WO2016192692A1 - Formes solides d'alafénamide de ténofovir - Google Patents

Formes solides d'alafénamide de ténofovir Download PDF

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Publication number
WO2016192692A1
WO2016192692A1 PCT/CZ2016/000059 CZ2016000059W WO2016192692A1 WO 2016192692 A1 WO2016192692 A1 WO 2016192692A1 CZ 2016000059 W CZ2016000059 W CZ 2016000059W WO 2016192692 A1 WO2016192692 A1 WO 2016192692A1
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WIPO (PCT)
Prior art keywords
tenofovir alafenamide
acid
solid form
exhibits
temperature
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PCT/CZ2016/000059
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English (en)
Inventor
Ondrej Dammer
Tereza SKALICKA
Lukas KREJCIK
Tomas Pekarek
Ludek Ridvan
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Zentiva K.S.
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Publication of WO2016192692A1 publication Critical patent/WO2016192692A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the invention relates to novel solid forms of (S)-isopropyl-2-(((5)-((((i-)-l-(6-amino- purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)arnino)propanoate formula (I),
  • Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor and an innovative prodrug of the pharmaceutical substance tenofovir. It is suitable for the treatment of HIV infection and viral hepatitis B. Compared to the currently used tenofovir tenofovir disoproxil, tenofovir alafenamide exhibits higher efficiency (the pharmaceutical composition will probably require a lower strength of the active ingredient), better patient tolerance (fewer side effects) and better distribution to lymphoid tissues. Tenofovir alafenamide is in Phase 3 clinical trials and it is expected to be present in the pharmaceutical composition in the form of a salt - fumarate or hemifumarate.
  • compositions are further expected to include, besides tenofovir alafenamide (hemi)iumarate, another active ingredient(s) acting as HTV protease inhibitors, HIV nucleotide/nucleotide reverse transcriptase inhibitors, CCR5 inhibitors - e.g. emtricitabine, cobicistat, elvitegravir, darunavir.
  • the patent application WO2013/025788 describes preparation and characterization of tenofovir alafenamide hemifumarate.
  • the main advantage of this salt is its ability to eliminate the principal diastereoisomeric impurity (GS7339) of tenofovir alafenamide as compared to the fumarate salt. Additionally, the hemifumarate salt exhibits better chemical and thermodynamical stability, low hygroscopicity (it absorbs 0.65% of water at 90% rel. humidity) and a higher melting point than the fumarate salt of tenofovir alafenamide.
  • the patent application WO2013/025788 also describes pharmaceutical compositions containing tenofovir alafenamide in the hemifumarate form.
  • the invention provides new solid forms of tenofovir alafenamide (salts, cocrystals) with inorganic and organic acids and methods for preparing the same. These substances are prepared by a reaction of tenofovir alafenamide with a selected acid in a suitable solvent or a mixture of solvents.
  • the prepared novel solid forms are of a crystalline or amorphous character and are prepared in a purity corresponding to the demands for their possible pharmaceutical use in formulation of new dosage forms.
  • Figure 1 X-ray powder pattern of the solid form of tenofovir alafenamide and hydrochloric acid (1:1)
  • Figure 2 DSC record of the solid form of tenofovir alafenamide and hydrochloric acid (1:1)
  • Figure 3 Infrared spectrum of the solid form of tenofovir alafenamide and hydrochloric acid (1:1)
  • Figure 4 X-ray powder pattern of the solid form of tenofovir alafenamide and hydrobromic acid (1:1)
  • Figure 5 DSC record of the solid form of tenofovir alafenamide and hydrobromic acid (1:1)
  • Figure 6 Infrared spectrum of the solid form of tenofovir alafenamide and hydrobromic acid (1:1)
  • Figure 7 X-ray powder pattern of the solid form of tenofovir alafenamide and sulphuric acid (1:1)
  • Figure 10 X-ray powder pattern of the solid form of tenofovir alafenamide and phosphoric acid (1: 1)
  • Figure 11 DSC record of the solid form of tenofovir alafenamide and phosphoric acid (1:1)
  • Figure 12 Infrared spectrum of the solid form of tenofovir alafenamide and phosphoric acid (1:1)
  • Figure 13 X-ray powder pattern of the solid form of tenofovir alafenamide and maleic acid 0:1)
  • Figure 15 Infrared spectrum of the solid form of tenofovir alafenamide and maleic acid (1:1)
  • Figure 16 X-ray powder pattern of the solid form of tenofovir alafenamide and citric acid (1:1)
  • Figure 17 DSC record of the solid form of tenofovir alafenamide and citric acid (1:1)
  • Figure 18 Infrared spectrum of the solid form of tenofovir alafenamide and citric acid (1:1)
