Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems

Definitions

• the invention provides novel soluble gaboxadol forms and methods of making and using the same. These forms include salts, polymorphs, hydrates, and solvates of gaboxadol.
• the invention also provides novel pharmaceutical compositions comprising these novel forms and related methods of treatment.
• compositions and methods of the invention of the invention are useful in the treatment of a number of conditions including sleep disorders.
• Gaboxadol is a tetrahydroisoxazolopyridinol that has the chemical name 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-oL Gaboxadol is also known as THIP.
• the molecular formula for gaboxadol is C 6 HgN 2 O 2 , which corresponds to a molecular weight of 140.14.
• Gaboxadol is a GABAA receptor agonist.
• Gaboxadol, which can exist as a zwitterion has the structure of Formula I:
• Gaboxadol is useful for the treatment of a number of conditions, including for example sleep disorders.
• gaboxadol forms that evidence improved properties, such as for example aqueous solubility and stability, and thereby enable the manufacture and use of a broad range of safe and effective gaboxadol pharmaceutical dosage forms.
• the invention provides novel forms of gaboxadol. These forms include novel salts, solvates, hydrates, and polymorphs of gaboxadol. In certain embodiments, novel gaboxadol forms of the invention are stable, readily formulated, and/or exhibit improved aqueous solubility when compared to known gaboxadol forms. [0008] The invention also provides novel pharmaceutical compositions comprising these novel forms and related methods of treatment.
• compositions and methods of the invention are useful in the treatment of sleeps disorders, for example.
• the compositions and methods of the invention are useful for treating one or more of the following: difficulties in falling asleep, frequent nocturnal arousals, early morning awakening and/or a dissatisfaction with the intensity of sleep.
• the compositions and methods of the invention are particularly suitable for the treatment of elderly patients.
• the invention provides a novel gaboxadol form formed by the reaction of gaboxadol and an organic acid, for example, maleic or tartaric acid.
• the invention provides a hydrated form of gaboxadol, including a gaboxadol monohydrate.
• the gaboxadol forms are more stable than known gaboxadol forms; cause less or no discoloration of solid pharmaceutical dosage forms comprising the improved forms; and/or are more water-soluble than known gaboxadol forms.
• the use of one or more gaboxadol forms described herein can be used in the preparation of a medicament for treating a subject in need of such treatment.
• the invention also provides novel medicaments comprising one or more of the novel forms described in the present application and related methods of treatment.
• FIG. IA illustrates the differential scanning calorimetry (DSC) measurements of a gaboxadol free base taken from approximately room temperature to
• FIG. IB illustrates a thermogravimetic analysis (TGA) of a gaboxadol free base taken from approximately room temperature to approximately 300 °C at 10
• FIG. 1C illustrates Fourier transform infrared (IR) spectroscopy of a gaboxadol free base.
• FIG. ID illustrates Raman spectroscopic measurements of a gaboxadol free base.
• FIG. IE illustrates powder X-ray diffraction (PXRD) measurements of a gaboxadol free base.
• FIG. 2A illustrates the DSC measurements of a maleic acid salt of gaboxadol taken from approximately room temperature to 300 0 C at 10 °C/minute.
• FIG. 2B illustrates a TGA of a maleic acid salt of gaboxadol taken from approximately room temperature to approximately 300 °C at 10 °C/minute.
• FIG. 2C illustrates IR spectroscopy of a maleic acid salt of gaboxadol.
• FIG. 2D illustrates Raman spectroscopic measurements of maleic acid salt of gaboxadol.
• FIG. 2E illustrates PXRD measurements of a maleic acid salt of gaboxadol.
• FIG. 3 A illustrates the DSC measurements of a gaboxadol monohydrate taken from approximately room temperature to 300 °C at 10 °C/minute.
• FIG. 3B illustrates a TGA of a gaboxadol monohydrate taken from approximately room temperature to approximately 300 0 C at 10 °C/minute.
• FIG. 3 C illustrates PXRD measurements of gaboxadol monohydrate.
• FIG. 4A illustrates the DSC measurements of a tartaric acid salt of gaboxadol taken from approximately room temperature to 300 0 C at 10 °C/minute.
• FIG. 4B illustrates a TGA of a tartaric acid salt of gaboxadol taken from approximately room temperature to approximately 300 °C at 10 °C/minute.
