WO2018076117A1 - Nouveaux sels de nilotinib et leurs formes cristallines - Google Patents

Nouveaux sels de nilotinib et leurs formes cristallines Download PDF

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Publication number
WO2018076117A1
WO2018076117A1 PCT/CA2017/051283 CA2017051283W WO2018076117A1 WO 2018076117 A1 WO2018076117 A1 WO 2018076117A1 CA 2017051283 W CA2017051283 W CA 2017051283W WO 2018076117 A1 WO2018076117 A1 WO 2018076117A1
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Prior art keywords
nilotinib
peaks
salt
expressed
degrees
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PCT/CA2017/051283
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English (en)
Inventor
Boris Gorin
Prabhudas Bodhuri
Alfredo Paul Ceccarelli
Probal Kanti Datta
Jenny L. GERSTER
Allan W. Rey
Gamini Weeratunga
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Apotex Inc.
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Priority to AU2017348665A priority Critical patent/AU2017348665A1/en
Priority to CA3041134A priority patent/CA3041134A1/fr
Publication of WO2018076117A1 publication Critical patent/WO2018076117A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/06—Glycolic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/10—Polyhydroxy carboxylic acids
    • C07C59/105—Polyhydroxy carboxylic acids having five or more carbon atoms, e.g. aldonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Such properties may provide for more suitable product qualities, such as a dosage form that is more resistant to discoloration when comprised of a particular salt and/or crystalline form.
  • Different physical properties of salts and/or crystalline forms may also affect their processing. For example, a particular salt and/or crystalline form may be more resistant to flow, or may be more difficult to filter and/or wash.
  • a glycerophosphate salt of Nilotinib In a preferred embodiment of the sixth aspect, the molar ratio of Nilotinib to glycerophosphoric acid is approximately 1 : 1 .
  • the glycerophosphate salt is Nilotinib glycerophosphate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 5.9° and 10.8°.
  • Figure 4 is a PXRD diffractogram of Nilotinib digentisate Form APO-III.
  • Multi-component solid forms comprising more than one type of molecule, such as solvates, may have some variability in the exact molar ratio of their components depending on a variety of conditions used.
  • a molar ratio of components within a solvate provides a person of skill in the art information as to the general relative quantities of the components of the solvate.
  • the molar ratio may vary by plus or minus 20% from a stated range.
  • a molar ratio of 1 :1 is understood to include the ratios 1 :0.8 and 1 : 1.2, as well as all of the individual ratios in between.
  • Nilotinib trihydrochloride dihydrate Form APO-VIII can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 5.7° and 8.8°.
  • the PXRD diffractogram further comprises at least four peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), selected from the group consisting of: 5.0°, 10.9°, 1 1 .8°, 12.7°, 15.0°, 15.4°, 16.6°, 17.4°, 21 .2° and 27.1 °.
  • the IDR of Nilotinib trihydrochloride dihydrate Form APO-VIII is approximately 27-fold higher than the IDR of Nilotinib hydrochloride monohydrate Form B, a property that can be exploited in the preparation of formulations where enhanced absorption of the Nilotinib or a faster onset of action is desired.
  • Nilotinib trihydrochloride dihydrate Form APO-VIII can be prepared from Nilotinib by gradually adding acetone, to a solution containing Nilotinib in concentrated hydrochloric acid. Nilotinib trihydrochloride dihydrate Form APO-VIII is obtained as a damp solid that can be dried under high vacuum. [0050] In a second and preferred embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib gentisate Form APO-I, wherein the molar ratio of Nilotinib to gentisic acid (2,5-dihydroxybenzoic acid) is approximately 1 : 1 .
  • Nilotinib gentisate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 5.3° and 15.4°.
  • the PXRD diffractogram further comprises at least four peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), selected from the group consisting of: 5.9°, 9.3°, 10.7°, 13.6°, 14.3°, 15.0°, 16.6°, 18.2°, 25.0° and 26.5°.
  • FIG. 2 An illustrative PXRD diffractogram of Nilotinib gentisate Form APO-I is shown in Figure 2.
  • a peak listing comprising peaks from the PXRD diffractogram in Figure 2, and their relative intensities, is provided in Table 2.
  • the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
  • the IDR of Nilotinib gentisate Form APO-I is within approximately 10 % of the IDR of Nilotinib hydrochloride monohydrate Form B, which is preferred for achieving bioequivalence.
  • Stability studies of uncapped samples of Form APO-I have shown that this crystal form is both crystallographically and chemically stable following storage at 40 °C/75 % RH (relative humidity) for at least 2 weeks. Additionally, stability studies of capped samples of Form APO-I have shown that this crystal form is chemically stable following storage at 60 °C for at least 2 weeks.
  • Nilotinib gentisate Form APO-I can be prepared from Nilotinib by adding acetone to a heated mixture of Nilotinib and gentisic acid and allowing the mixture to cool to room temperature. Nilotinib gentisate Form APO-I is obtained as a damp solid that can be dried under vacuum.
  • Nilotinib gentisate Form APO-I can be prepared by heating a mixture of Nilotinib and gentisic acid in refluxing acetone, and allowing the system to cool to room temperature. Nilotinib gentisate Form APO-I is obtained as a damp solid that can be dried under vacuum.
  • Nilotinib to gentisic acid is approximately 1 : 1 .
  • Nilotinib gentisate Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 4.7° and 6.3°.
  • the PXRD diffractogram further comprises at least four peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), selected from the group consisting of: 6.8°, 9.4°, 10.0°, 12.7°, 13.7°, 17.5°, 18.7°, 19.8°, 25.0° and 26.8°.
  • FIG. 3 An illustrative PXRD diffractogram of Nilotinib gentisate Form APO-II is shown in Figure 3.
  • Table 3 An illustrative of the PXRD diffractogram that is provided for the Nilotinib gentisate Form APO-II of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative
  • Nilotinib gentisate Form APO-II can be prepared from Nilotinib by adding Nilotinib to a solution of gentisic acid in hot ethyl acetate. After hot filtering the resulting suspension, and allowing the solution to cool, crystallization of Nilotinib gentisate Form APO-II can be induced by adding seed crystals of Nilotinib gentisate Form APO-I.
  • Nilotinib digentisate Form APO-III can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 9.8° and 15.7°.
  • the PXRD diffractogram further comprises at least four peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), selected from the group consisting of: 6.6°, 8.5°, 9.3°, 10.8°, 13.7°, 17.4°, 21 .0° and 21 .8°.
  • FIG. 4 An illustrative PXRD diffractogram of Nilotinib digentisate Form APO-III is shown in Figure 4.
  • a peak listing comprising peaks from the PXRD diffractogram in Figure 4, and their relative intensities, is provided in Table 4.
  • the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
  • Nilotinib digentisate Form APO-III can be prepared from Nilotinib by heating a mixture of Nilotinib and gentisic acid in ethyl acetate to reflux. Nilotinib digentisate Form APO-III is obtained by cooling the resulting suspension to 55 °C, isolating the solid by filtration, and pulping the filter cake in acetone. The resulting material can be dried under vacuum to provide Nilotinib digentisate Form APO-III.
  • a new salt of Nilotinib, Nilotinib dibenzoate Form APO-I wherein the molar ratio of Nilotinib to benzoic acid is approximately 1 :2.
  • Nilotinib dibenzoate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 5.3° and 8.0°.
  • the PXRD diffractogram further comprises at least four peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), selected from the group consisting of: 4.0°, 6.9°, 9.2°, 10.6°, 13.3°, 14.4°, 16.3°, 17.4°, 18.2° and 26.2°.
  • FIG. 5 An illustrative PXRD diffractogram of Nilotinib dibenzoate Form APO-I is shown in Figure 5.
  • a peak listing comprising peaks from the PXRD diffractogram in Figure 5, and their relative intensities, is provided in Table 5.
  • the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
  • Nilotinib dibenzoate Form APO-I can be prepared from Nilotinib by heating a mixture of Nilotinib and benzoic acid in ethyl acetate to reflux and slowly cooling the solution to room temperature. The resulting material can be washed with a mixture of heptanes and ethyl acetate to provide Nilotinib dibenzoate Form APO-I, which can be dried under high vacuum.
  • Nilotinib dilevulinate Form APO-I a new salt of Nilotinib, Nilotinib dilevulinate Form APO-I, wherein the molar ratio of Nilotinib to levulinic acid (4-oxo-pentanoic acid) is approximately 1 :2.
  • Nilotinib dilevulinate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 7.5° and 9.1 °.
  • Nilotinib saccharinate monohydrate Form APO-I is less than half of the IDR of Nilotinib hydrochloride monohydrate Form B, a property that can be exploited in the development of modified release dosage forms. Stability studies of uncapped samples of Form APO-I have shown that this crystal form is both crystallographically and chemically stable following storage at 40 °C/75 % RH for at least 2 weeks. Additionally, stability studies of capped samples of Form APO-I have shown that this crystal form is chemically stable following storage at 60 °C for at least 2 weeks. [0075] As described in Example 7, Nilotinib saccharinate monohydrate Form
  • APO-I can be prepared from Nilotinib saccharinate Form APO-II by heating a suspension of Nilotinib saccharinate Form APO-II in methanol to about 60 °C, and adding water, following which the solution can be heated to reflux. After cooling to around 50 °C, the resulting suspension can be filtered to provide Nilotinib saccharinate monohydrate Form APO-I, which can be dried under high vacuum.
  • FIG. 9 An illustrative PXRD diffractogram of Nilotinib diglycolate Form APO-I is shown in Figure 9.
  • a peak listing comprising peaks from the PXRD diffractogram in Figure 9, and their relative intensities, is provided in Table 9.
  • the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
  • Nilotinib diglycolate Form APO-I can be prepared from Nilotinib by stirring a suspension of Nilotinib and glycolic acid in ethyl acetate at room temperature. Nilotinib diglycolate Form APO-I is obtained following filtration, and can be dried under high vacuum.
  • a new salt of Nilotinib, Nilotinib glycerophosphate Form APO-I wherein the molar ratio of Nilotinib to glycerophosphoric acid (2,3-dihydroxypropyl dihydrogen phosphate) is approximately 1 : 1 .
  • Nilotinib glycerophosphate Form APO-I can be characterized by a PXRD comprising, among other peaks, characteristic peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), at 5.9° and 10.8°.
  • the PXRD diffractogram further comprises at least four peaks, expressed in degrees 2 ⁇ ( ⁇ 0.2°), selected from the group consisting of: 4.3°, 8.6°, 15.5°, 16.2°, 19.5°, 21 .2°, 22.6° and 23.6°.
  • FIG. 10 An illustrative PXRD diffractogram of Nilotinib glycerophosphate Form APO-I is shown in Figure 10.
  • a peak listing comprising peaks from the PXRD diffractogram in Figure 10, and their relative intensities, is provided in Table 10.
  • the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.
  • Nilotinib glycerophosphate Form APO-I can be prepared from Nilotinib by charging a slurry of Nilotinib in acetone with glycerophosphoric acid (37% in water). Following the addition of water, the resulting suspension is stirred at room temperature. Nilotinib glycerophosphate Form APO-I is obtained following filtration, and can be dried under high vacuum.
  • Example 1 Nilotinib trihydrochloride dihydrate Form APO-VIII
  • Example 2B Nilotinib gentisate Form APO-I
  • FIG. 4 depicts a PXRD diffractogram of a sample prepared by this method.
  • a suspension of Nilotinib (12.08 g, 22.81 mmol) in methanol (250 mL) was heated to 30 °C.
  • saccharin (9.64 g, 52.62 mmol)
  • the clear solution was maintained at 60 °C for 1 hour, cooled to 50 °C and maintained for 1 .5 hours.
  • the slurry was then cooled to 40 °C and maintained for 1 hour.
  • the slurry was again cooled to 30 °C, maintained for 1 hour, cooled to 20 °C and maintained for 1 hour further.
  • the white suspension was filtered and the filter cake was washed with cold (0 °C) methanol (3 x 15 mL).
  • FIG. 8 depicts a PXRD diffractogram of a sample prepared by this method.
  • Figure 9 depicts a PXRD diffractogram of a sample prepared by this method.
  • Example 1 1 Comparative intrinsic dissolution testing
  • IDR Intrinsic dissolution rate

