WO2017032350A1 - Crystalline form a of rilpivirine adipate and a method of its preparation - Google Patents

Crystalline form a of rilpivirine adipate and a method of its preparation Download PDF

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Publication number
WO2017032350A1
WO2017032350A1 PCT/CZ2016/000090 CZ2016000090W WO2017032350A1 WO 2017032350 A1 WO2017032350 A1 WO 2017032350A1 CZ 2016000090 W CZ2016000090 W CZ 2016000090W WO 2017032350 A1 WO2017032350 A1 WO 2017032350A1
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rilpivirine
adipate
preparation
solution
thf
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PCT/CZ2016/000090
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French (fr)
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Josef Cerny
Josef Zezula
Marketa Slavikova
Ondrej Dammer
Tomas Pekarek
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Zentiva, K.S.
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Publication of WO2017032350A1 publication Critical patent/WO2017032350A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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

Definitions

  • Crystalline Form A of rilpivirine adipate and a method of its preparation Field of the Invention The invention relates to crystalline Form A of rilpivirine adipate of formula I, with the systematic name 4-((4-((4-((lE)-2-Cyanoethenyl)-2,6- dimethyIphenyl)amino)-2-pyrimidinyl) amino)benzo- nitrile adipate and a preparation method of this crystalline form.
  • Rilpivirine was developed by the company Tibotec for the treatment of HIV infection. It belongs to the group of second generation NNRTIs (non-nucleoside reverse transcriptase inhibitors).
  • US 7 125 879 specifically mentions rilpivirine.
  • This patent contains various preparation methods of rilpivirine.
  • US 2006/0111379 Al contains the rilpivirine hydrochloride salt and its polymorphic Form A.
  • This document also describes solvates or pseudosolvates of the polymorphic form of rilpivirine hydrochloride (Form B, C, D).
  • WO 2009/007441 describes crystalline rilpivirine of US 7 125 879 as polymorphic form II.
  • Rilpivirine polymorphic form II is characterized by diffraction peaks (8.5, 12.4, 12.9, 17.6, 21.0, 24.8, 25.8 and 27.9 ⁇ 0.2° 2-theta) and the melting point of 243.2°C (DSC).
  • This document mentions another polymorphic form of rilpivirine (Form I), characterized by diffraction peaks (9.0, 11.3, 14.3, 17.1, 19.2, 24.2 and 27.6 ⁇ 0.2° 2-theta) and the melting point of 257.5°C (DSC). Disclosure of the Invention
  • the object of the invention is a novel crystalline Form A of rilpivirine adipate of formula I and a method of its preparation.
  • Crystalline Form A of rilpivirine adipate of formula I is characterized by the following characteristic reflections in the X-ray powder pattern 5.6; 9.6; 14.6; 18.2; 22.1 and 25.5 ⁇ 0.2° 2-theta, which were measured with the use of CuKa radiation.
  • Form A of rilpivirine adipate of formula I according to this invention is characterized by the X-ray powder pattern shown in Figure 1. The diffraction peaks of this Form Are summarized in Table 1.
  • Rilpivirine adipate of formula I was measured with Differential Scanning Calonmetry (DSC) and exhibits the main onset temperature of 203°C (see fig. 2).
  • Rilpivirine adipate of formula I is characterized by the following absorption peaks in the IR spectrum 3301, 2220, 1693, 1582, 1409, 1227 a 1173 cm ' ⁇ see fig. 3).
  • Rilpivirine adipate of formula I was characterized by means of Dynamic Vapor Sorption (DVS) and exhibits linear vapor sorption; at 90% RH a sample absorbs 1.1% of water (see fig. 4).
  • DVD Dynamic Vapor Sorption
  • Fig. 2 DSC record of Form A of rilpivirine adipate of formula I
  • Fig. 3 IR spectrum of Form A of rilpivirine adipate of formula I
  • Fig. 4 DVS record of Form A of rilpivirine adipate of formula I Compared to the well-known forms, the obtained Form A of rilpivirine adipate exhibits better solubility and it mainly offers a high dissolution rate, which is advantageous especially with respect to preparation of the selected drug form.
  • Another object of the invention is a preparation method of rilpivirine adipate of formula I.
  • the preparation comprises the following steps:
  • a solution of rilpivirine base in suitable solvents in step a) can be obtained in two ways.
  • the first one is direct dissolution of rilpivirine base in etheric solvents as THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), in a preferred embodiment in a 2-Me-THF/isopropanol mixture at an elevated temperature.
  • the other method consists in dissolution or suspension of a suitable salt of rilpivirine in etheric solvents and neutralization of the solution/suspension by adding an aqueous solution of an inorganic base.
  • Suitable salts especially comprise a hydrochloride.
  • Suitable etheric solvents comprise mainly THF,
  • 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), in a preferred embodiment a 2-Me-THF/isopropanol mixture at an elevated temperature.
  • Suitable inorganic bases comprise especially LiOH, NaOH, KOH, K 2 C0 3 , Na 2 C0 3 , NaHC0 3 , and KHC0 3 ; in a preferred embodiment KOH is used.
  • the solution of rilpivirine base obtained in step a) is heated up to a higher temperature than 50°C in step b) and a solution of adipic acid in a suitable alcohol or an alcohol/water mixture starts to be added to the solution.
