CN114133378A - Nilotinib hydrochloride eutectic and preparation method thereof - Google Patents

Nilotinib hydrochloride eutectic and preparation method thereof Download PDF

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CN114133378A
CN114133378A CN202111024753.2A CN202111024753A CN114133378A CN 114133378 A CN114133378 A CN 114133378A CN 202111024753 A CN202111024753 A CN 202111024753A CN 114133378 A CN114133378 A CN 114133378A
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degrees
crystal
nilotinib hydrochloride
tartaric acid
nilotinib
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CN114133378B (en
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王磊鑫
谷慧科
王颖
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Sichuan Qingmu Pharmaceutical Co ltd
Chengdu Easton Biopharmaceuticals Co Ltd
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Sichuan Qingmu Pharmaceutical Co ltd
Chengdu Easton Biopharmaceuticals Co Ltd
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • 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
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • 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
    • C07B2200/07—Optical isomers
    • 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 application relates to the field of pharmaceutical crystal forms, in particular to a nilotinib hydrochloride L-tartaric acid eutectic and a preparation method thereof. The nilotinib hydrochloride L-tartaric acid eutectic disclosed by the invention is high in solubility, high in bioavailability, good in stability, simple in preparation method, environment-friendly and good in repeatability, and is suitable for large-scale industrial production.

Description

Nilotinib hydrochloride eutectic and preparation method thereof
Technical Field
The invention belongs to the field of medicine crystal forms, and particularly relates to a nilotinib hydrochloride L-tartaric acid eutectic Form N and a preparation method thereof.
Background
Nilotinib hydrochloride (Nilotinib hydrochloride) has the chemical name: 4-methyl-N- [3- (4-methyl l-1 hydro-imidazol-1-yl) -5- (trifluoromethyl) phenyl ] -3- [ (4-pyridin-3-ylpyrimidin-2-yl) amino ] benzamide monohydrochloride monohydrate, having the structure shown in (I):
Figure BDA0003242959150000011
nilotinib capsules were approved for sale in the united states at 29/10 of 2007 for the treatment of gleevec (imatinib) resistant chronic myelogenous leukemia. Nilotinib can bind to and stabilize the inactive conformation of the ABL protein kinase site. Nilotinib inhibits BCR-ABL kinase mediated proliferation of murine leukemia cell lines and cell line proliferation derived from Ph + CML patients in vitro. Of the 33 mutations detected, nilotinib was able to overcome imatinib resistance caused by 32 BCR-ABL kinase mutations. Due to this biochemical activity, nilotinib selectively inhibits proliferation and induces apoptosis in BCR-ABL cell lines and philadelphia chromosome positive primary leukemia cells of all CML patients. But the solubility of the compound in water is only 0.2ug/ml, and in order to ensure the bioavailability, the compound is micronized by Nowa so as to increase the dissolution of the main drug. However, the micronization process causes environmental pollution.
The patent WO2007015870 discloses nilotinib hydrochloride crystal form A, crystal form A ', crystal form A, ' crystal form B, crystal form B ', and crystal form SBCrystal form SB', form C', form SCForm D, form SEAnd amorphous 13 crystal forms. Wherein the form C is unstable in water and can be converted into the form A, and the solubility of the form A and the form B in water is very low, so that a crystal form with higher solubility and stability needs to be developed.
Disclosure of Invention
The invention requests to protect a nilotinib hydrochloride L-tartaric acid eutectic new crystal Form N.
Nilotinib hydrochloride is represented by structural formula I:
Figure BDA0003242959150000021
l-tartaric acid is represented by structural formula II:
Figure BDA0003242959150000022
the invention provides a nilotinib hydrochloride L-tartaric acid eutectic Form N, wherein an X-ray powder diffraction pattern of the eutectic is shown in the specification of a diffraction angle 2 theta: characteristic peaks are arranged at 10.38 +/-0.2 degrees, 11.20 +/-0.2 degrees, 13.36 +/-0.2 degrees, 15.40 +/-0.2 degrees, 18.12 +/-0.2 degrees, 20.48 +/-0.2 degrees, 21.72 +/-0.2 degrees and 22.74 +/-0.2 degrees.
