WO2006009549A1 - Nouvelles formes cristallines de compositions de matière comprenant les éléments gallium, azote et oxygène - Google Patents

Nouvelles formes cristallines de compositions de matière comprenant les éléments gallium, azote et oxygène Download PDF

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WO2006009549A1
WO2006009549A1 PCT/US2004/019968 US2004019968W WO2006009549A1 WO 2006009549 A1 WO2006009549 A1 WO 2006009549A1 US 2004019968 W US2004019968 W US 2004019968W WO 2006009549 A1 WO2006009549 A1 WO 2006009549A1
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matter
crystalline
ray
crystalline composition
elements
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PCT/US2004/019968
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Valeriya N. Smolenskaya
Jeffrey S. Stults
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Genta Incorporated
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G15/00—Compounds of gallium, indium or thallium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/88—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by thermal analysis data, e.g. TGA, DTA, DSC
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity
    • C01P2006/82—Compositional purity water content

Definitions

  • the present invention relates to crystalline and amorphous forms of compositions of matter that include the elements Ga, N 5 and O and especially to crystalline or amorphous forms of gallium nitrate that are hydrates.
  • gallium administered in a variety of gallium-containing compounds to treat mammalian and human disease is well known.
  • Gallium was initially identified as an antineoplastic agent by Hart, et al. (Proc Natl Acad Sci USA, Vol. 68, 1971, pp. 1623- 1626), and has subsequently been reported to be effective against a variety of cancers, including particularly hematological malignancies such as leukemias, lymphomas (e.g., non-Hodgkin's lymphoma), multiple myeloma and Hodgkin's Disease. See, e.g., D. J. Straus, Semin Oncol Vol. 30(2 Suppl 5), April 2003, pp. 25-33; E. A.
  • gallium is a potent inhibitor of bone resorption, leading to its use to treat hypercalcemia associated with cancer (R. P. Warrell, et al., J Clin Invest, Vol. 73, May 1984, pp. 1487-1490) as well as other diseases characterized by accelerated bone loss, such as multiple myeloma (R. P. Warrell, et al., J Bone Mineral Res, Vol. 5 (Suppl 2), August 28, 1990, pp. S 106; R. P. Warrell, et ⁇ ., JClin Oncol, Vol. 11(12), December 1993, pp. 2443-2450), bone metastases (R. P. Warrell, Cancer, Vol. 80, 1997, pp.
  • gallium on bone The actions of gallium on bone are different from bisphosphonates, and appear to be mediated by inhibition of the ATPase-dependent proton pump of osteoclasts, which decreases acid secretion (R. Bockman, Semin Oncol Vol. 30(2 Suppl 5), April 2003, pp. 5-12).
  • Gallium is reported to accumulate at sites of inflammation and infection and has well-known immunosuppressive properties. Macrophages in particular have been shown to accumulate gallium, possibly as a result of their ability to engulf protein-iron complexes, resulting in inhibition of the release of inflammatory mediators from the cells. See N. Makkonen, et al. Inflamm Res, Vol. 44(12), December 1995, pp. 523-528.
  • Gallium has reported efficacy in animal models of autoimmune disease and hypersensitivity, including type 1 diabetes, experimental autoimmune encephalomyelitis, experimental pulmonary inflammation, cardiac allograft rejection, experimental autoimmune uveitis, endotoxic shock, and systemic lupus erythematosus (G. Apseloff, Am JTher, Vol. 6(6), November 1999, pp. 327-339).
  • Gallium therefore, holds particular promise as a therapy for disorders involving the immune system, in particular autoimmune diseases and conditions or diseases involving a cell-mediated (e.g., macrophage-mediated) immune response.
  • gallium as a component of a variety of compounds and complexes.
  • the compounds of the present invention comprising, inter alia, Ga 111 will therefore exhibit a similar range of therapeutic activities and utilities as described above.
  • gallium compounds that are better tolerated and have better bioavailability are needed.
  • the compositions of matter including the elements Ga, N, and O of the present invention were developed in part to address these needs. It is known that crystalline inorganic and organic compounds can sometimes crystallize with more than one type of molecular packing resulting in different crystal structures. This phenomenon - a single crystalline substance having different crystal structures - is often referred to as polymorphism. Reported examples of inorganic compounds that are polymorphic, that is they can crystallize in different crystal structures (forms), include CaCO 3 , TiO 2 and SiO 2 .
  • Crystalline materials in which a solvent molecule is incorporated in the crystal structure are often referred to as solvates or pseudopolymorphs. When the solvent is water, these materials are often referred to as hydrates.
  • solvates or pseudopolymorphs When the solvent is water, these materials are often referred to as hydrates.
  • hydrates Several types of hydrates are known. Crystalline hydrates have been divided into three classes according to whether (1) the water molecules are associated with a metal ion, (2) they are isolated from each other, or (3) engage in hydrogen bonding with other water molecules. Brittian, H.G., Polymorphism in Pharmaceutical , Solids p.
  • site hydrates water molecules (or collections of water molecules) are isolated from hydrogen bonding with the water molecules in an adjacent unit cell.
  • Site hydrates typically have high dehydration temperatures because the water molecules ire trapped, in the crystal lattice and because evaporation of a water molecule from a site does not destabilize other water molecules in the crystal (c.f. channel hydrates, below).
  • Dehydration of site hydrates often disrupts the repeat arrangement of the organic compound.
  • the disrupted lattice may remain disrupted, in which case the dehydrated compound is amorphic (Brittian, p. 215), Alternatively; the dehydrated compound may reorganize into the same polymorphic form or a different polymorphic form (Brittian, 199-200).
  • Site hydrates typically exhibit sharp O-H stretching frequencies due w the lack of hydrogen bonding and, like metal ion hydrates, reportedly undergo a sharp weight loss and endotherm under thermal analysis (Brittian, p. 16
  • water molecules form a hydrogen bonded network spanning more than one unit cell. Since the unit cell repeats, the network spans the lattice of a 2004/019968
  • the network may be one dimensional, in which case the crystal is spanned by closely-spaced parallel tunnels. Or, the network may be two dimensional in which case the crystal is spanned by planar gaps occupied by water molecules.
  • the gaps in the lattice are typically great enough that water molecules can migrate through the tunnel or plane without disrupting the arrangement, of the organic compound in the lattice.
  • a channel hydrate undergoes incremental, stoichiometric hydration at low levels of hydration.
