AU2017348665A1 - Novel salts of nilotinib and crystalline forms thereof - Google Patents

Novel salts of nilotinib and crystalline forms thereof Download PDF

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AU2017348665A1
AU2017348665A1 AU2017348665A AU2017348665A AU2017348665A1 AU 2017348665 A1 AU2017348665 A1 AU 2017348665A1 AU 2017348665 A AU2017348665 A AU 2017348665A AU 2017348665 A AU2017348665 A AU 2017348665A AU 2017348665 A1 AU2017348665 A1 AU 2017348665A1
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nilotinib
peaks
salt
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Prabhudas Bodhuri
Alfredo Paul Ceccarelli
Probal Kanti Datta
Jenny L. GERSTER
Boris Gorin
Allan W. Rey
Gamini Weeratunga
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Apotex Inc
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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
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    • 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 System
    • 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

Abstract

The present invention provides novel salts of Nilotinib and crystalline forms thereof. Specific salt and crystalline forms thereof provided by the present invention include Nilotinib trihydrochloride dihydrate Form APO-VIII, Nilotinib gentisate Form APO-I, Nilotinib gentisate Form APO-II, Nilotinib digentisate Form APO-III, Nilotinb dibenzoate Form APO-I, Nilotinib dilevulinate Form APO-I, Nilotinib saccharinate monohydrate Form APO-I, Nilotinib saccharinate Form APO-II, Nilotinib diglycolate Form APO-I and Nilotinib glycerophosphate Form APO-I.

Description

NOVEL SALTS OF NILOTINIB AND CRYSTALLINE FORMS THEREOF
TECHNICAL FIELD [0001] The present invention is directed to novel salts of Nilotinib and crystalline forms thereof.
BACKGROUND [0002] The compound 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide, commonly known as Nilotinib, is described in WO 2004/0005281 A1, for instance, in Example 92. The hydrochloride monohydrate form of Nilotinib (1) is marketed in the United States as TASIGNA®, and is indicated for the treatment of certain types of chronic myelogenous leukemia (CML).
Figure AU2017348665A1_D0001
.HCI. H2O (1) [0003] In addition to the free base and hydrochloride salt, a number of other salt forms of Nilotinib are reported, for example, in WO 2007/105870 A1, WO 2007/015871 A1, WO 2010/009402 A1, WO 2011/033307 A1, WO 2011/163222 A1, WO 2015/092624 A1, WO 2016/024289 A1, IP.COM 2010, 10(7B), 3, IP.COM2010, 10 (9A), 21, and IP.COM2010, 10(12A), 18.
[0004] Nilotinib is considered a low solubility/low permeability (Class IV) compound in the BCS (Biopharmaceutical Classification System). It is slightly soluble in acidic pH, with the solubility decreasing strongly with increasing pH. Nilotinib has multiple basic sites and the monohydrochloride monohydrate is
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-2reported to have a pKai and pKa2 of 2.1 and 5.4, respectively. Nilotinib is reported to have maximum solubility at pH 1 corresponding with protonation of at least two sites. However, diacid and triacid salts of Nilotinib can exhibit problems with stability, with the second or third acid equivalent showing lability and a tendency to disproportionation during certain conditions of solvent exposure and/or drying.
[0005] The solubility of individual salt and crystalline forms of a drug substance in an aqueous environment often correlates to their relative bioavailability, since the manner in which the salt or crystalline form dissolves can correspond to the amount of the drug substance that is available to be absorbed into the body to provide the intended therapeutic effect. One measure of solubility is intrinsic dissolution rate (IDR), which is defined as the dissolution rate of a substance under constant surface area conditions. For low solubility substances, higher IDR values can correlate with higher bioavailability following administration. However, if the goal is to establish bioequivalence to an approved form of a drug, such as Nilotinib hydrochloride, substances with similar IDR values to the approved form are preferred. Alternatively, for the development of extended or sustained release products, forms exhibiting lower IDR values are often preferable since they can provide slower dissolution of the drug independent of the excipients used in the formulation. Prediction of the solubility and IDR of an as yet undiscovered salt or crystalline form of a substance is currently not possible.
[0006] Some salts of Nilotinib are also reported to be hygroscopic, which presents challenges during manufacture of the active, as well as during formulation and tableting. For example, forms that exhibit hygroscopicity typically result in an increased burden on packaging and storage conditions, which can negatively impact the shelf life of the product.
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-3[0007] According to the publicly available European Public Assessment Report (EPAR) for Nilotinib hydrochloride (TASIGNA®), Nilotinib hydrochloride, exists in crystalline Forms A, B and C and an amorphous form. Of these forms, the Form B monohydrate, which is the form incorporated in TASIGNA®, is reported to exhibit the least hygroscopicity. However, as disclosed in WO 2007/015871 A1, Nilotinib hydrochloride monohydrate Form B is nevertheless reported to be hygroscopic, in some cases picking up 2% moisture at 60 % relative humidity (RH) and as much as 2.7 % moisture at 95 % RH.
[0008] Different salts and/or crystalline forms of the same compound may have different packing, thermodynamic, spectroscopic, kinetic, surface and mechanical properties. For example, different salts and/or crystalline forms may have different stability properties. A particular salt and/or crystalline form may be more sensitive to heat, relative humidity and/or light. Alternatively or additionally, a particular salt and/or crystalline form may provide more compressibility and/or density properties thereby providing more desirable characteristics for formulation and/or product manufacturing. Particular salt and/or crystalline forms may also have different dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific salt and/or crystalline forms to be used in order to achieve specific pharmacokinetic targets. Differences in stability may result from changes in chemical reactivity, such as differential oxidation. 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.
[0009] Although general approaches to salt and crystalline form screening of active pharmaceutical ingredients are known, it is well established that the prediction of whether any given compound will exhibit polymorphism is not possible. Furthermore, prediction of the properties of any unknown crystalline
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-4forms, and how they will differ from other crystalline forms of the same compound, remains even more elusive (Joel Bernstein, Polymorphism in
Molecular Crystals, Oxford University Press, New York, 2002, page 9).
[0010] Therefore, there exists a need for novel salts of Nilotinib and crystalline forms thereof for use in improved drug products containing Nilotinib and their manufacture.
SUMMARY [0011] The Nilotinib salts and crystalline forms of the present invention exhibit differences in properties when compared to the known salts and crystalline forms of Nilotinib, such as the monohydrochloride salt in the commercial product TASIGNA®. While not wishing to be bound by any particular theory, it is believed that these differences arise in the salts and crystalline forms of Nilotinib of the present invention owing to the specific ionic associations with the particular counter ions used, and the differing crystal arrangements that result from these pairings. Depending on the specific salts and crystalline forms of the invention used, properties that may differ between the invention and known salt and crystalline forms of Nilotinib include the following: packing properties such as molar volume, density and hygroscopicity, thermodynamic properties such as melting and solubility, kinetic properties such as intrinsic dissolution rate and chemical/crystalline form stability, surface properties such as crystal habit and mechanical properties such as hardness, tensile strength, compactibility, tableting, handling, flow, and blending. Furthermore, the salts and polymorphic forms of the present invention may be prepared by facile and industrially advantageous processes.