  • Figure 19 X-ray powder pattern of the solid form of tenofovir alafenamide and succinic acid (1 :1)
  • Figure 20 DSC record of the solid form of tenofovir alafenamide and succinic acid (1:1)
  • Figure 21 Infrared spectrum of the solid form of tenofovir alafenamide and succinic acid (1:1)
  • Figure 22 X-ray powder pattern of the solid form of tenofovir alafenamide and tartaric acid (1 :1)
  • Figure 23 DSC record of the solid form of tenofovir alafenamide and tartaric acid (1 :1)
  • Figure 24 Infrared spectrum of the solid form of tenofovir alafenamide and tartaric acid (1:1)
  • Figure 25 X-ray powder pattern of the solid form of tenofovir alafenamide and gallic acid (1:1)
  • Figure 26 DSC record of the solid form of tenofovir alafenamide and gallic acid (1:1)
  • Figure 27 Infrared spectrum of the solid form of tenofovir alafenamide and gallic acid (1:1)
  • Figure 28 X-ray powder pattern of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1)
  • Figure 30 Infrared spectrum of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1)
  • Figure 31 X-ray powder pattern of the solid form of tenofovir alafenamide and salicylic acid (1:1)
  • Figure 32 DSC record of the solid form of tenofovir alafenamide and salicylic acid (1:1)
  • Figure 33 Infrared spectrum of the solid form of tenofovir alafenamide and salicylic acid (1:1)
  • Figure 34 X-ray powder pattern of the solid form of tenofovir alafenamide and 4- aminobenzoic acid (1:1)
  • Figure 36 Infrared spectrum of the solid form of tenofovir alafenamide and 4-aminobenzoic acid (1:1)
  • compositions represent a wide group of solid forms of active pharmaceutical ingredients, they can exist in the form of hydrates/solvates. They usually exhibit better solubility and the related biological availability as compared to the neutral forms. They also tend to be chemically and thermodynamically more stable. Therefore, pharmaceutical salts/cocrystals are frequently used as active ingredients in the final pharmaceutical compositions.
  • the invention provides novel solid forms of tenofovir alafenamide with the following inorganic or organic acid: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, DL-tartaric, benzenesulfonic, salicylic, 4-aminobenzoic and gallic acid in various molar ratios, the molar ratio of 1:1 being preferred.
  • the invention provides crystalline or amorphous solid forms of tenofovir alafenamide or mixtures of amorphous and crystalline forms; crystalline forms are preferred.
  • novel solid forms of tenofovir alafenamide with the said inorganic or organic acids can be prepared in adequate ratios and yields with high chemical purity in a crystalline form, amorphous form, or in a mixture of amorphous and crystalline forms.
  • the prepared new solid forms of tenofovir alafenamide may exhibit various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystalline or amorphous forms or their mixtures in any ratio. These novel solid forms can be both anhydrous or non-solvated, and they can have the form of hydrates/solvates of the respective solvents.
  • Preparation of the novel solid forms of tenofovir alafenamide is carried out by reaction of tenofovir alafenamide with the corresponding acid, which is selected from the following group: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, DL-tartaric, benzenesulfonic, salicylic, 4-aminobenzoic and gallic acid.
  • the reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Acetonitrile can be preferably used.
  • Esters of a C3 to C5 alcohol and CI to C4 acids are preferred; the ester is preferably selected such that the total number of carbon atoms is 5 to 8.
  • the ester may be composed of primary, secondary or tertiary alcohols.
  • the carbon skeleton of the acid may be linear or branched.
  • esters of carbonic acid with C1-C3 alcohols can be used.
  • the above mentioned esters may be used either pure or in a mixture with another solvent, referred to as a co-solvent. Less polar solvents are selected as the co-solvents.
  • C6 to C9 aromatics or C6 to C9 alicyclic hydrocarbons, or CI to C4 chlorinated hydrocarbons, substituted with one or more chlorine atoms have proved to be suitable.
  • Examples may include cyclohexane, toluene or dichloromethane.
  • the resulting product is typically crystallized or precipitated at temperatures in the range of -10 to 75°C.
  • tenofovir alafenamide can be used for the preparation of tenofovir alafenamide fumarate or hemifumarate.
  • the crystalline solid form of tenofovir alafenamide and hydrochloric acid (1:1) is characterized by the reflections presented in Table 1.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and hydrochloric acid in accordance with this invention are: 3.4; 8.5; 10.4; 13.4; 14.8; 18.2 and 19 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 1.