  • Some channel hydrates are capable of expanding to absorb water continuously upon exposure to higher humidity, in which case they can absorb water in non-stoichiometric amounts. The expansion is, in principle, detectable by increased d-spacings in the x-ray diffraction pattern (Brittian, p. 150).
  • Solid state physical properties of crystalline forms of a pharmaceutically useful compound can be influenced by controlling the conditions under which the compound is obtained in solid form.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product.
  • a formulation specialist When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
  • glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
  • Another important solid state property of a pharmaceutical compound that can vary from one polymorph or pseudopolymorph to the next is its rate of dissolution in aqueous media, e.g., gastric fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state form of a compound may also affect its behavior
  • the present invention relates to a crystalline form of gallium nitrate that is a hydrate (form Al) characterized by x-ray reflections at about 13.4°, 14.2°, 19.7°, 21.6°, 22.1°, 22.4°, 23.5°, 24.6°, 27.5°, 29.8°, and 24.5° ⁇ 0.2° 2 ⁇ .
  • a crystalline form of gallium nitrate that is a hydrate (form Al) characterized by x-ray reflections at about 13.4°, 14.2°, 19.7°, 21.6°, 22.1°, 22.4°, 23.5°, 24.6°, 27.5°, 29.8°, and 24.5° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline form of gallium nitrate that is a hydrate (form B) characterized by x-ray reflections at about 37.7°, 38.0°, and 44.5° ⁇ 0.2° 2 ⁇ .
  • Form B a hydrate
  • Form Bl a crystalline form of gallium nitrate that is a hydrate (form Bl) characterized by x-ray reflections at about 37.7°, 38.0°, and 44.5° ⁇ 0.2° 2 ⁇ .
  • Form Bl can be further characterized by x-ray reflections at about 17.6°, 19.5°, 23.0°, 25.5 and 26.2° ⁇ 0.2°2 ⁇ .
  • the present invention relates to a crystalline form of gallium nitrate that is a hydrate (form C) characterized by x-ray reflections at about 24.4°and
  • Form C can be further characterized by x-ray reflections at about 12.7°, 19.0 and 25.4° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline form of gallium nitrate that is a hydrate (form E) characterized by x-ray reflections at about 10.9°, 14.8°, 32.7°, 32.9 and 35.0° ⁇ 0.2° 20.
  • Form E can be further characterized by x-ray reflections at about 12.7°, 21.8°, 22.0°, 25.5°, 26.9°, and 29.7° ⁇ 0.2° 20.
  • the present invention relates to a crystalline form of gallium nitrate that is a hydrate (form N) characterized by either x-ray reflections at about 18.2°, 40.3°, 47.6°, 49.5°, and 54.9° ⁇ 0.2° 2 ⁇ , or by FTIR bands at about 1383.97, 1356.04, 3338.19, 570.80, 832.70, 1042.12, 403.58, 2398.13, and 1765.37 cm '1 , or both.
  • FormN can be further characterized by x-ray reflections at about 12.9°, 22.3°, 25.9°, 31.8°, 35.7°, and 43.6° ⁇ 0.2° 20.
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form G) characterized either by x-ray reflections at about 10.0°, 12.6°, 15.4°, 19.9 20.4°, 24.1°, 25.2°, 27.0°, 29.7°, 32.8°, and 28.2° ⁇ 0.2° 2 ⁇ ; or FTIR bands at about 493, 686, 724, 829, 935, 960, 1001, 1046, 1303, 1345, 1384, 1424, 1439, 1750, 2383, 2920, 2962, and 3010 cm '1 , or both.
  • the present invention relates to A crystalline composition of matter comprising the elements Ga, N, and O (form D) characterized by x-ray reflections at about 14.5°, 27.6° and 28.8° ⁇ 0.2° 2 ⁇ .
  • Form D can be further characterized by x-ray reflections at about 7.0°, 10.9°, 14.0°, 14.3°, 17.0°, 17.6° and 21.9 ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form Dl) characterized by x-ray reflections at about 7.0°, 10.9°, 14.0°, 14.4°, 16.9°, 17.6°, 20.0°, 21.8°, 27.5°, and 34.1° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form H) characterized by x-ray reflections at about 13.0°and 18.7° ⁇ 0.2° 2 ⁇ .
  • Form H can be further characterized by x-ray reflections at about 10.9°, 18.3°, 29.7°, and 37.6° ⁇ 0.2° 29.
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form I) characterized by x-ray reflections at about 22.2°and 24.6° ⁇ 0.2° 20.
  • Form I can be further characterized by reflections at about 8.0°, 9.0°, 9.8°, 14.0°, 18.4°, and 24.0° ⁇ 0.2°2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form II) characterized by x-ray reflections at 9.2°, 22.7°, 27.5°, and 34.0° ⁇ 0.2° 2 ⁇ .
  • Form II can be further characterized by x-ray reflections at about 7.0°, 8.0°, 9.0°, 10.9°, 21.8°, and 03.1° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form J) characterized by x- ray reflections at about 11.5°, 14.2°, 17.6°, 19.6°, 23.1°, 25.5°, 26.2°, 26.9°, 31.7°, and 34.8° ⁇ 0.2°2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form Jl) characterized by x-ray reflections at about 10.9°, 11.5°, 13.1°, 14.3°, 17.6°, 19.6°, 21.7°, 22.3°, 23.1°, 25.0°, 25.6° 26.2°, 26.9°, 31.8°, 34.8°, and 37.6° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga 5 N, and O (form K) characterized by x-ray reflections at about 25.9° and 35.7° ⁇ 0.2° 2 ⁇ .
  • Form K can be further characterized by x-ray reflections at about 7.0 10.9°, 11.5°, 12.9°, 14.2°, 17.6°, 19.6°, 22.3°, 23.1°, 25.5°, 26.2°, 26.9°, and 31.8° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form L) characterized by either x-ray reflections at about 7.0°, 10.9°, 11.5°, 14.2°, 17.6°, 19.6°, 21.9°, 23.1°, and 25.6° ⁇ 0.2° 2 ⁇ ; or FTIR bands at about 410, 578, 824, 1040, 1384, 1566, 1672, 1762, 2395, and 3424 cm "1 , or both.
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form M) characterized by either x-ray reflections at about 6.3°, 10.2°, 11.9°, 12.2°, 21.2°, and 27.1 ° ⁇ 0.2° 20; or by FTIR bands at about 422, 430, 573, 819, 1358, 1384, 1661, and 3295 cm “1 , or both.