[0012] Differences in the properties of the salts and crystalline forms of the present invention provide practical advantages that can be exploited to meet specific needs in the manufacture and formulation of Nilotinib. For example, while hydrochloride salts of Nilotinib are known and currently marketed, there are often disadvantages associated with the use of hydrochloride salts of drug
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-5substances, including high acidity levels in formulations, a risk of corrosion to manufacturing equipment, or less than optimal solubility owing to salting out in the gastrointestinal tract of patients. Thus, it is desirable to have alternative salts and/or crystalline forms that provide more favourable properties. Depending on the need, it may be desirable to use a specific salt or crystalline form for taste masking purposes, or to reduce the solubility of the drug substance to mediate its release and absorption properties. Further, improved solubility in common industrial cleaning solvents, such as alcohols, can provide manufacturing advantages, particularly for low solubility compounds.
[0013] Depending on the specific salt and crystalline form of the invention used, the present invention provides opportunities for achieving specific formulation and dosage form goals. For example, salt and crystalline forms are provided that exhibit higher IDR values compared to the Form B monohydrochloride monohydrate of Nilotinib, which can be used to provide products with enhanced bioavailability. Salt and crystalline forms are also provided having similar IDR values to this form, which are preferable when trying to achieve bioequivalence between dosage forms. Further, the present invention provides salt and crystalline forms having lower IDR values that are preferred for used in the development of modified release dosage forms.
[0014] Thus, the present invention provides new salt and crystalline forms of Nilotinib having advantages over known forms of Nilotinib that can be exploited in the development of new formulations and dosage forms containing Nilotinib.
[0015] Accordingly, in a first aspect of the present invention, there is provided Nilotinib trihydrochloride dihydrate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.7° and 8.8°. In a preferred embodiment of the first aspect, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.0°, 10.9°, 11.8°, 12.7°, 15.0°, 15.4°, 16.6°, 17.4°, 21.2° and 27.1°. In a further preferred embodiment of the
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-6first aspect, the PXRD diffractrogram comprises peaks, expressed in degrees 20 (± 0.2°), at 5.0°, 5.7°, 8.8°, 10.9°, 11.8°, 12.7°, 15.0°, 15.4°, 16.6°, 17.4°, 21.2° and 27.1°.
[0016] In a second aspect of the present invention, there is provided a gentisate salt of Nilotinib. In a preferred embodiment of the second aspect, the molar ratio of Nilotinib to gentisic acid is approximately 1:1. In a first more preferred embodiment, the gentisate salt is Nilotinib gentisate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.3° and 15.4°. More preferably, the Nilotinib gentisate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°. In a further preferred embodiment, the Nilotinib gentisate is characterized by a PXRD diffractogram comprising peaks at 5.3°, 5.9°, 9.3°, 10.7°, 13.6°, 14.3°, 15.0°, 15.4°, 16.6°, 18.2°, 25.0° and 26.5°. In a second more preferred embodiment, the gentisate salt is Nilotinib gentisate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 4.7° and 6.3°. More preferably, the Nilotinib gentisate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°. In a further preferred embodiment, the Nilotinib gentisate is characterized by a PXRD diffractogram comprising peaks at 4.7°, 6.3°, 6.8°, 9.4°, 10.0°, 12.7°, 13.7°, 17.5°, 18.7°, 19.8°, 25.0° and 26.8°.
[0017] In a second preferred embodiment of the second aspect, the molar ratio of Nilotinib to gentisic acid is approximately 1:2. In a more preferred embodiment the digentisate salt is Nilotinib digentisate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 9.8° and 15.7°. More preferably, the Nilotinib digentisate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 6.6°, 8.5°, 9.3°, 10.8°, 13.7°, 17.4°,
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-721.0° and 21.8°. In a further preferred embodiment, the Nilotinib digentisate is characterized by a PXRD diffractogram comprising peaks at 6.6°, 8.5°, 9.3°, 9.8°, 10.8°, 13.7°, 15.7°, 17.4°, 21.0° and 21.8°.
[0018] In a third aspect of the invention, there is provided a benzoate salt of Nilotinib. In a preferred embodiment of the third aspect, the molar ratio of Nilotinib to benzoic acid is approximately 1:2. In a more preferred embodiment, the benzoate salt is Nilotinib dibenzoate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.3° and 8.0°. More preferably, the Nilotinib dibenzoate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°. In a further preferred embodiment, the Nilotinib dibenzoate is characterized by a PXRD diffractogram comprising peaks at 4.0°, 5.3°, 6.9°, 8.0°, 9.2°, 10.6°, 13.3°, 14.4°, 16.3°, 17.4°, 18.2° and 26.2°.
[0019] In a fourth aspect of the invention, there is provided a levulinate salt of Nilotinib. In a preferred embodiment of the fourth aspect, the molar ratio of Nilotinib to levulinic acid is approximately 1:2. In a more preferred embodiment, the levulinate salt is Nilotinib dilevulinate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 7.5° and 9.1°. More preferably, the Nilotinib dilevulinate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.1°, 6.4°, 12.5°, 15.3°, 15.9°, 17.2°, 18.4°, 20.8°, 21.5° and 23.2°. In a further preferred embodiment, the Nilotinib dilevulinate is characterized by a PXRD diffractogram comprising peaks at 5.1°, 6.4°, 7.5°, 9.1°, 12.5°, 15.3°, 15.9°, 17.2°, 18.4°, 20.8°, 21.5° and 23.2°.
[0020] In a fifth aspect of the invention, there is provided a saccharinate salt of Nilotinib. In a preferred embodiment of the fifth aspect, the molar ratio of Nilotinib to saccharin is approximately 1:1. In a first more preferred embodiment, the saccharin salt is Nilotinib saccharinate characterized by a PXRD diffractogram
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-8comprising peaks, expressed in degrees 20 (± 0.2°), at 7.2° and 18.6°. More preferably, the Nilotinib saccharinate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 8.7°, 12.3°, 14.5°, 15.4°, 16.7°, 20.5°, 21.8°, 24.0°, 24.6° and 25.7°. In a further preferred embodiment, the Nilotinib saccharinate is characterized by a PXRD diffractogram comprising peaks at 7.2°, 8.7°, 12.3°, 14.5°, 15.4°, 16.7°, 18.6°, 20.5°, 21.8°, 24.0°, 24.6° and 25.7°. In a second more preferred embodiment, the saccharin salt is Nilotinib saccharinate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 3.6° and 8.2°. More preferably, the Nilotinib saccharinate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.8°, 9.9°, 10.6°, 12.6°, 13.3°, 14.4°, 15.9°, 20.3° and 25.5°. In a further preferred embodiment, the Nilotinib saccharinate is characterized by a PXRD diffractogram comprising peaks at 3.6°, 5.8°, 8.2°, 9.9°, 10.6°, 12.6°, 13.3°, 14.4°, 15.9°, 20.3° and 25.5°.
