WO2012003413A1 - Nouvelles formes solides de tacédinaline - Google Patents

Nouvelles formes solides de tacédinaline Download PDF

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Publication number
WO2012003413A1
WO2012003413A1 PCT/US2011/042728 US2011042728W WO2012003413A1 WO 2012003413 A1 WO2012003413 A1 WO 2012003413A1 US 2011042728 W US2011042728 W US 2011042728W WO 2012003413 A1 WO2012003413 A1 WO 2012003413A1
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Prior art keywords
aminophenyl
acetylamino
disorder
benzamide
subject
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PCT/US2011/042728
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English (en)
Inventor
Edward Holson
Florence Wagner
G. Patrick Stahly
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The Broad Institute, Inc.
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Publication of WO2012003413A1 publication Critical patent/WO2012003413A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol

Definitions

  • the invention relates to novel solid forms of tacedinaline, pharmaceutical
  • compositions comprising the novel solid forms, and methods of treating and/or preventing various conditions by administering the novel solid forms.
  • the solid form (i.e., the crystalline or amorphous form) of a pharmaceutical compound can be important relative to its pharmacological properties and development as a viable active pharmaceutical ingredient ("API").
  • Crystalline forms of a compound may, in some cases, offer advantages over amorphous forms, such as improved solubility, stability, processing improvements, etc., and different crystalline forms (e.g.
  • polymorphs of the compound may offer greater or lesser advantages over one another.
  • crystalline forms of a compound are not predictable, and in fact, are not always possible. It is a well-accepted principle that the formation of a new polymorphic or crystalline form (e.g. a new crystalline salt form) of a compound is totally unpredictable, and until a particular polymorph is prepared, there is no way to know whether it might exist, how to prepare it, or what its properties might be. Bernstein, J. Polymorphism in Molecular Crystals. New York: Oxford University Press, 9 (2002).
  • amorphous forms Unlike a crystalline solid, which has an orderly array of unit cells in three dimensions, amorphous forms lack long-range order because molecular packing is more random. As a result, amorphous organic compounds tend to have different properties than their crystalline counterparts. For example, amorphous compounds often have greater solubility than crystalline forms of the same compound. Thus, by way of example only, in pharmaceutical formulations whose crystalline forms are poorly soluble, amorphous forms may present attractive formulation options. As such, amorphous APIs may be used to improve physical and chemical properties of drugs, such as, for example, dissolution and bioavailability.
  • Solid forms of a compound are of particular interest to the pharmaceutical industry, for example to those involved in the development of suitable dosage forms. If the solid form of the API (e.g. the crystalline polymorphic form or amorphous form) is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. In addition, regulatory agencies require solid form characterization and control of the API for approval. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations.
  • Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.
  • finding the right conditions to obtain a particular solid form of the desired API e.g. a particular crystalline polymorphic form or an amorphous form
  • pharmaceutically acceptable properties is critical to drug development, but can take significant time, resources, and effort.
  • Tacedinaline, 4-(acetylamino)-N-(2-aminophenyl)benzamide, (shown below) is a known API useful for treating and/or preventing a variety of conditions, such as, for example, combating neoplastic diseases, and is recognized as an HDAC inhibitor.
  • tacedinaline has positive indications for the treatment of prostate cancer.
  • the preparation and pharmacologic activity of tacedinaline are described in, for example, U.S. Patent No. 5,137,918, WO 2009/076234, Gediya, L.K. et al, Bioorganic & Medicinal Chemistry 2008, 16, 3352-3360; and Thomas, M. et al., Bioorganic & Medicinal Chemistry 2008, 16, 8109-8116, all of which are incorporated herein by reference.
  • each solid form of a drug candidate can have different solid state (physical and chemical) properties.
  • the differences in physical properties exhibited by a different solid form of an API, such as a polymorph of the original compound, can affect pharmaceutical parameters such as storage stability, compressibility and density, all of which may be important in formulation and product manufacturing, and solubility and dissolution rates, which may be important factors in determining bioavailability.
  • these practical physical properties can be influenced by the solid form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body.
  • finding the most adequate form for further drug development can reduce the time and the cost of that development. It may also be beneficial to identify and characterize additional crystal forms so that they may be recognized if they appear during drug development and/or manufacturing.
  • Crystalline forms often have more favorable chemical and physical properties than amorphous forms of the same compound.
  • one or more crystalline forms may possess more favorable pharmacology than amorphous forms or be easier to process, or may have better storage stability.
  • one crystalline form may possess more favorable pharmacology, may be easier to process, or may have better storage stability than another, or than an amorphous form, or vice versa.
  • thermodynamic stability is a pharmaceutical compound's dissolution rate in aqueous fluid.
  • the rate of dissolution of an API in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
  • Another such physical property is thermodynamic stability.
  • the thermodynamic stability of an active ingredient may have consequences on the manufacturing process and storage stability of the API and/or the formulation.