• FIG. 4C illustrates IR spectroscopy of a tartaric acid salt of gaboxadol.
• FIG. 4D illustrates Raman spectroscopic measurements of a tartaric acid salt of gaboxadol.
• FIG. 4E illustrates PXRD measurements of a tartaric acid salt of gaboxadol.
• Carboxylic acids include, but are not limited to, formic, acetic, propionic, butyric, isobutyric, valeric, isovaleric, pivalic, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, acrylic, crotonic, benzoic, cinnamic, and salicylic acids.
• Dicarboxylic acid includes, in certain embodiments, a compound of formula (II): wherein Ri and R 2 are each independently H, OH, Cl, Br, I, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl or Ri and R 2 taken together represent a double bond as well as stereochemically pure D or L salts of a compound of formula (II).
• dicarboxylic acid of formula (II) examples include but are not limited to succinic acid, maleic acid, tartaric acid, malic acid, or fumaric acid.
• Dicarboxylic acids of formula (II) that can be used to make compounds of the invention include, e.g., succinic acid, tartaric acid, malic acid, and fumaric acid.
• Dicarboxylic acids in addition to those of Formula II, such as malonic acid and adipic acid can also be used.
• Dicarboxylic acids can be in the form of a substantially pure (i?)-(+)-enantiomer; a substantially pure (i?)-(-)-enantiomer; a substantially pure (5)-(+)-enantiomer; a substantially pure (>S)-(-)-enantiomer, or a substantially pure racemic mixture, or any intermediate between a substantially pure enantiomer and a substantially pure racemic mixture thereof.
• Crystallization solvents include aromatic hydrocarbons, C 3 -Cg ketones, C 3 -C 9 branched alcohols, C 3 -C 9 esters, C 5 -C 9 hydrocarbons, C 3 -C 9 ethers, and cyclic ethers.
• Aromatic hydrocarbons used as crystallization solvents include C 4 -C 6 alkyl aromatic solvents which may include substituted aromatics. Examples of aromatic hydrocarbons include, but are not limited to toluene, benzene, and the like.
• C 5 -C 9 hydrocarbons refer to C 5 -C 9 alkyl solvents which may be substituted, branched or unbranched alkyl, Such hydrocarbon solvents include, but are not limited to straight or branched hexane, heptane, octane, pentane, and the like.
• C 3 -C 9 ketones refers to straight or branched ketones which may optionally be substituted.
• C 3 -C 9 esters refers to straight or branched esters which may optionally be substituted.
• ethers refer to lower alkyl (C 2 -C 8 ) alkyl ethers which may be straight, branched or substituted.
• ether shall include but is not limited to, for example, t-butyl methylether, and the like.
• cyclic ether includes C 5 -C 7 cyclic ether which may be optionally substituted.
• the ether solvent is dry.
• the ether solvent shall contain less than about 1% water.
• Urea and urea derivatives can also be used as crystallization solvents.
• Crystallization solvents are selected on the basis that gaboxadol must be at least partially soluble in the solvent selected, and the solvent selected must not form a solvate with gaboxadol. For example, a solvate dissolves in the solvent before the crystallization process is begun.
• Crystallization solvents used in making gaboxadol forms include 1,4- dioxane (dioxane), 1,2-dichloroethane, dimethoxyethane, glycols including ethylene glycol, propylene glycol, and diethylene glycol, dimethyl ether, tetrahydrofuran (THF), isopropyl acetate, diisopropyl ether, hexane, heptane, cyclohexane, toluene or xylene, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and tert-butanol, ketones such as methyl ethyl ketone or isobutyl methyl ketone, amides such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, pyridine, DMSO, xylene, urea or
• Salt forming compounds or “salt formers” include, but are not limited to, pharmaceutically acceptable acid addition salts prepared from inorganic and organic acids. Salts can be derived from inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Salts can also be derived from organic acids including acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]oct-2-ene-l-carboxy
• gaboxadol forms of the present invention are reasonably considered to exhibit activity at the GABAA receptor.
• Compositions of the invention are reasonably considered to be effective for a number of uses, including the treatment of sleep disorders, for example.
• the present invention is directed to a gaboxadol free base.