[0021] In a sixth aspect of the invention, there is provided a glycolate salt of Nilotinib. In a preferred embodiment of the sixth aspect, the molar ratio of Nilotinib to glycolic acid is approximately 1:2. In a more preferred embodiment, the glycolate salt is Nilotinib diglycolate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.7° and 9.2°. More preferably, the Nilotinib diglycolate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.9°, 11.4°, 12.3°, 13.1°, 13.9°, 15.6°, 17.0°, 17.9°, 18.4° and 19.3°. In a further preferred embodiment, the Nilotinib diglycolate is characterized by a PXRD diffractogram comprising peaks at 6.7°, 9.2°, 10.9°, 11.4°, 12.3°, 13.1°, 13.9°, 15.6°, 17.0°, 17.9°, 18.4° and 19.3°.
[0022] In a seventh aspect of the invention, there is provided 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. In a more preferred embodiment, the glycerophosphate salt is Nilotinib
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-9glycerophosphate characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.9° and 10.8°. More preferably, the Nilotinib glycerophosphate is characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°. In a further preferred embodiment, the Nilotinib glycerophosphate is characterized by a PXRD diffractogram comprising peaks at 4.3°, 5.9°, 8.6°, 10.8°, 15.5°, 16.2°, 19.5°, 21.2°, 22.6° and 23.6°.
[0023] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS [0024] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.
[0025] Figure 1 is a PXRD diffractogram of Nilotinib trihydrochloride dihydrate Form APO-VIII.
[0026] Figure 2 is a PXRD diffractogram of Nilotinib gentisate Form APO-I.
[0027] Figure 3 is a PXRD diffractogram of Nilotinib gentisate Form APO-II.
[0028] Figure 4 is a PXRD diffractogram of Nilotinib digentisate Form APO-I 11.
[0029] Figure 5 is a PXRD diffractogram of Nilotinib dibenzoate Form APO-I.
[0030] Figure 6 is a PXRD diffractogram of Nilotinib dilevulinate Form APO-I.
[0031] Figure 7 is a PXRD diffractogram of Nilotinib saccharinate monohydrate Form APO-I.
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-10[0032] Figure 8 is a PXRD diffractogram of Nilotinib saccharinate Form APO-
II.
[0033] Figure 9 is a PXRD diffractogram of Nilotinib diglycolate Form APO-I.
[0034] Figure 10 is a PXRD diffractogram of Nilotinib glycerophosphate Form APO-I.
DETAILED DESCRIPTION [0035] The present invention provides novel salts of Nilotinib and crystalline forms thereof providing improved properties over known salts of Nilotinib. Depending on the specific salts and crystalline forms of the invention used, properties that differ between the invention and known forms of Nilotinib include the following: packing properties such as molar volume, density and hygroscopicity, thermodynamic properties such as melting and solubility, kinetic properties such as dissolution rate and chemical/crystalline form stability, surface properties such as crystal habit and mechanical properties such as hardness, tensile strength, compactibility, tableting, handling, flow, and blending. Furthermore, the salts and crystalline forms of the present invention may be prepared by facile and industrially advantageous processes. The improved properties provided by the salts and crystalline forms of the present invention provide practical advantages over known forms of Nilotinib that can be exploited to meet specific needs in the manufacture and formulation of Nilotinib.
[0036] Depending on the manner in which the embodiments of the invention are prepared, the methodology and instrument used for PXRD analysis, and the scale selected to display results, the intensity of a given peak observed in the PXRD diffractogram may vary when compared to the same peak in the representative PXRD diffractograms provided in Figures 1 to 10 to illustrate the embodiments of the invention provided herein. Thus, differences in relative peak intensities between peaks in a PXRD diffractogram for a given crystalline form may be observed when compared to the relative peak intensities of the peaks in
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-11the representative PXRD diffractograms of Figures 1 to 10. Any such differences may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, the preparation of the sample for analysis, and the methodology applied for the analysis. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.
[0037] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractograms provided in Figures 1 to 10, it is understood that individual peak positions may vary between ±0.2° 20 from the values observed in the representative PXRD diffractograms provided in Figures 1 to 10 for the crystalline forms of the invention, or listed in Tables 1 to 10. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.
[0038] Further, it is understood that, depending on the instrument used for Xray analysis and its calibration, uniform offsets in the peak position of each peak in a PXRD diffractogram of greater that 0.2° 20 may be observed when compared to the representative PXRD diffractograms provided in Figures 1 to
10. Thus, PXRD diffractograms of the crystalline forms of the present invention may, in some circumstances, display the same relative peak positions as observed in the representative PXRD diffractograms provided in Figures 1 to 10, with the exception that each peak is offset in the same direction, and by approximately the same amount, such that the overall PXRD diffractogram is substantially the same in appearance as a PXRD diffractogram of Figures 1 to 10, with the exception of the uniform offset in peak positions. The observation of any such uniform peak shift in a PXRD diffractogram does not depart from the invention disclosed herein given that the relative peak positions of the individual peaks within the PXRD diffractogram remain consistent with the relative peak positions observed in the PXRD diffractograms of Figures 1 to 10 for the crystalline forms of the invention.
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-12[0039] As used herein, the term ‘crystalline form’ refers to a Nilotinib salt of fixed composition with a particular arrangement of components in its crystal lattice, and which may be identified by physical characterization methods such as PXRD. As used herein, the term crystalline form is intended to include singlecomponent and multiple-component crystalline forms of a Nilotinib salt. Singlecomponent forms of a Nilotinib salt consist solely of Nilotinib and the corresponding counterion in the repeating unit of the crystal lattice. Multiplecomponent forms of a Nilotinib salt include co-crystals and solvates of a Nilotinib salt wherein a co-former or solvent is also incorporated into the crystal lattice.
[0040] 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. For example, 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. In many cases, the molar ratio may vary by plus or minus 20% from a stated range. For example, 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.
[0041] As used herein, the term “v/v” in reference to a ratio refers to the ratio of each of the components on a volume per volume basis.
[0042] As used herein, the term “room temperature” refers to a temperature in the range of 20 °C to 25 °C.
[0043] As used herein, the term “overnight” refers to a time of 16 to 24 hours.
[0044] When describing the embodiments of the present invention there may be a common variance to a given temperature or time that would be understood or expected by the person skilled in the art to provide substantially the same result. For example, when reference is made to a particular temperature, it is to be understood by the person skilled in the art that there is an allowable variance of ±5 °C associated with that temperature. When reference is made to a
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-13particular time, it is to be understood that there is an allowable variance of ±10 minutes when the time is one or two hours, and ±1 hour when longer periods of time are referenced.
[0045] In a first embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib trihydrochloride dihydrate Form APO-VIII, wherein the molar ratio of Nilotinib to hydrochloric acid to water is approximately 1:3:2.
[0046] Nilotinib trihydrochloride dihydrate Form APO-VIII can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.7° and 8.8°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.0°, 10.9°, 11.8°, 12.7°, 15.0°,
15.4°, 16.6°, 17.4°, 21.2° and 27.1°.
[0047] An illustrative PXRD diffractogram of Nilotinib trihydrochloride dihydrate Form APO-VIII is shown in Figure 1. A peak listing, comprising peaks from the PXRD diffractogram in Figure 1, and their relative intensities, is provided in Table 1. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib trihydrochloride dihydrate Form APO-VIII 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 PXRD diffractogram and peak listing.
