WO2019008126A1 - Nouvelle forme cristalline d'inhibiteur bcl-2, procédé pour sa préparation et compositions pharmaceutiques la contenant - Google Patents

Nouvelle forme cristalline d'inhibiteur bcl-2, procédé pour sa préparation et compositions pharmaceutiques la contenant Download PDF

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Publication number
WO2019008126A1
WO2019008126A1 PCT/EP2018/068312 EP2018068312W WO2019008126A1 WO 2019008126 A1 WO2019008126 A1 WO 2019008126A1 EP 2018068312 W EP2018068312 W EP 2018068312W WO 2019008126 A1 WO2019008126 A1 WO 2019008126A1
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WO
WIPO (PCT)
Prior art keywords
compound
crystalline form
ppm
hcl
expressed
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PCT/EP2018/068312
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English (en)
Inventor
Michael Lynch
Julie Linol
Sylvie DHULUT
Alan LE BLANC
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Les Laboratoires Servier
Vernalis (R&D) Limited
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Publication of WO2019008126A1 publication Critical patent/WO2019008126A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to crystalline form II of N-(4-hydroxyphenyl)-3 - ⁇ 6- [((3 S)-3 -(4- mo holinylmethyl)-3,4-dihydro-2(lH)-isc ⁇ uinolinyl)carbonyl]-l ,3-benzodio ol-5-yl ⁇ -N- phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide hydrochloride, referred to herein as 'Compound A.HCF, and pharmaceutical compositions for oral administration comprising said crystalline form II.
  • the invention also relates to the use of such compositions for the treatment of cancer, diseases of the immune system and auto-immune diseases.
  • the present invention also describes a process for obtaining Compound A.HC1 in a well-defined, perfectly reproducible crystalline form having very good stability that is compatible with the industrial constraints of preparation, especially filtration, and storage of pharmaceutical compositions.
  • Figure 1 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form II.
  • Figure 2 shows the solid-state 13 C NMR spectrum of Compound A. HC1 crystalline form
  • Figure 3 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form I.
  • Figure 4 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form IV.
  • Figure 5 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form V.
  • composition for oral administration means for example a tablet, a dragee, a granule, a sublingual tablet, a capsule or a lozenge, in particular a tablet. Such tablet may optionally be film-coated.
  • the useful dosage varies according to the sex, age and weight of the patient, the administration route, the nature of the cancer and any associated treatments; the useful dosage ranges from 50 mg to 1500 mg of Compound A.HC1 per day expressed in terms of the free base. 'Compound A.
  • HO' or 'Compound A.HC1 salt' means the hydrochloride salt of N-(4- hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4-morpholinylmethyl)-3,4-dihydro-2(lH)- isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl ⁇ -N-phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide.
  • the term 'comprising' means 'including', and is not intended to exclude the presence of any additional component, unless the context suggests otherwise, for example when the components together sum to 100%.
  • alcohols means Ci-C 6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol.
  • ketones means a C 3 -C 6 ketone such as acetone, methyl ethyl ketone, 2- pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone, 3-hexanone, ethyl isopropyl ketone, methyl isopropyl ketone, 2,2-dimethyl-3 -butanone.
  • esters means C 3 -Cg ester such as ethyl formate, isopropyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ferf-butyl acetate, pentyl acetate, isopentyl acetate, hexyl acetate.
  • 'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancer (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. 'Cancer' includes cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
  • 'free molecule' and 'free base' are used interchangeably herein and refer to Compound A when not in salt form.
  • HCl characterised in that it has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 4.09; 8.19; 9.15; 10.82; 12.83; 15.23; 15.47; 16.40; 19.17; 19.87; 20.39; 20.88; 21.76; 23.19; 24.06.
  • HCl according to E2, characterised in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 4.09; 9.15; 10.82; 12.83; 15.47.
  • E6 Crystalline form II of Compound A. HC1 according to any of El to E5, characterised in that it has a solid-state l3 C CP/MAS NMR spectrum having the following peaks (expressed in ppm ⁇ 0.2 ppm): 170.6 ppm, 140.9 ppm, 1 13.0 ppm, 107.2 ppm, 104.5 ppm, 62.0 ppm, 60.4 ppm, 32.1 ppm, 25.0 ppm, 22.5 ppm, 18.7 ppm.
  • E7 Crystalline form II of Compound A. HC1 according to any of El to E6 which is a monohydrate.
  • composition comprising as active ingredient crystalline form II of Compound A. HC1 according to any one of El to E7 in association with one or more pharmaceutically acceptable excipients.
  • composition according to E9 wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
  • E16 Process for the preparation of crystalline form II of Compound A. HC1 according to El 5, wherein the polar medium is a binary mixture selected from: isopropanol/water, n- propanol/water, n-butanol/water, DMSO/water and acetone/water.
  • E17 Process for the preparation of crystalline form II of Compound A. HC1 according to El 6, wherein the percent of water in the binary mixture is comprised between 10 to 50 % in weight.
  • crystalline form II of Compound A.HC1 has the advantage of making it possible to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of stability. More specifically, crystalline form II of Compound A.HC1 obtained through a crystallisation step at a temperature of 60°C is especially valuable in an industrial context in view of its filtration property. Furthermore, the crystalline form II of Compound A. HC1 thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions for temperature, light, humidity or oxygen levels. In particular, the crystalline form II of Compound A. HC1 has been found to be very stable over periods of up to 18 months under at 25 °C with a humidity level of 60% in an airtight glass bottle.
