WO2015092595A1 - Forme cristalline de posaconazole - Google Patents

Forme cristalline de posaconazole Download PDF

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Publication number
WO2015092595A1
WO2015092595A1 PCT/IB2014/066592 IB2014066592W WO2015092595A1 WO 2015092595 A1 WO2015092595 A1 WO 2015092595A1 IB 2014066592 W IB2014066592 W IB 2014066592W WO 2015092595 A1 WO2015092595 A1 WO 2015092595A1
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WO
WIPO (PCT)
Prior art keywords
posaconazole
stirring
temperature
intensity
room temperature
Prior art date
Application number
PCT/IB2014/066592
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English (en)
Inventor
Domenico Badone
Claudio Negri
Alberto REPETTI
Original Assignee
Avanthera S.A.
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 Avanthera S.A. filed Critical Avanthera S.A.
Publication of WO2015092595A1 publication Critical patent/WO2015092595A1/fr

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    • 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
    • C07D405/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • Posaconazole a new crystalline form of Posaconazole, referred to as Form A, having new and distinctive chemical-physical characteristics herein described, in addition to a pharmaceutical composition comprising it. It is a further object of the present invention a process for preparing said Posaconazole, Form A. Posaconazole, amorphous solid obtained from Posaconazole, Form A, is also claimed..
  • Posaconazole of formula (I) is 2, 5-anhydre-l, 3, 4-trideoxy-2-C- (2, -difluorophenyl) -4- [[4-[4-[4-[l-[(lS,2S) -l-ethyl-2-hydroxypropyl] -1, 5- dihydro-5-oxo-4H-l, 2, 4-triazol-4-yl] phenyl] -1- piperazinyl] phenoxyjmethyl] -1- (lH-1, 2, 4-triazol-l-yl) -D- threo-pentitol.
  • WO95/17407 and WO 96/38443 disclose a compound of formula (I) and the use thereof in the treatment of fungal infections.
  • WO 10/000668 discloses a further crystalline form, Posaconazole, Form IV.
  • Posaconazole, Form V is discloses in WO 11/158248. .
  • Posaconazole which are more stable when used in pharmaceutical compositions and/or which have advantageous properties for the preparation and storage thereof .
  • the physical properties of an active ingredient in the solid state are crucial for the management of the material during its conversion into a pharmaceutical product.
  • the flowing properties are pointed out, in addition to the dissolution rate in an aqueous liquid.
  • the dissolution in water is particularly critical for Posaconazole, it being a highly lipophilic base.
  • the dissolution rate in an aqueous liquid affect the dissolution rate of the active ingredient in the stomach of a patient, with clear therapeutically consequences.
  • the dissolution rate has to be taken into high account also in the formulation of syrups, elixirs, and other liquid medicaments.
  • the polymorphic form may give rise to a thermal behavior that is different from that of the amorphous material or another polymorphic form.
  • the thermal behavior is measured in a laboratory by techniques such as capillary melting point, thermo- gravimetric analysis- (TGA) , and differential scanning calorimetry (DSC) , and it can be used to distinguish some polymorphic forms from other ones.
  • TGA thermo- gravimetric analysis-
  • DSC differential scanning calorimetry
  • a particular polymorphic form may also give rise to distinct spectroscopic properties, detectable by X-ray crystallography, NMR spectrometry, and IR spectrometry.
  • Posaconazole provides a new opportunity to improve the synthesis process of the pharmaceutical active ingredient (API) , resulting in a form of Posaconazole with improved characteristics, for example, in terms of fluidity and solubility, the need of which is felt in the state of the art.
  • API pharmaceutical active ingredient
  • a new crystalline form of Posaconazole is herein for the first time prepared, described, and characterized, having distinctive and advantageous chemical-physical characteristics, i.e., Posaconazole Form A.
  • the object of the present invention is to provide a new crystalline form of Posaconazole.
  • the main X-ray scattering peaks, the main bands and the characteristics of the FT-IR spectrum, differential scanning thermal analysis (DSC) , thermo- gravimetric analysis, evolved gas analysis (EGA) , absorption/desorption measurements of the humidity administered by gas flow (DVS) are set forth.
  • the X-ray powder diffractogram was obtained by using an X'Pert PRO PANalytical tool, equipped with X'Celerator detector and X-ray tube (Cu LFF PW3373/00 DK312503) with 40mA current intensity and 40kV voltage.