Table 1: Relative peak intensities of Nilotinib trihydrochloride dihydrate Form APO-VIII from Figure 1
Angle (° 20) Relative intensity (%)
4.27 8.34
4.95 18.95
5.72 100
8.84 96.87
10.94 37.44
11.76 28.25
12.73 45.33
14.97 41.52
15.42 21.31
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16.57 16.24
17.36 13.45
17.86 4.02
18.23 7.04
19.45 7.6
20.08 12.3
21.20 58.61
21.58 26.97
22.16 45.8
22.96 41.32
24.44 50.89
24.98 20.75
25.43 42.71
26.16 23.01
27.12 75.11
27.27 59.89
27.89 21.44
29.16 25.49
29.78 23.66
30.42 17.8
31.67 17.7
[0048] 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 5 enhanced absorption of the Nilotinib or a faster onset of action is desired.
Stability studies of capped samples of Form APO-I have shown that this crystal form is chemically stable following storage at both 40 °C and 60 °C for at least 2 weeks.
[0049] As described in Example 1, Nilotinib trihydrochloride dihydrate Form 10 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.
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-15[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.
[0051] Nilotinib gentisate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.3° and 15.4°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.9°, 9.3°, 10.7°, 13.6°, 14.3°, 15.0°, 16.6°, 18.2°, 10 25.0° and 26.5°.
[0052] 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. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib 15 gentisate Form APO-I 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 PXRD diffractogram and peak listing.
Table 2: Relative peak intensities of Nilotinib gentisate Form APO-I from Figure 2
Angle (° 20) Relative intensity (%)
5.28 33.64
5.90 10.77
9.28 30.97
10.34 12.08
10.74 100
11.93 7.6
13.57 25.95
14.28 13.32
15.01 23.24
15.43 25.37
16.08 8.05
16.60 16.31
17.59 8.8
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18.22 36.43
18.84 13.76
19.63 4.96
20.81 12.26
21.45 11.49
23.89 9.51
25.03 25.97
26.48 31.54
[0053] 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.
[0054] As described in Example 2A, 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. Alternatively, as described in Example 2B, 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.
[0055] In a third embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib gentisate Form APO-II, wherein the molar ratio of Nilotinib to gentisic acid is approximately 1:1.
[0056] Nilotinib gentisate Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 4.7° and 6.3°. Preferably, the PXRD diffractogram further
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-17comprises at least four peaks, expressed in degrees 20 (± 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°.
[0057] An illustrative PXRD diffractogram of Nilotinib gentisate Form APO-II is shown in Figure 3. A peak listing, comprising peaks from the PXRD diffractogram in Figure 3, and their relative intensities, is provided in Table 3. Although 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 10 relative intensity of the peaks observed may differ from those in the illustrative
PXRD diffractogram and peak listing.
Table 3: Relative peak intensities of Nilotinib gentisate Form APO-II from Figure 3
Angle (° 20) Relative intensity (%)
4.71 100.00
6.33 47.34
6.81 7.81
9.45 57.18
10.01 22.89
12.70 10.62
13.73 33.41
16.20 7.60
17.54 21.27
18.29 13.48
18.71 24.71
19.82 10.25
20.64 6.09
21.67 6.40
22.77 9.28
25.03 59.78
26.84 70.21
[0058] As described in Example 3, Nilotinib gentisate Form APO-II can be prepared from Nilotinib by adding Nilotinib to a solution of gentisic acid in hot 15 ethyl acetate. After hot filtering the resulting suspension, and allowing the
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-18solution to cool, crystallization of Nilotinib gentisate Form APO-II can be induced by adding seed crystals of Nilotinib gentisate Form APO-I.
[0059] In a fourth embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib digentisate Form APO-III, wherein the molar ratio of 5 Nilotinib to gentisic acid is approximately 1:2.
[0060] Nilotinib digentisate Form APO-III can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 9.8° and 15.7°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected 10 from the group consisting of: 6.6°, 8.5°, 9.3°, 10.8°, 13.7°, 17.4°, 21.0° and 21.8°.
[0061] 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. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib 15 digentisate Form APO-III 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 PXRD diffractogram and peak listing.
Table 4: Relative peak intensities of Nilotinib digentisate Form APO-III from Figure 4
Angle (° 20) Relative intensity (%)
6.64 30.37
8.49 25.56
9.26 43.72
9.78 100.00
10.82 23.01
13.67 44.73
15.70 85.50
17.40 74.31
20.99 36.32
21.76 17.37
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-19[0062] As described in Example 4, 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.
[0063] In a fifth embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib dibenzoate Form APO-I, wherein the molar ratio of Nilotinib to benzoic acid is approximately 1:2.
[0064] Nilotinib dibenzoate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.3° and 8.0°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 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°.
[0065] 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. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib dibenzoate Form APO-I 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 PXRD diffractogram and peak listing.
Table 5: Relative peak intensities of Nilotinib dibenzoate Form APO-I from Figure 5
Angle (° 20) Relative intensity (%)
4.02 59.87
5.29 100.00
6.90 21.85
7.34 28.93
7.96 84.06
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8.14 63.72
9.21 13.10
10.58 23.36
10.82 26.69
12.15 10.40
12.41 9.71
13.25 24.36
13.60 29.47
14.36 17.49
16.28 26.44
17.43 36.80
18.21 25.42
18.63 11.56
19.25 17.31
20.13 18.44
20.81 16.27
21.75 16.33
22.55 10.20
23.01 11.32
23.90 10.40
24.90 11.13
25.51 15.24
26.17 24.64
[0066] As described in Example 5, 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 5 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.
[0067] In a sixth embodiment of the present invention, there is provided 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.
[0068] Nilotinib dilevulinate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 7.5° and 9.1°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected from
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-21the group consisting of: 5.1°, 6.4°, 12.5°, 15.3°, 15.9°, 17.2°, 18.4°, 20.8°, 21.5° and 23.2°.
[0069] An illustrative PXRD diffractogram of Nilotinib dilevulinate Form APO-I is shown in Figure 6. A peak listing, comprising peaks from the PXRD diffractogram in Figure 6, and their relative intensities, is provided in Table 6.
Although illustrative of the PXRD diffractogram that is provided for the Nilotinib dilevulinate Form APO-I 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 10 PXRD diffractogram and peak listing.
Table 6: Relative peak intensities of Nilotinib dilevulinate Form APO-I from Figure 6
Angle (° 20) Relative intensity (%)
3.73 14.55
5.10 32.58
6.35 6.19
7.46 72.27
9.11 100.00
12.51 43.05
12.74 23.94
15.27 22.16
15.47 12.66
15.91 32.88
17.18 7.75
18.39 63.71
19.41 13.15
20.76 19.96
21.54 25.18
23.24 16.68
24.49 16.64
25.63 19.63
[0070] As described in Example 6, Nilotinib dilevulinate Form APO-I can be prepared from Nilotinib by heating a suspension of Nilotinib and levulinic acid in ethyl acetate to about 50 °C. After aging at about 40 °C, the mixture can be 15 cooled to 30 °C for further aging in the presence of heptanes. The resulting
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-22material can be isolated by filtration and dried under high vacuum to provide Nilotinib dilevulinate Form APO-I.