Preferably, the nilotinib hydrochloride L-tartaric acid eutectic Form N has an X-ray powder diffraction pattern that varies at diffraction angles 2 θ: 8.02 +/-0.2 degrees, 10.38 +/-0.2 degrees, 11.20 +/-0.2 degrees, 12.58 +/-0.2 degrees, 13.36 +/-0.2 degrees, 14.18 +/-0.2 degrees, 15.40 +/-0.2 degrees, 16.00 +/-0.2 degrees, 16.96 +/-0.2 degrees, 18.12 +/-0.2 degrees, 19.84 +/-0.2 degrees, 20.48 +/-0.2 degrees, 21.72 +/-0.2 degrees, 22.74 +/-0.2 degrees, 24.06 +/-0.2 degrees, 24.72 +/-0.2 degrees, 25.76 +/-0.2 degrees, 27.35 +/-0.2 degrees, 28.28 +/-0.2 degrees, 36.28 +/-0.2 degrees and 38.38 +/-0.2 degrees.
Preferably, the nilotinib hydrochloride L-tartaric acid co-crystal Form N has an X-ray powder diffraction pattern substantially as shown in fig. 1.
Preferably, the nilotinib hydrochloride L-tartaric acid eutectic Form N differential scanning calorimetry spectrum has an endothermic peak at 196.44 ℃.
Preferably, the differential scanning calorimetry spectrum of the nilotinib hydrochloride L-tartaric acid co-crystal Form N is substantially as shown in fig. 2.
Preferably, the thermogravimetric spectrum of the nilotinib hydrochloride L-tartaric acid cocrystal Form N is substantially as shown in fig. 3.
Preferably, the nuclear magnetic spectrum of the nilotinib hydrochloride L-tartaric acid eutectic Form N is substantially as shown in fig. 4.
The invention also provides a preparation method of the nilotinib hydrochloride L-tartaric acid eutectic Form N, which comprises the following steps:
dissolving nilotinib hydrochloride and L-tartaric acid in a solvent, stirring until crystals are separated out after the nilotinib hydrochloride and the L-tartaric acid are dissolved clearly, cooling, filtering and drying to obtain the nilotinib hydrochloride crystal.
Preferably, the feeding molar ratio of the nilotinib hydrochloride to the L-tartaric acid is 1: 1-3.
More preferably, the feeding molar ratio of the nilotinib hydrochloride to the L-tartaric acid is 1: 2.
Preferably, the solvent is methanol.
Preferably, the volume of the solvent used is 10 to 30 times of the mass of the charged nilotinib hydrochloride.
More preferably, the volume of solvent used is 20 times the mass of the charged amount of nilotinib hydrochloride.
Preferably, the dissolution temperature is 30 ℃ to 60 ℃.
More preferably, the dissolution temperature is 50 ℃.
Preferably, the temperature is reduced to 0-20 ℃, and the mixture is filtered and dried.
More preferably, the temperature is reduced to 15 ℃ and filtered and dried.
The beneficial technical effects are as follows:
the invention provides a novel nilotinib hydrochloride L-tartaric acid eutectic Form N, which has high solubility, high bioavailability and good stability compared with the prior art.
The preparation method of the hydrochloric nilotinib L-tartaric acid eutectic Form N provided by the invention is simple, environment-friendly, good in repeatability and suitable for large-scale industrial production.
