WO2016192691A1 - Solid forms of daclatasvir - Google Patents

Solid forms of daclatasvir Download PDF

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Publication number
WO2016192691A1
WO2016192691A1 PCT/CZ2016/000058 CZ2016000058W WO2016192691A1 WO 2016192691 A1 WO2016192691 A1 WO 2016192691A1 CZ 2016000058 W CZ2016000058 W CZ 2016000058W WO 2016192691 A1 WO2016192691 A1 WO 2016192691A1
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WO
WIPO (PCT)
Prior art keywords
daclatasvir
salt
exhibits
acid
ray powder
Prior art date
Application number
PCT/CZ2016/000058
Other languages
English (en)
French (fr)
Inventor
Pavel ZVATORA
Ondrej Dammer
Lukas KREJCIK
Marcela Tkadlecova
Jakub Hert
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2016192691A1 publication Critical patent/WO2016192691A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention relates to new solid forms of Methyl [(25)-l- ⁇ (2S)-2-[4-(4'- ⁇ 2-[(2S)-l- ⁇ (2S)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl ⁇ -2-pyrrolidinyl]- 1 H-imidazol-4-yl ⁇ -4- biphenylyl)- 1 H-imidazol-2-yl] - 1 -pyrrolidinyl ⁇ -3 -methyl- 1 -oxo-2-butany 1] carbamate of formula I,
  • 1009119-64-5 belongs to the group of antiviral agents suitable for the treatment of hepatitis
  • Daclatasvir dihydrochloride has been approved under the trade name Daklmza by the organization European Medicines Agency (EMA) for hepatitides of C type.
  • EMA European Medicines Agency
  • the invention provides new solid forms of daclatasvir in the form of pharmaceutically acceptable salts with inorganic and organic acids and methods of their preparation. These salts are prepared by reaction of daclatasvir in the basic form (formula I) with selected acids in a suitable solvent or mixtures of solvents.
  • the prepared new solid forms have suitable physical-chemical characteristics for use in the pharmaceutical industry and formulation of new dosage forms.
  • Figure 22 1H NMR spectrum of daclatasvir besylate (according to Example 9)
  • Figure 23 X-Ray powder pattern of daclatasvir maleate (according to Example 10)
  • Figure 29 X-Ray powder pattern of daclatasvir fumarate (1 :1) (according to Example 12)
  • Figure 30 DSC record of the amorphous form of daclatasvir fumarate (1:1) (according to
  • Figure 32 X-Ray powder pattern of daclatasvir fumarate (1:2) (according to Example 13)
  • Figure 33 DSC record of the amorphous form of daclatasvir fumarate (1:2) (according to
  • Salts of pharmaceutically active substances generally have higher solubility and bioavailability than their corresponding basic forms.
  • This invention provides salts of daclatasvir in the solid phase in amorphous forms, in a crystalline form, or in a mixed amorphous and crystalline form.
  • the invention provides novel solid forms of daclatasvir with hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and methanesulfonic acid in variable molar ratios.
  • the molar ratios of 2: 1, 1 :1 and 1 :2 are preferred.
  • novel solid forms of daclatasvir with these 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.
  • novel solid forms can be both anhydrous and/or non-solvated, and they can have the form of hydrates/solvates of the respective solvents.
  • the prepared new solid forms of daclatasvir may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratios.
  • novel solid forms are suitable for preparation of daclatasvir with a high chemical purity.
  • Preparation of the novel solid forms of daclatasvir is performed by reaction of the free base with hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or methanesulfonic 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.
  • Aliphatic Ci-C 4 alcohols, esters or their mixtures are preferred.
  • the most commonly used solvents are ethyl acetate, methanol, ethanol, water or their mixtures.
  • the final product is typically precipitated or crystallized at temperatures in the range of -30°C to the boiling point of the solvent.
  • an amorphous form of daclatasvir dihydrochloride is preferred, which, due to its amorphous character, has higher solubility and bioavailability than the corresponding crystalline form.
  • the prepared amorphous forms of daclatasvir dihydrochloride show a high glass transition temperature, which makes them sufficiently stable for use in dosage forms. It has been found out that during storage of amorphous daclatasvir dihydrochloride at the temperature of 80°C and relative air humidity of 75% for at least three days no changes of its amorphous purity or changes of the amorphous character of the sample occur.
  • daclatasvir maleate and daclatasvir fumarate are preferred. These crystalline forms of daclatasvir can be prepared and isolated with high chemical purity.
