrared spectrometers under standard conditions.
  • Peak intensities can be derived from according figures, but one skilled in the art will appreciate that differences in peak intensities due to degree of crystallinity, sample preparation, measurement method and other factors can also occur in infrared spectroscopy. Peak intensities should therefore be taken as qualitative measure only.
  • the crystalline form of iclaprim mesylate of the present invention may be referred to herein as being characterized by a powder X-ray diffractogram or an FTIR spectrum "as shown in" a figure.
  • a powder X-ray diffractogram or an FTIR spectrum as shown in a figure.
  • factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations, for example relating to the exact reflection and peak positions and their intensities.
  • a comparison of the graphical data in the figures herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
  • solid-state form refers to any crystalline and/or amorphous phase of a compound.
  • anhydrous form refers to a crystalline solid were no water is cooperated in or accommodated by the crystal structure.
  • Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.
  • an anhydrous form does not contain more than 2.0 w-%, preferably not more than 1.0 w-% of water, based on the weight of the crystalline form.
  • non-solvated when talking about a crystalline solid indicates that no organic solvent is cooperated in or accommodated by the crystal structure.
  • Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.
  • a non- solvated form does not contain more than 2.0 w-%, preferably not more than 1.0 w-%, and most preferably not more than 0.5 w-% of organic solvents, based on the weight of the crystalline form.
  • A“predetermined amount” as used herein with regard to the crystalline form of iclaprim mesylate of the present invention refers to the initial amount of the crystalline form of iclaprim mesylate used for the preparation of a pharmaceutical composition having a desired dosage strength of relugolix.
  • iclaprim mesylate of the present invention encompasses an amount of the crystalline form of iclapirm mesylate, which causes the desired therapeutic and/or prophylactic effect.
  • the term“about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
  • Figure 1 illustrates a representative PXRD of the crystalline form of iclaprim mesylate of the present invention.
  • the x-axis shows the scattering angle in °2-Theta
  • the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.
  • Figure 2 illustrates a representative FTIR spectrum of the crystalline form of iclaprim mesylate of the present invention.
  • the x-axis shows the wavenumbers in cm 1
  • the y-axis shows the relative intensity in percent transmittance.
  • Figure 3 illustrates a representative DSC curve of the crystalline form of iclaprim mesylate of the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.
  • Figure 4 illustrates a representative TGA curve of the crystalline form of iclaprim mesylate of the present invention.
  • the x-axis shows the temperature in degree Celsius (°C)
  • the y-axis shows the mass (loss) of the sample in weight percent (w-%).
  • the present invention relates to a crystalline form of iclaprim mesylate.
  • Iclaprim mesylate is characterized by the chemical structure according to Formula (II) Formula (II), wherein n is in the range of from 0.7 to 1.3, preferably in the range of from 0.8 to 1.2, more preferably in the range of from 0.9 to 1.1, even more preferably in the range of from 0.95 to 1.05 and most preferably n is about 1.0.
  • n is selected from the group consisting of about 0.7, 0.8, 0.9, 0.95, 1.0, 1.05, 1.1, 1.2 and 1.3.
  • the crystalline form of iclaprim mesylate of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them.
  • the crystalline form of iclaprim mesylate of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of:
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of (4.0 ⁇ 0.2)°, (10.2 ⁇ 0.2)°, (10.4 ⁇ 0.2)°, (14.0 ⁇ 0.2)°, (17.8 ⁇ 0.2)°, (20.5 ⁇ 0.2)°, (24.2 ⁇ 0.2)° (24.3 ⁇ 0.2)°, (24.9 ⁇ 0.2)° and (26.8 ⁇ 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of (4.0 ⁇ 0.1)°, (10.2 ⁇ 0.1)°, (10.4 ⁇ 0.1)°, (14.0 ⁇ 0.1)°, (17.8 ⁇ 0.1)°, (20.5 ⁇ 0.1)°, (24.2 ⁇ 0.1)° (24.3 ⁇ 0.1)°, (24.9 ⁇ 0.1)° and (26.8 ⁇ 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
  • the present invention also relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
  • the present invention also relates to a crystalline form of iclaprim mesylate, characterized by having an FTIR spectrum essentially the same as shown in Figure 2 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with a diamond ATR cell.
  • the present invention also relates to a crystalline form of iclaprim mesylate, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having an onset at a temperature of (221 ⁇ 5)°C, preferably of (221 ⁇ 3)°C, even more preferably of (221 ⁇ 2)°C and most preferably of (221 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the invention relates to a crystalline form of iclaprim mesylate, characterized by having a melting point onset temperature of (221 ⁇ 5)°C, preferably of (221 ⁇ 3)°C, even more preferably of (221 ⁇ 2)°C and most preferably of (221 ⁇ 1)°C, when measured with DSC at a heating rate of 10 K/min.
  • the present invention also relates to a crystalline form of iclaprim mesylate, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak maximum at a temperature of (222 ⁇ 5)°C, preferably of (222 ⁇ 3)°C, even more preferably of (222 ⁇ 2)°C and most preferably of (222 ⁇ 1)°C, when measured at a heating rate of 10 K/min.
  • the invention relates to a crystalline form of iclaprim mesylate, characterized by having a melting point peak temperature of (222 ⁇ 5)°C, preferably of (222 ⁇ 3)°C, even more preferably of (222 ⁇ 2)°C and most preferably of (222 ⁇ 1)°C, when measured with DSC at a heating rate of 10 K/min.
  • the invention relates to a crystalline form of iclaprim mesylate, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, with an enthalpy of (112 ⁇ 5) J/g, preferably of (112 ⁇ 3) J/g, even more preferably of (112 ⁇ 2) J/g and most preferably of (112 ⁇ 1) J/g, when measured at a heating rate of 10 K/min.
  • the present invention relates to a crystalline form of iclapirm mesylate, characterized by having a TGA curve showing a mass loss of not more than 1.0 w-%, preferably of not more than 0.9 w-%, more preferably of not more than 0.8 w-%, even more preferably of not more than 0.7 w-% or 0.6 w-% and most preferably of not more than 0.5 w-%, for example of not more than 0.4 w%, based on the weight of the crystalline form, when heated from 25 to 230 °C at a rate of 10 K/min.
  • the present invention relates to a crystalline form of iclaprim mesylate, characterized as being an anhydrous form.
  • the present invention relates to a crystalline form iclaprim mesylate, characterized as being a non-solvated form.
  • the inventors of the present invention have also found that iclapirm free base can be obtained in high chemical purity, when iclaprim free base is crystallized or recrystallized from acetonitrile.
  • the invention relates to a process for the purification of iclaprim free base comprising the steps of:
  • step (b) optionally, filtering the solution obtained in step (a);
  • step (d) separating at least a part of the crystals obtained in step (c) from the mother liquor;
  • step (e) drying the isolated crystals of step (d);