  • the sample is arranged on a support and analyzed using the following parameters:
  • the FT-IR spectrum (Fourier transform IR spectroscopy) was recorded using the Nicolet FT-IR 6700 apparatus (ThermoFischer) , equipped with a KBr splitter and a DTGS KBr detector. The spectrum was acquired in 16 scans at a resolution of 4 cm -1 .
  • the DSC analyses were obtained by the use of a differential scanning calorimeter DSC 200 F3 aia®. The samples have been loaded on aluminum crucibles and heated to 350° C at a heating rate of lOK/min.
  • Measurement range from 0 mW to ⁇ 600 mW.
  • Cooling options forced-air (to room temperature), liquid nitrogen (to -170 ° C)
  • thermograms were obtained by the use of a Mettler Toledo Stare System thermobalance .
  • the samples were loaded on aluminum crucibles and heated to 460° C at a heating rate of 10 K/min.
  • Fig. 1 XRPD spectrum of Posaconazole, Form A.
  • Fig. 2 FT-IR spectrum of Posaconazole, Form A.
  • Fig. 3 DSC analysis of Posaconazole, Form A.
  • Fig. 4 TGA analysis of Posaconazole, Form A.
  • Fig. 5 EGA analysis of Posaconazole, Form A.
  • Fig. 6 comparison between the absorption profile of the gas released at about 50° C from Posaconazole, Form A, and the water profile as available from the database.
  • Fig. 7 DVS analysis of Posaconazole, Form A.
  • Fig. 8 XRPD analysis of the powder obtained after DVS analysis compared to Posaconazole Form A and Form I.
  • Fig. 9 XRPD analysis of the wet and dry sample.
  • Fig. 10 XRPD analysis of the wet and dry sample.
  • Fig. 11 XRPD analysis of the wet and dry sample.
  • Fig. 12 XRPD analysis of the wet and dry sample.
  • Fig. 13 XRPD analysis of the wet and dry sample.
  • Fig. 14 XRPD analysis of the wet and dry sample.
  • Fig. 15 XRPD analysis of the wet and dry sample.
  • Fig. 16 XRPD analysis of the wet and dry sample.
  • Fig. 17 XRPD analysis of the wet and dry sample.
  • Fig. 18 comparison between the XRPD patterns of the samples obtained in the examples A to I and the reference Form A.
  • Fig. 19 XRPD spectrum of Posaconazole, low- crystallinity form.
  • Fig. 20 XRPD spectrum of Posaconazole, amorphous solid. Detailed description of the invention:
  • Posaconazole Form A of the present invention is characterized by the following chemical-physical parameters.
  • the XRPD analysis leads to achieving the characteristic spectrum set forth in Fig. 1.
  • the main peaks at 2theta +/- 0.3 degrees are: 4.3, 6.3, 9.3, 12.7, 15.4, 16.8, 17.8, 18.1, 18.7, 20.7, 23.1, 26.4.
  • the following table 1 sets forth the significant peaks of the spectrum.
  • the FT- I R analys i s gives the spect rum that i s set forth in Fi g . 2 .
  • the DSC analys is , set forth in Fig . 3 , point s out a fi rst endothe rmic event at about 50 ° C , associated to the water los s , an endothermic pea k at about 98 ° C corresponding to the melting point, an exothermic peak at about 117° C. associated to a re-crystallization event, a second endothermic peak at about 170° C associated to the melting.
  • thermogram set forth in Fig. 4 sets forth a weight loss of about 3.6% at about 50° C, which corresponds to the water loss, as confirmed by the EGA analysis described herein below. Furthermore, there is a continuous weight loss passing from about 400° C to about 450° C. The events characteristic of the measured weight loss are best noticed on the DTG curve, which is set forth on the same graph.
  • the DTG curve represents the derivate of the thermogram and allows observing events at about 170° C and at about 410° C, associated to the sample degradation following a heating.
  • step ii) occurs at a temperature of about 35-40° C, and said solvent is acetone.
  • said antisolvent is water, and the water/acetone ratio is 3/1 v/v.
  • step v) the suspension is kept under stirring for about 1 hour, preferably at room temperature.
  • the product obtained is Posaconazole, Form A claimed in the present invention.
  • Said process comprises:
  • step i) keeping under vacuum at room temperature during at least 3 hours, or during 6 hours, or during about 18 hours Posaconazole, Form A; ii) bringing the product resulting from step i) at a temperature ranging between 35 and 50° C, or between 37 and 45° C, or between 38 and 43° C, preferably at about 40° C under vacuum, where said conditions are kept for at least 30 minutes, or for at least 60 minutes, preferably for about 90 minutes.
  • the resulting product is Posaconazole, amorphous solid having the XRPD spectrum a's set forth in Fig. 20.
  • the following table 3 sets forth the spectrum significant peaks .
  • Said crystalline form and said amorphous solid of Posaconazole can find application in pharmaceutical compositions.