  • the prepared novel solid forms of daclatasvir can be used as an alternative of the crystalline form of daclatasvir dihydrochloride for the composition of a new medicinal product.
  • Crystalline daclatasvir dihydrochloride was prepared according to the procedure disclosed in a patent (WO 2009/020828).
  • the free base of daclatasvir was prepared by neutralization of daclatasvir dihydrochloride with the use of a solution of sodium hydroxide according to the procedure described in Example 1.
  • the X-ray powder pattern of the free base of daclatasvir (prepared according to Example 1) is shown in Fig. 1.
  • the DSC record of the free base of daclatasvir (prepared according to Example 1) is shown in Fig. 2.
  • the glass transition temperature of the free base of daclatasvir is 121°C.
  • the X-ray powder pattern of the amorphous form of daclatasvir dihydrochloride (prepared according to Example 2) is shown in Fig. 3.
  • the DSC record of daclatasvir dihydrochloride (prepared according to Example 2) is shown in Fig. 4. According to this example the glass transition temperature of daclatasvir dihydrochloride is 191°C.
  • the X-ray powder pattern of the amorphous form of daclatasvir dihydrochloride (prepared according to Example 3) is shown in Fig. 5.
  • the DSC record of daclatasvir dihydrochloride (prepared according to Example 3) is shown in Fig. 6. According to this example the glass transition temperature of daclatasvir dihydrochloride is 187°C.
  • the X-ray powder pattern of the amorphous form of daclatasvir dihydrobromide (prepared according to Example 4) is shown in Fig. 7.
  • the DSC record of daclatasvir dihydrobromide (prepared according to Example 4) is shown in Fig. 8. According to this example the glass transition temperature of daclatasvir dihydrobromide is 183°C.
  • the X-ray powder pattern of the amorphous form of daclatasvir dihydrobromide (prepared according to Example 5) is shown in Fig. 9.
  • the DSC record of daclatasvir disulphate (prepared according to Example 5) is shown in Fig. 10. According to this example the glass transition temperature of daclatasvir disulphate is 176°C.
  • the crystalline form of daclatasvir naphtalene sulfonate (1 :1) is characterized by the reflections presented in Table 1.
  • Table 1 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of daclatasvir tosylate in accordance with this invention are: 5.0; 6.3; 10.2; 13.7; 18.6 and 21.0 ⁇ 0.2 0 2-theta.
  • the X-ray powder pattern is shown in Fig. 11.
  • the melting point of daclatasvir naphthalene sulfonate (1 :1) ( Figure 12) is 97°C and 223°C (DSC).
  • Figure 13 shows an example of 1H NMR spectrum of the prepared daclatasvir naphtalene sulfonate (prepared according to Example 6).
  • the crystalline form of daclatasvir tosylate (1 :1) is characterized by the reflections presented in Table 2, Table 2 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of daclatasvir tosylate in accordance with this invention are: 5.0; 6.3; 10.2; 13.7; 18.6 and 21.0 ⁇ 0.2 0 2-theta.
  • the X-ray powder pattern is shown in Fig. 14.
  • the melting point of daclatasvir tosylate (1 :1) ( Figure 15) is 122°C and 234°C (DSC).
  • Figure 16 shows an example of the ! H N R spectrum of the prepared daclatasvir tosylate (prepared according to Example 7).
  • the X-ray powder pattern of daclatasvir mesylate (prepared according to Example 8) is shown in Fig. 17.
  • the DSC record of daclatasvir mesylate (prepared according to Example 8) is shown in Fig. 18. According to this example, the glass transition temperature of daclatasvir mesylate is 103°C.
  • Figure 19 shows an example of 1H NMR spectrum of the prepared daclatasvir mesylate (prepared according to Example 8).
  • the X-ray powder pattern of daclatasvir besylate (prepared according to Example 9) is shown in Fig. 20.
  • the DSC record of daclatasvir besylate (prepared according to Example 9) is shown in Fig. 21.
  • the glass transition temperature of daclatasvir besylate is 108°C.
  • Figure 22 shows an example of the 1 H NMR spectrum of the prepared daclatasvir besylate (prepared according to Example 9).
  • the crystalline form of daclatasvir maleate (1:1) is characterized by the reflections presented in Table 3.
  • Table 3 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of daclatasvir maleate in accordance with this invention are: 9.1; 15.8; 17.9; 21.5; 24.7 and 26.3 ⁇ 0.2 ° 2-theta.