  • Form M can be further characterized by x-ray reflections at about 6.6°, 7.0°, 10.9°, 14.1°, and 26.8° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form 1) characterized by x-ray reflections at about 7.0° and 10.4° ⁇ 0.2° 20.
  • the present invention relates to a crystalline composition of matter including the elements Ga, N, and O (form 2) characterized by x- ray reflections at about 13.4° and 18.9° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N 5 and O (form 3) and characterized by x-ray reflections at about 15.2°, 17.0°, 20.4°, 21.6°, 23.4°, 24.1°, 26.1°, 26.8 and 32.0° ⁇ 0.2°2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N and O (form 4) characterized by x-ray reflections at about 8.0°, 9.8°, and 12.8° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form 5) characterized by x-ray reflections at about 6.8°, 7.4°, and 9.7° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter including the elements Ga, N, and O (form 6) characterized by x-ray reflections at about 15.8°, 17.9°, 29.0°, 32.9°, 39.1°, and 40.1° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to a crystalline composition of matter comprising the elements Ga, N, and O (form 7) characterized by an x-ray reflection at about 5.8° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to pharmaceutical compositions, especially in the form of solid oral dosage forms, including at least one of the compositions of matter including the elements Ga, N, and O of the present invention, especially crystalline forms of gallium nitrate that are hydrates, and at least one pharmaceutically acceptable excipient.
  • the present invention relates to the use of at least one of the compositions of matter including the elements Ga, N, and O of the present invention, especially crystalline forms of gallium nitrate that are hydrates, for the manufacture of pharmaceutical compositions for parenteral administration.
  • Figure 1 is a representative x-ray diffraction diagram of form A
  • Figure 2 is a representative x-ray diffraction diagram of gallium nitrate form Al.
  • Figure 3 is a representative x-ray diffraction diagram gallium nitrate form B.
  • Figure 4 is a representative x-ray diffraction diagram of gallium nitrate form Bl.
  • Figure 5 is a representative x-ray diffraction diagram of gallium nitrate form C.
  • Figure 6 is a representative x-ray diffraction diagram of gallium nitrate form E.
  • Figure 7 is a representative x-ray diffraction diagram of gallium nitrate form N.
  • Figure 8 is an FTIR spectrum of gallium nitrate form N.
  • Figure 9 is an x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form.
  • Figure 10 is a FTIR spectrum of a crystalline composition of matter including the elements Ga, N, and O denominated form D.
  • Figure 11 is an x-ray diffraction diagram of crystalline composition of matter including the elements Ga, N, and O denominated form D.
  • Figure 12 is an x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form D 1.
  • Figure 13 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form H.
  • Figure 14 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form I.
  • Figure 15 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form Il .
  • Figure 16 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form J.
  • Figure 17 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form Jl .
  • Figure 18 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form K.
  • Figure 19 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form L.
  • Figure 20 is a representative FTIR spectrum of a crystalline composition of matter including the elements Ga, N, and O denominated form L.
  • Figure 21 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form M.
  • Figure 22 is a representative FTIR spectrum of a crystalline composition of matter including the elements Ga, N, and O denominated form M.
  • Figure 23 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 1.
  • Figure 24 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 2.
  • Figure 25 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 3.
  • Figure 26 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 4.
  • Figure 27 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 5.
  • Figure 28 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 6.
  • Figure 29 is a representative x-ray diffraction diagram of a crystalline composition of matter including the elements Ga, N, and O denominated form 7.
  • Figure 30 is a representative combined DSC - TGA thermogram of a crystalline form of gallium nitrate denominated form Al.
  • Figure 31 is a representative combined DSC - TGA thermogram of an amorphous form of gallium nitrate denominated form F.
  • Figure 32 is a representative x-ray diffraction diagram of an amorphous form of gallium nitrate denominated form F.
  • Figure 33 is a representative DSC thermogram of a crystalline composition of matter including the elements Ga, N, and O denominated form G.
  • Figure 34 is a representative combined DSC - TGA thermogram of a crystalline composition of matter including the elements Ga, N, and O denominated form D.
  • Figure 35 is a representative combined DSC - TGA thermogram of a crystalline composition of matter including the elements Ga, N, and O denominated form Dl.
  • Figure 36 is a combined DSC - TGA thermogram of a crystalline composition of matter including the elements Ga, N, and O denominated form M.
  • the present invention provides crystalline compositions of matter including the elements gallium (Ga), nitrogen (N), and oxygen, especially in the atomic ratio of about 0.5:1:3.
  • these compositions of matter are crystalline forms of Gallium nitrate [Ga(NO 3 ) 2 ] that are crystalline hydrates.
  • Crystalline hydrates of organic and inorganic compounds are well known in the art. Crystalline hydrates are crystalline compounds that have water of crystallization. The hydrates can be "regular", wherein the water occupies regular positions in the unit sell, or they can be so-called channel hydrates as known in the art.
  • Crystalline forms of gallium nitrate that are hydrates share the characteristic of converting to gallium nitrate hydrate form A, now commercially available and useful as a starting material for the preparation of the novel crystalline compositions of matter of the present invention.
  • This conversion can be effected in the presence of water, especially by suspending or dissolving a crystalline form of gallium nitrate that is a hydrate in water under ambient conditions
  • ambient conditions refers to ambient or room temperature (about
  • low humidity or low humidity conditions refers to a relative humidity of less than about 14%, typically 12% to 14 RH.
  • Gallium nitrate form A is now available commercially and is thought to be a hydrate of gallium nitrate. Crystalline gallium nitrate form A is characterized by x-ray reflections at about 13.5°, 14.2°, 19.7°, 21.7°, 22.1°, 22.4°, 23.5°, 24.6°, 29.8°, and 34.5° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of gallium nitrate form A is shown in Figure 1.
  • compositions of matter including Ga, N, and O of the present invention can be characterized by the well-known technique of x-ray diffraction, in particular powder x-ray diffraction.
  • the various compositions of matter can be characterized by, among other things, their characteristic reflections in x-ray diffraction analysis.
  • X-ray powder diffraction (XRPD) analyses were performed using a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation.
  • the instrument is equipped with a long fine focus X-ray tube.
  • the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm.
  • Diffracted radiation was detected by a NaI scintillation detector.