• the gaboxadol free base can be characterized according to a number of physical features.
• One such feature is the powder X-ray diffraction pattern of the gaboxadol free base.
• the gaboxadol free base is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 2.4, 12.7, 14.3, 15.0, 16.1, 18.1, 19.4, 21.1, 21.9, 24.5, 25.7, 26.2, 27.9, 28.3, 30.7, 31.5, 32.8, 34.2, 36.3, 37.1, and 39.4 degrees 2-theta.
• the gaboxadol free base is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 2.42, 12.65, 14.26, 15.03, 16.05, 18.13, 19.42, 21.14, 21.92, 24.55, 25.68, 26.25, 27.86, 28.35, 30.72, 31.52, 32.83, 34.19, 36.32, 37.12, and 39.36 degrees 2-theta.
• the gaboxadol free base is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately the 2-theta peaks listed in Figure IE.
• the gaboxadol free base is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 2.4, 12.7, 14.3, 15.0, 16.1, 18.1, 19.4, 21.1, 21.9, 24.5, 25.7, 26.2, 27.9, 28.3, 30.7, 31.5, 32.8, 34.2, 36.3, 37.1, and 39.4 degrees 2- theta.
• the gaboxadol free base is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 2.42, 12.65, 14.26, 15.03, 16.05, 18.13, 19.42, 21.14, 21.92, 24.55, 25.68, 26.25, 27.86, 28.35, 30.72, 31.52, 32.83, 34.19, 36.32, 37.12, and 39.36 degrees 2-theta.
• gaboxadol free base is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group shown in Figure IE.
• the gaboxadol free base is characterized as having peaks at approximately 12.7, 16.1, 19.4, 24.5, and 26.2 degrees 2-theta.
• the gaboxadol free base has a powder X-ray diffraction pattern that is substantially the same as the pattern shown in Figure IE.
• a further physical characteristic of the gaboxadol free base of the present invention includes its Raman spectrum.
• certain embodiments of the gaboxadol free base of the present invention are characterized as having at least one unique Raman spectroscopic peak selected from the group consisting of approximately 2999, 1680, 1453, 1385, 1332, 1302, 1240, 1200, 1102, 1054, 1012, 971, 906, 858, 778, 713, 665, 599, 568, 508, 449, 409, 376, 345, 300, and 158 cm “1 .
• the gaboxadol free base is characterized as having at least one unique Raman spectroscopic peak selected from the group consisting of approximately the peaks (cm "1 ) listed in Figure ID.
• the gaboxadol free base is characterized as having at least two, three, four, five, or six unique Raman spectroscopic peaks selected from the group consisting of approximately 2999, 1680, 1453, 1385, 1332, 1302, 1240, 1200, 1102, 1054, 1012, 971, 906, 858, 778, 713, 665, 599, 568, 508, 449, 409, 376, 345, 300, and 158 cm '1 .
• a gaboxadol free base is characterized as having at least two, three, four, five, or six unique Raman spectroscopic peaks selected from the peaks shown in Figure ID.
• the gaboxadol free base has a Raman spectroscopic pattern that is substantially the same as the pattern shown in Figure ID.
• a further physical characteristic of the gaboxadol free base of the present invention includes its Fourier-transform infrared (IR) spectrum.
• IR infrared
• certain embodiments of the gaboxadol free base of the present invention are characterized as having at least one unique IR spectroscopic peak selected from the group consisting of approximately 3138, 2997, 2787, 2428, 2284, 1677, 1445, 1383, 1307, 1194, 1166, 1051, 1008, 956, 858, 777, 739, 663, 569, 521 and 450 cm '1 .
• the gaboxadol free base is characterized as having at least one unique IR spectroscopic peak selected from the group consisting of approximately the peaks (cm "1 ) listed in Figure 1C.
• the gaboxadol free base is characterized as having a IR spectrum that is substantially the same as the pattern shown in Figure 1C.
• the gaboxadol free base is characterized as having an exothermic transition at about 244-252 0 C.
• the gaboxadol free base is characterized as exhibiting a weight loss, as determined by TGA, substantially similar to that shown in Figure IB.
• the gaboxadol free base in certain embodiments is 97%, 98%, 99%, or 99.9% free of impurities including solvent molecules.
• the present invention is directed to a maleic acid salt of gaboxadol.