  • a crystalline form of a compound generally possesses distinct crystallographic and spectroscopic properties when compared to other crystalline forms having the same chemical composition. Crystallographic and spectroscopic properties of the particular form are typically measured by one or more techniques such as x-ray powder diffraction (XRPD), single crystal x- ray crystallography, solid state NMR spectroscopy, infrared spectroscopy (IR), or Raman spectroscopy, among other techniques.
  • XRPD x-ray powder diffraction
  • single crystal x- ray crystallography solid state NMR spectroscopy
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • U.S. Patent No. 5,137,918 describes the synthesis and basic activities of a family of compounds including tacedinaline.
  • the tacedinaline disclosed therein is reported as having a melting point of 243.7°C.
  • novel crystalline forms of tacedinaline including the three forms referred to herein as Forms A, B, and D, and a novel crystalline tacedinaline TFA salt form.
  • the invention in various embodiments also relates to pharmaceutical compositions and formulations comprising the novel crystalline forms, and methods of treating and/or preventing various conditions by administering the novel crystalline forms.
  • the invention relates to a novel amorphous form of tacedinaline, as well as pharmaceutical compositions and formulations comprising the novel amorphous form, and methods of treating and/or preventing various conditions by administering the novel amorphous form.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms, including pseudopolymorphs.
  • the terms "pseudopolymorph” and “pseudomorph” as used herein are interchangeable and are meant to include hydrates (i.e., water present in the crystalline structure) and solvates (i.e., solvents other than water) of the compound, of both a fixed or stoichiometric and variable nature.
  • hydrates i.e., water present in the crystalline structure
  • solvates i.e., solvents other than water
  • XRPD refers to x-ray powder diffraction. Unless otherwise noted, XRPD analyses were performed either on a Scintag Xi Advanced Diffraction system or a Rigaku Smart Lab X-ray diffraction system.
  • the Scintag Xi Advanced Diffraction system is equipped with a Vortex Silicon Multi-Cathode detector. Data were collected using Cu K radiation. The X-ray tube voltage and amperage were set to 45 kV and 40 mA, respectively. The slits used were a 1 mm divergence slit, a 2 mm tube scatter slit, a 0.5 mm detector scatter slit, and a 0.3 mm reference slit. Data were collected in continuous mode from 2 to 40 °2 ⁇ using a 0.04 degree step and a 2 second collection time per step. Each specimen was prepared for analysis by placing it in the 1-mm deep, round well of a stainless steel holder and leveling the surface with a glass slide.
  • the Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg- Brentano geometry using a line source X-ray beam.
  • the x-ray source is a Cu Long Fine Focus tube was operated at 40 kV and 44 ma. That source provides an incident beam profile at the specimen that changes from a narrow line at high angles to a broad rectangle at low angles.
  • Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line.
  • the Bragg-Brentano geometry is a para- focusing geometry controlled by passive divergence and receiving slits with the specimen itself acting as the focusing component in the optics.
  • the inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 °2 ⁇ or less.
  • the axial divergence of the X-ray beam is controlled by 5.0° Soller slits in both the incident and diffracted beam paths.
  • Each powder specimen was prepared in a low background Si holder using light manual pressure to keep the sample surface flat and level with the reference surface of the sample holder.
  • the single crystal Si low background holders have a small circular recess (7 mm diameter and about 1mm depth) that holds between 5 and 10 mg of powdered material.
  • the standard measurement range was from 2 to 40 °2 ⁇ using a continuous scan of 3 °2 ⁇ per minute with an effective step size of 0.02 °2 ⁇ .
  • IR refers to infrared spectroscopy. Unless otherwise noted, IR spectra were obtained on a Nicolet 6700 FT-IR system. Samples were analyzed using a Nicolet SMART iTR attenuated total reflectance device.
  • mp refers to melting point. Melting points were determined on a Stuart SMP3 apparatus that was calibrated using a caffeine USP melting point standard. A ramp rate of 1 °C/minute was used.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • LC/MS refers to tandem liquid chromatography/mass spectrometry.
  • LC/MS data referenced herein were acquired on a Waters 2795 Alliance HPLC coupled with a Waters 2996 Photodiode Array Detector and a Waters ZQ Mass Spectrometer.
  • the column was an XBridge 4.6x30mm, 3.5 ⁇ , using a 5 to 95 % acetonitrile/water gradient containing 0.01 % formic acid over 2.5 minutes.
  • UPLC/MS refers to tandem Ultra Performance Liquid Chromatography/Mass Spectrometer.
  • UPLC/MS data referenced herein was acquired on a Waters Acquity UPLC coupled with a Waters Acquity PDA Detector and a Waters SQ Mass Spectrometer (single quadrupole).
  • the column was an Acquity BEH CI 8 1.0x50mm, 1.7um, using 5 to 95% acetonitrile/water gradient containing 0.05% trifluoroacetic acid (water) and 0.1% triflouroacetic acid (acetonitrile) over 15 minutes.
  • XRPD results may vary slightly from sample to sample, despite the fact that the samples are, within accepted scientific principles, the same crystalline form, and this may be due to, for example, preferred orientation or varying solvent or water content. It is well within the ability of those skilled in the art, looking at the data as a whole, to appreciate whether such differences indicate the same or a different form, and thus determine whether analytical data being compared to those disclosed herein are or are not substantially the same or similar to the solid form it is being compared with.