  • the X-ray powder pattern is shown in Fig. 23. Table 3
  • the melting point of daclatasvir maleate (1:1) ( Figure 24) is 165°C (DSC).
  • Figure 25 shows an example of 1H NMR spectrum of the prepared daclatasvir maleate (prepared according to Example 10).
  • the crystalline form of daclatasvir maleate (1:2) is characterized by the reflections presented in Table 4.
  • Table 4 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of daclatasvir maleate in accordance with this invention are: 9.0; 15.6; 17.8; 21.4; 23.0 and 24.5 ⁇ 0.2 0 2-theta.
  • the X-ray powder pattern is shown in Fig. 26. Table 4
  • the melting point of daclatasvir maleate (1:2) ( Figure 27) is 166°C (DSC).
  • Figure 28 shows an example of 1H NMR spectrum of the prepared daclatasvir maleate (prepared according to Example 11).
  • the crystalline form of daclatasvir fumarate (1:1) is characterized by the reflections presented in Table 5.
  • Table 5 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of daclatasvir fumarate in accordance with this invention are: 8.1 ; 11.7; 15.1 ; 20.3; 22.7 and 24.4 ⁇ 0.2 0 2-theta.
  • the X-ray powder pattern is shown in Fig. 29. Table 5
  • the melting point of daclatasvir fumarate (1:1) ( Figure 30) is 112°C and 179°C (DSC).
  • Figure 31 shows an example of 1H NMR spectrum of the prepared daclatasvir fumarate (prepared according to Example 12).
  • the crystalline form of daclatasvir fumarate (1:2) is characterized by the reflections presented in Table 6.
  • Table 6 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of daclatasvir fumarate in accordance with this invention are: 6.6; 8.2; 13.0; 15.4 and 20.5 ⁇ 0.2 0 2-theta.
  • the X-ray powder pattern is shown in Figure 32.
  • the melting point of daclatasvir fumarate (1 :1) ( Figure 33) is 154°C and 200°C (DSC).
  • Figure 34 shows an example of l H NMR spectrum of the prepared daclatasvir fumarate (prepared according to Example 13).
  • 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.
  • ATR (Ge - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS Br detector, in the measurement range of 600-4000 cm “1 and the spectral resolution of 4.0 cm “1 .
  • the data were obtained at 64 spectrum accumulations.
  • the OMNIC 6.2 software was used to process the spectra.
  • the records of the novel solid forms of daclatasvir were measured with the Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ ) was between 4-5 and 5 mg and the heating rate was 5°C/min.
  • As the carrier gas 5.0 N 2 was used at the flow of 50 ml /min.
  • Crystalline daclatasvir dihydrochloride was prepared according to the procedure disclosed in a patent (WO 2009/020828).
  • the obtained solution was thoroughly shaken.
  • the organic solvent layer was separated from the aqueous phase, washed with 8 ml of water.
  • Crystalline daclatasvir dihydrochloride prepared according to Example 1 in the amount of 300 mg was dissolved in 1.5 ml of methanol at 40°C.
  • the resulting solution was filtered and evaporated in a vacuum evaporator at the temperature of 45 °C and pressure of 2 kPa.
  • the resulting product was left to dry in a vacuum drier at the temperature of 40 °C and the pressure of 20 kPa for 12 hours.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/CZ2016/000058 2015-05-29 2016-05-26 Solid forms of daclatasvir WO2016192691A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-366A CZ2015366A3 (cs) 2015-05-29 2015-05-29 Pevné formy Daclatasviru
CZPV2015-366 2015-05-29

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021927A2 (en) 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2009020825A1 (en) * 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Process for synthesizing compounds useful for treating hepatitis c
WO2009020828A1 (en) 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt
WO2015109445A1 (zh) * 2014-01-21 2015-07-30 杭州普晒医药科技有限公司 一种化合物的盐及晶型或无定型物、其制备方法、含有它们的药物组合物和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021927A2 (en) 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2009020825A1 (en) * 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Process for synthesizing compounds useful for treating hepatitis c
WO2009020828A1 (en) 2007-08-08 2009-02-12 Bristol-Myers Squibb Company Crystalline form of methyl ((1s)-1-(((2s)-2-(5-(4'-(2-((2s)-1-((2s)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1h-imidazol-5-yl)-4-biphenylyl)-1h-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt
WO2015109445A1 (zh) * 2014-01-21 2015-07-30 杭州普晒医药科技有限公司 一种化合物的盐及晶型或无定型物、其制备方法、含有它们的药物组合物和用途

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