Drawings
FIG. 1X-ray powder diffractogram of nilotinib hydrochloride L-tartaric acid cocrystal Form N
FIG. 2 differential scanning calorimetry thermogram of nilotinib hydrochloride L-tartaric acid eutectic Form N
FIG. 3 thermogravimetric spectrum of nilotinib hydrochloride L-tartaric acid cocrystal Form N
FIG. 4 NMR spectra of nilotinib hydrochloride L-tartaric acid cocrystal Form N
FIG. 5 XRD pattern of stability experiment of nilotinib hydrochloride L-tartaric acid eutectic Form N
FIG. 6 XRD pattern of stability experiment of nilotinib hydrochloride L-tartaric acid cocrystal Form I
FIG. 7 XRD (X-ray diffraction) spectrum of accelerated stability experiment of nilotinib hydrochloride L-tartaric acid eutectic Form N
FIG. 8 mean drug concentration-time curves in plasma of female rats after a single oral administration
Detailed Description
The present application will be described in further detail with reference to the following examples, which are only for illustrating the technical solutions of the present application and are not intended to limit the spirit and scope of the present application.
The terms used in this application are explained as follows:
the term "eutectic" refers to a composition of two or more phases; the phases refer to substances with the same composition, crystal structure and properties.
The term XRD refers to X-ray powder diffraction. In the invention, the related powder X-ray diffraction test instrument is as follows: powder diffractometer DANDONGYUAN DX-2700B; and (3) testing conditions are as follows: ray of Cu K instrument, 40kV, 40mA,
Figure BDA0003242959150000041
3-40°。
the term DSC refers to a differential scanning calorimeter. Differential Scanning Calorimetry (DSC) as referred to in the present invention: mettler-toledo DSC 1; and (3) testing conditions are as follows: 25-250 ℃ and 10 ℃/min; n2(50 mL/min).
The term TGA refers to a thermogravimetric analyzer. In the present invention, the thermogravimetric analyzer (TGA) concerned: TGA 2; and (3) testing conditions are as follows: 30-250 ℃ and 10 ℃/min; n2(50 mL/min).
The nuclear magnetic resonance spectrometer of the invention is Bruker; and (3) testing conditions are as follows: 400MHz, solvent deuterated DMSO, hydrogen spectrum.
In the context of the present invention, the diffraction angle 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (. degree.).
The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.
The crystal has an X-ray powder diffraction peak whose measure of the 2theta or diffraction peak of the X-ray powder diffraction pattern has experimental error which may differ slightly between one machine and another and between one sample and another, the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units, and thus the value of the 2theta or diffraction peak cannot be considered absolute.
The Differential Scanning Calorimetry (DSC) curve of the crystal has experimental errors, the position and peak value of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so that the value of the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
The thermogravimetric analysis curve (TGA) of the crystal has experimental errors, the endothermic curve or the weight loss rate may slightly differ between one machine and another and between one sample and another, the numerical value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, and thus the thermogravimetric analysis curve or the weight loss rate thereof cannot be regarded as absolute.
Example 1
Weighing 50mg of nilotinib hydrochloride and 15mg of L-tartaric acid, dissolving in 1ml of methanol at 50 ℃, continuously stirring until solid is separated out after dissolving, slowly cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and drying in vacuum to obtain 26.5mg of light yellow solid, wherein an XRD (X-ray diffraction) pattern is shown in figure 1. A DSC spectrum is shown in figure 2, a TGA spectrum is shown in figure 3, and a nuclear magnetic spectrum is shown in figure 4; the relevant data are shown in table 1.
TABLE 1
Figure BDA0003242959150000051
Example 2
Weighing 200mg of nilotinib hydrochloride and 60mg of L-tartaric acid, dissolving in 4ml of methanol at 50 ℃, continuously stirring until solid is separated out after dissolving, slowly cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and drying in vacuum to obtain 22.5mg of light yellow solid, wherein the XRD pattern is basically consistent with that of figure 1. The DSC, TGA and nmr charts are substantially in accordance with fig. 2, 3 and 4, respectively.