  • FIGS. 1 A and IB show exemplary XRPD patterns of crystalline tacedinaline Form A.
  • FIG. 2 shows an exemplary IR spectrum of an embodiment of crystalline tacedinaline Form A.
  • FIG. 3 shows an exemplary TGA profile of an embodiment of crystalline tacedinaline Form A.
  • FIG. 4 shows an exemplary DSC thermogram of an embodiment of crystalline tacedinaline Form A.
  • FIGS. 5A - 5C show exemplary 1 H-NMR spectra of an embodiment of crystalline tacedinaline Form A.
  • FIG. 6 shows exemplary LC/MS data for an embodiment of crystalline tacedinaline Form A.
  • FIGS. 7A and 7B show exemplary XRPD patterns of crystalline tacedinaline Form B.
  • FIG. 8 shows an exemplary IR spectrum of an embodiment of crystalline tacedinaline Form B.
  • FIG. 9 shows an exemplary TGA profile of an embodiment of crystalline tacedinaline Form B.
  • FIG. 10 shows an exemplary DSC thermogram of an embodiment of crystalline tacedinaline Form B.
  • FIGS. 11A - 11C show exemplary 1 H-NMR spectra of an embodiment of crystalline tacedinaline Form B.
  • FIG. 12 shows exemplary LC/MS data for an embodiment of crystalline tacedinaline Form B.
  • FIG. 13 shows an exemplary XRPD pattern of an embodiment of a mixture of crystalline tacedinaline Forms B and D.
  • FIG. 14 shows an exemplary IR spectrum of an embodiment of a mixture of crystalline tacedinaline Forms B and D.
  • FIG. 15 shows an exemplary TGA profile of an embodiment of a mixture of crystalline tacedinaline Forms B and D.
  • FIG. 16 shows an exemplary DSC thermogram of an embodiment of a mixture of crystalline tacedinaline Forms B and D.
  • FIGS. 17A - 17C show exemplary 1 H-NMR spectra of an embodiment of a mixture of crystalline tacedinaline Forms B and D.
  • FIG. 18 shows exemplary LC/MS data for an embodiment of a mixture of crystalline tacedinaline Forms B and D.
  • FIG. 19 is an XRPD pattern of crystalline tacedinaline Form C.
  • FIG. 20 is an IR spectrum of crystalline tacedinaline Form C.
  • FIG. 21 is a TGA profile of crystalline tacedinaline Form C.
  • FIG. 22 is a DSC thermogram of crystalline tacedinaline Form C.
  • FIGS. 23A - 23C are 1H- MR spectra of crystalline tacedinaline Form C.
  • FIG. 24 is LC/MS data for crystalline tacedinaline Form C.
  • FIG. 25 shows a comparison of exemplary XRPD patterns for crystalline tacedinaline Forms A, B, C, and D, crystalline tacedinaline TFA salt, and amorphous tacedinaline (top to bottom).
  • FIG. 26 shows an exemplary XRPD pattern of crystalline tacedinaline Form D.
  • FIG. 27 shows an exemplary IR spectrum of an embodiment of crystalline tacedinaline Form D.
  • FIG. 28 shows an exemplary TGA profile of an embodiment of crystalline tacedinaline Form D.
  • FIG. 29 shows an exemplary DSC thermogram of an embodiment of crystalline tacedinaline Form D.
  • FIG. 30 shows an exemplary XRPD pattern of an embodiment of a mixture of amorphous tacedinaline and N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide.
  • FIG. 31 A shows an exemplary 1 H-NMR spectrum of an embodiment of a mixture of amorphous tacedinaline and N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide
  • FIG. 3 IB shows an 1 H-NMR spectrum of N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide.
  • FIG. 32A shows exemplary LC/MS data of an embodiment of a mixture of amorphous tacedinaline and N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide
  • FIG. 32B shows LC/MS data for N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide.
  • FIG. 33 shows an exemplary XRPD pattern of an embodiment of crystalline tacedinaline TFA salt.
  • FIG. 34 shows an exemplary IR spectrum of an embodiment of crystalline tacedinaline TFA salt.
  • FIG. 35 shows an exemplary TGA profile of an embodiment of crystalline tacedinaline TFA salt.
  • FIG. 36 shows an exemplary DSC thermogram of an embodiment of crystalline tacedinaline TFA salt.
  • FIG. 37 shows an exemplary 1 H-NMR spectrum of an embodiment of crystalline tacedinaline TFA salt.
  • FIG. 38 shows exemplary LC/MS data for an embodiment of crystalline tacedinaline TFA salt.
  • FIGS. 39A - 39C show an exemplary 1 H-NMR spectrum of an embodiment of crystalline tacedinaline Form D.
  • FIGS. 40A - 40C show exemplary UPLC/MS data for an embodiment of crystalline tacedinaline Form D.
  • FIG. 41 shows the Plasma Concentration-Time Curve of crystalline tacedinaline Form A in Sprague-Dawley rats following intravenous injection and oral administration at 1 mg/kg.