  • the addition rate is selected in such a way that the internal temperature of the solution of rilpivirine does not drop below 40°C.
  • Suitable alcohols comprise especially methanol, ethanol, «-propanol, isopropanol or tert-butanol, in a preferred embodiment a mixture of isopropanol and water is used.
  • a necessary precondition for the subsequent crystallization is that after completion of addition of the adipic acid solution a clear single-phase solution is obtained.
  • Adipic acid is added in the molar ratio of approximately 0.5 - 1 equivalent with respect to rilpivirine base, in a preferred embodiment 0.7 - 0.8 equivalents.
  • the solution obtained this way is inoculated in step c) at 40 ⁇ 5°C with the addition of 0.5 - 2% of Form A of rilpivirine adipate.
  • 1% of Form A of rilpivirine adipate is used.
  • the inoculation has an essential influence on product isolation.
  • a single-phase solution must be inoculated, otherwise there is a risk of obtaining a semi-crystalline or oily form of the product.
  • the suitably inoculated reaction mixture is subsequently cooled down to the isolation temperature in the range of 0 to -20°C, in a preferred embodiment to a temperature of - 10 ⁇ 1°C, which is followed by product isolation.
  • the product is washed with a suitable solvent or mixtures of solvents as ether - alcohol solvents, in a preferred embodiment with a mixture of 2-Me- THF/isopropanol or ketones as acetone, 2-butanone.
  • the product obtained this way is dried at an elevated temperature, preferably at 120 to 130°C.
  • Form A of rilpivirine adipate can be crystallized from suitable solvents as ethers (THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE)), ketones (acetone, 2-butanol, cyclohexanone) or carbonates (dimethyl carbonate, diethyl carbonate).
  • suitable solvents as ethers (THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE)
  • ketones acetone, 2-butanol, cyclohexanone
  • carbonates dimethyl carbonate, diethyl carbonate
  • Form A obtained this way is suitable for pharmaceutical application because Form A of rilpivirine adipate is very well soluble with a high dissolution rate, which are suitable conditions for using the compound for formulation of the final drug form.
  • a flat powder sample was used that was placed on a Si plate.
  • 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
  • For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
  • IR Spectroscopy The spectra were measured using a FTIR Nicolet Nexus device (Thermo, USA). Each spectrum was obtained by taking 12 scans in the resolution of 4 cm “1 .
  • the records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer. The sample charge in a standard Al pot was 3 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 300°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
  • the dynamic vapor sorption (DVS) records were measured with a DVS Advantage 1 device made by the company Surface Measurement Systems.
  • the sample charge in a quartz pot was 21 mg and the temperature in the device is between 25.2°C and 25.4°C.
  • Rilpivirine base (50 g; 136 mmol, purity (HPLC) 96.05%) is suspended in 750 ml of 2-Me- THF and 80 ml of 2-propanol and the reaction mixture is heated up to 65°C.
  • a prepared solution of adipic acid (14 g; 95 mmol) in 225 ml of isopropyl alcohol and 35 ml of water is added to the obtained solution by dripping at 65°C.
  • the clear solution is cooled down to 40°C and an inoculum of Form A of rilpivirine adipate (0.5 g) is added.
  • the resulting suspension is cooled down to 10°C.
  • the separated substance is aspirated and washed with a minimal quantity of a 2-Me-THF mixture.
  • the final product is then dried in a vacuum drier at 130°C.
  • the amount of 45 g (75% of the theoretical quantity, HPLC purity 98.14%) of crystalline Form A of rilpivirine adipate corresponding to the XRPD record presented in fig. 1 and DSC shown in fig. 2 was obtained.
  • Rilpivirine hydrochloride (2.8 kg; 6.95 mol, purity (HPLC) 94.18%) is suspended in a mixture of 2-Me-THF (38 1) and 2-propanol (4.2 1). The suspension is heated up to the temperature of 65°C. An aqueous solution of KOH (585 g in 5.5 1) is poured to the suspension and the reaction mixture is vigorously agitated for 30 minutes. The aqueous phase is separated and the organic phase is washed with 8 liters of water and then with 5 liters of a 10% NaCl solution.
  • the temperature of the solution is adjusted to 60°C and a solution of adipic acid (411 kg; 4.78 mol) in 11.5 1 of isopropanol and 1.8 1 of water is added.
  • the reaction mixture is cooled down to 40°C and an inoculum of Form A of rilpivirine adipate (30 g) is added.
  • 30 1 of distillate is removed from the obtained suspension by distillation.
  • the resulting suspension is cooled down to 10°C.
  • the separated substance is aspirated and washed with 3 1 of acetone.
  • the final product is then dried in a vacuum drier at 130°C.
  • Rilpivirine adipate (100 g, 228 mmol, purity (HPLC) 98.14%) is dissolved under boiling in 2.5 1 of acetone. The reaction mixture is concentrated by removing of 1.5 1 of acetone by distillation. The resulting suspension is cooled down to 10°C, the separated compound is aspirated and washed with acetone (0.3 1). The final product is then dried in a vacuum drier at 130°C. The amount of 92 g (92% of the theoretical quantity, purity (HPLC) 99.73%) of Form A of rilpivirine adipate corresponding to the XRPD record presented in fig. 1 and DSC shown in fig. 2 was obtained.