  • Example 1 Process for obtaining crystalline form II of Compound A. HC1
  • Example 2 Process for obtaining crystalline form II of Compound A.
  • HC1 seeding 1 kg of Compound A (free base) was placed in 4.711 kg of isopropanol at ambient temperature. The mixture was then heated at 60°C. A hydrochloric solution (0.197 kg of HC1 10N + 1.4 kg of water) was then added. The mixture was stirred for 30 minutes, before being seeded with crystalline form II of Compound A. HC1 (1% to 2% in weight of starting material). The mixture was further stirred for 60 minutes and was cooled to 10°C. When the crystallisation was complete, the suspension was filtered, washed with water and dried at 50°C. After drying, crystalline form II of Compound A. HC1 was obtained in a yield of about 80% and with a purity greater than 97%. The solid was characterised by the X-ray powder as set out in Example 4.
  • the seeding step with crystalline form II of Compound A. HC1 was performed before the addition of the hydrochloric solution.
  • Example 4 Crystalline form II of Compound A. HCl (X-ray powder diffraction diagram)
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°, Measurement time per step: 34.9250 s.
  • Example 5 Tablet comprising Compound A.HC1 (standard formulation)
  • Example 1 The product obtained in Example 1 or 2 is then micronised before being blended with excipients as follows:
  • the micronised product is mixed with sodium lauryl sulfate. Then, the premix is added to microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypopylcellulose. The mixing is granulated using wet granulation (conventional manufacturing process) in a planetary granulator. After being dried in the planetary granulator or in an oven system, the granulate is sifted. Magnesium stearate (lubricant) and silica (glidant) are then added for the external phase: the lubricated granulate is sifted and compressed to obtain the tablets. Finally, tablets are film-coated with a white premix (Sepifilm No. 37781 RBC).
  • composition per tablet with film coating (% weight per weight of tablet):
  • the hygroscopicity of crystalline form II of Compound A. HCl was assessed using the dynamic vapour sorption (DVS) technique. 5 to 10 mg of the micronised drug substance test sample were accurately weighed into a DVS sample pan working at 25°C under controlled humidity. The mass of the sample was recorded at 50 per cent RH (relative humidity) until reaching a stable value. Thereafter the mass variation was recorded between 50 per cent RH and 90 per cent RH at a rate of 10 per cent per hour. Mass variations were also recorded between 90 per cent RH and 0 per cent RH and from 0 per cent RH back to 50 per cent RH. The relative humidity was maintained constant when it reached either 0 or 90 per cent RH until the mass variation was less than 0.002 per cent per minute within a limit of time of 15 h.
  • DVS dynamic vapour sorption
  • a decrease in sample mass was of approximately 1.0 per cent was recorded between 90% to 0% RH, whilst an increase in sample mass of approximately 0.5 per cent was recorded between 0% to 50% RH.
  • the DVS profile shows that water sorption and desorption are perfectly reversible.
  • HC1 can be considered as being slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.).
  • the water content of micronised crystalline form II of Compound A. HC1 was determined by coulometric titration using a Metrohm Coulometer composed of a 774 oven sample processor, a 774 SC controller, 831 KF coulometer and a 846 Dosing interface with Tiamo 1.2 software. About 10 mg of accurately weighed micronised drug substance were introduced in vials heated for 10 min at 140 °C.
  • the water content in the test samples amounted to 2.5% in weight, corresponding to a monohydrate.
  • Crystalline form II of Compound A HCl remains stable towards temperature and humidity after an 18 -month storage period at 25°C with a humidity level of 60% in airtight glass bottles and after a 6-month storage period in open glass bottles in various conditions.
  • a 24-month storage period in airtight glass bottles at 25 °C/60 % RH a 12-month storage period in airtight glass bottles at 30°C/65 % RH
  • a 6-month storage period in open glass bottles at 25°C/90 % RH and 40°C/75 % RH and after a 6-week storage period in airtight and open glass bottles at 70°C the physical parameters tested such as identification by IR and water content did not show significant signs of modifications in relation to the initial control.
  • the chemical parameters no significant increase of the related substances nor the isomer content was observed.
  • the drug substance content (determined using LC) remained constant over storage in airtight or
  • Compound A HCl crystalline form II can be defined by the presence of the following peaks in the NMR spectrum (expressed in ppm ⁇ 0.2 ppm):
  • Example 10 Process for obtaining crystalline form I of Compound A. HCl and X-ray powder diffraction diagram of the same
  • the solid was isolated by filtration and dried during 15 hours at 50°C.
  • the solid was characterised by the X-ray powder as described below.
  • Example 11 Process for obtaining crystalline form IV of Compound A. HCl and X- ray powder diffraction diagram of the same
  • Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
  • Example 12 Process for obtaining crystalline form V of Compound A. HC1 and X- ray powder diffraction diagram of the same
  • HC1 amorphous or crystalline
  • ethanol/water 50/50 10 mL
  • This suspension was heated to reflux during 15 minutes.
  • This solution was cooled to 30°C and 5 mL of ethanol/water 50/50 was added.
  • the suspension was cooled to 5°C.
  • the solid was isolated by filtration and dried during 15 hours at 40°C.
  • the solid was characterised by the X-ray powder as described below.