  • FIG. 42 shows an exemplary DSC thermogram of an embodiment of a mixture of amorphous tacedinaline and N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide
  • FIG. 32B shows LC/MS data for N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide.
  • the invention relates to novel crystalline Forms A, B, and D of tacedinaline, as well as novel amorphous tacedinaline and a novel crystalline tacedinaline TFA salt form. Exemplary methods of preparing these novel solid forms are found in the examples below.
  • the invention relates to pharmaceutical compositions and formulations comprising the novel solid forms of tacedinaline, and methods of treating and/or preventing various conditions by administering the novel solid forms.
  • Crystalline tacedinaline Form A was obtained in a crystalline solid form that is characterized by a unique XRPD pattern substantially as shown in FIGS. 1 A and IB, and a unique IR spectrum substantially as shown in FIG. 2. Crystalline tacedinaline Form A was found to be an anhydrate, as suggested by the representative TGA plot in FIG. 3, exhibiting no weight loss prior to decomposition. The anhydrous nature of tacedinaline Form A was confirmed by the single crystal structure. Tacedinaline Form A has a melting temperature in the range of about 239 - 240 °C, as found by visual determination, and exhibits a corresponding endothermic event at about 247 °C, as shown by the representative DSC trace in FIG. 4.
  • tacedinaline Form A undergoes a thermally activated dehydrative intramolecular cyclization to form N-(4-(l-H-benzo[d]imidazol-2-yl)acetamide, which exhibits a characteristic endothermic event at about 310 °C.
  • tacedinaline Form A can be found in Table 1.
  • An exemplary listing of representative IR peaks of an embodiment of tacedinaline Form A can be found in Table 2.
  • Crystalline tacedinaline Form A exhibits improved properties relative to other forms of tacedinaline, including that disclosed in the art (Form C). For example, Form A has improved thermal stability relative to tacedinaline Form C, which contains methanol and may be undesirable in various embodiments. Additionally, Form A is more thermodynamically stable under certain conditions relative to Forms B and D, as shown in Examples 11 and 12.
  • Crystalline tacedinaline Form B was obtained in a crystalline solid form that is characterized by a unique XRPD pattern substantially as shown in FIGS. 7A and 7B, and an IR spectrum substantially as shown in FIG. 8. Crystalline tacedinaline Form B was found to be an anhydrate, as suggested by the representative TGA plot in FIG. 9 that exhibits no weight loss prior to decomposition. Tacedinaline Form B has a melting temperature in the range of about 236 - 238 °C, as found by visual determination, and exhibits a corresponding endothermic event at about 241 °C, as shown by the representative DSC trace in FIG. 10. Subsequent to this endothermic event, tacedinaline Form B undergoes a thermally activated dehydrative
  • tacedinaline Form B can be found in Table 3.
  • An exemplary listing of representative IR peaks of an embodiment of tacedinaline Form B can be found in Table 4.
  • Crystalline tacedinaline Form B exhibits improved properties relative to the form of tacedinaline disclosed in the art (Form C). For example, Form B has improved thermal stability relative to tacedinaline Form C. In addition, Form B does not contain methanol, which may be undesirable in various embodiments. Further, the solubility of Form B in water is superior to that of Forms A and D.
  • Crystalline tacedinaline Form D was obtained in a crystalline solid form that is characterized by a unique XRPD pattern substantially as shown in FIG. 26, and an IR spectrum substantially as shown in FIG. 27, the 1H-NMR as shown in FIGS. 39A - 39C, and the UPLC/MS as shown in FIGS. 40 A - 40C.
  • Tacedinaline Form D was found to be an anhydrate, as suggested by the representative TGA plot in FIG. 28 that exhibits no weight loss prior to decomposition. The anhydrous nature of Form D was confirmed by the single crystal structure.
  • Form D has a melting temperature in the range of about 240 - 244 °C, as found by visual determination, and exhibits a corresponding endothermic event at about 238 °C, as shown by the representative DSC trace in FIG. 29. Subsequent to this endothermic event, tacedinaline Form D undergoes a thermally activated dehydrative intramolecular cyclization to form N-(4-(l-H- benzo[d]imidazol-2-yl)acetamide, which exhibits a characteristic endothermic event at about 310 °C.
  • tacedinaline Form D can be found in Table 5.
  • An exemplary listing of representative IR peaks of an embodiment of tacedinaline Form D can be found in Table 6.
  • Crystalline tacedinaline Form D exhibits improved properties relative to other forms of tacedinaline, including that disclosed in the art (Form C). For example, Form D has improved thermal stability relative to tacedinaline Form C. In addition, Form D does not contain methanol, which may be undesirable in various embodiments. Further, Form D is more thermodynamically stable under certain conditions relative to Form B, as shown in Examples 10A and 12.