  • the pharmaceutical composition comprising said crystalline form and/or said amorphous solid may contain additives, such as sweeteners, flavors, coating substances, inert diluents, such as lactose and talc, binders, such as starch, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Any conventional technique can be uses for preparing pharmaceutical formulations in accordance with the present invention.
  • Example 1 Preparation of Posaconazole, Form A, lab scale .
  • Posaconazole, Form I were loaded in a flask. Increasing amounts of acetone were added under stirring at room temperature until complete dissolution of the solid to verify the saturation concentration. A total amount of 16.5 ml was added, corresponding to a concentration of about 23g/l.
  • Posaconazole, Form I were loaded in a 250-mL reactor with 100 ml acetone. The suspension was kept under stirring (150 rpm) at 25° C. after an hour, the powder was not completely dissolved. The reactor was heated to 35° C, thus obtaining a complete dissolution. 100 ml water was added as the antisolvent (1/1 v/v) under stirring in about 2 minutes (3 L/h) . The formation of the precipitate was almost immediate. In a few seconds, the reactor was packed by the solid, whereby the stirring was brought to 200 rpm. The suspension was cooled to 20° C in an hour: the stirring was not able to move the solid present in the upper portion of the reactor.
  • the reactor was then unloaded of the suspension and washed three times with water using 100 ml of it for every washing.
  • the suspension was filtered under vacuum for 10 minutes.
  • the solid was analyzed by XRPD immediately after the filtration ("wet") and after drying at room temperature and pressure (“dry”) .
  • the analysis led to the scattering pattern set forth in Fig. 10. About 2.4 g hydrate was obtained.
  • the solid was analyzed by XRPD immediately after the filtration ("wet") and after drying at room temperature and pressure ("dry”) .
  • the analysis led to the scattering pattern set forth in Fig. 12. About 1.3 g of hydrate was obtained .
  • the solid was analyzed by XRPD immediately after the filtration ("wet") and after drying at room temperature and pressure ("dry”) .
  • the analysis led to the scattering pattern set forth in Fig. 13. About 1.3 g of hydrate were obtained.
  • Example 6 Preparation of Posaconazole, Form A, scale up . 15 g Posaconazole, Form I were loaded in a 2 L reactor with 1 L acetone. The suspension was kept under stirring
  • Example 8 Preparation of Posaconazole, Form A, optimized process scale up.
  • the room temperature drying process does not induce a phase transition in the samples: the weak widening observed suggests a light amorphization of the sample.
  • the antisolvent addition rate does not affect the crystallization process, therefore, it should not be considered as a critical parameter.
  • the concentration of Posaconazole, Form I also if it is not to be considered as problematic for the polymorphism, was observed to heavily affect the workability of the suspension, given the formation of a tacky solid during the precipitation. The results are summarized in the following Table 4.
  • the XRPD spectrum of the product obtained by keeping 18 hours Posaconazole, Form A at room temperature is set forth in Fig. 19.
  • the XRPD spectrum peaks are set forth in Table 6.
  • Example 11 Preparation of Posaconazole, amorphous solid, starting from Posaconazole, Form A.
  • Posaconazole, Form A of the present invention is kept for 18 hours under vacuum at room temperature.
  • the obtained product has a low crystallinity, as showed by the XRPD spectrum in Fig. 19.
  • the low-crystallinity product is then re-heated to a 40° C temperature and kept at such temperature under vacuum for 90 minutes.
  • the product obtained at the end of the further drying step is Posaconazole, amorphous solid, characterized by the XRPD spectrum of Fig. 20.
  • Posaconazole, Form A of the present invention is a particularly stable form, the manufacturing process of which was implemented on a large scale, while keeping the chemical-physical characteristics of the obtained product unaltered. Therefore, the Posaconazole ' Form A described and claimed herein is a form of Posaconazole advantageous by virtue of the stability characteristics it showed. Furthermore, Posaconazole, Form A of the present invention results in obtaining Posaconazole, amorphous solid when exposed to the drying conditions described and claimed herein.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Macromonomer-Based Addition Polymer (AREA)
  • Liquid Crystal Substances (AREA)
  • Paints Or Removers (AREA)