  • Iclaprim free base deployed in step a) can be prepared according to the procedures described in example 5 of WO 1997/020839 A1 or example 11 of WO 2005/014587 Al .
  • the solvent used in the dissolution step (a) comprises acetonitrile, preferably acetonitrile is the only solvent present.
  • the iclaprim concentration of the mixture in step (a) is in the range of from 2 - 10 g/L, preferably of from 5 - 8 g/L and most preferably of from 6 - 7 g/L.
  • the solution is preferably prepared by heating the mixture to a temperature above 60°C, preferably above 70°C, more preferably above 80°C e.g. to reflux temperature.
  • the solution is optionally filtered in order to remove any undissolved particles present.
  • Crystallization in step (c) is initiated by decreasing the temperature of the solution e.g. to room temperature.
  • the cooling rate is not critical, e.g. natural cooling can be applied.
  • iclaprim seed crystals can be added in order to initiate crystallization and/or promote crystal growth.
  • the amount of seed crystals employed may range from about 1 to 20 w-%, preferably from about 1 to 10 w-% and most preferably from about 1 to 5 w-%, based on the weight of applied iclaprim starting material.
  • the temperature may be further decreased e.g. to about 10 °C, 5°, 0°C, (-5)°C, (-10°), (-15)°C, (-20)°C or (-25)°C in order to improve the yield.
  • the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.
  • the isolated crystals are washed with acetonitrile.
  • the obtained crystals may then be dried. Drying may be performed at a temperature in the range of from about 20 to 80 °C, preferably in the range of from about 20 to 60 °C and most preferably in the range of from about 20 to 40 °C e.g. at room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably from about 6 to 18 hours. Drying may be performed at ambient pressure and/ or under reduced pressure.
  • drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less and most preferably of about 30 mbar or less, for example a vacuum of about 20 mbar or less such as about 1 mbar.
  • the thus obtained material can be used as starting material for the preparation of the crystalline form of iclaprim mesylate of the present invention.
  • the present invention relates to a process for the preparation of the crystalline form of icalprim mesylate of the present invention comprising:
  • step (b) optionally, filtering the solution obtained in step (a);
  • step (d) separating at least a part of the crystals obtained in step (c) from the mother liquor;
  • step (e) drying the isolated crystals of step (d);
  • the solvent used for the acid base reaction in step (a) comprises ethanol, preferably ethanol is the only solvent present.
  • the iclaprim concentration of the reaction mixture in step (a) is in the range of from 15 - 25 g/L, preferably of from 20 - 22 g/L.
  • the solution is preferably prepared by heating the mixture to a temperature above 60°C, preferably above 70°C, more preferably above 75°C e.g. to reflux temperature. The solution is optionally filtered in order to remove any undissolved particles present.
  • Crystallization in step (c) is initiated by decreasing the temperature of the solution e.g. to room temperature.
  • the cooling rate is not critical, e.g. natural cooling can be applied.
  • part of the solvent may be removed before the cooling step in order to increase the iclaprim mesylate concentration of the solution.
  • iclaprim mesylate seed crystals can optionally be added in order to initiate crystallization and/or promote crystal growth.
  • the amount of seed crystals employed may range from about 1 to 20 w-%, preferably from about 1 to 10 w-% and most preferably from about 1 to 5 w-%, based on the weight of applied iclaprim starting material.
  • the temperature may optionally be further decreased e.g. to about 10 °C, 5°, 0°C, (-5)°C, (-10°), (-15)°C, (-20)°C or (-25)°C in order to improve the yield.
  • the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.
  • the isolated crystals are washed with ethanol.
  • the obtained crystals may then be dried. Drying may be performed at a temperature in the range of from about 20 to 80 °C, preferably in the range of from about 20 to 60 °C and most preferably in the range of from about 20 to 40 °C e.g. at room temperature.
  • Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably from about 6 to 18 hours. Drying may be performed at ambient pressure and/ or under reduced pressure. Preferably, drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less and most preferably of about 30 mbar or less, for example a vacuum of about 20 mbar or less such as about 1 mbar.
  • the present invention relates to a composition comprising the crystalline form of iclaprim mesylate of the present invention as defined in any one of the embodiments described above, said composition being essentially free of any other solid form of iclaprim mesylate.
  • a composition comprising the crystalline form of iclapirm mesylate of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid form of iclaprim mesylate, based on the weight of the composition.
  • the any other solid form of iclaprim mesylate is the crystalline form mentioned in WO 2017/192744 Al, paragraph [0014] or amorphous.
  • the invention relates to a composition
  • a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the crystalline form of iclaprim mesylate as defined in any one of the embodiments described above, based on the total weight of the composition.
  • the remaining material may comprise other solid form(s) of iclaprim mesylate such as the crystalline form mentioned in WO 2017/192744 Al, paragraph [0014] or amorphous and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
  • the present invention relates to the use of the crystalline form of iclaprim mesylate of the present invention or the composition comprising the same as defined in any one of the embodiments described above for the preparation of a pharmaceutical composition.
  • the pharmaceutical composition may be intended for parenteral or oral administration.
  • compositions for parenteral use can be prepared starting from the crystalline form of iclaprim mesylate of the present invention, for example by a process comprising the step of dissolving the crystalline form of iclaprim mesylate of the present invention.
  • the preparation of stable aqueous compositions comprising iclaprim mesylate is described in detail in WO 2009/124586, the whole content of which is hereby incorporated by reference.
  • the present invention therefore also relates to a composition
  • a composition comprising iclaprim mesylate in a solution consisting essentially of a physiologically acceptable solvent and iclaprim mesylate, wherein the oxygen concentration in the solution is 0.8 ppm or less, and wherein the starting material for said composition is the crystalline form of iclaprim mesylate of the present invention.
  • Preferred physiologically acceptable solvents are water or ethanol or a water/ethanol mixture. When a water/ethanol mixture is used, ethanol is preferably comprised in a concentration range of from 5% to 45%, such as from 20% to 35%.
  • Sodium chloride can be comprised in the solution, for example in a concentration of from 0.1% to 3%.
  • the pH of the solution is preferably in a range of from 4.2 to 5.7, such as from 4.6 to 5.2.