• the maleic acid salt of gaboxadol is a salt wherein the gaboxadol and the maleic acid are present in a ratio of about 2: 1 to about 1 :2 or in a ratio of about 1:1.
• the maleic acid salt of gaboxadol can be characterized according to a number of physical features.
• One such feature is the powder X-ray diffraction pattern of the salt.
• the maleic acid salt of gaboxadol is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 5.9, 10.2, 11.9, 13.5, 14.4, 15.1, 16.3, 17.5, 18.7, 19.2, 20.1, 21.1, 21.6, 22.4, 23.2, 24.1, 25.5, 26.0, 27.2, 28.1, 29.0, 29.4, 30.5, 32.1, 33.3, 34.8, 35.8, and 38.2 degrees 2-theta.
• the maleic acid salt of gaboxadol is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 5.94, 10.17, 11.86, 13.47, 14.36, 15.12, 16.31, 17.53, 18.68, 19.18, 20.11, 21.10, 21.63, 22.44, 23.24, 24.11, 25.50, 26.04, 27.16, 28.06, 28.97, 29.41, 30.46, 32.06, 33.29, ' 34.8I, 35.81, and 38.19 degrees 2-theta.
• the maleic acid salt of gaboxadol is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately the 2-theta peaks listed in Figure 2E.
• the maleic acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 5.9, 10.2, 11.9, 13.5, 14.4, 15.1, 16.3, 17.5, 18.7, 19.2, 20.1, 21.1, 21.6, 22.4, 23.2, 24.1, 25.5, 26.0, 27.2, 28.1, 29.0, 29.4, 30.5, 32.1, 33.3, 34.8, 35.8, and 38.2 degrees 2-theta.
• the maleic acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 5.94, 10.17, 11.86, 13.47, 14.36, 15.12, 16.31, 17.53, 18.68, 19.18, 20.11, 21.10, 21.63, 22.44, 23.24, 24.11, 25.50, 26.04, 27.16, 28.06, 28.97, 29.41, 30.46, 32.06, 33.29, 34.81, 35.81, and 38.19 degrees 2-theta.
• the maleic acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group shown in Figure 2E.
• the maleic acid salt of gaboxadol has a powder X- ray diffraction pattern that is substantially the same as the pattern shown in Figure 2E.
• a further physical characteristic of the maleic acid salt of gaboxadol of the present invention includes its Raman spectrum.
• certain embodiments of the maleic acid salt of gaboxadol of the present invention are characterized as having at least one unique Raman spectroscopic peak selected from the group consisting of approximately 1709, 1678, 1621, 1491, 1451, 1389, 1332, 1289, 1248, 1217, 1056, 1006, 970, 937, 905, 877, 850, 803, 779, 730, 707, 653, 601, 542, 498, 451, 391, 295, 195, and 154 cm "1 .
• the maleic acid salt of gaboxadol is characterized as having at least one unique Raman spectroscopic peak selected from the group consisting of approximately the peaks (cm "1 ) listed in Figure 2D.
• the maleic acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique Raman spectroscopic peaks selected from the group consisting of approximately 1709, 1678, 1621, 1491, 1451, 1389, 1332, 1289, 1248, 1217, 1056, 1006, 970, 937, 905, 877, 850, 803, 779, 730, 707, 653, 601, 542, 498, 451, 391, 295, 195, and 154 cm "1 .
• a maleic acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique Raman spectroscopic peaks selected from the group recited above, or alternatively shown in Figure 2D.
• the maleic acid salt of gaboxadol has a Raman spectrum that is substantially the same as the pattern shown in Figure 2D.
• a further physical characteristic of the maleic acid salt of gaboxadol of the present invention includes its IR spectrum.
• certain embodiments of the maleic acid salt of gaboxadol of the present invention are characterized as having at least one unique IR spectroscopic peak selected from the group consisting of approximately 1705, 1673, 1564, 1538, 1457, 1438, 1371, 1354, 1331, 1300, 1264, 1240, 1218, 1192, 1004, 933, 897, 865, 815, 721, and 704 cm "1 .
• the maleic acid salt of gaboxadol is characterized as having at least one unique IR spectroscopic peak selected from the group consisting of approximately the peaks (cm "1 ) listed in Figure 2C.