Abstract

Cette invention concerne une nouvelle forme cristalline de Posaconazole, appelée forme A, présentant de nouvelles caractéristiques physicochimiques spécifiques, ainsi qu'une composition pharmaceutique la comportant. Cette invention se rapporte à un procédé pour préparer ledit Posaconazole, la forme A de Posaconazole, et un solide amorphe obtenu à partir de la forme A de Posaconazole.
PCT/IB2014/066592 2013-12-18 2014-12-04 Forme cristalline de posaconazole WO2015092595A1 (fr)

Applications Claiming Priority (2)

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ITMI2013A002114 2013-12-18
IT002114A ITMI20132114A1 (it) 2013-12-18 2013-12-18 Una forma cristallina di posaconazolo

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017032908A1 (fr) 2016-07-08 2017-03-02 Synthon B.V. Composition pharmaceutique comprenant du posaconazole amorphe
EP3342399A1 (fr) 2016-12-31 2018-07-04 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques comprenant du posaconazole et procédé de fabrication
JP2018528247A (ja) * 2015-09-23 2018-09-27 バイオコン・リミテッドＢｉｏｃｏｎ Ｌｉｍｉｔｅｄ 結晶形態のポサコナゾール中間体および非晶質ポサコナゾールの調製のためのプロセス

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995017407A1 (fr) 1993-12-21 1995-06-29 Schering Corporation Tetrahydrofuranes antifongiques
WO1996038443A1 (fr) 1995-06-02 1996-12-05 Schering Corporation Antifongiques au tetrahydrofurane
WO1999018097A1 (fr) 1997-10-07 1999-04-15 Schering Corporation Olymorphe antifongique cristallin
WO2009147075A2 (fr) * 2008-06-02 2009-12-10 Sandoz Ag Compositions pharmaceutiques contenant une forme cristalline de posaconazole
EP2141159A1 (fr) * 2008-07-03 2010-01-06 Sandoz AG Formule cristalline de posaconazole
WO2011003992A1 (fr) * 2009-07-09 2011-01-13 Sandoz Ag Forme cristalline du posaconazole
WO2011158248A2 (fr) 2010-05-12 2011-12-22 Glenmark Generics Limited Procédé pour la préparation de posaconazole et forme polymorphique cristalline v de posaconazole
WO2013042138A2 (fr) * 2011-09-19 2013-03-28 Msn Laboratories Limited Procédé pour la préparation de médicament antifongique triazole, ses intermédiaires et polymorphes de celui-ci

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995017407A1 (fr) 1993-12-21 1995-06-29 Schering Corporation Tetrahydrofuranes antifongiques
WO1996038443A1 (fr) 1995-06-02 1996-12-05 Schering Corporation Antifongiques au tetrahydrofurane
WO1999018097A1 (fr) 1997-10-07 1999-04-15 Schering Corporation Olymorphe antifongique cristallin
WO2009147075A2 (fr) * 2008-06-02 2009-12-10 Sandoz Ag Compositions pharmaceutiques contenant une forme cristalline de posaconazole
EP2141159A1 (fr) * 2008-07-03 2010-01-06 Sandoz AG Formule cristalline de posaconazole
WO2010000668A1 (fr) 2008-07-03 2010-01-07 Sandoz Ag Forme cristalline de posaconazole
WO2011003992A1 (fr) * 2009-07-09 2011-01-13 Sandoz Ag Forme cristalline du posaconazole
WO2011158248A2 (fr) 2010-05-12 2011-12-22 Glenmark Generics Limited Procédé pour la préparation de posaconazole et forme polymorphique cristalline v de posaconazole
WO2013042138A2 (fr) * 2011-09-19 2013-03-28 Msn Laboratories Limited Procédé pour la préparation de médicament antifongique triazole, ses intermédiaires et polymorphes de celui-ci

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018528247A (ja) * 2015-09-23 2018-09-27 バイオコン・リミテッドＢｉｏｃｏｎ Ｌｉｍｉｔｅｄ 結晶形態のポサコナゾール中間体および非晶質ポサコナゾールの調製のためのプロセス
JP7054381B2 (ja) 2015-09-23 2022-04-13 バイオコン・リミテッド 結晶形態のポサコナゾール中間体および非晶質ポサコナゾールの調製のためのプロセス
WO2017032908A1 (fr) 2016-07-08 2017-03-02 Synthon B.V. Composition pharmaceutique comprenant du posaconazole amorphe
EP3342399A1 (fr) 2016-12-31 2018-07-04 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques comprenant du posaconazole et procédé de fabrication

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