  • concentration of iclaprim mesylate in the solution is preferably from 0.2% w/w to 8.0% w/w, such as from 0.5% w/w to 5.0% w/w, in particular from 0.7% w/w to 2.5% w/w.
  • the solution may further comprise a wetting agent, such as a wetting agent selected from N-methylpyrrolidone, polyvinylpyrrolidone, cyclodextrine, macrogol hydroxystearate and macrogol glycerol ricinoleate, particularly at a concentration of from 0% to 20%, such as from 0.1% to 10%, in particular of from 2% to 10%.
  • the pharmaceutical composition of the present invention intended for parenteral administration may be a sterile concentrate comprising iclaprim mesylate already in solution.
  • the concentrate may be further diluted before administration e.g. with normal saline, 5% dextrose or lactated ringers.
  • the pharmaceutical composition of the present invention intended for oral administration may be an oral solid dosage form, such as a tablet or a capsule. More preferably, the pharmaceutical composition of the present invention is a tablet e.g. a film-coated tablet.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form of iclaprim mesylate of the present invention or the composition comprising the same as defined in any one of the embodiments described above, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.
  • the at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is preferably selected from the group consisting of fillers/diluents, binders, disintegrants, lubricants, stabilizers, coating materials and combinations thereof. Preferably, all of these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention.
  • the present invention relates to a pharmaceutical composition as describe above, wherein the predetermined and/or effective amount of the crystalline form of iclaprim mesylate of the present invention is selected from the group consisting of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 229 mg, 230 mg and 240 mg.
  • the invention relates to a pharmaceutical composition as describe above, wherein the predetermined and/or effective amount of the crystalline form of iclaprim mesylate of the present invention is selected from the group consisting of 80 mg, 160 mg and 240 mg. Most preferably, the predetermined and/or effective amount of the crystalline form of iclaprim mesylate of the present invention is 80 mg or 160 mg.
  • the present invention relates to the crystalline form of iclaprim mesylate of the present invention, the composition comprising the same or the pharmaceutical composition comprising the same as defined in any one of the above described embodiments for use as a medicament.
  • the present invention relates to the crystalline form of iclaprim mesylate of the present invention, the composition comprising the same or the pharmaceutical composition comprising the same as defined in any one of the above described embodiments for use in the treatment and/or prophylaxis of bacterial infections caused by Gram-positive bacteria.
  • the bacterial infection is selected from complicated skin and skin structure infections and nosocomial pneumonia.
  • the present invention is directed to a method of treating and/or prophylactically preventing bacterial infections caused by Gram-positive bacteria.
  • the bacterial infection is selected from complicated skin and skin structure infections and nosocomial pneumonia.
  • Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions.
  • a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
  • the infrared spectrum was recorded on an MKII Golden GateTM Single Reflection Diamond ATR (attenuated total reflection) cell with a Bruker Tensor 27 FTIR spectrometer with 4 cm -1 resolution at ambient conditions.
  • IR infrared spectrum
  • a spatula tip of the sample was applied to the surface of the diamond in powder form. Then the sample was pressed onto the diamond with a sapphire anvil and the spectrum was recorded.
  • a spectrum of the clean diamond was used as background spectrum.
  • a typical precision of the wavenumber values is in the range of about ⁇ 4 cm -1 , preferably of about ⁇ 2 cm -1 .
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis was performed on a Mettler Toledo TGA/DSC 1 instrument. About 8.1 mg of the sample was heated in a 100 m ⁇ aluminium pan closed with an aluminium lid. The lid was automatically pierced at the beginning of the measurement. The samples was initially kept at 25°C for 2 1 ⁇ 2 minutes and then heated from room temperature to 250°C at a rate of 10°C/min. Nitrogen (purge rate 30 ml/min) was used as purge gas.
  • Example 1 Preparation of the crystalline form of iclaprim mesylate of the present invention Step 1: Recrystallization of iclaprim free base
  • Iclaprim free base 500 mg, 1.41 mmol, e.g. prepared according to example 11 of WO 2005/014587 Al
  • acetonitrile 75 mL
  • the resulting clear solution was slowly cooled to room temperature overnight and then kept at (- 20)°C to increase the yield.
  • the resulting white solid was collected by filtration and dried in high vacuum at room temperature.
  • Step 2 Salt formation and crystallization of iclaprim mesylate according to the present invention
  • Iclaprim free base (1.00 g, 2.82 mmol, obtained according to the procedure of step 1) was suspended in ethanol (35 mL) and heated to reflux. Heating was interrupted to add a solution of methanesulfonic acid (183 pL, 2.82 mmol) in ethanol (5 mL) in a drop-wise manner, then refluxing was resumed. Further 10 mL of ethanol were added to obtain a clear solution. The solution was then concentrated to a volume of about 45-47 mL and slowly let cool to room temperature, leading to the formation of columnar crystals. The crystals were collected by filtration and dried in high vacuum at room temperature overnight (yield: 900 mg).
  • Example 2 Solid-state characterization of the crystalline form of iclaprim mesylate of the present invention obtained according to Example 1
  • a representative diffractogram of the crystalline form of iclaprim mesylate of the present invention is displayed in Figure 1 herein.
  • the corresponding reflection list is provided in Table 1 below.
  • Table 1 PXRD reflections of the crystalline form of iclaprim mesylate in the range of from 2 to 30° 2- Theta; A typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta, preferably of ⁇ 0.1° 2-Theta.
  • a representative FTIR spectrum of the crystalline form of iclaprim mesylate of the present invention is displayed in Figure 2 herein.
  • the corresponding peak list is provided in Table 2 below.
  • Table 2 FTIR peak list of the crystalline form of iclaprim mesylate; A typical precision of the wavenumbers is in the range of ⁇ 4 cm 1 , preferably of ⁇ 2 cm 1 .
  • the DSC curve of the crystalline form of iclaprim mesylate of the present invention which is displayed in Figure 3 hereinafter shows a single sharp endothermic peak (onset: 220.6 °C, peak: 222.4 °C, AH: 112.2 J/g) which is due to the melting of the sample.
  • the TGA curve of the crystalline form of iclaprim mesylate of the present invention is displayed in Figure 4 hereinafter and shows a mass loss of only about 0.4 w-% from the start of the measurement until about 230 °C, which can be assigned to the release of residual water and/or solvent.
  • Thermoanalysis indicates that the crystalline form of iclaprim mesylate of the present invention is an anhydrous and non-solvated form possessing a significant higher melting point compared to the iclaprim mesylate form mentioned in WO 2017/192744 Al, paragraph [0014]