  • the crystalline solid form of tenofovir alafenamide and hydrobromic acid (1:1) is characterized by the reflections presented in Table 2.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and hydrobromic acid in accordance with this invention are: 3.4; 10.5; 18.4; 21.1 and 24.3; ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 4.
  • the melting point of the solid form of tenofovir alafenamide and hydrobromic acid (1:1) is 35°C (DSC).
  • the crystalline solid form of tenofovir alafenamide and sulphuric acid (1:1) is characterized by the reflections presented in Table 3.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and sulphuric acid in accordance with this invention are: 3.6; 9.2; 18.5; 22.4 and 24.5 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 7.
  • the melting point of the solid form of tenofovir alafenamide and sulphuric acid (1 :1) is 115°C (DSC).
  • the crystalline solid form of tenofovir alafenamide and phosphoric acid (1:1) is characterized by the reflections presented in Table 4.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and phosphoric acid in accordance with this invention are: 3.4; 8.1; 10.2; 13.6; 17.0 and 18,9 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Figure 10.
  • the crystalline solid form of tenofovir alafenamide and maleic acid (1 :1) is characterized by the reflections presented in Table 5.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and maleic acid in accordance with this invention are: 4.5; 7.7; 12.5; 17.9; 20.9 and 25.6 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Figure 13.
  • the melting point of the solid form of tenofovir alafenamide and maleic acid (1:1) ( Figure 14) is 98°C (DSC).
  • the crystalline solid form of tenofovir alafenamide and citric acid (1:1) is characterized by the reflections presented in Table 6.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and citric acid in accordance with this invention are: 5.8; 8.0; 12.6; 15.9; 17.9; 20.5 and 26.9 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Figure 16.
  • the melting point of the solid form of tenofovir alafenamide and citric acid (1:1) ( Figure 17) is 148°C (DSC).
  • the crystalline solid form of tenofovir alafenamide and succinic acid (1:1) is characterized by the reflections presented in Table 7.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and succinic acid in accordance with this invention are: 5.3; 9.4; 10.5; 14.1 ; 16.9 and 21.6 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 19.
  • the melting point of the solid form of tenofovir alafenamide and succinic acid (1:1) is 108°C (DSC).
  • the crystalline solid form of tenofovir alafenamide and DL-tartaric acid (1:1) is characterized by the reflections presented in Table 8.
  • the characteristic diffraction peaks of the solid form of tenofovir alafenamide and tartaric acid in accordance with this invention are: 3.7; 8.0; 9.6; 16.8; 18.2; 18.9 and 20.5 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Figure 22.
  • the solid form of tenofovir alafenamide and gallic acid (1 :1) corresponds to a prominently amorphous form and is characterized by the diffractogram shown in Figure 25.
  • the diffractogram may contain reflections at 12.4; 19 and 26.1 ⁇ 0.2° 2-theta.
  • the melting point of the solid form of tenofovir alafenamide and gallic acid (1:1) ( Figure 26) is 125°C (DSC).
  • the glass transition temperature of the amorphous solid form of tenofovir alafenamide and benzenesulfonic acid (1:1) (Figure 29) is 22°C (MDSC).
  • the glass transition temperature of the amorphous solid form of tenofovir alafenamide and salicylic acid (1:1) ( Figure 32) is 24°C (MDSC).
  • the glass transition temperature of the amorphous solid form of tenofovir alafenamide and 4-aminobenzoic acid (1:1) (Figure 35) is 34°C (MDSC).
  • a 10mm mask and a 1/4° fixed anti- dispersion slit were used.
  • the irradiated area of the sample is 10 mm, programmable divergence slits were used.
  • For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used. Infrared spectroscopy
  • ATR ZnSe - single reflection infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS detector, in the measurement range of 600-4000 cm “1 and the spectral resolution of 4.0 cm “1 . The data were obtained at 12 spectrum accumulations.
  • the OMNIC 8.3 software was used to process the spectra.
  • the DSC records were measured using a Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 iL was 1-5 mg.
  • As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.
  • the DSC method was used for the crystalline sample:
  • the temperature program that was used consists of 1 minute of stabilization at the temperature of -10°C and then of heating up to 300°C at the rate of 10°C/min.