Abstract

The invention relates to crystalline Form A of rilpivirine adipate of formula I, with the systematic name 4-((4-((4-((lE)-2-Cyanoethenyl)-2,6- dimethyIphenyl)amino)-2-pyrimidinyl) amino)benzo- nitrile adipate and a preparation method of this crystalline form.

Description

Crystalline Form A of rilpivirine adipate and a method of its preparation Field of the Invention The invention relates to crystalline Form A of rilpivirine adipate of formula I, with the systematic name 4-((4-((4-((lE)-2-Cyanoethenyl)-2,6- dimethyIphenyl)amino)-2-pyrimidinyl) amino)benzo- nitrile adipate and a preparation method of this crystalline form.
Figure imgf000002_0001
Background Art
Rilpivirine was developed by the company Tibotec for the treatment of HIV infection. It belongs to the group of second generation NNRTIs (non-nucleoside reverse transcriptase inhibitors).
US 7 125 879 specifically mentions rilpivirine. This patent contains various preparation methods of rilpivirine. US 2006/0111379 Al contains the rilpivirine hydrochloride salt and its polymorphic Form A. This document also describes solvates or pseudosolvates of the polymorphic form of rilpivirine hydrochloride (Form B, C, D).
WO 2009/007441 describes crystalline rilpivirine of US 7 125 879 as polymorphic form II. Rilpivirine polymorphic form II is characterized by diffraction peaks (8.5, 12.4, 12.9, 17.6, 21.0, 24.8, 25.8 and 27.9 ± 0.2° 2-theta) and the melting point of 243.2°C (DSC). This document mentions another polymorphic form of rilpivirine (Form I), characterized by diffraction peaks (9.0, 11.3, 14.3, 17.1, 19.2, 24.2 and 27.6 ± 0.2° 2-theta) and the melting point of 257.5°C (DSC). Disclosure of the Invention
The object of the invention is a novel crystalline Form A of rilpivirine adipate of formula I and a method of its preparation. Crystalline Form A of rilpivirine adipate of formula I is characterized by the following characteristic reflections in the X-ray powder pattern 5.6; 9.6; 14.6; 18.2; 22.1 and 25.5 ± 0.2° 2-theta, which were measured with the use of CuKa radiation. Form A of rilpivirine adipate of formula I according to this invention is characterized by the X-ray powder pattern shown in Figure 1. The diffraction peaks of this Form Are summarized in Table 1.
Tab. 1: Diffraction peaks of Form A of rilpivirine adipate of formula I.
Pos. [°2Th.] d [A]=0.1nm Rel. Int. [%]
5.20 16.971 18.3
5.57 15.843 23.3
8.52 10.371 50.3
9.56 9.243 58.5
10.69 8.270 18.1
12.64 6.999 32.4
14.60 6.063 100.0
18.15 4.883 63.3
18.63 4.759 39.1
19.23 4.611 17.2
19.97 4.444 7.1
21.40 4.149 27.4
21.66 4.100 20.8
22.05 4.028 50.2
23.23 3.826 20.8
24.03 3.700 7.0
25.48 3.494 72.4 27.31 3.263 7.4
27.78 3.209 5.2
Pos. [°2Th.] d [A]=0.1nm Rel. Int. [%]
30.11 2.966 8.8
33.76 2.653 4.8
Rilpivirine adipate of formula I was measured with Differential Scanning Calonmetry (DSC) and exhibits the main onset temperature of 203°C (see fig. 2).
Rilpivirine adipate of formula I is characterized by the following absorption peaks in the IR spectrum 3301, 2220, 1693, 1582, 1409, 1227 a 1173 cm'^see fig. 3).
Rilpivirine adipate of formula I was characterized by means of Dynamic Vapor Sorption (DVS) and exhibits linear vapor sorption; at 90% RH a sample absorbs 1.1% of water (see fig. 4).
Brief Description of the Drawings Fig. 1: X-ray powder pattern of Form A of rilpivirine adipate of formula I
Fig. 2: DSC record of Form A of rilpivirine adipate of formula I
Fig. 3: IR spectrum of Form A of rilpivirine adipate of formula I
Fig. 4: DVS record of Form A of rilpivirine adipate of formula I Compared to the well-known forms, the obtained Form A of rilpivirine adipate exhibits better solubility and it mainly offers a high dissolution rate, which is advantageous especially with respect to preparation of the selected drug form.
Another object of the invention is a preparation method of rilpivirine adipate of formula I. The preparation comprises the following steps:
a) preparing a solution of rilpivirine base in suitable solvents by dissolving rilpivirine base or by neutralization of a suitable salt of rilpivirine in suitable solvents by addition of a solution of an inorganic base; b) heating up the obtained solution and adding a solution of adipic acid dissolved in an alcohol or in an alcohol/water mixture by dripping and
c) adding crystallization inocula of Form A of rilpivirine adipate, cooling the obtained solution, crystal growth, cooling to the isolation temperature and isolation.
A solution of rilpivirine base in suitable solvents in step a) can be obtained in two ways. The first one is direct dissolution of rilpivirine base in etheric solvents as THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), in a preferred embodiment in a 2-Me-THF/isopropanol mixture at an elevated temperature. The other methodconsists in dissolution or suspension of a suitable salt of rilpivirine in etheric solvents and neutralization of the solution/suspension by adding an aqueous solution of an inorganic base. Suitable salts especially comprise a hydrochloride. Suitable etheric solvents comprise mainly THF,
2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), in a preferred embodiment a 2-Me-THF/isopropanol mixture at an elevated temperature. Suitable inorganic bases comprise especially LiOH, NaOH, KOH, K2C03, Na2C03, NaHC03, and KHC03; in a preferred embodiment KOH is used.
The solution of rilpivirine base obtained in step a) is heated up to a higher temperature than 50°C in step b) and a solution of adipic acid in a suitable alcohol or an alcohol/water mixture starts to be added to the solution. The addition rate is selected in such a way that the internal temperature of the solution of rilpivirine does not drop below 40°C. Suitable alcohols comprise especially methanol, ethanol, «-propanol, isopropanol or tert-butanol, in a preferred embodiment a mixture of isopropanol and water is used. A necessary precondition for the subsequent crystallization is that after completion of addition of the adipic acid solution a clear single-phase solution is obtained. This can be achieved through a suitable selection of the temperature (above 40°C). Adipic acid is added in the molar ratio of approximately 0.5 - 1 equivalent with respect to rilpivirine base, in a preferred embodiment 0.7 - 0.8 equivalents.
The solution obtained this way is inoculated in step c) at 40 ± 5°C with the addition of 0.5 - 2% of Form A of rilpivirine adipate. In a preferred embodiment, 1% of Form A of rilpivirine adipate is used. The inoculation has an essential influence on product isolation. To obtain Form A of rilpivirine adipate a single-phase solution must be inoculated, otherwise there is a risk of obtaining a semi-crystalline or oily form of the product. The suitably inoculated reaction mixture is subsequently cooled down to the isolation temperature in the range of 0 to -20°C, in a preferred embodiment to a temperature of - 10±1°C, which is followed by product isolation. The product is washed with a suitable solvent or mixtures of solvents as ether - alcohol solvents, in a preferred embodiment with a mixture of 2-Me- THF/isopropanol or ketones as acetone, 2-butanone. The product obtained this way is dried at an elevated temperature, preferably at 120 to 130°C.
Form A of rilpivirine adipate can be crystallized from suitable solvents as ethers (THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE)), ketones (acetone, 2-butanol, cyclohexanone) or carbonates (dimethyl carbonate, diethyl carbonate).
Form A obtained this way is suitable for pharmaceutical application because Form A of rilpivirine adipate is very well soluble with a high dissolution rate, which are suitable conditions for using the compound for formulation of the final drug form.
Examples
The samples in the examples below were characterized using the X-ray Powder Diffraction, IR Spectroscopy and Differential Scanning Calorimetry (DSC) methods.