[0071] In a seventh embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib saccharinate monohydrate Form APO-I, wherein 5 the molar ratio of Nilotinib to saccharin to water is approximately 1:1:1.
[0072] Nilotinib saccharinate monohydrate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 7.2° and 18.6°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 10 0.2°), selected from the group consisting of: 8.7°, 12.3°, 14.5°, 15.4°, 16.7°,
20.5°, 21.8°, 24.0°, 24.6° and 25.7°.
[0073] An illustrative PXRD diffractogram of Nilotinib saccharinate monohydrate Form APO-I is shown in Figure 7. A peak listing, comprising peaks from the PXRD diffractogram in Figure 7, and their relative intensities, is 15 provided in Table 7. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib saccharinate monohydrate Form APO-I 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 PXRD diffractogram and peak listing.
Table 7: Relative peak intensities of Nilotinib saccharinate monohydrate Form APO-I from Figure 7
Angle (° 20) Relative intensity (%)
7.16 100.00
8.74 23.32
12.35 21.00
14.45 45.27
15.36 9.56
15.99 5.96
16.67 13.54
17.25 6.90
18.60 37.42
18.85 10.88
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19.31 12.65
20.23 13.82
20.49 47.56
21.79 11.52
22.91 9.50
23.36 7.75
24.01 22.44
24.57 20.80
25.71 15.92
26.05 13.96
[0074] The IDR of 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.
[0076] In an eighth embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib saccharinate Form APO-II, wherein the molar ratio of Nilotinib to saccharin is approximately 1:1.
[0077] Nilotinib saccharinate Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 3.6° and 8.2°. Preferably, the PXRD diffractogram further
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-24comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.8°, 9.9°, 10.6°, 12.6°, 13.3°, 14.4°, 15.9°, 20.3° and 25.5°.
[0078] An illustrative PXRD diffractogram of Nilotinib saccharinate Form APO5 II is shown in Figure 8. A peak listing, comprising peaks from the PXRD diffractogram in Figure 8, and their relative intensities, is provided in Table 8. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib saccharinate 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
PXRD diffractogram and peak listing.
Table 8: Relative peak intensities of Nilotinib saccharinate Form APO-II from Figure 8
Angle (° 20) Relative intensity (%)
3.60 61.08
5.27 55.90
5.81 100.00
8.18 78.83
9.86 35.45
10.60 13.37
12.63 15.20
13.26 15.17
14.43 28.57
15.88 39.86
17.33 10.88
18.03 12.64
20.29 35.77
25.50 28.01
[0079] As described in Example 8, Nilotinib saccharinate Form APO-II can be prepared from Nilotinib by heating a suspension of Nilotinib in methanol to about 15 30 °C, followed by the addition of saccharin. After heating to 60 °C, the solution can be gradually cooled to room temperature, during which time a slurry is formed. Nilotinib saccharinate Form APO-II is obtained following filtration, and can be dried under high vacuum.
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-25[0080] In a ninth embodiment of the present invention, there is provided a new salt of Nilotinib, Nilotinib diglycolate Form APO-I, wherein the molar ratio of Nilotinib to glycolic acid is approximately 1:2.
[0081] Nilotinib diglycolate Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 6.7° and 9.2°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.9°, 11.4°, 12.3°, 13.1°, 13.9°, 15.6°, 17.0°, 17.9°, 18.4° and 19.3°.
[0082] 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. Although illustrative of the PXRD diffractogram that is provided for the Nilotinib diglycolate Form APO-I 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 PXRD diffractogram and peak listing.
Table 9: Relative peak intensities of Nilotinib diglycolate Form APO-I from Figure 9
Angle (° 20) Relative intensity (%)
6.65 100.00
9.17 50.45
10.93 24.66
11.36 11.93
12.28 44.69
13.13 35.91
13.89 29.08
14.91 7.94
15.58 26.50
17.00 31.55
17.90 22.14
18.40 12.85
18.83 30.03
19.32 69.89
20.91 16.00
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21.42 14.71
22.98 14.94
24.06 21.39
24.65 24.24
25.21 30.16
25.79 19.34
[0083] The IDR of Nilotinib diglycolate Form APO-I is approximately 5-fold higher than the IDR of Nilotinib hydrochloride monohydrate Form B. 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.
[0084] As described in Example 9, 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.
[0085] In a tenth embodiment of the present invention, there is provided 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.
[0086] Nilotinib glycerophosphate Form APO-I can be characterized by a PXRD comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 5.9° and 10.8°. Preferably, the PXRD diffractogram further comprises at least four peaks, expressed in degrees 20 (± 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°.
[0087] 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.
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-27Although illustrative of the PXRD diffractogram that is provided for the Nilotinib glycerophosphate Form APO-I 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 5 PXRD diffractogram and peak listing.
Table 10: Relative peak intensities of Nilotinib glycerophosphate Form APO-I from Figure 10
Angle (° 20) Relative intensity (%)
4.26 60.23
5.91 69.37
7.64 16.10
8.56 100.00
10.79 40.39
15.49 25.21
16.22 46.42
16.97 12.65
18.04 14.18
19.53 77.81
21.18 65.00
22.08 35.98
22.58 38.38
23.59 55.10
[0088] As described in Example 10, 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 10 resulting suspension is stirred at room temperature. Nilotinib glycerophosphate
Form APO-I is obtained following filtration, and can be dried under high vacuum.
EXAMPLES [0089] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein.
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-28Powder X-Ray Diffraction Analysis:
[0090] Data were acquired on a PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and an X’Celerator RTMS detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2-theta range of 3° to 40° using CuKa radiation at a power of 40 mA and 45 kV. ΟυΚβ radiation was removed using a divergent beam nickel filter. A step size of 0.017° was used. Samples were rotated to reduce preferred orientation effects. Samples were lightly ground prior to analysis.
Example 1: Nilotinib trihydrochloride dihydrate Form APO-VIII [0091] To a clear yellow solution of Nilotinib (10.49 g, 19.81 mmol) in concentrated (37 wt %) aqueous hydrochloric acid (53 mL) was added acetone (260 mL) in five portions over 30 minutes. The orange suspension was stirred at room temperature for 4.5 hours, filtered and the filter cake was washed with acetone (3 x 20 mL). The damp solid was dried under high vacuum at 30 °C for 18 hours to afford Nilotinib trihydrochloride dihydrate Form APO-VIII as an orange solid (13.09 g, 98 % yield); HPLC purity 99.86 % (area %); 18.30 % chloride content by titration; 5.5 % water content by KF (Karl Fischer) titration corresponding with a dihydrate. Figure 1 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.37 (3H, s), 2.39 )3H, s), 5.20-6.8 (3H, broad s), 7.47 (1H, d, J = 8.1 Hz), 7.70 (1H, d, J = 5.2 Hz), 7.95-7.97 (2H, m), 8.08 (1H, s), 8.16 (1H, dd, J = 8.2, 5.6 Hz), 8.32 (1H, d, J = 1.4 Hz), 8.40 (1H, s), 8.68 (1H, d, J = 5.2 Hz), 8.73 (1H, s), 9.04 (1H, d, J = 5.6 Hz), 9.14 (1H, d, J = 8.2 Hz), 9.49-9.53 (2H, m), 9.76 (1H, d, J= 1.6 Hz), 11.12 (1H,s).