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a crystalline form of iclaprim mesylate and a process for its preparation. The invention also relates to a pharmaceutical composition comprising the crystalline form of iclaprim mesylate of the present invention, preferably in a predetermined and/or effective amount and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prophylaxis of bacterial infections caused by Gram positive bacteria.

Description

CRYSTALLINE FORM OF ICLAPRIM MESYLATE
FIELD OF THE INVENTION
The present invention relates to a crystalline form of iclaprim mesylate and a process for its preparation. The invention also relates to a pharmaceutical composition comprising the crystalline form of iclaprim mesylate of the present invention, preferably in a predetermined and/or effective amount and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prophylaxis of bacterial infections caused by Gram positive bacteria.
BACKGROUND OF THE INVENTION
Iclaprim is an antibiotic belonging to the class of diaminopyrimidines. It acts as a selective and potent inhibitor of bacterial dihydrofolate reductase (DHFR), a key enzyme in the bacterial folate synthesis pathway. Iclaprim is active against the clinically most relevant Gram-positive bacteria including resistant strains such as multidrug-resistant Staphylococcus aureus (MRSA). It is being studied for the treatment of various infections caused by Gram-positive bacteria including multidrug-resistant bacteria comprising skin and skin structure infections and nosocomial pneumonia. Chemically, iclaprim can be designated as 5-[(2ft)-2-cyclopropyl-7,8- dimethoxy-2iT-chromen-5-ylmethyl]pyrimidine-2, 4-diamine or 5-[[(2//k)-2-cyclopropyl-7,8- dimethoxy-2iT-l-benzopyran-5-yl]methyl]pyrimidine-2, 4-diamine and is represented by the following chemical structure according to Formula (I)
Figure imgf000003_0001
Formula (I).
Iclaprim is a racemate, and both enantiomers have been shown to be equipotent against various bacterial DHFR enzymes and to exhibit similar antimicrobial activity against a broad range of bacteria. The (//(-enantiomer is represented by the chemical structure according to Formula (la) and the (//(-enantiomer is represented by the chemical structure according to Formula (lb) Formula (la) Formula (lb).
WO 1997/020839 Al describes in example 5 the preparation of iclaprim free base, which was obtained as white crystals after recrystallization from ethanol.
In example 11 of WO 2005/014587 Al iclaprim free base crystals having a melting point of 226-227 °C are described.
WO 2017/192744 Al, paragraph [0014] mentions iclaprim mesylate having general properties such as a melting point range of 200-204 °C. The application does not provide a concrete procedure for the production of iclaprim mesylate but refers to the synthesis described in US5,773,446, which is the US equivalent of above mentioned WO 1997/020839 Al .
A compound intended to be used for pharmaceutical purpose requires particular physicochemical properties, which ensure safe production and storage of the drug substance and the finished dosage form containing the drug substance. These properties are mainly determined by the crystal structure of the active pharmaceutical ingredient. For example, for the preparation of an oral solid dosage form it is important that a stable solid-state form of the drug substance is used, in order to ensure reliable safety and efficacy of the drug product over the whole shelf-life. Hence, a crystalline form of the active pharmaceutical ingredient having a high melting point, high chemical stability and high thermodynamic stability is desirable.
SUMMARY OF THE INVENTION
WO 2017/192744 Al, paragraph [0014], mentions iclaprim mesylate having general properties including i.a. a melting point in the range of 200-204 °C indicating that only one crystalline form iclaprim mesylate exists. The present inventors now surprisingly found that iclaprim mesylate exists in more than one crystalline form i.e. exhibits polymorphism.
The novel form discovered by the inventors of the present invention is more stable compared to the iclaprim mesylate form mentioned in WO 2017/192744 Al, which is indicated by its high melting point of 221-222 °C. Abbreviations
PXRD powder X-ray diffractogram
FTIR Fourier transform infrared spectroscopy
DSC differential scanning calorimetry
TGA thermogravimetric analysis
RT room temperature
w-% weight percent
EtOH ethanol
MeCN acetonitrile
Definitions
In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise.
As used herein the term“room temperature” refers to a temperature in the range of from 20 to
30°C.
As used herein, the term“measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature. Standard conditions can mean a temperature of about 22°C. Typically, standard conditions can additionally mean a measurement under 20-80% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% relative humidity.
The term“reflection” with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see“Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).
The term“essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-Theta. Thus, a reflection that usually appears at 4.0° 2-Theta for example can appear between 3.8° and 4.2° 2-Theta, preferably between 3.9 and 4.1° 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
The term“essentially the same” with reference to infrared spectrometry means that variabilities in peak positions and relative intensities of the peaks are to be taken into account. For example, a typical precision of the wavenumber values is in the range of ± 4 cm 1, preferably in the range of ± 2 cm 1 . Thus, a peak at 1638 cm 1 for example can appear between 1634 and 1642 cm 1, preferably between 1636 and 1640 cm 1 on most infrared spectrometers under standard conditions. Peak intensities can be derived from according figures, but one skilled in the art will appreciate that differences in peak intensities due to degree of crystallinity, sample preparation, measurement method and other factors can also occur in infrared spectroscopy. Peak intensities should therefore be taken as qualitative measure only.
The crystalline form of iclaprim mesylate of the present invention may be referred to herein as being characterized by a powder X-ray diffractogram or an FTIR spectrum "as shown in" a figure. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations, for example relating to the exact reflection and peak positions and their intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
The term“solid-state form” as used herein refers to any crystalline and/or amorphous phase of a compound.
The term“anhydrous form” as used herein refers to a crystalline solid were no water is cooperated in or accommodated by the crystal structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. Typically, an anhydrous form does not contain more than 2.0 w-%, preferably not more than 1.0 w-% of water, based on the weight of the crystalline form.
The term“non-solvated” as used herein, when talking about a crystalline solid indicates that no organic solvent is cooperated in or accommodated by the crystal structure. Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. Typically, a non- solvated form does not contain more than 2.0 w-%, preferably not more than 1.0 w-%, and most preferably not more than 0.5 w-% of organic solvents, based on the weight of the crystalline form. A“predetermined amount” as used herein with regard to the crystalline form of iclaprim mesylate of the present invention refers to the initial amount of the crystalline form of iclaprim mesylate used for the preparation of a pharmaceutical composition having a desired dosage strength of relugolix.
The term“effective amount” as used herein with regard to the crystalline form of iclaprim mesylate of the present invention encompasses an amount of the crystalline form of iclapirm mesylate, which causes the desired therapeutic and/or prophylactic effect.
As used herein, the term“about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: illustrates a representative PXRD of the crystalline form of iclaprim mesylate of the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.
Figure 2: illustrates a representative FTIR spectrum of the crystalline form of iclaprim mesylate of the present invention. The x-axis shows the wavenumbers in cm 1, the y-axis shows the relative intensity in percent transmittance.
Figure 3: illustrates a representative DSC curve of the crystalline form of iclaprim mesylate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.