• the maleic acid salt of gaboxadol is characterized as having a IR spectrum that is substantially the same as the pattern shown in Figure 2C.
• the maleic acid salt of gaboxadol is characterized as having an endothermic transition at about 100-106 0 C.
• a specific embodiment of a maleic acid salt of gaboxadol exhibits a DSC scan substantially as shown in Figure 2A.
• Certain embodiments of a maleic acid salt of gaboxadol exhibit a weight loss of about 22% over a temperature range of about 80 °C to about 160 0 C, as determined by TGA.
• the maleic acid salt of gaboxadol is characterized as exhibiting a weight loss, as determined by TGA, substantially similar to that shown in Figure 2B.
• the maleic acid salt of gaboxadol in certain embodiments is 97%, 98%, 99%, or 99.9% free of impurities including solvate molecules.
• the present invention is directed to a gaboxadol monohydrate form.
• the gaboxadol monohydrate has a ratio of gaboxadol to water from about 1.5:1 to about 1:1.5; from about 1.1:1 to about 1:1.1; or of about 1:1.
• the gaboxadol monohydrate can be characterized according to a number of physical features.
• One such feature is the powder X-ray diffraction pattern of the gaboxadol monohydrate.
• the gaboxadol monohydrate is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 11.6, 13.5, 15.6, 17.5, 18.1, 18.8, 21.5, 23.2, 24.3, 24.9, 26.7, 27.5, 28.7, 30.3, 31.5, 35.2, and 37.5 degrees 2-theta.
• the gaboxadol monohydrate is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 11.58, 13.53, 15.56, 17.49, 18.06, 18.84, 21.50, 23.24, 24.33, 24.89, 26.74, 27.54, 28.69, 30.33, 31.54, 35.17, and 37.51 degrees 2-theta.
• the gaboxadol monohydrate is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately the 2-theta peaks listed in Figure 3 C.
• the gaboxadol monohydrate is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 11.6, 13.5, 15.6, 17.5, 18.1, 18.8, 21.5, 23.2, 24.3, 24.9, 26.7, 27.5, 28.7, 30.3, 31.5, 35.2, and 37.5 degrees 2-theta.
• the gaboxadol monohydrate is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 11.58, 13.53, 15.56, 17.49, 18.06, 18.84, 21.50, 23.24, 24.33, 24.89, 26.74, 27.54, 28.69, 30.33, 31.54, 35.17, and 37.51 degrees 2- theta.
• the gaboxadol monohydrate is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group shown in Figure 3C.
• the gaboxadol monohydrate is characterized as having peaks at approximately 11.6, 18.1, and 24.9 degrees 2-theta.
• the gaboxadol monohydrate has a powder X-ray diffraction pattern that is substantially the same as the pattern shown in Figure 3 C.
• the gaboxadol monohydrate is characterized as having an endothermic transition at about 87-88 °C.
• the gaboxadol monohydrate is characterized as having an endothermic transition at about 96-102 °C.
• a specific embodiment of a gaboxadol monohydrate exhibits a DSC scan substantially as shown in Figure 3 A.
• a gaboxadol monohydrate exhibit a weight loss of about 12% over a temperature range from about 40 0 C to about 115 °C, as determined by TGA.
• the gaboxadol monohydrate is characterized as exhibiting a weight loss, as determined by TGA, substantially similar to that shown in Figure 3B.
• the present invention is directed to a tartaric acid salt of gaboxadol.
• the tartaric acid salt of gaboxadol can be characterized according to a number of physical features.
• One such feature is the powder X-ray diffraction pattern of the tartaric acid salt of gaboxadol.
• the tartaric acid salt of gaboxadol is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately 2.4, 7.1, 10.0, 11.7, 14.5, 15.1, 16.3, 17.7, 18.7, 19.5, 21.6, 22.1, 23.6, 24.5, 25.4, 26.7, 27.1, 28.3, 29.3, 29.9, 30.4, 32.7, 33.7, 34.2, 36.7, 37.8, and 39.3 degrees 2-theta.