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Abstract

La présente invention concerne une forme solide d'alafénamide de ténofovir avec un acide inorganique ou organique sélectionné parmi le groupe suivant : acide chlorhydrique, bromhydrique, sulfurique, phosphorique, maléique, citrique, succinique, tartrique, gallique, benzène sulfonique, salicylique, 4-aminobenzoïque. Un autre aspect de la présente invention prévoit une composition pharmaceutique, qui comprend la forme solide de l'alafénamide de ténofovir et au moins un excipient pharmaceutiquement acceptable, la composition étant utilisée comme médicament pour le traitement de l'infection par le VIH et l'hépatite virale B.
PCT/CZ2016/000059 2015-06-05 2016-05-30 Formes solides d'alafénamide de ténofovir WO2016192692A1 (fr)

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CZPV2015-384 2015-06-05
CZ2015-384A CZ2015384A3 (cs) 2015-06-05 2015-06-05 Pevné formy Tenofovir alafenamidu

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
WO2018115046A1 (fr) 2016-12-23 2018-06-28 Sandoz Ag Formes solides cristallines de ténofovir alafénamide
US10155781B2 (en) 2015-06-17 2018-12-18 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
US10287307B2 (en) 2017-01-31 2019-05-14 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2021165995A1 (fr) 2020-02-20 2021-08-26 Cipla Limited Nouveaux sels et/ou co-cristaux de ténofovir alafénamide
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide

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WO2002008241A2 (fr) 2000-07-21 2002-01-31 Gilead Sciences, Inc. Promedicaments a base d"analogues nucleotidiques de phosphonate et leurs methodes de selection et d"elaboration
WO2013025788A1 (fr) 2011-08-16 2013-02-21 Gilead Sciences, Inc. Hémifumarate de ténofovir alafénamide
WO2014195724A1 (fr) * 2013-06-07 2014-12-11 Cipla Limited Procédé efficace pour séparer les diastéréomères de la 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)éthyl]amino]phénoxyphosphinyl]méthoxy]propyl]-adénine
WO2015040640A2 (fr) * 2013-09-20 2015-03-26 Laurus Labs Private Limited Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci
WO2015107451A2 (fr) * 2014-01-14 2015-07-23 Mylan Laboratories Ltd. Purification de ténofovir alafénamide et de ses intermédiaires
WO2015176602A1 (fr) * 2014-05-20 2015-11-26 四川海思科制药有限公司 Complexe de ténofovir alafénamide, son procédé de préparation et utilisation

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WO2002008241A2 (fr) 2000-07-21 2002-01-31 Gilead Sciences, Inc. Promedicaments a base d"analogues nucleotidiques de phosphonate et leurs methodes de selection et d"elaboration
WO2013025788A1 (fr) 2011-08-16 2013-02-21 Gilead Sciences, Inc. Hémifumarate de ténofovir alafénamide
WO2014195724A1 (fr) * 2013-06-07 2014-12-11 Cipla Limited Procédé efficace pour séparer les diastéréomères de la 9-[(r)-2-[[(r,s)-[[(s)-1-(isopropoxycarbonyl)éthyl]amino]phénoxyphosphinyl]méthoxy]propyl]-adénine
WO2015040640A2 (fr) * 2013-09-20 2015-03-26 Laurus Labs Private Limited Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci
WO2015107451A2 (fr) * 2014-01-14 2015-07-23 Mylan Laboratories Ltd. Purification de ténofovir alafénamide et de ses intermédiaires
WO2015176602A1 (fr) * 2014-05-20 2015-11-26 四川海思科制药有限公司 Complexe de ténofovir alafénamide, son procédé de préparation et utilisation

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J. WOUTERS: "Pharmaceutical Salts and Co-crystals", 14 November 2011, RSC PUBLISHING, article "Chapter 16: Monographs of most Frequent Co-Crystal Formers", XP008180802, DOI: http://pubs.rsc.org/en/content/chapter/bk9781849731584-00338/978-1-84973-158-4#!divabstract *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10155781B2 (en) 2015-06-17 2018-12-18 Gilead Sciences, Inc. Co-crystals, salts and solid forms of tenofovir alafenamide
WO2018115046A1 (fr) 2016-12-23 2018-06-28 Sandoz Ag Formes solides cristallines de ténofovir alafénamide
US10287307B2 (en) 2017-01-31 2019-05-14 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
US11440928B2 (en) 2017-01-31 2022-09-13 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
CN107522743A (zh) * 2017-09-30 2017-12-29 深圳科兴生物工程有限公司 一种半富马酸替诺福韦艾拉酚胺工业化连续生产方法
WO2021165995A1 (fr) 2020-02-20 2021-08-26 Cipla Limited Nouveaux sels et/ou co-cristaux de ténofovir alafénamide
US11667656B2 (en) 2021-01-27 2023-06-06 Apotex Inc. Crystalline forms of Tenofovir alafenamide

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