  • a novel tacedinaline TFA (trifluroacetate) salt was obtained in a crystalline solid form, characterized by a unique XRPD pattern as shown in FIG. 33. Representative TGA plot can be found in FIG. 35, and representative DSC can be found in FIG. 36. Subsequent to the endothermic event at about 257 °C, as can be seen in the DSC trace, it appears that the novel crystalline tacedinaline TFA salt undergoes a thermally activated dehydrative intramolecular cyclization to form N-(4-(l-H-benzo[t ]imidazol-2-yl)acetamide, which exhibits a characteristic endothermic event at about 310 °C.
  • the use of trifluroacetic acid provides optimal reaction conditions and yields for the deprotection of the BOC intermediate (see Example 15, below).
  • the isolation of the resulting trifluroacetate salt allowed for decreased residual TFA, reduced reaction volumes during the neutralization reaction, increased reaction yields, shorter reaction times, and/or higher purity of the resulting free base.
  • Amorphous tacedinaline was obtained in a solid form as a mixture with N-(4-(l-H- benzo[d]imidazol-2-yl)acetamide, and is characterized by an XRPD pattern having a classic "amorphous halo", as shown in FIG. 30.
  • the amorphous tacedinaline mixture has a glass transition temperature at about 82 °C, exhibits an endothermic event at about 132 °C, and two endothermic events at about 227 °C and 232 °C, as shown by the representative DSC trace in FIG. 42.
  • crystalline tacedinaline Forms A, B, C, and D, and the novel crystalline tacedinaline TFA salt each exhibit unique crystallographic properties, and each represents a distinct crystal form of the compound.
  • the amorphous mixture exhibits a broad, featureless diffraction pattern, as is typical of a non-crystalline form.
  • the invention in various exemplary embodiments relates to pure or substantially pure crystalline tacedinaline Form A, crystalline tacedinaline Form B, crystalline tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, or amorphous tacedinaline.
  • the invention may relate to a batch or lot of tacedinaline which is 50% or more, such as 60%> or more, 75%> or more, 90%> or more, 95%> or more, 98%> or more, or 99% or more, crystalline tacedinaline Form A, crystalline tacedinaline Form B, crystalline tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, or amorphous tacedinaline.
  • the invention relates to pharmaceutical compositions and/or formulations comprising pure or substantially pure crystalline tacedinaline Form A, crystalline tacedinaline Form B, crystalline tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, or amorphous tacedinaline.
  • the invention relates to crystalline tacedinaline Form A, crystalline tacedinaline Form B, crystalline tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline in a mixture, such as a mixture of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, or in a mixture comprising additional known or as yet unknown solid forms of tacedinaline.
  • the mixture may comprise one or more of crystalline tacedinaline Forms A, B, and D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline in combination with Form C.
  • novel solid forms of tacedinaline of the invention possess substantially the same pharmacological activity as the known form of tacedinaline, and are therefore useful in methods of treating, alleviating, and/or preventing various conditions including, for example, neoplastic diseases, memory loss, and cognitive function disorders/impairments.
  • Neoplastic diseases include, for example, cancers such as prostate, breast, colon, and brain, including without limitation glioblastoma.
  • Exemplary cognitive function disorders that may be treated, alleviated, and/or prevented according to various embodiments of the invention include, but are not limited to, those disclosed in WO 2011/053876 Al, incorporated herein by reference in its entirety.
  • cognitive function disorders/impairments that may be treated, alleviated, and/or prevented include those associated with Alzheimer's disease, Huntington's disease, seizure- induced memory loss, schizophrenia, Rubinstein-Taybi syndrome, Rett syndrome, Fragile X, Lewy body dementia, vascular dementia, attention deficit hyperactivity disorder (ADHD), dyslexia, bipolar disorder, anxiety disorders, conditioned fear response, panic disorders, obsessive compulsive disorders, post-traumatic stress disorder, phobias, social anxiety disorders, substance dependence recovery, and social, cognitive, and learning disorders associated with autism, traumatic head injury, or attention deficit disorder (ADD).
  • ADHD attention deficit hyperactivity disorder
  • bipolar disorder anxiety disorders
  • anxiety disorders conditioned fear response
  • panic disorders obsessive compuls
  • treating or “alleviating” herein, it is meant decreasing the symptoms, markers, and/or any negative effects of a condition in any appreciable degree in a patient who currently has the condition.
  • preventing it is meant preventing entirely or preventing to some extent, such as, for example, by inhibiting all together or delaying the onset or lessening the degree to which a patient develops a condition.
  • a "normal subject” is a subject that has not been diagnosed with a disorder associated with impaired cognitive function. Improving cognitive function includes promoting cognitive function in a subject so that the subject more closely resembles or exceeds the function of an age-matched normal, unimpaired subject.
  • a therapeutically effective amount refers to an amount of a therapeutic agent sufficient to treat, alleviate, and/or prevent a condition by administration of a composition of the invention. That amount is any amount sufficient to exhibit a detectable therapeutic and/or preventative and/or ameliorative effect, and can be determined by routine experimentation by those of skill in the art.
  • the effect may include treatment, alleviation, and/or prevention of any of the disorders or conditions listed herein, for example, as well as symptoms associated therewith.