Example 2A: Nilotinib qentisate Form APO-I [0092] To a heated mixture (55 °C) of Nilotinib (4.0 g, 7.55 mmol) and gentisic acid (5.82 g, 37.77 mmol) was added acetone (100 mL) in two portions over 30 minutes. A further portion of gentisic acid (5.82 g, 37.77 mmol) was added,
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-29followed by acetone (50 mL), and the mixture was stirred for 0.5 hours and cooled to room temperature. The suspension was stirred overnight at room temperature, filtered and washed with acetone (2 x 40 mL). The damp cake was dried under vacuum at 52 °C for 5 hours and at room temperature under vacuum overnight to afford Nilotinib gentisate Form APO-I as an off-white solid (4.45 g, 87 % yield). Figure 2 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.19 (3H, s), 2.37 (3H, s), 6.77 (1H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 8.8, 3.1 Hz), 7.15 (1H, d, J = 3.1 Hz), 7.45-
7.54 (4H, m), 7.74-7.78 (2H, m), 8.17 (1H, s), 8.27 (1H, d, J= 1.1 Hz), 8.32-8.34 (2H, m), 8.45 (1H, dt, J = 8.1, 1.9 Hz), 8.56 (1H, d, J = 5.2 Hz), 8.68 (1H, dd, J = 4.7, 1.5 Hz), 9.0-9.40 (1H, broad s), 9.19 (1H, s), 9.29 (1H, d, J = 2.0 Hz), 10.63 (1H,s).
Example 2B: Nilotinib gentisate Form APO-I [0093] A mixture of Nilotinib (15.0 g, 28.32 mmol) and gentisic acid (43.66 g, 283.27 mmol) in acetone (450 mL) was heated to reflux for 2 hours. The suspension was cooled to room temperature and stirred overnight. To the thick, yellow suspension was added acetone (120 mL) to enable efficient mixing. The suspension was stirred at room temperature for 4 hours, filtered and the filter cake washed with acetone (2 x 150 mL). The damp cake was pulped in acetone (400 mL) at reflux for 1 hour, cooled to room temperature and stirred at this temperature for 24 hours. The white suspension was filtered and washed with acetone (2 x 100 mL). The damp cake was dried under vacuum at 48 °C for 24 hours to afford Nilotinib gentisate Form APO-I as an off-white solid (16.02 g, 83 % yield); 0.35 % water content by KF titration. The PXRD diffractogram of this sample is consistent with Figure 2.
Example 3: Nilotinib gentisate Form APO-II [0094] To a solution of gentisic acid (582 mg, 3.78 mmol) in hot ethyl acetate (30 mL) was added Nilotinib (500 mg, 0.94 mmol). To this heated (85 °C), yellow suspension was added additional hot ethyl acetate (200 mL) and this hot solution
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-30was filtered through a cotton plug and maintained without stirring for five days. After this time, a few crystals of Nilotinib gentisic acid (1:1) salt were added and the reaction solution was maintained without agitation for an additional five days. The crystals were filtered, washed with ethyl acetate (2 x 8 mL) and suction dried for 2 hours to afford Nilotinib gentisate Form APO-II as white crystals (400 mg, 62 % yield). Figure 3 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.19 (3H, s), 2.37 (3H, s), 6.77 (1H, d, J = 8.9 Hz), 6.95 (1H, dd, J = 8.8, 3.1 Hz), 7.16 (1H, d, J = 3.1 Hz), 7.45-
7.54 (4H, m), 7.74-7.79 (2H, m), 8.17 (1H, s), 8.28 (1H, d, J= 1.3 Hz), 8.32 -8.34 (2H, m), 8.45 (1H, dt, J = 8.1 Hz), 8.56 (1H, d, J = 5.1 Hz), 8.68 (1H, d, J = 4.8,
1.5 Hz), 8.90-9.30 (1H, broad s), 9.18 (1 H,s), 9.29 (1H, d, J= 1.7 Hz), 10.63 (1H, s).
Example 4: Nilotinib digentisate Form APO-III [0095] A mixture of Nilotinib (5.0 g, 9.44 mmol) and gentisic acid (21.83 g, 141.63 mmol) in ethyl acetate (200 mL) was heated to reflux for 2 hours. The yellow suspension was cooled to 55 °C, filtered and washed with ethyl acetate (2 x 20 mL). The damp cake was pulped in acetone (400 mL) at reflux for 1 hour, cooled to room temperature and stirred at this temperature for 24 hours. The white suspension was filtered and washed with acetone (2 x 100 mL). The damp cake was dried under vacuum at 58 °C for 18 hours to afford Nilotinib digentisate Form APO-III as an off-white solid (16.02 g, 83 % yield). Figure 4 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.36 (3H, s), 2.50 (3H, s), 6.78 (2H, d, J = 8.7 Hz), 6.95 (2H, dd, J = 9.0, 3.0 Hz), 7.15 (2H, d, J = 3.0 Hz), 7.45-7.53 (3H, m), 7.74 (1H, broad s), 7.77 (1H, dd, J = 7.9, 1.3 Hz), 8.17 (1H, broad s), 8.31-8.33 (2H, m), 8.45 (1H, dt, J = 8.0, 1.8 Hz), 8.55 (1H, d, J = 5.3 Hz), 8.68 (1H, dd, J = 4.7, 1.3 Hz), 9.0-9.30 (1H, broad s), 9.17 (1H, s), 9.29 (1H, d, J = 1.9 Hz), 10.63 (1H, s), 11.0-13.50 (3H, broad s).
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-31Example 5: Nilotinib dibenzoate Form APO-I [0096] A suspension of Nilotinib (10.0 g, 18.88 mmol) and benzoic acid (34.6 g, 283.27 mmol) in ethyl acetate (200 mL) was heated to reflux. Complete dissolution was observed at 76 °C. The solution was filtered hot through a Buchner funnel, to remove un-dissolved particulate followed by a rinse with ethyl acetate (5 mL). The filtrate was slowly cooled to room temperature (crystallization was seen at 57 °C). The suspension was filtered and the filter cake was washed with heptanes:ethyl acetate (1:1 v/v, 100 mL). The damp solid was dried under high vacuum at room temperature for 24 hours to afford Nilotinib dibenzoate Form APO-I as an off-white solid (12.26 g, 84 % yield). Figure 5 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.19 (3H, s), 2.38 (3H, s), 7.39-7.54 (8H, m), 7.61-7.66 (2H, m), 7.74-7.80 (2H, m), 7.95-7.98 (4H, m), 8.18 (1H, s), 8.23 (1H, d, J = 1.0 Hz), 8.32 (1H, s), 8.36 (1H, d, J = 1.2 Hz), 8.46 (1H, dt, J = 8.1, 1.8 Hz), 8.57 (1H, d, J = 5.2 Hz), 8.69 (1H, dd, J = 4.8, 1.4 Hz), 9.20 (1H, s), 9.30 (1H, d, J =