Measurement parameters of the X-ray powder diffraction: The diffractograms were measured using an X ERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ=0.1542 nm (1.542 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ. For the measurement a flat powder sample was used that was placed on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a ¼° anti-diffusion slit were used. For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
Measuring parameters of IR Spectroscopy: The spectra were measured using a FTIR Nicolet Nexus device (Thermo, USA). Each spectrum was obtained by taking 12 scans in the resolution of 4 cm"1. The records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer. The sample charge in a standard Al pot was 3 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 300°C at the heating rate of 10°C/min. As the carrier gas 4.0 N2 was used at the flow of 20 ml/min.
The dynamic vapor sorption (DVS) records were measured with a DVS Advantage 1 device made by the company Surface Measurement Systems. The sample charge in a quartz pot was 21 mg and the temperature in the device is between 25.2°C and 25.4°C. Used measurement program: the sample was loaded with two cycles with the course from the relative humidity of 0% to 90% (sorption) and then from 90% to 0% RH (desorption). This procedure was repeated in the second cycle. As the carrier gas 4.0 N2 was used at the flow of 200 seem.
Example 1:
Rilpivirine base (50 g; 136 mmol, purity (HPLC) 96.05%) is suspended in 750 ml of 2-Me- THF and 80 ml of 2-propanol and the reaction mixture is heated up to 65°C. A prepared solution of adipic acid (14 g; 95 mmol) in 225 ml of isopropyl alcohol and 35 ml of water is added to the obtained solution by dripping at 65°C. The clear solution is cooled down to 40°C and an inoculum of Form A of rilpivirine adipate (0.5 g) is added. The resulting suspension is cooled down to 10°C. The separated substance is aspirated and washed with a minimal quantity of a 2-Me-THF mixture. The final product is then dried in a vacuum drier at 130°C. The amount of 45 g (75% of the theoretical quantity, HPLC purity 98.14%) of crystalline Form A of rilpivirine adipate corresponding to the XRPD record presented in fig. 1 and DSC shown in fig. 2 was obtained.
Example 2:
Rilpivirine hydrochloride (2.8 kg; 6.95 mol, purity (HPLC) 94.18%) is suspended in a mixture of 2-Me-THF (38 1) and 2-propanol (4.2 1). The suspension is heated up to the temperature of 65°C. An aqueous solution of KOH (585 g in 5.5 1) is poured to the suspension and the reaction mixture is vigorously agitated for 30 minutes. The aqueous phase is separated and the organic phase is washed with 8 liters of water and then with 5 liters of a 10% NaCl solution. The temperature of the solution is adjusted to 60°C and a solution of adipic acid (411 kg; 4.78 mol) in 11.5 1 of isopropanol and 1.8 1 of water is added. The reaction mixture is cooled down to 40°C and an inoculum of Form A of rilpivirine adipate (30 g) is added. 30 1 of distillate is removed from the obtained suspension by distillation. The resulting suspension is cooled down to 10°C. The separated substance is aspirated and washed with 3 1 of acetone. The final product is then dried in a vacuum drier at 130°C. The amount of 2,7 g (87% of the theoretical quantity, purity (HPLC) 99.35%) of crystalline Form A of rilpivirine adipate corresponding to the XRPD record presented in fig. 1 and DSC shown in fig. 2 was obtained.
Example 3:
Rilpivirine adipate (100 g, 228 mmol, purity (HPLC) 98.14%) is dissolved under boiling in 2.5 1 of acetone. The reaction mixture is concentrated by removing of 1.5 1 of acetone by distillation. The resulting suspension is cooled down to 10°C, the separated compound is aspirated and washed with acetone (0.3 1). The final product is then dried in a vacuum drier at 130°C. The amount of 92 g (92% of the theoretical quantity, purity (HPLC) 99.73%) of Form A of rilpivirine adipate corresponding to the XRPD record presented in fig. 1 and DSC shown in fig. 2 was obtained.