  • the actual amount required for treatment of any particular patient will depend upon a variety of factors including the disorder being treated and its severity; the specific pharmaceutical composition employed; the age, body weight, general health, sex and diet of the patient; the mode of administration; the time of administration; the route of administration; and the rate of excretion of tacedinaline; the duration of the treatment; any drugs used in combination with or coincidental to the treatment; and other such factors well known in the medical arts.
  • the invention in various exemplary embodiments relates to pharmaceutical compositions and formulations comprising crystalline tacedinaline Form A, tacedinaline Form B, tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, in any amount.
  • the invention in various embodiments relates to pharmaceutical compositions and formulations comprising even one or a few crystals of tacedinaline Form A, tacedinaline Form B, and/or tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, and/or one or a few particles of amorphous tacedinaline.
  • the pharmaceutical compositions and formulations may comprise crystalline tacedinaline Form A, Form B, and/or Form D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, in an amount sufficient to be detected by analytical methods known in the art, such as, for example, IR, XRPD, Raman spectroscopy, and the like.
  • the invention relates to pharmaceutical compositions and formulations comprising a therapeutically effective amount of tacedinaline comprising any amount of crystalline tacedinaline Form A, tacedinaline Form B, and/or tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline.
  • a therapeutically effective amount of tacedinaline comprising any amount of crystalline tacedinaline Form A, tacedinaline Form B, and/or tacedinaline Form D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline.
  • compositions and formulations are therapeutically effective amounts in various exemplary pharmaceutical compositions and formulations.
  • the pharmaceutical composition and/or formulation is within the scope of the invention.
  • a pharmaceutical composition of the invention may be in any pharmaceutical form which contains any amount of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, as described herein.
  • the pharmaceutical compositions of the invention may be formulated in unit dosage form for ease of administration and uniformity of dosage.
  • a "unit dosage form" refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated.
  • the pharmaceutical composition of the invention is a solid unit dosage form that maintains the solid form of at least some amount of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline.
  • Unit dosage forms include, but are not limited to, those disclosed in WO 2011/053876 Al .
  • Solid unit dosage forms useful for oral administration according to the invention include, for example, capsules, tablets, pills, powders, and granules.
  • the active ingredient may optionally be administered in a formulation that provides quick release, sustained release or delayed release after administration to the patient.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier, such as sodium citrate or dibasic calcium phosphate, or any other pharmaceutically acceptable carrier known in the art.
  • pharmaceutically acceptable carrier depends upon the pharmaceutical form and the desired method of administration to be used.
  • a carrier should be chosen that maintains the solid form of at least some amount of at least one of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or the amorphous form.
  • the carrier should not substantially alter the solid form of the entire quantity of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or the amorphous form.
  • tacedinaline TFA salt form and/or amorphous tacedinaline, present.
  • the carrier be otherwise incompatible with tacedinaline itself, or with crystalline tacedinaline Forms A, B, and D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, as described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.
  • the solid unit dosage form may also include one or more other component typically used in formulating pharmaceutical dosage forms, as well known in the art, such as, for example: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i)
  • the solid unit dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Other components useful in the unit dosage forms according to the invention include, but are not limited to, those disclosed in WO 2011/053876 Al . Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical techniques for the preparation thereof.
  • Solid unit dosage forms of pharmaceutical compositions of the invention can also be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Solid unit dosage forms comprising the amorphous form of tacedinaline described herein may also comprise stabilizing excipients. Because crystalline forms are often more thermodynamically stable than amorphous forms, there is a driving force toward crystallization of the amorphous state, and thus a need to stabilize the formulation.
  • stabilizing excipients may include, but are not limited to, polymers, celluloses, and organic acids. Exemplary stabilizing excipients include polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl methacrylamide (HMPA), polyethylene glycols (PEGs), and citric acid, to name a few.
  • any of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline may also be used in, or used in preparation of, non-solid formulations, such as, for example, a solution, an injectable or inhalable formulation, or a patch.
  • non-solid formulations are known in the art.
  • the crystalline and/or amorphous form may, in various embodiments, not be maintained.
  • the crystalline and/or amorphous form may be dissolved in a liquid carrier.
  • the crystalline and/or amorphous forms of the invention may provide advantages of handling stability and purity to the process of making such formulations.
  • the crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline may be administered in a suspension.
  • any of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline may be used as a starting material or intermediate in a process of preparing a different solid form of tacedinaline, or by converting one solid form to another.
  • any of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline may be used in the preparation of solid formulations that do or do not ultimately contain any of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline (for example, by conversion of one or more of crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, to some other solid form).
  • the term "converting" with regard to converting one form to another is intended to include any step or condition that changes the solid form of the compound, such as, for example, a process that uses a particular form as an intermediate; a formulating step that causes intentional or unintended conversion, such as direct compression or wet granulation; exposure to heat and/or humidity; etc.
  • the crystalline tacedinaline TFA salt form described herein may be used in a process for preparing crystalline tacedinaline Forms A and/or B, for example as an intermediate product.
  • the invention in various embodiments also relates to the treatment, prevention, and/or alleviation of neoplastic diseases, memory loss, and cognitive function
  • crystalline tacedinaline Forms A, B, and/or D comprising administering to a subject crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, or a pharmaceutical composition comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline.