1.7 Hz), 10.64 (1H, s), 11.80-13.90 (2H, broad s).
Example 6: Nilotinib dilevulinate Form APO-I [0097] A suspension of Nilotinib (5.0 g, 9.44 mmol) and levulinic acid (17.04 g, 146.74 mmol) in ethyl acetate (10 mL) was heated to 50 °C. The solution was filtered hot through a Buchner funnel to remove un-dissolved particulate, rinsing with a 7.5 mL portion of hot (50 °C) levulinic acid:ethyl acetate (1:2 v/v). The clarified reaction mixture was cooled to 40 °C and aged for 1 hour. The temperature was then lowered to 30 °C and the slurry was further aged for 18 hours following the addition of ethyl acetate (15 mL) and heptanes (15 mL). Following aging, the mixture was further diluted with ethyl acetate (15 mL) and heptanes (15 mL). The reaction mixture was filtered and the filter cake was washed with 1:1 v/v heptanes:ethyl acetate (3x10 mL). The damp solid was dried under high vacuum at 20 °C for 24 hours to afford Nilotinib dilevulinate Form APO-I as an off-white solid (6.64 g, 92 % yield). Figure 6 depicts a PXRD
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-32diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.10 (6H, s), 2.19 (3H, s), 2.31-2.41 (7H, m), 2.64-2.68 (4H, m), 7.45-
7.54 (4H, m), 7.73-7.79 (2H, m), 8.17-8.22 (2H, m), 8.31-8.34 (2H, m), 8.45 (1H, dt, J = 8.0, 1.8 Hz), 8.56 (1H, d, J= 5.1 Hz), 8.69 (1H, dd, J = 4.8, 1.4 Hz), 9.19 (1H, s), 9.29 (1H, d, J= 1.8 Hz), 10.63 (1H, s), 11.60-12.70 (1H, broad s).
Example 7: Nilotinib saccharinate monohydrate Form APO-I [0098] A suspension of Nilotinib saccharinate Form APO-II (23.52 g, 33.00 mmol, as prepared in Example 8) in methanol (470 mL) was heated to 60 °C. To the clear solution was added deionized water (76 mL) and the clear solution was heated to reflux. Upon reaching reflux, the solution was cooled to 60 °C and maintained for 4 hours. The slurry was then cooled to 50 °C and maintained for
1.5 hours. The white suspension was filtered hot and the filter cake was washed with methanol (2 x 25 mL). The damp solid was dried under high vacuum at 20 °C for 15 hours to afford Nilotinib saccharinate monohydrate Form APO-I as a white solid (20.17 g, 84 % yield); 2.5 % water content by KF titration corresponding with a monohydrate. Figure 7 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.32 (3H, s), 2.38 (3H, s), 7.46-7.55 (3H, m), 7.69-7.89 (7H, m), 8.23 (1H, s), 8.35 (1H, s), 8.46 (1H, dt, J = 8.1, 1.7 Hz), 8.52 (1H, s), 8.56 (1H, d, J = 5.2 Hz), 8.69 (1H, dd, J = 4.7, 1.4 Hz), 9.21 (2H, s), 9.29 (1H, d, J = 1.6 Hz), 10.77 (1H, s).
Example 8: Nilotinib saccharinate Form APO-II [0099] A suspension of Nilotinib (12.08 g, 22.81 mmol) in methanol (250 mL) was heated to 30 °C. To this suspension was added saccharin (9.64 g, 52.62 mmol) and the suspension was heated to 60 °C. 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 (3x15 mL). The damp solid was dried under high
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-33vacuum at 30 °C for 13 hours to afford Nilotinib saccharinate Form APO-II as a white solid (14.14 g, 87 % yield). Figure 8 depicts a PXRD diffractogram of a sample prepared by this method.
Example 9: Nilotinib diglycolate Form APO-I [0100] A suspension of Nilotinib (2.00 g, 3.78 mmol) and glycolic acid (0.93 g, 12.23 mmol) in ethyl acetate (50 mL) was stirred at room temperature for 3 hours. Additional ethyl acetate was added (20 mL) and the suspension was stirred for 13 hours at room temperature. The slurry was filtered and the filter cake was washed with ethyl acetate (3x10 mL). The damp solid was dried under high vacuum at 30 °C for 6 hours to afford Nilotinib diglycolate Form APO-I as a yellow solid (2.50 g, 97 % yield). Figure 9 depicts a PXRD diffractogram of a sample prepared by this method. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.19 (3H, s), 2.37 (3H, s), 7.45-7.54 (4H, m), 7.73-7.79 (2H, m), 8.17-8.22 (2H, m), 8.318.34 (2H, m), 8.44-8.47 (1H, m), 8.56 (1H, d, J = 5.2 Hz), 8.69 (1H, dd, J = 4.8,
1.5 Hz), 9.18 (1H, s), 9.29 (1H, d, J= 1.8 Hz), 10.63 (1H, s).
Example 10: Nilotinib glycerophosphate Form APO-I [0101] A slurry of Nilotinib (0.2 g, 0.38 mmol) in acetone (25 mL) was charged with glycerophosphoric acid (35 wt % in water) (0.37 g, 0.75 mmol). To the resulting gummy solid was added deionized water (15 mL) and the freely mobile solids were stirred at room temperature for 45 hours. The yellow suspension was filtered and the filter cake was washed with acetone (10 mL). The damp solid was dried under high vacuum at 30 °C for 24 hours to afford Nilotinib glycerophosphate Form APO-I as a yellow solid (0.21 g, 81 % yield). Figure 10 depicts a PXRD diffractogram of a sample prepared by this method.
Example 11: Comparative intrinsic dissolution testing [0102] Intrinsic dissolution rate (IDR) measurements were performed using a Woods apparatus. Samples were prepared by compression at 2.0 metric tons for 1 minute. A dissolution medium consisting of 900 mL 0.1 N HCI buffer was
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-34used and the apparatus was rotated at 50 rpm for each experiment. Results are provided in Table 11.
Table 11: Comparative intrinsic dissolution rates for crystalline forms of the invention with Nilotinib hydrochloride monohydrate Form B
Form Intrinsic Dissolution Rate (mg min'1 cm'2)
Nilotinib trihydrochloride dihydrate Form APO-VIII 6.1852
Nilotinib gentisate Form APO-I 0.2557
Nilotinib saccharinate monohydrate Form APO-I 0.0840
Nilotinib diglycolate Form APO-I 1.1137
Nilotinib hydrochloride monohydrate Form B (Prior Art) 0.2282
Example 12: Comparative stability testing [0103] Samples of Nilotinib gentisate Form APO-I, Nilotinib saccharinate monohydrate Form APO-I and Nilotinib diglycolate Form APO-I were stored as indicated for 2 weeks. PXRD and/or chromatographic purity analysis of the samples was conducted before and after storage. The results are provided in Table 12
Table 12: Results of stability studies in open (uncapped) and closed (capped) containers
Form 40 °C, capped 60 °C, capped 40 °C/75 %RH, uncapped
CP CP CP CF
Nilotinib trihydrochloride dihydrate Form APO-VIII NC NC C C
Nilotinib gentisate Form APO-I NC NC NC NC
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Nilotinib saccharinate monohydrate Form APO-I NC NC NC NC
Nilotinib diglycolate Form APO-I NC NC NC NC
CP: Chromatographic purity; CF: Crystalline form; NC: No change; C:
Change.
