Patent Application
20230068593
The invention relates to processes for preparing various crystalline forms of tucatinib. These crystalline forms can then be used in preparing medicaments containing tucatinib.
Tucatinib, having the chemical designation, (N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, is a tyrosine kinase inhibitor of HER2. Tucatinib has the following structure:
Tucatinib is marketed under the tradename TUKYSA®. TUKYSA® is indicated in combination with trastuzumab and capecitabine for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.
U.S. Pat. No. 9,168,254 discloses Forms A-P of tucatinib and processes for their preparation.
The present invention is directed to processes of making crystalline forms of tucatinib, designated herein as Form I, Form II, and Form III of tucatinib.
The present disclosure is directed to processes of making various polymorphs of tucatinib, designated herein as Form I, Form II, and Form III of tucatinib.
As used herein and unless otherwise specified, the term “solid-state form” includes crystalline or polymorphic forms, amorphous phase, and solvates.
As used herein and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, e.g., that describing a DSC or TGA thermal event, including, e.g., melting, dehydration, desolvation or glass transition events; a mass change, such as, e.g., a mass change as a function of temperature or humidity; a solvent or water content, in terms of, e.g., mass or a percentage; or a peak position, such as, e.g., in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form.
As used herein and unless otherwise specified, the term “crystalline” and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, mean that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
As used herein and unless otherwise specified, the terms “polymorph,” “polymorphic form” or related term herein, refer to a crystal form of an API (active pharmaceutical ingredient) free base or salt thereof that can exist in two or more forms, as a result of different arrangements or conformations of the molecule, ions of the salt, or addition and arrangement of solvents within the crystalline lattice.
As used herein and unless otherwise specified, the terms “substantially” or “substantially free/pure” with respect to a polymorph or polymorphic form means that the form contains about less than 30 percent, about less than 20 percent, about less than 15 percent, about less than 10 percent, about less than 5 percent, or about less than 1 percent by weight of impurities. Impurities may, for example, include other polymorphic forms, water and solvents other than that in a solvated crystalline polymorphic form.
Techniques for characterizing crystal and amorphous forms include but are not limited to differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), gravimetric vapor sorption (GVS), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction (SCXRD), proton nuclear magnetic resonance (1H-NMR), Fourier transform infrared spectroscopy (FTIR Spectroscopy), and Optical Microscopy.
XRPD data are collected using either a Bruker AXS D8 Advance diffractometer (used for Form I and Form II) or a PANalytical Empyrean diffractometer (used for Form III), using the methods set forth below.
XRPD diffractograms are collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through a 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. The software used for data collection and analysis is Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.
Samples are run under ambient conditions as flat plate specimens using powder as received. The sample is prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample is rotated in its own plane.
The details of the data collection method are:
XRPD diffractograms are collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror are used on the incident beam. A PIXcel3D detector, placed on the diffracted beam, is fitted with a receiving slit and 0.04 rad Soller slits. The software used for data collection is X'Pert Data Collector using X'Pert Operator Interface. The data are analysed and presented using Diffrac Plus EVA or HighScore Plus.
Samples are prepared and analysed in a metal 96 well-plate in transmission mode. X-ray transparent film is used between the metal sheets on the metal well-plate and powders (approximately 1-2 mg) are used as received.
The scan mode for the metal plate uses the gonio scan axis.
The details of the data collection method are:
TGA data are collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. Typically, 5-10 mg of each sample is loaded onto a pre-tared aluminium DSC pan and heated at 10° C./min from ambient temperature to 350° C. A nitrogen purge at 60 ml/min is maintained over the sample.
The instrument control software is Advantage for Q Series and Thermal Advantage and the data are analysed using Universal Analysis.
DSC data are collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminium pan, is heated at 10° C./min from 25° C. to 300° C. A purge of dry nitrogen at 50 ml/min is maintained over the sample.
Sorption isotherms are obtained using a Hiden IGASorp moisture sorption analyser, controlled by Isochema HISorp 2019 software (v4.02.0074). The sample temperature is maintained at 25° C. by a Grant LT ecocool 150 re-circulating water bath. The humidity is controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 250 ml·min−1. The relative humidity is measured by a calibrated Vaisala RH probe (dynamic range of 0-95% RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of % RH is constantly monitored by the microbalance (accuracy ±0.001 mg).
Typically, 20-30 mg of sample is placed in a tared mesh stainless steel basket under ambient conditions. The sample is loaded and unloaded at 40% RH and 25° C. (typical room conditions). A moisture sorption isotherm is performed as outlined below (2 scans giving 1 complete cycle). The standard isotherm is performed at 25° C. at 10% RH intervals over a 0-90% RH range. Typically, a double cycle (4 scans) is carried out. Data analysis is carried out within the Isochema HISorp 2019 software and exported into Microsoft Excel to present accordingly.