  • methods of improving cognitive function in a normal subject and/or methods of promoting fear extinction in a subject comprising administering to a subject crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, or a pharmaceutical composition comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, are disclosed.
  • a pharmaceutical composition administered comprises an effective amount of tacedinaline comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline.
  • tacedinaline comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline.
  • These solid forms and pharmaceutical compositions containing them may, according to various embodiments, be administered using any amount, any form of pharmaceutical composition, and any route of administration effective for the desired treatment.
  • the crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, according to the invention may be administered by any route known, such as, for example, orally, transdermally, intravenously, cutaneously, subcutaneously, nasally, intramuscularly, intraperitoneally, intracranially, and
  • the tacedinaline comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, may be administered at dosage levels of greater than about 0.001 mg/kg, such as greater than about 0.01 mg/kg or greater than about 0.1 mg/kg.
  • the dosage level may be from about 0.001 mg/kg to about 50 mg/kg, such as from about 0.01 mg/kg to about 25 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 5 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dosages smaller than 0.001 mg/kg or greater than 50 mg/kg can also be administered to a subject.
  • a dosage of up to about 0.4 mg/kg, once a day for at least 2 consecutive days, such as for 14 consecutive days, may be administered.
  • administration could be on an intermittent schedule.
  • a dosage of up to about 0.1 mg/kg once a day for up to 56 consecutive days may be administered followed by a dosing holiday, and then an additional dosing schedule.
  • administration less frequently than daily such as, for example, every other day
  • administration with at least 2 days between doses may be chosen.
  • dosing may be every third day, biweekly, or weekly.
  • a dosage of up to about 0.8 mg/kg every other day may be given.
  • a single, acute dose may be administered.
  • a one-time dose of up to about 50 mg/kg may be administered, such as about 10 mg/kg, or about 2.2 mg/kg.
  • the amount required for treatment of a particular patient will depend upon a variety of factors well known in the medical arts, and may vary depending on, for example, the condition being treated.
  • the pharmaceutical composition comprising the crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, may be administered as a unit dosage form.
  • the subject to which the crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, is administered may undergo additional therapies in combination therewith.
  • the combination therapies may be any therapy appropriate for the disease or disorder being treated.
  • the combination therapy may include behavioral therapy and/or additional pharmaceutical compounds.
  • Exemplary behavioral therapies and additional pharmaceutical compounds that may be useful in combination therapies contemplated herein may include, but are not limited to, those disclosed in WO 2011/053876 Al .
  • the pharmaceutical compositions or formulations comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, may be assembled into therapeutic, diagnostic, or research kits to facilitate their use in a particular application.
  • Such a kit may comprise, for example, a housing, an effective amount of tacedinaline comprising crystalline tacedinaline Forms A, B, and/or D, the novel crystalline tacedinaline TFA salt form, and/or amorphous tacedinaline, formulated for oral, transdermal, intraveneous, cutaneous, subcutaneous, nasal, intramuscular, intraperitoneal, intracranial, and intracerebroventricular administration, and instructions for administering the tacedinaline to a subject in need thereof.
  • Exemplary kits that may be useful include, but are not limited to, those disclosed in WO 2011/053876 Al .
  • Analytical data were obtained on the final product 2.2: the XRPD pattern was as shown in FIG. 1 A, the IR spectrum was as shown in FIG. 2, the TGA profile was as shown in FIG. 3, the DSC trace was as shown in FIG. 4, the 1 H-NMR spectrum was as shown in FIGS. 5A - 5C, and the LC/MS data was as shown in FIG. 6.
  • a single crystal suitable for x-ray diffraction analysis was selected from the product 2.1 of Example 2, above.
  • the crystallographic data collection and single crystal parameters for the tacedinaline Form A crystal are set forth in Table 9.
  • a mixture of 204.0 mg of crystalline tacedinaline, which is a mixture of Forms B and D, and 15 mL of a 2: 1 (volume:volume) solution of THF:ethanol was brought to gentle reflux. Most of the solid dissolved.
  • the mixture was filtered hot through hardened filter paper and the filter cake was retained. The clear filtrate was reheated to gentle reflux and reduced in volume by boiling. Crystallization occurred at a volume of about 8 mL. When the volume was about 5 mL, the mixture was removed from the hot plate and allowed to cool to ambient temperature. It was then covered and placed in the refrigerator overnight. Filtration and drying of the filter cake (ambient temperature, diaphragm pump pressure, 90 minutes) gave 121.6 mg of crystalline solid.
  • XRPD data was obtained and the crude product was determined to be a mixture of Forms B and D.
  • the visual melting point was obtained and was about 236 ° C, although it is noted that the procedure in the above mentioned paper reports a melting point of about 216 ° C.
  • a sample of 506.9 mg of the mixture of crystalline tacedinaline Form B and Form D (1.6) from Example 1 was placed in a vial and treated drop wise with DMF, with warming on a hot plate, until a solution resulted. About 1.5 mL of DMF were required. The solution was added to 10 mL of cooled dichloromethane. The resulting slurry was placed in the freezer for about 10 minutes and vacuum filtered. The filter cake was placed in a dessicator under diaphragm pump pressure for about 30 minutes to give 424.7 mg (84% yield) of crystalline product.