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

Abstract

L'invention concerne la forme cristalline II du composé A.HCl : (formule) caractérisée par son diagramme de diffraction de rayons X sur poudres et le spectre RMN 13C à l'état solide, et des compositions pharmaceutiques la contenant.
PCT/EP2018/068312 2017-07-06 2018-07-05 Nouvelle forme cristalline d'inhibiteur bcl-2, procédé pour sa préparation et compositions pharmaceutiques la contenant WO2019008126A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019134970A1 (fr) * 2018-01-05 2019-07-11 Les Laboratoires Servier Nouveaux sels d'un inhibiteur de bcl-2, formes cristallines associées, leur procédé de préparation et compositions pharmaceutiques les contenant
US11311347B2 (en) 2016-11-11 2022-04-26 Intuitive Surgical Operations, Inc. Teleoperated surgical system with surgical instrument wear tracking

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013110890A1 (fr) 2012-01-24 2013-08-01 Les Laboratoires Servier Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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Publication number Priority date Publication date Assignee Title
FR3008979B1 (fr) * 2013-07-23 2015-07-24 Servier Lab Nouveaux derives phosphates, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013110890A1 (fr) 2012-01-24 2013-08-01 Les Laboratoires Servier Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Non-Patent Citations (2)

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Title
CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 *
JOHN F BAUER: "Pharmaceutical Solids- The Amorphous Phase", JOURNAL OF VALIDATION TECHNOLOGY, vol. 15, no. 3, 1 January 2009 (2009-01-01), Netherlands, pages 63 - 68, XP055280414 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11311347B2 (en) 2016-11-11 2022-04-26 Intuitive Surgical Operations, Inc. Teleoperated surgical system with surgical instrument wear tracking
WO2019134970A1 (fr) * 2018-01-05 2019-07-11 Les Laboratoires Servier Nouveaux sels d'un inhibiteur de bcl-2, formes cristallines associées, leur procédé de préparation et compositions pharmaceutiques les contenant

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