  • a theta-two theta continuous scan at 3 °/min (0.4 sec/0.02° step) from 2.5 to 40 °2 ⁇ was used.
  • a silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1. Samples were prepared for analysis by placing them in an aluminum holder with silicon insert.
  • X-ray powder diffraction (XRPD) analyses were alternatively performed using an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2 ⁇ range of 120°.
  • Real time data were collected using Cu-Ka radiation starting at approximately 4 °2 ⁇ at a resolution of 0.03 °2 ⁇ .
  • the tube voltage and amperage were set to 40 kV and 30 mA, respectively.
  • the monochromator slit was set at 5 mm by 80 or 160 ⁇ m.
  • the pattern is displayed from 2.5-60 °2 ⁇ or 2.5-80 °2 ⁇ .
  • An aluminum sample holder with silicon insert was used. Samples were also prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for 5-60 min. Instrument calibration was performed using a silicon reference standard.
  • X-ray powder diffraction (XRPD) analyses were also performed using a Bruker D8 Discover diffractometer using Cu Ka radiation.
  • the instrument is equipped with a fine focus X-ray tube.
  • the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the X-ray beam is focused using a G ⁇ bel mirror, and is then passed through a 0.5-mm slit and a 0.5-mm collimator.
  • Diffracted radiation was detected by a Seimens position-sensitive area detector located approximately 15 cm from the sample which provides an effective 20 range of ⁇ 37°. Samples were prepared for analysis by placing them in a capillary tube.
  • samples are analyzed with the X-ray source positioned at an incident angle (B 1 ) of 0°.
  • the detector angle (O 2 ) is 22°.
  • O 1 and ⁇ 2 are moved in tandem over a 5-10° range, while keeping the difference between them constant ( ⁇ scan). Analysis times range from 3 to 20 minutes, with the specific analysis time depending primarily on sample size, and slit and collimator configuration).
  • a silicon standard was analyzed to check the instrument alignment.
  • a 2- ⁇ position check was performed using a silicon standard, and a source intensity check using a specific position on the aluminum stage as the target.
  • Data were collected using GADDS (General Area Diffraction Software) v. 4.1.14.
  • the 2D diffraction data acquired is integrated from 5 to 39 °2 ⁇ with a ⁇ range of -140 to -40°.
  • the diffraction patterns are integrated with a step size of 0.05 °2 ⁇ and the intensity is normalized by solid angle.
  • the integrated data is imported into EVA v.7.0 rev.O for further processing.
  • VVT-XRPD Variable-temperature XRPD
  • Shimadzu XRD- 6000 X-ray powder diffractometer equipped with an Anton Paar HTK 1200 high temperature stage. Samples were packed in a ceramic holder and analyzed from 2.5 to 80 °2 ⁇ at 3 °/min (0.4 sec/0.02° step. A silicon standard was analyzed to check the instrument alignment. Temperature calibration was performed using vanillin and sulfapyridine standards. Data were collected and analyzed using XRD-6000 v. 4.1.
  • thermogravimetric analysis TGA
  • DSC Differential scanning calorimetry
  • TGA thermogravimetric analysis
  • thermogravimetric analyzer 2050 or 2950 thermogravimetric analyzer. Samples were placed in an aluminum sample pan and inserted into the TG furnace. Samples were first equilibrated at 25 0 C, and then heated under nitrogen at a rate of 10 °C/min, up to a final temperature of 350°C. Nickel and AlumelTM were used as the calibration standards. Differential scanning calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter 2920. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid and then crimped. In some analyses the pan was covered with a lid perforated with a laser pinhole to allow for pressure release, and then hermetically sealed (see tables for pan types and scan rates).
  • DSC Differential scanning calorimetry
  • the sample cell was equilibrated at ambient or 25°C and heated under a nitrogen purge at a rate of 10°C/min, up to a final temperature of 200 or 350 0 C.
  • Indium metal was used as the calibration standard. Reported temperatures are at the transition maxima (i.e. peak maxima).
  • TG-IR Thermogravimetric infrared analyses were acquired on a TA Instruments thermogravimetric (TG) analyzer model 2050 interfaced to a Magna 560 ® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever- GIo mid/far IR source, a potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
  • TG instrument 20 °C/min.
  • the TG instrument was started first, immediately followed by the FT-IR instrument.
  • Each IR spectrum represents 8 co-added scans collected at a spectral resolution of 4 cm "1 .
  • IR spectra were collected every 8 seconds for 7.5-8 minutes.
  • a background scan was collected before the beginning of the experiment.
  • Wavelength calibration was performed using polystyrene.
  • the TG calibration standards were nickel and AlumelTM. Volatiles were identified from a search of the High Resolution Nicolet TGA Vapor Phase spectral library (Notebook 1489-42, 44).
  • Vibrational spectroscopy infra red or "IR” spectroscopy
  • IR infra red or "IR” spectroscopy
  • Infrared spectra were acquired on a Magna-IR 860 ® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
  • FT-IR Fourier transform infrared
  • DTGS deuterated triglycine sulfate
  • a diffuse reflectance accessory was used for sampling.
  • Each spectrum represents 128 or 256 co- added scans collected at a spectral resolution of 4 cm "1 .
  • Sample preparation consisted of placing the sample into either a 3 -mm or 13 -mm diameter sample cup (KBr-diluted samples were mixed with KBr) and leveling the material.
  • a background data set was acquired with air or an alignment mirror (for samples diluted in KBr).
  • Wavelength calibration was performed using polystyrene.
  • FT-Raman spectra were acquired on an FT-Raman 960 or 860 spectrometer (Thermo Nicolet). This spectrometer uses an excitation wavelength of 1064 nm.
  • Nd YVO 4 laser power was used to irradiate the sample.
  • the Raman spectra were measured with an indium gallium arsenide (InGaAs) detector.
  • the samples were prepared for analysis by placing the material in a glass tube and positioning the tube in a gold-coated tube holder in the accessory.
  • a total of 128 or 256 sample scans were collected from 3704 or 3600 to 100 cm '1 at a spectral resolution of 4 or 8 cm "1 , using Happ-Genzel apodization.
  • Wavelength calibration was performed using sulfur and, cyclohexane Depending on the objective of the analysis, moisture content was determined by one of several techniques, principally the well-known Karl Fisher method.