Example 3
Weighing 1.0g of nilotinib hydrochloride and 300mg of L-tartaric acid, dissolving in 20ml of methanol at 50 ℃, continuously stirring until solid is separated out after the dissolution is clear, slowly cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and drying in vacuum to obtain 0.55g of light yellow solid, wherein the XRD pattern is basically consistent with that of figure 1. The DSC, TGA and nmr charts are substantially in accordance with fig. 2, 3 and 4, respectively.
Example 4
Weighing 1.0g of nilotinib hydrochloride and 600mg of L-tartaric acid, dissolving in 20ml of methanol at 50 ℃, continuously stirring until solid is separated out after the dissolution is clear, slowly cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and drying in vacuum to obtain 0.74g of light yellow solid, wherein the XRD pattern is basically consistent with that of figure 1. The DSC, TGA and nmr charts are substantially in accordance with fig. 2, 3 and 4, respectively.
Example 5
Weighing 10.0g of nilotinib hydrochloride and 6.0g L-tartaric acid, dissolving in 200ml of methanol at 50 ℃, continuously stirring after dissolving to separate out a solid, slowly cooling to 15 ℃, continuously stirring for 24h at 15 ℃, filtering, and drying in vacuum to obtain 7.6g of light yellow solid, wherein the XRD pattern is basically consistent with that of figure 1. The DSC, TGA and nmr charts are substantially in accordance with fig. 2, 3 and 4, respectively.
Example 6
The equilibrium solubilities of nilotinib hydrochloride L-tartaric acid neo-cocrystal Form N, nilotinib hydrochloride L-tartaric acid cocrystal Form I, nilotinib hydrochloride L-tartaric acid cocrystal Form II, Form a, Form B and Form C in water at 25 ℃ and 50 ℃ respectively were tested, and the results are given in the following table:
Figure BDA0003242959150000061
the result shows that the solubility of the hydrochloric nilotinib L-tartaric acid eutectic Form N in water is the maximum at 25 ℃ and 50 ℃, and the obvious advantage of solubility is achieved.
Example 7
The nilotinib hydrochloride L-tartaric acid eutectic Form N is placed under the light and the high temperature (60 ℃) respectively for 20 days for influencing factor experiments, the crystal Form is not transformed, an XRD (X-ray diffraction) pattern is shown in figure 5, and the specific results are shown in the following table:
conditions of the experiment Days of storage Crystal form
High temperature (60 ℃ C.) 20 days Nilotinib hydrochloride L-tartaric acid co-crystal
Illumination of light 20 days Nilotinib hydrochloride L-tartaric acid co-crystal
Example 8
The nilotinib hydrochloride L-tartaric acid eutectic Form I is placed in high humidity (RH 92.5%) and high temperature (60 ℃) for 15 days to carry out influence factor experiments, the experimental result shows that the nilotinib hydrochloride L-tartaric acid eutectic Form I is converted into nilotinib hydrochloride common crystal Form A under the high humidity condition, the crystal Form of the eutectic is unstable under the high humidity condition, and the XRD spectrum is shown in figure 6.
Example 9 nilotinib hydrochloride L-tartaric acid cocrystal Form N accelerated stability test
The nilotinib hydrochloride L-tartaric acid eutectic Form N is placed under the conditions of 25 ℃/RH 60% and 40 ℃/RH 75% for 6 months respectively to carry out an accelerated stability experiment, the experimental result shows that the new eutectic Form N has stable crystal Form and does not generate crystal transformation, and an XRD (X-ray diffraction) spectrum is shown in figure 7.
Test example in vivo pharmacokinetic test in rats
1. Purpose of the experiment
Under the condition of the same administration dose, the concentration level of nilotinib in blood plasma and the pharmacokinetic characteristics of nilotinib are observed after rats are orally administered with nilotinib hydrochloride L-tartaric acid cocrystal Form I, Form II and Form N for a single time.