  • a slurry of 113.6 mg of a mixture of crystalline tacedinaline Forms B and D was mixed in about 2 mL of a 1 : 1 (v:v) mixture of acetone:water and heated on a hot plate with stirring until it refluxed gently. Additional portions of a 1 : 1 (v:v) mixture of acetone:water were added until all the solid dissolved. About 8 mL total were required.
  • the solution was filtered through a glass wool plug and the filtrate was allowed to stand at ambient temperature in a closed vial overnight, during which time crystallization occurred. The mixture was vacuum filtered and the crystals were dried under diaphragm pump pressure for about 15 minutes.
  • a single crystal of tacedinaline Form D suitable for x-ray diffraction analysis was selected and analyzed.
  • the crystallographic data collection and single crystal parameters for the tacedinaline Form D crystal are set forth in Table 11.
  • a slurry containing 25.8 mg tacedinaline Form A, 25.8 mg of a mixture of tacedinaline Forms B and D, a few milligrams of tacedinaline Form B, and 0.5 mL of tetrahydrofuran (THF) was stirred overnight and filtered to give 38.6 mg of a white solid.
  • the white solid was analyzed by XRPD and determined to be tacedinaline Form A.
  • a calibration curve was prepared using 5 samples (samples 02 - 06) of various concentrations in water, as set forth in Table 12.
  • the starting material was Form B.
  • the UV parameters were: scan range: 190-800 nm; 480 nm/min; 1 cm cuvette.
  • IV formulation The test article was dissolved in 10% DMSO/45% PEG400/45% Saline to yield a final concentration of 0.5 mg/ml for intravenous injection.
  • PO formulation The test article was suspended in 0.5% methylcellulose in water to yield a final concentration of 0.2 mg/ml for oral administration.
  • the plasma may be initially placed on ice prior to being stored in the -80°C freezer). All the plasma samples were labeled with detailed information such as study number, animal number, matrix, time points of collection and date of collection.
  • Cmax time to reach maximum plasma concentration
  • T max time to reach maximum plasma concentration
  • CL clearance
  • V z volume of distribution

Abstract

L'invention concerne de nouvelles formes solides de tacédinaline (4-(acétylamino)-N-(2-aminophényl)benzamide), dont des formes de tacédinaline cristalline A, B et D, un nouveau sel de tacédinaline cristalline TFA et de la tacédinaline amorphe. L'invention concerne également des compositions pharmaceutiques contenant les formes de tacédinaline cristalline A, B et D, le nouveau sel de tacédinaline cristalline TFA et/ou la tacédinaline amorphe, et des procédés de traitement de différents états par l'administration desdites nouvelles formes solides.
PCT/US2011/042728 2010-06-30 2011-07-01 Nouvelles formes solides de tacédinaline WO2012003413A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9545414B2 (en) 2005-06-13 2017-01-17 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form
US9744181B2 (en) 2003-01-14 2017-08-29 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6469058B1 (en) * 1998-09-25 2002-10-22 Warner-Lambert Company Chemotherapy of cancer with actyldinaline in combination with gemcitabine capecitabine or cisplatin
EP1273296B1 (fr) * 2001-07-02 2003-11-26 Warner-Lambert Company Combinaison de l'acetyldinaline et de docetaxel
WO2009076234A2 (fr) * 2007-12-07 2009-06-18 University Of Maryland, Baltimore Procédés de synthèse d'inhibiteurs de l'histone désacétylase (hdaci)
US20110224303A1 (en) * 2009-10-30 2011-09-15 Li-Huei Tsai Use of ci-994 and dinaline for the treatment of memory/cognition and anxiety disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6469058B1 (en) * 1998-09-25 2002-10-22 Warner-Lambert Company Chemotherapy of cancer with actyldinaline in combination with gemcitabine capecitabine or cisplatin
EP1273296B1 (fr) * 2001-07-02 2003-11-26 Warner-Lambert Company Combinaison de l'acetyldinaline et de docetaxel
WO2009076234A2 (fr) * 2007-12-07 2009-06-18 University Of Maryland, Baltimore Procédés de synthèse d'inhibiteurs de l'histone désacétylase (hdaci)
US20110224303A1 (en) * 2009-10-30 2011-09-15 Li-Huei Tsai Use of ci-994 and dinaline for the treatment of memory/cognition and anxiety disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GEDIYA ET AL.: "Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts.", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 16, 2008, pages 3352 - 3360, XP022558568, DOI: doi:10.1016/j.bmc.2007.12.007 *
RIVA ET AL.: "Pharmacokinetics and Cerebrospinal Fluid Penetration of CI-994 (N-Acetyldinaline) in the Nonhuman Primate.", CLIN CANCER RES, vol. 6, 2000, pages 994 - 997 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9744181B2 (en) 2003-01-14 2017-08-29 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9545414B2 (en) 2005-06-13 2017-01-17 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form

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