  • KF Volumetric Karl-Fischer analysis for water determination was performed using a Mettler Toledo DL38 Karl Fischer titrator. Approximately 77 to 98 mg of sample was placed in the KF titration vessel containing Hydranal® Methanol dry and mixed to ensure dissolution. The sample was then titrated with Hydranal® Composite 5 titrant to an appropriate endpoint. Three replicates were obtained to ensure reproducibility. The titrant was standardized with Hydranal Water Standard 10.0. Moisture sorption/desorption data were collected on a VTI SGA-100 Vapor
  • Sorption Analyzer Sorption and desorption data were collected over a range of 5% to 95% relative humidity (RH) at 10% RH intervals under a nitrogen purge. Samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.0100% weight change in 2 minutes, with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. NaCl and PVP were used as calibration standards. The behavior of the crystalline compositions of matter including the elements Ga, N, and O of the present invention was also observed by hot stage microscopy. Hot stage microscopy was performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope.
  • Equilibrium criteria used for analysis were less than 0.0100% weight change in 2 minutes, with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. NaCl and PVP were used as calibration standards.
  • compositions of matter including the elements Ga, N, and O, especially those that that are crystalline forms of gallium nitrate that are hydrates, can be made by one or more of the following techniques.
  • One technique useful in making the crystalline compositions of matter of the present invention is the crystallization method.
  • a suitable gallium nitrate i.e. gallium nitrate of commerce; form A
  • crystallization of the crystalline composition of matter including the elements Ga, N, and O can be effected by slow evaporation, preferably at ambient conditions, or by combining the solution with an anti- solvent, which can also be referred to as a precipitant.
  • Anti-solvents are liquids, preferably freely miscible with the solvent chosen to prepare the solution, in which the desired crystalline composition of matter is at best sparingly soluble. Anti-solvent can be combined with solution at ambient temperature, or cold (crash precipitation).
  • a sample of gallium nitrate hydrate was dissolved in an appropriate solvent at ambient and filtered into an antisolvent cooled in a dry ice bath to approximately -2 to -7 °C (crash precipitation, CP).
  • This procedure can also be carried out using both ambient solvent and anti-solvent (crash precipitation, CP(RT)).
  • an antisolvent at ambient was added to a hot solution (HCP). Any solids formed in any variation of the crystallization method were removed (recovered) by filtration. If no solids were present, solutions were allowed to stand at room temperature to effect crystallization.
  • any solid materials formed were recovered by filtration and analyzed.
  • the wet solid was allowed to dry under ambient conditions before the analysis.
  • Solids obtained were analyzed by X-ray powder diffraction (XRPD).
  • solvent is allowed to slowly evaporate from a solution of gallium nitrate in the desired amount of the chosen solvent.
  • gallium nitrate starting material e.g. form A
  • agitation with a slurry solvent in which gallium nitrate is at best sparingly soluble.
  • Certain embodiments of the crystalline compositions of matter that include the elements Ga, N, and O can be made by the capillary method.
  • Solutions of gallium nitrate hydrate, form A ⁇ see starting material, infra) were prepared by treating the compound with enough solvent to provide a solution concentration of approximately 20-40 mg/mL.
  • the solutions of gallium nitrate hydrate prepared in a given solvent or solvent mixture were filtered prior to adding the solution to an XRPD-quality capillary.
  • the solvent was allowed to evaporate from the capillaries under various conditions (examples, Table 00 infra).
  • the resulting samples were analyzed by optical microscopy and/or XRPD.
  • the present invention provides a crystalline form of gallium nitrate [Ga(NO 3 ) 2 ] that is a hydrate, and here denominated form Al.
  • Form Al is characterized by x- ray reflections at about 13.4°, 14.2°, 19.7°, 21.6°, 22.1°, 22.4°, 23.5°, 24.6°, 27.5°, 29.8°, and 24.5° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form Al is shown in Figure 2.
  • Representative DSC and TGA thermograms of form Al are shown in Figure 30.
  • form Al When examined by hot stage microscopy, form Al liquefies at about 51° to 52° C.
  • the water content of form Al corresponds to about 7 moles water per mole GaN(O 3 ) 2 .
  • Form Al can be made by, for example, grinding form A under ambient conditions.
  • Form Al can also be made in admixture with form G of the crystalline form of Ga(NO 3 ) 2 that is a hydrate by freeze drying (lyophilizing) an aqueous solution of GaN(Os) 2 having a slight excess of nitric acid.
  • the present invention provides a crystalline form of gallium nitrate that is a hydrate, denominated form B that can be characterized by x ray reflections at about 37.7°, 38.0°, and 44.5° ⁇ 0.2° 26.
  • Form B can be further characterized by x-ray reflection at about 17.6°, 19.5°, 23.0°, 25.5°, and 26.2° ⁇ 0.2°. 2 ⁇ .
  • a typical x-ray diffraction diagram of form B is shown in Figure 3.
  • Form B can be made by concentrating an aqueous solution of a gallium nitrate hydrate.
  • Form B so prepared had a water content corresponding to about 7.4 mole water per mole GaN(O 3 ) 2 , but the water content can be as low as about 6.2 mole/mole GaN(O 3 ) 2 .
  • Form B can also be prepared by concentrating an aqueous solution of a gallium nitrate hydrate, e.g. Form A, (150 mg/mL; 0.6 M excess HNO 3 ) .
  • Form B can convert to form Bl ⁇ infra) upon storage, but typically converts to form A.
  • the present invention provides a crystalline form of gallium nitrate that is a hydrate, denominated form Bl, characterized by an x-ray reflection at about 11.5° ⁇ 0.2° 20.
  • Form Bl can be further characterized by x-ray reflections at about 12.9°, 17.6°, 19.6°, 23.1°, 25.6°, 25.9°, 26.2°, 26.9°, 31.8°, and 35.7° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form B 1 is shown in Figure 4.
  • the present invention provides a crystalline form of gallium nitrate that is a hydrate, denominated from C, characterized by x-ray reflections at about 24.4° and 41.7° ⁇ 0.2° 2 ⁇ .
  • Form C can be further characterized by x-ray reflections at about 12.7°, 19.0°, and 25.4° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form C is shown in Figure 5.
  • Form C can be made by, for example, concentrating at room temperature an aqueous solution of gallium nitrate (15 mg/niL; 0.6M excess HNO 3 ) to about one-half its initial volume and isolating form C from the slurry so obtained.
  • Form C converts to form A upon prolonged storage at low relative humidity (12%-14%).