Figure 4: illustrates a representative TGA curve of the crystalline form of iclaprim mesylate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in weight percent (w-%).
PET ATT /ED DESCRIPTION OF THE INVENTION
The present invention relates to a crystalline form of iclaprim mesylate. Iclaprim mesylate, is characterized by the chemical structure according to Formula (II) Formula (II), wherein n is in the range of from 0.7 to 1.3, preferably in the range of from 0.8 to 1.2, more preferably in the range of from 0.9 to 1.1, even more preferably in the range of from 0.95 to 1.05 and most preferably n is about 1.0. For example, n is selected from the group consisting of about 0.7, 0.8, 0.9, 0.95, 1.0, 1.05, 1.1, 1.2 and 1.3.
The crystalline form of iclaprim mesylate of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the crystalline form of iclaprim mesylate of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
The present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of:
(4.0 ± 0.2)°, (10.4 ± 0.2)° and (17.8 ± 0.2)°; or
(4.0 ± 0.2)°, (10.4 ± 0.2)°, (17.8 ± 0.2)° and (24.2 ± 0.2)°; or
(4.0 ± 0.2)°, (10.4 ± 0.2)°, (17.8 ± 0.2)°, (24.2 ± 0.2)° and (24.9 ± 0.2)°; or
(4.0 ± 0.2)°, (10.2 ± 0.2)°, (10.4 ± 0.2)°, (17.8 ± 0.2)°, (24.2 ± 0.2)° and (24.9 ± 0.2)°; or
(4.0 ± 0.2)°, (10.2 ± 0.2)°, (10.4 ± 0.2)°, (14.0 ± 0.2)°, (17.8 ± 0.2)°, (24.2 ± 0.2)° and (24.9 ±
0.2)°; or
(4.0 ± 0.2)°, (10.2 ± 0.2)°, (10.4 ± 0.2)°, (14.0 ± 0.2)°, (16.1 ± 0.2)°, (17.8 ± 0.2)°, (24.2 ± 0.2)° and (24.9 ± 0.2)°; or
(4.0 ± 0.2)°, (10.2 ± 0.2)°, (10.4 ± 0.2)°, (14.0 ± 0.2)°, (16.1 ± 0.2)°, (17.8 ± 0.2)°, (24.2 ± 0.2)°, (24.9 ± 0.2)° and (26.8 ± 0.2)°; or (4.0 ± 0.2)°, (10.2 ± 0.2)°, (10.4 ± 0.2)°, (14.0 ± 0.2)°, (16.1 ± 0.2)°, (17.8 ± 0.2)°, (20.5 ± 0.2)°, (24.2 ± 0.2)°, (24.9 ± 0.2)° and (26.8 ± 0.2)°;
when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
Alternatively, the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of:
(4.0 ± 0.1)°, (10.4 ± 0.1)° and (17.8 ± 0.1)°; or
(4.0 ± 0.1)°, (10.4 ± 0.1)°, (17.8 ± 0.1)° and (24.2 ± 0.1)°; or
(4.0 ± 0.1)°, (10.4 ± 0.1)°, (17.8 ± 0.1)°, (24.2 ± 0.1)° and (24.9 ± 0.1)°; or
(4.0 ± 0.1)°, (10.2 ± 0.1)°, (10.4 ± 0.1)°, (17.8 ± 0.1)°, (24.2 ± 0.1)° and (24.9 ± 0.1)°; or
(4.0 ± 0.1)°, (10.2 ± 0.1)°, (10.4 ± 0.1)°, (14.0 ± 0.1)°, (17.8 ± 0.1)°, (24.2 ± 0.1)° and (24.9 ±
0.1)°; or
(4.0 ± 0.1)°, (10.2 ± 0.1)°, (10.4 ± 0.1)°, (14.0 ± 0.1)°, (16.1 ± 0.1)°, (17.8 ± 0.1)°, (24.2 ± 0.1)° and (24.9 ± 0.1)°; or
(4.0 ± 0.1)°, (10.2 ± 0.1)°, (10.4 ± 0.1)°, (14.0 ± 0.1)°, (16.1 ± 0.1)°, (17.8 ± 0.1)°, (24.2 ± 0.1)°, (24.9 ± 0.1)° and (26.8 ± 0.1)°; or
(4.0 ± 0.1)°, (10.2 ± 0.1)°, (10.4 ± 0.1)°, (14.0 ± 0.1)°, (16.1 ± 0.1)°, (17.8 ± 0.1)°, (20.5 ± 0.1)°, (24.2 ± 0.1)°, (24.9 ± 0.1)° and (26.8 ± 0.1)°;
when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
Moreover, the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of (4.0 ± 0.2)°, (10.2 ± 0.2)°, (10.4 ± 0.2)°, (14.0 ± 0.2)°, (17.8 ± 0.2)°, (20.5 ± 0.2)°, (24.2 ± 0.2)° (24.3 ± 0.2)°, (24.9 ± 0.2)° and (26.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.
Alternatively, the present invention relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD comprising reflections at 2-Theta angles of (4.0 ± 0.1)°, (10.2 ± 0.1)°, (10.4 ± 0.1)°, (14.0 ± 0.1)°, (17.8 ± 0.1)°, (20.5 ± 0.1)°, (24.2 ± 0.1)° (24.3 ± 0.1)°, (24.9 ± 0.1)° and (26.8 ± 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
The present invention also relates to a crystalline form of iclaprim mesylate, characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. Moreover, the present invention relates to a crystalline form of iclaprim mesylate, characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
(1638 ± 4) cm1, (1131 ± 4) cm1 and (1036 ± 4) cm1; or
(3408 ± 4) cm1, (1638 ± 4) cm1, (1131 ±4) cm1 and (1036 ± 4) cm1; or
(3408 ± 4) cm1, (3180 ± 4) cm1, (1638 ± 4) cm1, (1131 ±4) cm1 and (1036 ± 4) cm1; or
(3408 ± 4) cm1, (3180 ± 4) cm1, (1638 ± 4) cm1, (1501 ± 4) cm1, (1131 ± 4) cm1 and (1036
± 4) cm1; or
(3408 ± 4) cm1, (3180 ± 4) cm1, (1638 ± 4) cm1, (1501 ± 4) cm1, (1422 ± 4) cm1, (1131 ± 4) cm1 and (1036 ± 4) cm1; or
(3408 ± 4) cm1, (3180 ± 4) cm1, (1638 ± 4) cm1, (1501 ± 4) cm1, (1422 ± 4) cm1, (1298 ± 4) cm1, (1131 ±4) cm1 and (1036 ± 4) cm1; or
(3408 ± 4) cm1, (3180 ± 4) cm1, (1638 ± 4) cm1, (1501 ± 4) cm1, (1422 ± 4) cm1, (1298 ± 4) cm1, (1195 ± 4) cm1, (1131 ±4) cm1 and (1036 ± 4) cm1; or
(3408 ± 4) cm1, (3180 ± 4) cm1, (1638 ± 4) cm1, (1501 ± 4) cm1, (1422 ± 4) cm1, (1298 ± 4) cm1, (1195 ± 4) cm1, (1131 ±4) cm1, (1036 ± 4) cm1 and (763 ± 4) cm1; when measured at a temperature in the range of from 20 to 30 °C with a diamond ATR cell.
Alternatively, the present invention relates to a crystalline form of iclaprim mesylate, characterized by having an FTIR spectrum comprising peaks at wavenumbers of:
(1638 ± 2) cm1, (1131 ± 2) cm1 and (1036 ± 2) cm1; or
(3408 ± 2) cm1, (1638 ± 2) cm1, (1131 ±2) cm1 and (1036 ± 2) cm1; or
(3408 ± 2) cm1, (3180 ± 2) cm1, (1638 ± 2) cm1, (1131 ± 2) cm1 and (1036 ± 2) cm1; or
(3408 ± 2) cm1, (3180 ± 2) cm1, (1638 ± 2) cm1, (1501 ± 2) cm1, (1131 ± 2) cm1 and (1036
± 2) cm1; or
(3408 ± 2) cm1, (3180 ± 2) cm1, (1638 ± 2) cm1, (1501 ± 2) cm1, (1422 ± 2) cm1, (1131 ± 2) cm1 and (1036 ± 2) cm1; or
(3408 ± 2) cm1, (3180 ± 2) cm1, (1638 ± 2) cm1, (1501 ± 2) cm1, (1422 ± 2) cm1, (1298 ± 2) cm1, (1131 ±2) cm1 and (1036 ± 2) cm1; or
(3408 ± 2) cm1, (3180 ± 2) cm1, (1638 ± 2) cm1, (1501 ± 2) cm1, (1422 ± 2) cm1, (1298 ± 2) cm1, (1195 ± 2) cm1, (1131 ±2) cm1 and (1036 ± 2) cm1; or
(3408 ± 2) cm1, (3180 ± 2) cm1, (1638 ± 2) cm1, (1501 ± 2) cm1, (1422 ± 2) cm1, (1298 ± 2) cm1, (1195 ± 2) cm1, (1131 ±2) cm1, (1036 ± 2) cm1 and (763 ± 2) cm1; when measured at a temperature in the range of from 20 to 30 °C with a diamond ATR cell.
The present invention also relates to a crystalline form of iclaprim mesylate, characterized by having an FTIR spectrum essentially the same as shown in Figure 2 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with a diamond ATR cell.
Furthermore, the present invention also relates to a crystalline form of iclaprim mesylate, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having an onset at a temperature of (221 ± 5)°C, preferably of (221 ± 3)°C, even more preferably of (221 ± 2)°C and most preferably of (221 ± 1)°C, when measured at a heating rate of 10 K/min.
Preferably, the invention relates to a crystalline form of iclaprim mesylate, characterized by having a melting point onset temperature of (221 ± 5)°C, preferably of (221 ± 3)°C, even more preferably of (221 ± 2)°C and most preferably of (221 ± 1)°C, when measured with DSC at a heating rate of 10 K/min.
The present invention also relates to a crystalline form of iclaprim mesylate, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak maximum at a temperature of (222 ± 5)°C, preferably of (222 ± 3)°C, even more preferably of (222 ± 2)°C and most preferably of (222 ± 1)°C, when measured at a heating rate of 10 K/min.
Preferably, the invention relates to a crystalline form of iclaprim mesylate, characterized by having a melting point peak temperature of (222 ± 5)°C, preferably of (222 ± 3)°C, even more preferably of (222 ± 2)°C and most preferably of (222 ± 1)°C, when measured with DSC at a heating rate of 10 K/min.
Moreover, the invention relates to a crystalline form of iclaprim mesylate, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, with an enthalpy of (112 ± 5) J/g, preferably of (112 ± 3) J/g, even more preferably of (112 ± 2) J/g and most preferably of (112 ± 1) J/g, when measured at a heating rate of 10 K/min.
In addition, the present invention relates to a crystalline form of iclapirm mesylate, characterized by having a TGA curve showing a mass loss of not more than 1.0 w-%, preferably of not more than 0.9 w-%, more preferably of not more than 0.8 w-%, even more preferably of not more than 0.7 w-% or 0.6 w-% and most preferably of not more than 0.5 w-%, for example of not more than 0.4 w%, based on the weight of the crystalline form, when heated from 25 to 230 °C at a rate of 10 K/min.
Furthermore, the present invention relates to a crystalline form of iclaprim mesylate, characterized as being an anhydrous form.
In another embodiment, the present invention relates to a crystalline form iclaprim mesylate, characterized as being a non-solvated form. The inventors of the present invention have also found that iclapirm free base can be obtained in high chemical purity, when iclaprim free base is crystallized or recrystallized from acetonitrile.
Hence, in another aspect the invention relates to a process for the purification of iclaprim free base comprising the steps of:
(a) providing a solution comprising iclaprim free base and acetonitrile;
(b) optionally, filtering the solution obtained in step (a);
(c) allowing for the crystallization of iclaprim free base;
(d) separating at least a part of the crystals obtained in step (c) from the mother liquor;
(e) drying the isolated crystals of step (d);
Iclaprim free base deployed in step a) can be prepared according to the procedures described in example 5 of WO 1997/020839 A1 or example 11 of WO 2005/014587 Al . The solvent used in the dissolution step (a) comprises acetonitrile, preferably acetonitrile is the only solvent present. The iclaprim concentration of the mixture in step (a) is in the range of from 2 - 10 g/L, preferably of from 5 - 8 g/L and most preferably of from 6 - 7 g/L. The solution is preferably prepared by heating the mixture to a temperature above 60°C, preferably above 70°C, more preferably above 80°C e.g. to reflux temperature. The solution is optionally filtered in order to remove any undissolved particles present.
Crystallization in step (c) is initiated by decreasing the temperature of the solution e.g. to room temperature. The cooling rate is not critical, e.g. natural cooling can be applied. Optionally, iclaprim seed crystals can be added in order to initiate crystallization and/or promote crystal growth. The amount of seed crystals employed may range from about 1 to 20 w-%, preferably from about 1 to 10 w-% and most preferably from about 1 to 5 w-%, based on the weight of applied iclaprim starting material.
After crystallization took place the temperature may be further decreased e.g. to about 10 °C, 5°, 0°C, (-5)°C, (-10°), (-15)°C, (-20)°C or (-25)°C in order to improve the yield.
Then, at least a part of the crystals is separated from the mother liquor. Preferably, the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration. Optionally, in a further step the isolated crystals are washed with acetonitrile.
The obtained crystals may then be dried. Drying may be performed at a temperature in the range of from about 20 to 80 °C, preferably in the range of from about 20 to 60 °C and most preferably in the range of from about 20 to 40 °C e.g. at room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably from about 6 to 18 hours. Drying may be performed at ambient pressure and/ or under reduced pressure. Preferably, drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less and most preferably of about 30 mbar or less, for example a vacuum of about 20 mbar or less such as about 1 mbar.
The thus obtained material can be used as starting material for the preparation of the crystalline form of iclaprim mesylate of the present invention.
Hence, in another aspect the present invention relates to a process for the preparation of the crystalline form of icalprim mesylate of the present invention comprising:
(a) providing a solution comprising iclaprim free base, methanesulfonic acid and ethanol;
(b) optionally, filtering the solution obtained in step (a);
(c) allowing for the crystallization of the crystalline form of iclaprim mesylate of the present invention;
(d) separating at least a part of the crystals obtained in step (c) from the mother liquor;
(e) drying the isolated crystals of step (d);
The solvent used for the acid base reaction in step (a) comprises ethanol, preferably ethanol is the only solvent present. The iclaprim concentration of the reaction mixture in step (a) is in the range of from 15 - 25 g/L, preferably of from 20 - 22 g/L. The solution is preferably prepared by heating the mixture to a temperature above 60°C, preferably above 70°C, more preferably above 75°C e.g. to reflux temperature. The solution is optionally filtered in order to remove any undissolved particles present.
Crystallization in step (c) is initiated by decreasing the temperature of the solution e.g. to room temperature. The cooling rate is not critical, e.g. natural cooling can be applied. Optionally, part of the solvent may be removed before the cooling step in order to increase the iclaprim mesylate concentration of the solution. Also iclaprim mesylate seed crystals can optionally be added in order to initiate crystallization and/or promote crystal growth. The amount of seed crystals employed may range from about 1 to 20 w-%, preferably from about 1 to 10 w-% and most preferably from about 1 to 5 w-%, based on the weight of applied iclaprim starting material.
After crystallization took place the temperature may optionally be further decreased e.g. to about 10 °C, 5°, 0°C, (-5)°C, (-10°), (-15)°C, (-20)°C or (-25)°C in order to improve the yield.
Then, at least a part of the crystals is separated from the mother liquor. Preferably, the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration. Optionally, in a further step the isolated crystals are washed with ethanol. The obtained crystals may then be dried. Drying may be performed at a temperature in the range of from about 20 to 80 °C, preferably in the range of from about 20 to 60 °C and most preferably in the range of from about 20 to 40 °C e.g. at room temperature. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably from about 2 to 48 hours, more preferably from about 4 to 24 hours and most preferably from about 6 to 18 hours. Drying may be performed at ambient pressure and/ or under reduced pressure. Preferably, drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less and most preferably of about 30 mbar or less, for example a vacuum of about 20 mbar or less such as about 1 mbar.
In a further aspect, the present invention relates to a composition comprising the crystalline form of iclaprim mesylate of the present invention as defined in any one of the embodiments described above, said composition being essentially free of any other solid form of iclaprim mesylate. For example, a composition comprising the crystalline form of iclapirm mesylate of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid form of iclaprim mesylate, based on the weight of the composition. Preferably, the any other solid form of iclaprim mesylate is the crystalline form mentioned in WO 2017/192744 Al, paragraph [0014] or amorphous.
Furthermore, the invention relates to a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the crystalline form of iclaprim mesylate as defined in any one of the embodiments described above, based on the total weight of the composition. The remaining material may comprise other solid form(s) of iclaprim mesylate such as the crystalline form mentioned in WO 2017/192744 Al, paragraph [0014] or amorphous and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
In a further aspect the present invention relates to the use of the crystalline form of iclaprim mesylate of the present invention or the composition comprising the same as defined in any one of the embodiments described above for the preparation of a pharmaceutical composition. The pharmaceutical composition may be intended for parenteral or oral administration.
Pharmaceutical compositions for parenteral use can be prepared starting from the crystalline form of iclaprim mesylate of the present invention, for example by a process comprising the step of dissolving the crystalline form of iclaprim mesylate of the present invention. The preparation of stable aqueous compositions comprising iclaprim mesylate is described in detail in WO 2009/124586, the whole content of which is hereby incorporated by reference. Items [0046] to [0056] of EP2280688B1 describe in detail processes for the preparation of a stable aqueous solution of iclaprim in items [0046] to [0053], for the preparation of a ready-to-use injection solution in items [0054] to [0055] and for the preparation of a container comprising a solution of iclaprim in item [0056] The present invention relates to analogous processes, wherein the crystalline form of iclaprim mesylate of the present invention is used as the active pharmaceutical ingredient to be used as starting material. A stock solution can be prepared from the crystalline form of iclaprim mesylate of the present invention for example according to Example 4 of EP2280688B1.