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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne de nouveaux sels de nilotinib et leurs formes cristallines. Le sel spécifique et les formes cristallines de celui-ci fournis par la présente invention comprennent la forme APO-VIII dihydrate trihydrochloride Nilotinib, la forme APO-I Nilotinib gentisate, la forme APO-II Nilotinib gentisate, la forme APO-III Nilotinib digentisate, la forme APO-I Nilotinib dibenzoate, la forme APO-I Nilotinib dilevulinate, la forme APO-I Nilotinib saccharinate monohydrate, la forme APO-II Nilotinib saccharinate, la forme APO-I Nilotinib diglycolate et la forme APO-I Nilotinib glycérophosphate.
PCT/CA2017/051283 2016-10-28 2017-10-27 Nouveaux sels de nilotinib et leurs formes cristallines WO2018076117A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2017348665A AU2017348665A1 (en) 2016-10-28 2017-10-27 Novel salts of nilotinib and crystalline forms thereof
CA3041134A CA3041134A1 (fr) 2016-10-28 2017-10-27 Nouveaux sels de nilotinib et leurs formes cristallines

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US201662414399P 2016-10-28 2016-10-28
US62/414,399 2016-10-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021161347A1 (fr) 2020-02-15 2021-08-19 Cipla Limited Nouveaux sels de nilotinib et formes polymorphes de celui-ci

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305667A2 (fr) * 2008-07-17 2011-04-06 Teva Pharmaceutical Industries Ltd. Produits intermédiaires du nilotinib et préparation de ceux-ci
WO2011163222A1 (fr) * 2010-06-21 2011-12-29 Teva Pharmaceutical Industries Ltd. Sels de nilotinib et formes cristallines de ceux-ci
WO2017160703A1 (fr) * 2016-03-14 2017-09-21 Pliva Hrvatska D.O.O. Formes solides de sels de nilotinib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305667A2 (fr) * 2008-07-17 2011-04-06 Teva Pharmaceutical Industries Ltd. Produits intermédiaires du nilotinib et préparation de ceux-ci
WO2011163222A1 (fr) * 2010-06-21 2011-12-29 Teva Pharmaceutical Industries Ltd. Sels de nilotinib et formes cristallines de ceux-ci
WO2017160703A1 (fr) * 2016-03-14 2017-09-21 Pliva Hrvatska D.O.O. Formes solides de sels de nilotinib

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021161347A1 (fr) 2020-02-15 2021-08-19 Cipla Limited Nouveaux sels de nilotinib et formes polymorphes de celui-ci

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