  • the present invention provides a crystalline form of gallium nitrate that is a hydrate, denominated form E, characterized by x-ray reflection at about 10.9°, 14.8°, 32.7°, 32.9°, and 35.0° ⁇ 0.2° 2 ⁇ .
  • Form E is further characterized by x-ray reflections at about 12.7°; 21.8°, 22.0°, 25.5°, 26.9°, and 29.7° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form E is shown in Figure 6.
  • Form E can be made by, for example, a crystallization method in which gallium nitrate hydrate form A is slurried with methylene chloride. Form E converts to form Al upon prolonged storage at low relative humidity (12%- 14%).
  • the present invention provides a crystalline form of gallium nitrate that is a hydrate, denominated form N, characterized by either x-ray reflections at about 18.2°, 40.3°, 47.6°, 49.5°, and 54.9° ⁇ 0.2° 2 ⁇ ; or by FTIR bands at about 1383.97, 1356.04, 3338.19, 570.80, 832.70, 1042.12, 403.58, 2398.13, and 1765.37 cm '1 .
  • Form N can be further characterized by x-ray reflections at about 12.9°, 22.3°, 25.9°, 31.8°, 35.7°, and 43.6° ⁇ 0.2° 20.
  • a representative x-ray diffraction diagram of form N is shown in Figure 7.
  • a representative FTIR spectrum of form N is shown in Figure 8.
  • the present invention provides an amorphous form of gallium nitrate, denominated form F. Some characteristics of form F are collected in Table 2.
  • the DSC thermogram of form F shows a broad endotherm at ca. 138°, overlapping with decomposition.
  • the weight loss at 55 0 C was ca. 3.49%.
  • the sample was not birefringent and shrank at ca. 160 0 C. Therefore the endothermic transition in DSC is thought to be due to dehydration-decomposition of the sample.
  • FIG. 32 A representative x-ray diffraction diagram of form F is shown in Figure 32.
  • Form F can be made by, for example, the slurry method using a slurry solvent selected from acetone, diethyl ether, ethyl acetate, and mixtures of ethyl acetate and methanol.
  • a slurry solvent selected from acetone, diethyl ether, ethyl acetate, and mixtures of ethyl acetate and methanol.
  • the present invention provides a crystalline composition of matter that includes the elements gallium (Ga), nitrogen (N),and oxygen (O), and here designated simply form G, characterized by either x-ray reflections at 10.0°, 12.6°, 15.4°, 19.9°, 20.4°, 24.1°, 25.2°, 27.0°, 29.7°, 32.8°, and 38.2° ⁇ 0.2° 29 or FTIR bands at about 493, 686, 724, 829, 935, 960, 1001, 1046, 1303, 1345, 1384, 1424, 1439, 1750, 2383, 2920, 2962, and 3010 cm “1 .
  • a representative x-ray diffraction diagram of form G is shown in Figure 9.
  • a representative FTIR spectrum form G is shown in figure 10.
  • the DSC thermogram of form G shows an endotherm at about 123°C, followed by decompositions.
  • Minimal weight loss (TGA) was observed at about 55 0 C (0.14%) and 125°C (1.9%).
  • TGA Minimal weight loss
  • the material was found in loose birefringence at about 126°C.
  • the broad intensive band in the region of 3300 to 3500 Cm -1 (H 2 O stretching) is not observed in the IR spectrums of form G, indicative of a lower state of hydration.
  • From G can be made by, for example, a slurry method using DMSO or other slurry solvent.
  • the present invention provides a crystalline composition of matter that includes the elements Ga, N, and O, here simply denoted form D, that is characterized by x-ray reflection at about 14.5°, 27.6°, and 28.8° ⁇ 0.2° 29.
  • Form D can be further characterized by x-ray reflection at about 7.0°, 10.9°, 14.0°, 14.3°, 17.0°, 17.6° and 21.9° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form D is shown in Figure 11. Further characteristics of form D are given in Table 4.
  • DSC and TGA thermograms of form D are shown in Figure 34.
  • the DSC shows a broad endotherm with a minimum at about 115°C followed by decomposition.
  • the TGA thermogram shows a weight loss of about 3.8% at about 55°C.
  • a sample of form D lost birefringence at about 82°C.
  • Form D can be made by, for example, a slurry method using diethyl ether as the slurry solvent.
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, here simply denominated form Dl, and characterized by x-ray reflections at about 7.0°, 10.9°, 14.0°, 14.4°, 16.9°, 17.6°. 20.0°, 21.8°, 27.5°, and 34.1° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form Dl is shown in Figure 12.
  • Representative DSC and TGA thermograms of form Dl are shown in Figure 35.
  • the DSC shows a broad endotherm peaking at about 115°C, followed by decomposition.
  • a sample of form Dl lost birefringence at about 82°C.
  • Form Dl can be prepared by, for example, a slurry method using acetonitrile, methyl ethyl ketone, or ethyl acetate as slurry solvent.
  • Form Dl can also be prepared by a crystallization method where gallium nitrate is dissolved in ethanol and slowly evaporating the solvent at low relative humidity (12%-
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, here simply designated form H, characterized by x-ray reflections at about 13.0° and 18.7° ⁇ 0.2° 20.
  • Form H can be further characterized by x-ray reflections at about 10.9°, 18.3°, 29.7°, and 37.6° ⁇ 0.2° 20.
  • a representative x-ray diffraction diagram is shown in Figure 13.
  • Form H can be prepared by , for example, a slurry method in which mixed hexanes are the slurry solvents for about one week. Upon storage at low relative humidity (12%-14%), form H converts to form J. Further storage results in transformation to form Jl .
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, here simply described as form I, characterized by x-ray reflections at about 22.2° and 24.6° ⁇ 0.2° 2 ⁇ .
  • Form I can be further characterized by x-ray reflections at about 8.0°, 9.0°, 9.8°, 14.0°, 18.4°, and 24.0° ⁇ 0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form I is shown in Figure 14.
  • Form I can be prepared by, for example, slow evaporation, under ambient conditions, of ethanolic or methanolic solutions of gallium nitrate (modification of the crystallization method).
  • the present invention relates to a crystalline composition of matter including the elements, Ga, N, and O, here denominated simply as form II, characterized by x-ray reflections at about 9.2°, 22.7°. 27.5° and 34.0° +1-0.2° 2 ⁇ .