The present invention therefore also relates to a composition comprising iclaprim mesylate in a solution consisting essentially of a physiologically acceptable solvent and iclaprim mesylate, wherein the oxygen concentration in the solution is 0.8 ppm or less, and wherein the starting material for said composition is the crystalline form of iclaprim mesylate of the present invention. Preferred physiologically acceptable solvents are water or ethanol or a water/ethanol mixture. When a water/ethanol mixture is used, ethanol is preferably comprised in a concentration range of from 5% to 45%, such as from 20% to 35%. Sodium chloride can be comprised in the solution, for example in a concentration of from 0.1% to 3%. The pH of the solution is preferably in a range of from 4.2 to 5.7, such as from 4.6 to 5.2. The concentration of iclaprim mesylate in the solution is preferably from 0.2% w/w to 8.0% w/w, such as from 0.5% w/w to 5.0% w/w, in particular from 0.7% w/w to 2.5% w/w. The solution may further comprise a wetting agent, such as a wetting agent selected from N-methylpyrrolidone, polyvinylpyrrolidone, cyclodextrine, macrogol hydroxystearate and macrogol glycerol ricinoleate, particularly at a concentration of from 0% to 20%, such as from 0.1% to 10%, in particular of from 2% to 10%.
The pharmaceutical composition of the present invention intended for parenteral administration may be a sterile concentrate comprising iclaprim mesylate already in solution. The concentrate may be further diluted before administration e.g. with normal saline, 5% dextrose or lactated ringers.
The pharmaceutical composition of the present invention intended for oral administration may be an oral solid dosage form, such as a tablet or a capsule. More preferably, the pharmaceutical composition of the present invention is a tablet e.g. a film-coated tablet.
Therefore, the present invention also relates to a pharmaceutical composition comprising the crystalline form of iclaprim mesylate of the present invention or the composition comprising the same as defined in any one of the embodiments described above, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.
The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is preferably selected from the group consisting of fillers/diluents, binders, disintegrants, lubricants, stabilizers, coating materials and combinations thereof. Preferably, all of these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention.
Furthermore, the present invention relates to a pharmaceutical composition as describe above, wherein the predetermined and/or effective amount of the crystalline form of iclaprim mesylate of the present invention is selected from the group consisting of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 229 mg, 230 mg and 240 mg. Preferably, the invention relates to a pharmaceutical composition as describe above, wherein the predetermined and/or effective amount of the crystalline form of iclaprim mesylate of the present invention is selected from the group consisting of 80 mg, 160 mg and 240 mg. Most preferably, the predetermined and/or effective amount of the crystalline form of iclaprim mesylate of the present invention is 80 mg or 160 mg.
In a further aspect, the present invention relates to the crystalline form of iclaprim mesylate of the present invention, the composition comprising the same or the pharmaceutical composition comprising the same as defined in any one of the above described embodiments for use as a medicament.
In yet another aspect, the present invention relates to the crystalline form of iclaprim mesylate of the present invention, the composition comprising the same or the pharmaceutical composition comprising the same as defined in any one of the above described embodiments for use in the treatment and/or prophylaxis of bacterial infections caused by Gram-positive bacteria. Preferably, the bacterial infection is selected from complicated skin and skin structure infections and nosocomial pneumonia.
In another embodiment, the present invention is directed to a method of treating and/or prophylactically preventing bacterial infections caused by Gram-positive bacteria. Preferably, the bacterial infection is selected from complicated skin and skin structure infections and nosocomial pneumonia.
EXAMPLES
The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention.
Analytical Methods
Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
The infrared spectrum (IR) was recorded on an MKII Golden Gate™ Single Reflection Diamond ATR (attenuated total reflection) cell with a Bruker Tensor 27 FTIR spectrometer with 4 cm-1 resolution at ambient conditions. To record a spectrum a spatula tip of the sample was applied to the surface of the diamond in powder form. Then the sample was pressed onto the diamond with a sapphire anvil and the spectrum was recorded. A spectrum of the clean diamond was used as background spectrum. A typical precision of the wavenumber values is in the range of about ± 4 cm-1, preferably of about ± 2 cm-1.
Differential scanning calorimetry (DSC) was performed on a Mettler Toledo Polymer DSC R instrument. About 5.1 mg of the sample was heated in a 40 mΐ aluminium pan with a pierced aluminium lid from room temperature to 250°C at a rate of 10°C/min. Nitrogen (purge rate 50 ml/min) was used as purge gas.
Thermogravimetric analysis (TGA) was performed on a Mettler Toledo TGA/DSC 1 instrument. About 8.1 mg of the sample was heated in a 100 mΐ aluminium pan closed with an aluminium lid. The lid was automatically pierced at the beginning of the measurement. The samples was initially kept at 25°C for 2 ½ minutes and then heated from room temperature to 250°C at a rate of 10°C/min. Nitrogen (purge rate 30 ml/min) was used as purge gas.
Example 1: Preparation of the crystalline form of iclaprim mesylate of the present invention Step 1: Recrystallization of iclaprim free base
Figure imgf000017_0001
Iclaprim impure Iclaprim pure
Iclaprim free base (500 mg, 1.41 mmol, e.g. prepared according to example 11 of WO 2005/014587 Al) was suspended in acetonitrile (75 mL) and heated to reflux. The resulting clear solution was slowly cooled to room temperature overnight and then kept at (- 20)°C to increase the yield. The resulting white solid was collected by filtration and dried in high vacuum at room temperature.
Step 2: Salt formation and crystallization of iclaprim mesylate according to the present invention
Figure imgf000018_0001
Iclaprim pure Iclaprim mesylate
Iclaprim free base (1.00 g, 2.82 mmol, obtained according to the procedure of step 1) was suspended in ethanol (35 mL) and heated to reflux. Heating was interrupted to add a solution of methanesulfonic acid (183 pL, 2.82 mmol) in ethanol (5 mL) in a drop-wise manner, then refluxing was resumed. Further 10 mL of ethanol were added to obtain a clear solution. The solution was then concentrated to a volume of about 45-47 mL and slowly let cool to room temperature, leading to the formation of columnar crystals. The crystals were collected by filtration and dried in high vacuum at room temperature overnight (yield: 900 mg).
Example 2: Solid-state characterization of the crystalline form of iclaprim mesylate of the present invention obtained according to Example 1
Powder X-ray diffraction
A representative diffractogram of the crystalline form of iclaprim mesylate of the present invention is displayed in Figure 1 herein. The corresponding reflection list is provided in Table 1 below.
Figure imgf000018_0002
Table 1: PXRD reflections of the crystalline form of iclaprim mesylate in the range of from 2 to 30° 2- Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
Fourier transform infrared spectroscopy
A representative FTIR spectrum of the crystalline form of iclaprim mesylate of the present invention is displayed in Figure 2 herein. The corresponding peak list is provided in Table 2 below.
Figure imgf000019_0001
Table 2: FTIR peak list of the crystalline form of iclaprim mesylate; A typical precision of the wavenumbers is in the range of ± 4 cm 1, preferably of ± 2 cm 1.
Thermoanalvsis
The DSC curve of the crystalline form of iclaprim mesylate of the present invention, which is displayed in Figure 3 hereinafter shows a single sharp endothermic peak (onset: 220.6 °C, peak: 222.4 °C, AH: 112.2 J/g) which is due to the melting of the sample. The TGA curve of the crystalline form of iclaprim mesylate of the present invention is displayed in Figure 4 hereinafter and shows a mass loss of only about 0.4 w-% from the start of the measurement until about 230 °C, which can be assigned to the release of residual water and/or solvent. Thermoanalysis indicates that the crystalline form of iclaprim mesylate of the present invention is an anhydrous and non-solvated form possessing a significant higher melting point compared to the iclaprim mesylate form mentioned in WO 2017/192744 Al, paragraph [0014]
Figure imgf000020_0001
Table 3: Comparison of the melting points/ ranges of different iclaprim mesylate forms