2. Materials and methods
2.1 test drugs
Nilotinib hydrochloride L-tartaric acid co-crystal Form I, supplied by the crystal Form research division of medeton biopharmaceutical gmbh, lot number B-20255-31-05;
nilotinib hydrochloride L-tartaric acid co-crystal Form II, supplied by the crystal Form research division of medeton biopharmaceutical gmbh, lot number B-20255-31-06;
nilotinib hydrochloride L-tartaric acid neococrystal Form N, supplied by the crystal Form research division of medeton biopharmaceutical corporation, lot number C-19233-74-02;
2.2 test animals
SD rat, female, body weight 220-: SCXK (Xiang) 2019-.
2.3 test methods
After the tested medicine is prepared into 1.25mg/kg uniform suspension by corn oil, the uniform suspension is immediately orally administered to rats according to the volume of 4mL/kg, 0.1mL of blood is taken from jugular veins 15min, 30min, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h and 24h before and after administration, the mixture is placed in an EDTA-K2 tube for 3000r/min, centrifuged for 10min, and plasma is separated and refrigerated and stored in a refrigerator at minus 80 ℃.
2.4, LC/MS/MS biological sample analysis:
mixing 50 μ L of plasma with 5 μ L of working solution or blank diluent, adding 150 μ L of internal standard acetonitrile precipitant, vortex shaking for 2min, centrifuging at 12000r/min for 10min, mixing supernatant 2 μ L with 200 μ L of pure water: acetonitrile (1:1) was mixed well and analyzed by sample injection at a volume of 3. mu.L.
2.5, test results:
the nilotinib hydrochloride L-tartaric acid cocrystal Form I, Form II and Form N were subjected to animal experiments, that is, the average API concentration (ng · mL-1) in plasma at different times was tested after a single oral administration to female rats, and the results are shown in fig. 8 as the average drug concentration-time curve in plasma after a single oral administration to female rats, and the main pharmacokinetic parameters are as follows:
parameter(s) Form I Form II Form N
T1/2(h) 8.99±5.24 3.06±0.79 6.21±4.07
Tmax(h) 4.67±2.31 4.67±1.15 6.00±2.00
Cmax(ng·mL-1) 1050±345 2013±1541 2350.00±760.99
AUClast(h·ng·mL-1) 13687±4196 12101±5288 30298.51±7532.21
Cl_F_obs(mL/hr/kg) 1236±182 1832±658 606.17±77.16
MRT(h) 8.59±1.88 5.80±1.08 8.10±1.25
The experimental result shows the AUC of the hydrochloric acid nilotinib L-tartaric acid new cocrystal Form NlastAUC greater than FormI and Form IIlastThat is, the total amount absorbed into the blood circulation is much higher than FormI and FormII, so FormN has a higher bioavailability than FormI and FormII and is more advantageous.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds of the present application and the methods of making the same without departing from the spirit or scope of the application, and therefore, the scope of the invention encompasses all modifications and variations that fall within the scope of the claims and their equivalents.

Claims (10)

1. A nilotinib hydrochloride L-tartaric acid co-crystal Form N, characterized in that the X-ray powder diffraction pattern of the co-crystal is represented by the formula (I): characteristic peaks are arranged at 10.38 +/-0.2 degrees, 11.20 +/-0.2 degrees, 13.36 +/-0.2 degrees, 15.40 +/-0.2 degrees, 18.12 +/-0.2 degrees, 20.48 +/-0.2 degrees, 21.72 +/-0.2 degrees and 22.74 +/-0.2 degrees.
2. The co-crystal of claim 1, having an X-ray powder diffraction pattern that varies from diffraction angle 2 Θ: 8.02 +/-0.2 degrees, 10.38 +/-0.2 degrees, 11.20 +/-0.2 degrees, 12.58 +/-0.2 degrees, 13.36 +/-0.2 degrees, 14.18 +/-0.2 degrees, 15.40 +/-0.2 degrees, 16.00 +/-0.2 degrees, 16.96 +/-0.2 degrees, 18.12 +/-0.2 degrees, 19.84 +/-0.2 degrees, 20.48 +/-0.2 degrees, 21.72 +/-0.2 degrees, 22.74 +/-0.2 degrees, 24.06 +/-0.2 degrees, 24.72 +/-0.2 degrees, 25.76 +/-0.2 degrees, 27.35 +/-0.2 degrees, 28.28 +/-0.2 degrees, 36.28 +/-0.2 degrees and 38.38 +/-0.2 degrees.