Claims

C L A I M S
1. Form A of nlpivirine adipate of formula I, exhibiting the following characteristic reflections in an X-ray powder pattern measured with the use of Cu a radiation 5.6; 9.6;
14.6; 18.2; 22.1; 25.5 and 0.2 ± 2° 2-theta.
Figure imgf000009_0001
Form A of nlpivirine adipate according to claim 1, further exhibiting the following characteristic reflections in an X-ray powder pattern measured with the use of CuKa radiation 5.2; 8.5; 12.6; 18.6 and 23.2 ± 0.2° 2-theta.
Form A of rilpivirine adipate according to claims 1 and 2, exhibiting the main onset temperature of 203.0°C in a differential scanning calorimetry (DSC) record.
Form A or rilpivirine adipate according to claims 1 to 3, exhibiting the characteristic absorption peaks of 3301, 2220, 1693, 1582, 1409, 1227 and 1173 cm-1 in an IR spectrum.
5. Use of Form A of rilpivirine adipate, characterized in claims 1 to 4, for the preparation of a pharmaceutical composition.
6. The preparation method of Form A of rilpivirine adipate characterized in claims 1 to 4, characterized in that it comprises mixing of a solution of rilpivirine base in an etheric solvent with a solution of adipic acid in a C1-C4 alcohol or a mixture of C1-C4 alcohol and water, addition of crystallization inocula of Form A of rilpivirine adipate and cooling.
7. The preparation method of Form A of rilpivirine adipate according to claim 6, characterized in that the etheric solvent is selected from the group of THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether or tert-butyl methyl ether (MTBE), preferably 2-Me-THF.
8. The preparation method in accordance with claim 6, characterized in that the alcohol for the preparation of the adipic acid solution is selected from the group of propanol, isopropanol, 2-butanol, preferably isopropanol.
9. The preparation method in accordance with claim 6, characterized in that adipic acid dissolved in an alcohol is added in the molar ratio of 0.5 to 1 equivalent with respect to rilpivirine base and the addition rate is selected in such a way that the temperature of the solution of rilpivirine does not drop below 40°C.
10. The preparation method in accordance with claim 6, characterized in that rilpivirine base is obtained either by dissolution of rilpivirine base in an etheric solvent or by neutralization of a suitable salt of rilpivirine, preferably hydrochloride, in an etheric solvent by addition of a solution of an inorganic base selected from LiOH, NaOH, KOH, K2C03, Na2C03, NaHC03, and KHC03, preferably KOH.
11. The preparation method in accordance with claim 6, characterized in that the inoculation is carried out at 35 to 45°C by addition of 0.5 to 2% of Form A of rilpivirine adipate, preferably 1% of Form A of rilpivirine adipate.
12. The preparation method in accordance with claim 6, characterized in that rilpivirine base is prepared either by dissolution in 2-methyl tetrahydrofuran (2-Me-THF), or is produced by neutralization of rilpivirine hydrochloride with the use of KOH in 2-Me- THF and a solution of adipic acid in isopropanol is added to the solution at 65°C by dripping in the molar ratio of 0.5 to 1 equivalent with respect to rilpivirine base, subsequently during cooling to 35 to 45°C crystallization inocula of Form A of rilpivirine adipate are added and after cooling down to 10°C the desired product is separated.
PCT/CZ2016/000090 2015-08-27 2016-08-12 Crystalline form a of rilpivirine adipate and a method of its preparation WO2017032350A1 (en)

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