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Claims (43)

  1. What is claimed is:
    1. Nilotinib trihydrochloride dihydrate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.7° and 8.8°.
  2. 2. The Nilotinib trihydrochloride dihydrate of claim 1, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.0°, 10.9°, 11.8°, 12.7°, 15.0°, 15.4°, 16.6°, 17.4°, 21.2° and 27.1°.
  3. 3. The Nilotinib trihydrochloride dihydrate of claim 1, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 5.0°, 10.9°, 11.8°, 12.7°, 15.0°, 15.4°, 16.6°, 17.4°, 21.2° and 27.1°.
  4. 4. A gentisate salt of Nilotinib.
  5. 5. The gentisate salt of Nilotinib of claim 4, wherein the molar ratio of Nilotinib to gentisic acid is approximately 1:1.
  6. 6. The gentisate salt of claim 5, wherein the gentisate salt is Nilotinib gentisate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.3° and 15.4°.
  7. 7. The Nilotinib gentisate of claim 6, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°.
  8. 8. The Nilotinib gentisate of claim 6, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°) at 5.9°, 9.3°, 10.7°, 13.6°, 14.3°, 15.0°, 16.6°, 18.2°, 25.0° and 26.5°.
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  9. 9. The gentisate salt of claim 5, wherein the gentisate salt is Nilotinib gentisate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 4.7° and 6.3°.
  10. 10. The Nilotinib gentisate of claim 9, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°.
  11. 11. The Nilotinib gentisate of claim 9, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 6.8°, 9.4°, 10.0°, 12.7°, 13.7°, 17.5°, 18.7°, 19.8°, 25.0° and 26.8°.
  12. 12. The gentisate salt of Nilotinib of claim 4, wherein the molar ratio of Nilotinib to gentisic acid is approximately 1:2.
  13. 13. The gentisate salt of claim 12, wherein the gentisate salt is Nilotinib digentisate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 9.8° and 15.7°.
  14. 14. The Nilotinib digentisate of claim 13, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°.
  15. 15. The Nilotinib digentisate of claim 13, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 6.6°, 8.5°, 9.3°, 10.8°, 13.7°, 17.4°, 21.0° and 21.8°.
  16. 16. A benzoate acid salt of Nilotinib.
  17. 17. The benzoate salt of Nilotinib of claim 16, wherein the molar ratio of Nilotinib to benzoic acid is approximately 1:2.
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  18. 18. The benzoate salt of claim 17, wherein the benzoate salt is Nilotinib dibenzoate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.3° and 8.0°.
  19. 19. The Nilotinib dibenzoate of claim 18, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°.
  20. 20. The Nilotinib dibenzoate of claim 18, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 4.0°, 6.9°, 9.2°, 10.6°, 13.3°, 14.4°, 16.3°, 17.4°, 18.2° and 26.2°.
  21. 21. A levulinate salt of Nilotinib.
  22. 22. The levulinate salt of Nilotinib of claim 21, wherein the molar ratio of Nilotinib to levulinic acid is approximately 1:2.
  23. 23. The levulinate salt of Nilotinib of claim 22, wherein the levulinate salt is Nilotinib dilevulinate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 7.5° and 9.1°.
  24. 24. The Nilotinib dilevulinate of claim 23, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.1°, 6.4°, 12.5°, 15.3°, 15.9°, 17.2°, 18.4°, 20.8°, 21.5° and 23.2°.
  25. 25. The Nilotinib dilevulinate of claim 23, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 5.1°, 6.4°, 12.5°, 15.3°, 15.9°, 17.2°, 18.4°, 20.8°, 21.5° and 23.2°.
  26. 26. A saccharinate salt of Nilotinib.
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  27. 27. The saccharinate salt of Nilotinib of claim 26, wherein the molar ratio of Nilotinib to saccharin is approximately 1:1.
  28. 28. The saccharinate salt of Nilotinib of claim 27, wherein the saccharinate salt is Nilotinib saccharinate monohydrate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 7.2° and 18.6°.
  29. 29. The Nilotinib saccharinate monohydrate of claim 28, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 8.7°, 12.3°, 14.5°, 15.4°, 16.7°, 20.5°, 21.8°, 24.0°, 24.6° and 25.7°.
  30. 30. The Nilotinib saccharinate monohydrate of claim 28, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 8.7°, 12.3°, 14.5°, 15.4°, 16.7°, 18.6°, 20.5°, 21.8°, 24.0°, 24.6° and 25.7°.
  31. 31. The saccharinate salt of Nilotinib of claim 27, wherein the saccharinate salt is Nilotinib saccharinate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 3.6° and 8.2°.
  32. 32. The Nilotinib saccharinate of claim 31, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.8°, 9.9°, 10.6°, 12.6°, 13.3°, 14.4°, 15.9°, 20.3° and 25.5°.
  33. 33. The Nilotinib saccharinate of claim 31, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 5.8°, 9.9°, 10.6°, 12.6°, 13.3°, 14.4°, 15.9°, 20.3° and 25.5°.
  34. 34. A glycolate salt of Nilotinib.
  35. 35. The glycolate salt of Nilotinib of claim 34, wherein the molar ratio of Nilotinib to glycolic acid is approximately 1:2.
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  36. 36. The glycolate salt of claim 35, wherein the glycolate salt is Nilotinib diglycolate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 6.7° and 9.2°.
  37. 37. The Nilotinib diglycolate of claim 36, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 10.9°, 11.4°, 12.3°, 13.1°, 13.9°, 15.6°, 17.0°, 17.9°, 18.4° and 19.3°.
  38. 38. The Nilotinib diglycolate of claim 36, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 10.9°, 11.4°, 12.3°, 13.1°, 13.9°, 15.6°, 17.0°, 17.9°, 18.4° and 19.3°.
  39. 39. A glycerophosphate salt of Nilotinib.
  40. 40. The glycerophosphate salt of claim 39, wherein the molar ratio of Nilotinib to glycerophosphoric acid is approximately 1:1.
  41. 41. The glycerophosphate salt of claim 40, wherein the glycerophosphate salt is Nilotinib glycerophosphate characterized by a powder X-ray diffraction (PXRD) diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 5.9° and 10.8°.
  42. 42. The Nilotinib glycerophosphate of claim 41, characterized by a PXRD diffractogram further comprising at least four peaks, expressed in degrees 20 (± 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°.
  43. 43. The Nilotinib glycerophosphate of claim 41, characterized by a PXRD diffractogram further comprising peaks, expressed in degrees 20 (± 0.2°), at 4.3°, 8.6°, 15.5°, 16.2°, 19.5°, 21.2°, 22.6° and 23.6°.
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