3. The co-crystal of claim 1, wherein the X-ray powder diffraction pattern of the co-crystal is substantially as shown in fig. 1.
4. The co-crystal of any one of claims 1 to 3, wherein the co-crystal has a differential scanning calorimetry pattern with an endothermic peak at 196.44 ℃.
5. The co-crystal of any one of claims 1 to 3, wherein the differential scanning calorimetry pattern of the co-crystal is substantially as shown in figure 2.
6. The co-crystal of any one of claims 1 to 3, wherein the co-crystal has a thermogravimetric profile substantially as shown in figure 3.
7. The co-crystal of any one of claims 1 to 3, wherein the co-crystal has a nuclear magnetic spectrum substantially as shown in figure 4.
8. A preparation method of the nilotinib hydrochloride L-tartaric acid co-crystal according to claim 1, wherein the preparation method comprises the following steps: dissolving nilotinib hydrochloride and L-tartaric acid in a solvent, stirring until crystals are separated out after the nilotinib hydrochloride and the L-tartaric acid are dissolved clearly, cooling, filtering and drying to obtain the nilotinib hydrochloride crystal.
9. The preparation method according to claim 8, wherein the feeding molar ratio of the nilotinib hydrochloride to the L-tartaric acid is 1: 1-3; the solvent is methanol; the volume of the used solvent is 10 to 30 times of the mass of the feeding material of nilotinib hydrochloride; the dissolving temperature is 30-60 ℃; cooling to 0-20 ℃.
10. The preparation method according to any one of claims 8 or 9, wherein the feeding molar ratio of nilotinib hydrochloride to L-tartaric acid is 1: 2; the volume of the used solvent is 20 times of the feeding mass of nilotinib hydrochloride; the dissolving temperature is 50 ℃, and the temperature is reduced to 15 ℃.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080200487A1 (en) * 2005-07-20 2008-08-21 Manley Paul W Salts of 4-Methyl-N-[3-(4-Methyl-Imidazol-1-Yl)-5-Trifluoromethyl-Phenyl]-3-(4-Pyridin-3-Yl-Pyrimidin-2-Ylamino)-Benzamide
US20080269269A1 (en) * 2005-07-20 2008-10-30 Manley Paul W Crystalline Forms of 4-Methyl-N- [3-(4-Methyl-Imidazol-1-Yl)-5-Trifluoromethyl-Phenyl]-3- (4-Pyridin-3-Yl-Pyrimidin-2-Ylamino) -Benzamide
US20190071426A1 (en) * 2016-03-14 2019-03-07 Pliva Hrvatskad.O.O. Solid state forms of nilotinib salts

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080200487A1 (en) * 2005-07-20 2008-08-21 Manley Paul W Salts of 4-Methyl-N-[3-(4-Methyl-Imidazol-1-Yl)-5-Trifluoromethyl-Phenyl]-3-(4-Pyridin-3-Yl-Pyrimidin-2-Ylamino)-Benzamide
US20080269269A1 (en) * 2005-07-20 2008-10-30 Manley Paul W Crystalline Forms of 4-Methyl-N- [3-(4-Methyl-Imidazol-1-Yl)-5-Trifluoromethyl-Phenyl]-3- (4-Pyridin-3-Yl-Pyrimidin-2-Ylamino) -Benzamide
US20190071426A1 (en) * 2016-03-14 2019-03-07 Pliva Hrvatskad.O.O. Solid state forms of nilotinib salts

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