Form I of tucatinib is prepared comprising:
Form II of tucatinib is prepared comprising:
In another embodiment of the invention, Form II of tucatinib is prepared comprising:
In another embodiment of the invention, Form II of tucatinib is prepared comprising:
Form III of tucatinib is prepared comprising:
Examples 1-10, which follow herein, disclose the preparation of Form I, Form II, and Form III of tucatinib.
The Examples are presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are illustrative of the present disclosure and the disclosure is not intended to be limited to the examples described herein and shown.
Tucatinib (25 mg) is dissolved in DMSO (50 μl, 2 volumes) at 60° C. Water (25 μl, 1 volume) is added sequentially until a final ratio of DMSO/water (1:5 v/v) is achieved, resulting in the formation of a precipitate. The suspension is filtered over a frit under gentle positive pressure to remove excess solvent. The isolated solid is identified as Form I of tucatinib.
XRPD 2θ pattern peaks and relative % intensity values for the peaks of Form I of tucatinib are shown in Table I.
The angle measurements are ±0.2° 2⊖. Key defining peaks for solid-state Form I of tucatinib include peaks at 15.9, 17.7, 22.9, and 23.1° 2⊖.
An XPRD pattern for a representative sample of Form I of tucatinib is shown in
TGA analysis shows a loss of about 3.5-3.8 weight % up to about 160° C. A representative TGA thermogram of Form I of tucatinib is depicted in
DSC analysis of Form I of tucatinib shows the onset of endothermic events at about 154° C. and 239° C., and a possible third endothermic event with an onset at about 253° C., and as depicted in
A representative GVS isotherm plot of Form I of tucatinib is depicted in
Tucatinib (500 mg) is dissolved in DMSO (1.0 ml, 2 volumes) at 60° C. with stirring. Seeds of Form I of tucatinib prepared in Example 1 are suspended in water (2 ml, 4 volumes). The water suspension is slowly added to the DMSO solution. A suspension forms on addition and after 10 minutes stirring is isolated by Buchner filtration (Grade 1 Whatman filter) and dried in a vacuum oven for 3 hours (50° C., ˜5 mbar). The isolated solid is identified as Form I of tucatinib.
Tucatinib (500 mg) is dissolved in DMSO (1.0 ml, 2 volumes) at 60° C. with stirring (400 rpm). Seeds of Form I of tucatinib (˜5 mg) prepared in Example 2 are suspended in water (4.0 ml, 8 volumes) and added dropwise to the hot DMSO solution. Precipitation occurs on the water addition. Stirring is increased to 600 rpm and stirred for 90 minutes at 60° C. The resulting suspension is vacuum filtered and the filter cake is washed with acetonitrile (2.0 ml) and dried under vacuum for 15 minutes. The recovered material is dried in a vacuum oven at 50° C. (˜5 mbar) for ˜4 hours. The isolated material is determined to be Form I of tucatinib.
Tucatinib (1.00 g) is dissolved in DMSO (4.0 ml, 4 volumes) with stirring (500 rpm) at 65° C. The solution is cooled to 60° C. and seeds of Form I of tucatinib (25 mg, 2.5 wt %) are suspended in water (1.0 ml) and added dropwise. Precipitation occurs during addition. Additional water (3.0 ml) is added dropwise at 60° C. and results in additional precipitation. The mixture is cooled to 25° C. and vacuum filtered. The filter cake is washed with water (2 ml) and then acetone (1.0 ml) and dried under vacuum for 15 minutes. The recovered material is dried in a vacuum oven at 40° C. (˜5 mbar) for ˜14 hours. The isolated material is determined to be Form I of tucatinib.
Tucatinib (55 mg) is suspended in DMSO/water (5:1 v/v) and stirred (500 rpm) at 10° C. for 30 minutes. The mixture is heated to 80° C. at 0.5° C./minute and stirred isothermally at 80° C. for 10 minutes, and then cooled to 10° C. at 0.5° C./minute. The suspension is filtered over a frit under gentle positive pressure to remove excess solvent. The isolated solid is identified as Form II of tucatinib.
XRPD 2θ pattern peaks and relative % intensity values for the peaks of Form II of tucatinib are shown in Table 2.
The angle measurements are ±0.2° 2⊖. Key defining peaks for solid-state Form II of tucatinib include peaks at 10.0, 15.6, 17.7, and 23.5° 2⊖.