Claims

1) A crystalline form of 5-[(2ft)-2-cyclopropyl-7,8-dimethoxy-2i7-chromen-5- ylmethyl]pyrimidine-2, 4-diamine mesylate (iclaprim mesylate), characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (4.0 ± 0.2)°, (10.4 ± 0.2)° and (17.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
2) The crystalline form of claim 1, characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (24.2 ± 0.2)° and (24.9 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
3) The crystalline form according to claim 1 or 2, characterized by having a Fourier transform infrared spectrum comprising peaks at wavenumbers of (1638 ± 4) cm 1, (1131 ± 4) cm 1 and (1036 ± 4) cm 1, when measured at a temperature in the range of from 20 to 30 °C with a diamond ATR cell.
4) The crystalline form of claim 3, characterized by having a Fourier transform infrared spectrum comprising additional peaks at wavenumbers of (3408 ± 4) cm 1 and (3180 ± 4) cm 1, when measured at a temperature in the range of from 20 to 30 °C with a diamond ATR cell.
5) The crystalline form as defined in any one of the preceding claims, characterized by having a melting point onset temperature of (221 ± 5)°C, when measured with differential scanning calorimetry at a heating rate of 10 K/min.
6) The crystalline form as defined in any one of the preceding claims, characterized by having a thermogravimetric analysis curve showing a mass loss of not more than 0.5 w- % based on the weight of the crystalline form, when heated from 25 to 230 °C at a rate of 10 K/min.
7) The crystalline form as defined in any one of the preceding claims, characterized as being an anhydrous form.
8) The crystalline form as defined in any one of the preceding claims, characterized as being a non-solvated form.
9) A composition comprising the crystalline form as defined in any one of the preceding claims and at most 10 w-% of any other solid form of iclaprim mesylate, based on the weight of the composition. 10) Use of the crystalline form as defined in any one of claims 1 to 8 or the composition of claim 9 for the preparation of a pharmaceutical composition.
11) The use according to claim 10, wherein the pharmaceutical composition is intended for parenteral or oral administration.
12) Process for the preparation of pharmaceutical composition for parenteral use comprising iclaprim mesylate, comprising the step of dissolving the crystalline form of iclaprim mesylate according to any one of claims 1 to 8 in a physiologically acceptable solvent.
13) A pharmaceutical composition comprising the crystalline form as defined in any one of claims 1 to 8 or the composition of claim 9 and at least one pharmaceutically acceptable excipient.
14) The pharmaceutical composition as defined in claim 13, wherein the pharmaceutical composition is an oral solid dosage form.
15) The crystalline form as defined in any one of claims 1 to 8, the composition of claim 9 or the pharmaceutical composition as defined in claims 13 or 14 or the product obtainable from the process of claim 12 for use in the treatment and/or prophylaxis of bacterial skin an skin structure infection and nococomial pneumonia.
PCT/EP2020/053094 2019-02-07 2020-02-07 Crystalline form of iclaprim mesylate WO2020161284A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19155863.4 2019-02-07
EP19155863 2019-02-07

Publications (1)

Publication Number Publication Date
WO2020161284A1 true WO2020161284A1 (en) 2020-08-13

Family

ID=65363085

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/053094 WO2020161284A1 (en) 2019-02-07 2020-02-07 Crystalline form of iclaprim mesylate

Country Status (1)

Country Link
WO (1) WO2020161284A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997020839A1 (en) 1995-12-04 1997-06-12 F. Hoffmann-La Roche Ag Diaminopyrimidines, pharmaceutical compositions containing them and their use as antibacterial
WO2005014587A1 (en) 2003-08-08 2005-02-17 Arpida Ag Novel process for the preparation of 2h-chromenes
US20090253722A1 (en) * 2008-04-08 2009-10-08 Arpida Ag Aqueous pharmaceutical formulation
WO2009124586A1 (en) 2008-04-08 2009-10-15 Arpida Ag Aqueous pharmaceutical formulation
WO2017192744A1 (en) 2016-05-04 2017-11-09 Motif BioSciences Inc. Systems and methods for treating bacterial infection

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997020839A1 (en) 1995-12-04 1997-06-12 F. Hoffmann-La Roche Ag Diaminopyrimidines, pharmaceutical compositions containing them and their use as antibacterial
US5773446A (en) 1995-12-04 1998-06-30 Hoffmann-La Roche Inc. Diamino pyrimidines
WO2005014587A1 (en) 2003-08-08 2005-02-17 Arpida Ag Novel process for the preparation of 2h-chromenes
US20090253722A1 (en) * 2008-04-08 2009-10-08 Arpida Ag Aqueous pharmaceutical formulation
WO2009124586A1 (en) 2008-04-08 2009-10-15 Arpida Ag Aqueous pharmaceutical formulation
EP2280688B1 (en) 2008-04-08 2012-01-25 Acino Pharma AG Aqueous pharmaceutical formulation
WO2017192744A1 (en) 2016-05-04 2017-11-09 Motif BioSciences Inc. Systems and methods for treating bacterial infection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VITALIJ K. PECHARSKYPETER Y. ZAVALIJ: "Fundamentals of Powder Diffraction and Structural Characterization of Materials", 2003, KLUWER ACADEMIC PUBLISHERS, pages: 3

Similar Documents

Publication Publication Date Title
JP6028016B2 (en) Polymorphs of linagliptin benzoate
US7230006B2 (en) Crystalline form III of anhydrous moxifloxacin hydrochloride and a process for preparation thereof
US11028100B2 (en) Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, and methods of production
EP3205653B1 (en) Crystal form of bisulfate of jak inhibitor and preparation method therefor
CN112105616B (en) Pharmaceutical compounds, salts thereof, formulations thereof, and methods of making and using the same
US10023577B2 (en) Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof
EP3891151A1 (en) Crystalline phosphate salt of selective jak1 inhibitor upadacitinib
WO2021044437A1 (en) Olaparib co-crystals and process of preparation thereof
WO2022189599A1 (en) Crystalline forms of mavacamten for the treatment of hcm
US20240199585A1 (en) Solid forms of (3r)-n-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide
TWI808069B (en) New solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
KR20080090661A (en) Crystalline hydrate of bepotastine metal salt, method for preparing same and pharmaceutical composition comprising same
WO2020161284A1 (en) Crystalline form of iclaprim mesylate
WO2020182978A1 (en) Crystalline salt of a 5-ht2a receptor antagonist
WO2021259732A1 (en) Multi-component compounds comprising zanubrutinib and a benzoic acid derivative
US20200407382A1 (en) Polymorphic forms of (9-[(r)-2-[[(s)-[[(s)-1-(isopropoxycarbonyl)ethyl]amino]phenoxy phosphinyl]methoxy]propyl] adenine and pharmaceutically acceptable salts thereof
EP3587421A1 (en) Crystalline forms of (s)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-alpha]pyrazin-1-yl-n-(pyridin-2-yl)benzamide
KR20200134928A (en) Crystal form of Valsartan-Sacubitril 3 Sodium hydrate and Method for the preparation thereof
JP2021533111A (en) Crystal form of LTA4H inhibitor
EP4126237B1 (en) Dimaleate form of 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea
WO2020187674A1 (en) Crystalline (s)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl][3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemisuccinate
EP4378942A1 (en) Crystal form of a pde3/4 inhibitor
KR101307712B1 (en) Crystalline hydrate of bepotastine metal salt, method for preparing same and pharmaceutical composition comprising same
WO2016127962A1 (en) An amorphous solid form of suvorexant with sulphuric acid
US20170369475A1 (en) Flibanserin Hydrate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20704274

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20704274

Country of ref document: EP

Kind code of ref document: A1