  • Form Il can be further characterized by x-ray reflections at about 7.0°, 8.0°, 9.0°, 10.9°, 21.8°, and 30.1° +1-0.2° 20.
  • a representative x-ray diffraction diagram of form Il is shown in Figure 15.
  • Form Il was not birefringent when viewed between crossed polars.
  • the present invention provides a crystalline composition of matter including the elements Ga, N and O, here simply denominated form J, characterized by x-ray reflections as about 11.5°, 14.2°, 17.6°, 19.6°, 23.1°, 25.5°, 26.2°, 26.9°, 31.7°, and 34.8° +1-0.2 20.
  • a representative x-ray diffraction diagram of form J is shown in Figure 16.
  • the present invention provides a crystalline composition of matter including the elements Ga, N and O, and here designated form Jl, characterized by x-ray reflections at about 10.9°, 11.5°, 13.1°, 14.3°, 17.6°, 19.6°, 21.7°, 22.3°, 23.1°, 25.0°, 25.6°, 26.2°, 26.9°, 31.8°, 34.8°, and 37.6° +1-0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form Jl is shown in Figure 17.
  • Form Jl can be obtained by storage of form J at low relative humidity (12% - 14%).
  • the present invention provides a crystalline composition of matter including the elements Ga, N and O, and herein denominated form K, characterized by x-ray reflections at about 25.9° and 35.7° +1-0.2° 2 ⁇ .
  • Form K can be further characterized by x-ray reflections at about 7.0°, 10.9°, 11.5°, 12.9°, 14.2°, 17.6°, 19.6°, 22.3°, 23.1°, 25.5°, 26.2°, 26.9° and 31.8° +1-02° 20.
  • a representative x-ray diffraction diagram of form K is shown in Figure 18.
  • Form K can be obtained by treatment of form A in a moisture determination apparatus (moisture balance).
  • the present invention provides a crystalline composition of matter comprising the elements Ga, N, and O, and herein denominated form L, characterized by either x-ray reflections at about 7.0°, 10.9°, 11.5°, 14.2°, 17.6°, 19.6°, 21.9°, 23.1°, and 25.6° +1-0.2° 2 ⁇ ; or by FTIR bands at about 410, 578, 824, 1040, 1384, 1566, 1672, 1762, 2395, and 3424 cm "1 .
  • a representative x-ray diffraction diagram of form L is shown in Figure 19.
  • a representative FTIR spectrum of form L is shown in Figure 20.
  • the DSC thermograms of form L exhibits an endotherm at about 45°C, followed by decomposition, a weight loss of about 4.5° at about 55°C in thermogravemetric analysis.
  • a sample of form L lost birefringence without liquefying at about 44°C when observed by hot stage microscopy.
  • Form L can be made by, for example, slow evaporation of a solution of gallium nitrate in tetrahydrofuran (THF).
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here denominated from M, characterized by either x-ray reflections at about 6.3°, 10.2°, 11.9°, 12.2°, 21.2°, and 27.1° +1-0.2° 2 ⁇ ; or by FTIR bands at about 422, 430, 573, 819, 1358, 1384, 1661, and 3295 cm '1 .
  • a representative x-ray diffraction diagram of form M is shown in Figure 21.
  • a representative FTIR spectrum of form M is shown in Figure 8.
  • Representative DSC and TGA thermograms of form M are shown in Figure 36.
  • the DSC thermogram of form M exhibits broad, overlapping endotherms at about 86°, 104°, and 121°C. A weight loss of about 1.8% was observed at about 55 0 C in TGA.
  • Form M can be obtained by, for example, slow evaporation of a methanolic solution of Ga(NO3)2 at low humidity (e.g., 12% - 14% relative humidity).
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here denominated form 1 (form one), characterized by x-ray reflections at about 7.0° and 10.4° +1-0.2° 2 ⁇ .
  • form 1 A representative x- ray diffraction diagram of form 1 is shown in Figure 23.
  • Form 1 can be obtained by the capillary method using methanol solvent (vacuum oven).
  • the present invention provides a crystalline composition of matter comprising the elements Ga, N, and O, here denominated form 2, characterized by x-ray reflections at about 13.4° and 18.9° +1-02° 2 ⁇ .
  • Form 2 can be further characterized by x-ray reflections at about 7.8°, 19.4°, 20.4°, 21.6°, 23.4°, 24.1°, 24.5°, and 30.2° +1-0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form 2 is shown in Figure 24.
  • Form 2 can be made by, for example, a capillary method in which form A is vapor stressed with acetone at ambient conditions.
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here simply denominated form 3, characterized by x-ray reflections at about 15.2°, 17.0°, 20.4°, 21.6°, 23.4°, 24.1°, 24.5° and 30.2° +1-0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form 3 is shown in Figure 25.
  • Form 3 can be obtained by a capillary method using a 1 :2 mixture of water and trifluoroethanol as the solvent.
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here denominated form 4, characterized by x-ray reflections at about 8.0°, 9.8°, and 12.8° +1-0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form 4 is shown in Figure 26.
  • Form 4 can be prepared by a capillary method.
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here denominated form 5, characterized by x-ray reflections at about 6.8°, 7.4°, and 9.7° +1-0.2° 2 ⁇ .
  • a representative x-ray diffraction diagram of form 5 is shown in Figure 27.
  • Form 5 can be obtained by a capillary method in which form A is vapor stressed with vapors of acetonitrile .
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here simply denominated form 6, characterized by x-ray reflections at about 15.8°, 17.9°, 29.0°, 32.9°, 39.1°, and 40.1° +1- 0.2° 20.
  • a representative x-ray diffraction diagram of form 6 is shown in Figure 28.
  • Form 6 can be prepared by a capillary method in which form A is stressed with vapors of acetonitrile.
  • the present invention provides a crystalline composition of matter including the elements Ga, N, and O, and here simply denominated form 7, characterized by an x-ray reflection at about 5.8° +1-0.2° 20.
  • Form 7 can be further characterized by x-ray reflections at about 8.1 ° and 10.1° +1 -0.2° 2 ⁇ .
  • the present invention provides pharmaceutical compositions, especially for oral administration that include at least one of the novel crystalline forms of gallium nitrate that are hydrates, i.e., gallium nitrate forms Al, B, Bl, C, E, and N; and at least one pharmaceutically acceptable excipient.
  • compositions are non-toxic in the amounts used and do not significantly interfere with the bioavailability or efficacy of the active pharmaceutical ingredient with which they are used. Excipients are used in pharmaceutical compositions for a variety of purposes.
  • Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AVICEL®, microfme cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • microcrystalline cellulose e.g. AVICEL®, microfme cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates,
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g.
  • METHOCEL® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition which aid in the break-up of the solid oral dosage form in the alimentary tract.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) and starch.
  • Glidants can be added to improve the flow properties of non-compacted solid compositions and improve the accuracy of dosing in tableting equipment.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, to mention just a few.
  • a solid dosage form such as a tablet is made by compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Flavoring agents and flavor enhancers make the oral dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid ethyl maltol, and tartaric acid.
  • compositions may also be colored using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • the solid pharmaceutical compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • compositions of matter including the elements Ga, N, and O of the present invention are also well suited for the formulation and preparation of pharmaceutical compositions for parenteral administration, especially by subcutaneous or intravenous injection.
  • the formulation and manufacture of pharmaceutical compositions for parenteral administration is well known in the art.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs.
  • An especially preferred dosage form of the present invention is a tablet.
  • the gallium nitrate hydrate form A used as starting material for the preparation of the novel crystalline compositions of matter that include the elements Ga, N, and O, and
  • the material resulted from pattern B material upon storing at -12-14 % RH as detected by XRPD.
  • Example 4 Form C Starting material 4, 16 mL, was rotary evaporated to approx. 8 ml (concentrated by a factor of 2) at ambient conditions. Small crystals formed in solution. Rapid crystallization occurred upon transferring the material to a vial. The resulting thick slurry was stored in a desiccator. After storing overnight, 2 spatulas of the material were vacuum filtered, analyzed by XRPD and returned to the desiccator. Conversion of the retained material to form A was detected by XRPD after 18 days.
  • Example 6 Form Dl a) Starting material 1, 78.3 mg, was slurried in 11 mL of acetonitrile for 8 days. The sample was vacuum filtered and stored at -12-14% RH. b) Starting material 1, 79.5 mg, was slurried in 11 mL of methyl ethyl ketone for 8 days. The sample was vacuum filtered and stored at -12-14% RH. c) Starting material 1, 77.3 mg, was slurried in 11 mL of ethyl acetate for 8 days.
  • Example 11 Form I a) Starting material 1, 73.5 mg, was dissolved in 0.5 mL of ethanol. The solution was filtered through a 0.2 ⁇ m nylon filter and allowed to evaporate in a vial covered with perforated Al foil. A small amount of solvent had remained upon evaporation overnight, no crystallization was observed. The sample was placed in a vacuum oven at ambient temperature. A solid material formed upon drying for 10 days and was stored at -12-14 % RH. XRPD of the sample after 35 days indicated a low crystalline pattern I with a new peak (form II). b) Starting material 1, 85.5 mg, was dissolved in 0.5 mL of methanol.
  • Example 12 Form Il a) The material upon storing form I at -12-14 % RH as detected by XRPD (see pattern I). b) The material resulted upon storing form I at -12-14 % RH as detected by
  • Example 13 Form J Form H was stored -12-14 % RH as detected by XRPD (see pattern H) to yield form J.
  • the capillary screen is summarized in Table 7 below.
  • the representative capillary screen experiments for gallium nitrate hydrate are listed in Table 7. They resulted in 2 known and 7 new XRPD patterns.
  • An amorphous pattern material was generated by evaporating a solution in 2:1 methanol :acetonitrile at ambient temperature followed by vacuum drying.
  • a low crystalline pattern D material, form Dl resulted from evaporation of an aqueous solution at 60°C followed by vacuum drying.
  • the new XRPD patterns 1 to 7 are shown in the Figures. They resulted from evaporations or vapor stress (7-12 days) experiments (Table 7). Form 1 and 2 materials were generated using ambient conditions: evaporation of a methanol solution (1) and acetone vapor stress (2). Forms 3, 4, 5, 6 and 7 materials were obtained from evaporations or stress experiments at 58 or 60°C. Temperature stress conditions possibly resulted in dehydration of the gallium nitrate hydrate.
  • Form 1, 2, 6 and 7 materials were analyzed by Raman spectroscopy.
  • the Raman 0 spectrum of form 2 indicated a different composition compared to the gallium nitrate hydrate. None of the spectra exhibited splitting of the band at —1050 cm "1 .

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Abstract

L’invention concerne des formes de compositions de matière comprenant les éléments Ga, N et O et, en particulier, les formes cristallines de nitrate de gallium qui sont des hydrates. Est également décrit du nitrate de gallium amorphe.
PCT/US2004/019968 2004-06-21 2004-06-21 Nouvelles formes cristallines de compositions de matière comprenant les éléments gallium, azote et oxygène WO2006009549A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100398449C (zh) * 2006-03-16 2008-07-02 余泉茂 硝酸镓的制备方法
JP2008211411A (ja) * 2007-02-26 2008-09-11 Hitachi Communication Technologies Ltd 無線通信システムおよび端末
WO2024054226A1 (fr) * 2022-09-06 2024-03-14 Hoang Ba Xuan Composition de nitrate de gallium et de diméthylsulfoxyde pour traitement respiratoire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1204235A2 (fr) * 2000-11-01 2002-05-08 NTT DoCoMo, Inc. Récupération de l'horloge de symboles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1204235A2 (fr) * 2000-11-01 2002-05-08 NTT DoCoMo, Inc. Récupération de l'horloge de symboles

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Title
EINHORN L. ET AL: "Gallium nitrate in the treatment of bladder cancer.", SEMINARS IN ONCOLOGY., vol. 30, no. 2, April 2003 (2003-04-01), pages 34 - 41, XP008051480 *
FLUKA CHEMIKA-BIOCHEMIKA., 1993, FLIKA CHEMIE AG., SWITZERLAND *
MILWAUKEE, WI.: "Aldrich Catalog of Fine Chemicals.", 1992, ALDRICH CHEMICAL COMPANY, INC. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100398449C (zh) * 2006-03-16 2008-07-02 余泉茂 硝酸镓的制备方法
JP2008211411A (ja) * 2007-02-26 2008-09-11 Hitachi Communication Technologies Ltd 無線通信システムおよび端末
WO2024054226A1 (fr) * 2022-09-06 2024-03-14 Hoang Ba Xuan Composition de nitrate de gallium et de diméthylsulfoxyde pour traitement respiratoire

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