An XPRD pattern for a representative sample of Form II of tucatinib is shown in
TGA analysis shows a loss of about 3.7-5.0 weight % up to about 165-175° C. A representative TGA thermogram of Form II of tucatinib is depicted in
DSC analysis of Form II of tucatinib shows the onset of endothermic events at about 134° C. and 238° C. or at about 93° C., 240° C., and 250° C., as depicted in
A representative GVS isotherm plot of Form II of tucatinib is depicted in
Tucatinib (1.00 g) is suspended in DMSO/water (9:1 v/v) (10.0 ml, 10 volumes) and dissolved at 65° C. with stirring (400 rpm). The solution is cooled to 50° C. The solution is seeded with Form I of tucatinib (˜5 mg) prepared in Example 3 and the seeds dissolve. Water (˜1.5 ml) is added dropwise until sample remains turbid. The mixture is seeded with Form I of tucatinib (˜5 mg) and the seeds persist. A suspension develops over ˜5 minutes. Further water (˜3.5 ml) is added dropwise. A total of 5.0 ml (5 volumes) water is added. The mixture is cooled to 25° C. at 0.5° C./minute and stirred at the isolation temperature overnight. The suspension is vacuum filtered. The filter cake is washed with water (2.0 ml) followed by acetone (1.0 ml) and dried under vacuum for (15 minutes). The material is dried in a vacuum oven at 40° C. (˜5 mbar) for 2 hours. The isolated material is determined to be Form II of tucatinib.
Tucatinib (5.00 g) is dissolved in DMSO (25.0 ml, 5 volumes) at 65° C. The solution is cooled to 60° C. and water (5.0 ml, ˜15% v/v) is added dropwise. Some precipitation is observed on contact which redissolves. A yellow solution forms by the end of the addition. The solution is cooled to 40° C. at 1° C./min. The solution becomes turbid at ˜56° C. At 40° C., and the mixture is seeded with Form II of tucatinib (250 mg, 2.5 wt %) prepared in Example 6. The mixture is cooled to 25° C. at 1° C./min. Water (20.0 ml, 4 volumes) is added dropwise. The mixture is filtered, washed with water (10 ml), then acetone (5 ml), and the filter cake is dried under vacuum for 15 minutes. The recovered solid is placed in vacuum oven (40° C., 5 mbar) to dry for 3 days. The isolated material is determined to be Form II of tucatinib.
Tucatinib (5.00 g) is dissolved in DMSO (25.0 ml, 5 volumes) at 60° C. with stirring (150 rpm) and held at that temperature for ˜40 minutes. The solution is cooled to 40° C. at 1° C./minute and kept at held at that temperature for ˜10 minutes. A yellow solution persists. The stirring is increased to 300 rpm and water (2.5 ml, ˜9 vol %) is added. Some initial precipitation may occur which redissolves. After stirring, a yellow solution persists. Seeds of Form II of tucatinib (250 mg, 5 wt %) prepared in Example 7 are suspended in water (2.5 ml) and added dropwise to the DMSO solution. The seeds appear to take. A further 1.0 ml water aliquot is used to transfer residual seed material. The mixture is stirred for 10 minutes and a suspension forms. The suspension is cooled to 25° C. at 1° C./minute. At 25° C., further water (21.5 ml) is added dropwise over 10 minutes. The mixture is stirred for 30 minutes. The suspension is filtered under vacuum and the filter cake washed with water (10 ml, 2 volumes) and then acetone (5 ml, 1 volume). The filter cake is dried under vacuum for 15 minutes. The recovered solid is dried in a vacuum oven at 40° C. (˜5 mbar) for ˜17 hours. The isolated solid is determined to be Form II of tucatinib.
Tucatinib (1.00 g) is dissolved in DMSO (4.0 ml, 4 volumes) at 60° C. with stirring (500 rpm). The solution is cooled to 35° C. Seeds of Form II of tucatinib (50 mg, 5 wt %) prepared in Example 8 are suspended in water (4.0 ml) and stirred at room temperature. The DMSO solution is added dropwise to the water suspension over 10 minutes. Precipitation is observed on addition and a suspension results after the final addition. The suspension is stirred at room temperature for 10 minutes. The suspension is filtered under vacuum and the filter cake washed with water (1.0 ml) and then acetone (0.5 ml). The filter cake is dried under vacuum for ˜30 minutes. The recovered solid is dried in a vacuum oven at 40° C. (˜5 mbar) for ˜6 hours. The isolated solid is determined to be Form II of tucatinib.
Tucatinib (25 mg) is dissolved in THF/water (9:1 v/v) (437.5 μL, 17.5 volumes) at 60° C. with stirring (400 rpm). The solution is cooled to 40° C. and the solution evaporated to approximately one quarter of the starting volume of solvent. The resulting suspension is filtered over a frit under gentle positive pressure to remove excess solvent. The solid is isolated and determined to be Form III of tucatinib.
XRPD 2θ pattern peaks and relative % intensity values for the peaks of Form III of tucatinib are shown in Table 3.
The angle measurements are ±0.2° 2⊖. Key defining peaks for solid-state Form III of tucatinib includes peaks at 20.3, 21.9, and 23.2° 2⊖.
An XPRD pattern for a representative sample of Form III of tucatinib is shown in
The above examples are set forth to aid in the understanding of the disclosure and are not intended and should not be construed to limit in any way the disclosure set forth in the claims which follow hereafter.
| Number | Date | Country | |
|---|---|---|---|
| 63203545 | Jul 2021 | US |