• the tartaric acid salt of gaboxadol is characterized as having at least one unique powder X- ray diffraction peak selected from the group consisting of approximately 2.40, 7.13, 9.95, 11.72, 14.49, 15.08, 16.33, 17.75, 18.66, 19.55, 21.62, 22.06, 23.55, 24.47, 25.38, 26.68, 27.13, 28.30, 29.26, 29.94, 30.43, 32.72, 33.73, 34.17, 36.71, 37.83, and 39.33 degrees 2-theta.
• the tartaric acid salt of gaboxadol is characterized as having at least one unique powder X-ray diffraction peak selected from the group consisting of approximately the 2-theta peaks listed in Figure 4E.
• the tartaric acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 2.4, 7.1, 10.0, 11.7, 14.5, 15.1, 16.3, 17.7, 18.7, 19.5, 21.6, 22.1, 23.6, 24.5, 25.4, 26.7, 27.1, 28.3, 29.3, 29.9, 30.4, 32.7, 33.7, 34.2, 36.7, 37.8, and 39.3 degrees 2-theta.
• the tartaric acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group consisting of approximately 2.40, 7.13, 9.95, 11.72, 14.49, 15.08, 16.33, 17.75, 18.66, 19.55, 21.62, 22.06, 23.55, 24.47, 25.38, 26.68, 27.13, 28.30, 29.26, 29.94, 30.43, 32.72, 33.73, 34.17, 36.71, 37.83, and 39.33 degrees 2-theta.
• the tartaric acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique powder X-ray diffraction peaks selected from the group shown in Figure 4E.
• the tartaric acid salt of gaboxadol is characterized as having peaks at approximately 17.7, 19.5, and 21.6 degrees 2-theta.
• the tartaric acid salt of gaboxadol has a powder X- ray diffraction pattern that is substantially the same as the pattern shown in Figure 4E.
• a further physical characteristic of the tartaric acid salt of gaboxadol of the present invention includes its Raman spectrum.
• certain embodiments of the tartaric acid salt of gaboxadol of the present invention are characterized as having at least one unique Raman spectroscopic peak selected from the group consisting of approximately 1681, 1652, 1512, 1447, 1390, 1331, 1262, 1243, 1150, 1088, 1045, 992, 963, 888, 839, 809, 755, 726, 705, 641, 602, 523, 478, 443, 393, 282, 239, 209, 168, and 146 cm '1 .
• the tartaric acid salt of gaboxadol is characterized as having at least one unique Raman spectroscopic peak selected from the group consisting of approximately the peaks (cm '1 ) listed in Figure 4D.
• the tartaric acid salt of gaboxadol is characterized as having at least two, three, four, five, or six unique Raman spectroscopic peaks selected from the group consisting of approximately 1681, 1652, 1512, 1447, 1390, 1331, 1262, 1243, 1150, 1088, 1045, 992, 963, 888, 839, 809, 755, 726, 705, 641, 602, 523, 478, 443, 393, 282, 239, 209, 168, and 146 cm “1 .
• a tartaric acid salt of gaboxadol is characterized as having at least two, three, four, five, or six Raman spectroscopic peaks selected from the group recited above, or alternatively shown in Figure 4D.
• the tartaric acid salt of gaboxadol has a Raman spectrum that is substantially the same as the pattern shown in Figure 4D.
• a further physical characteristic of the tartaric acid salt of gaboxadol of the present invention includes its IR spectrum.
• certain embodiments of the tartaric acid salt of gaboxadol of the present invention are characterized as having at least one unique IR spectroscopic peak selected from the group consisting of approximately 3408, 3359, 2916, 1731, 1678, 1633, 1536, 1511, 1454, 1401, 1324, 1291, 1220, 1138, 1093, 984, 917, 885, 868, 831, 763, 719, 685, 664, and 653 cm '1 .
• the tartaric acid salt of gaboxadol is characterized as having at least one unique IR spectroscopic peak selected from the group consisting of approximately the peaks (cm '1 ) listed in Figure 4C.
• the tartaric acid salt of gaboxadol is characterized as having a IR spectrum that is substantially the same as the pattern shown in Figure 4C.
• the tartaric acid salt of gaboxadol is characterized as having a broad endothermic transition at about 89-100 °C.
• the tartaric acid salt of gaboxadol is characterized as having an endothermic transition at about 142-145 °C.
• a specific embodiment of a tartaric acid salt of gaboxadol exhibits a DSC thermogram substantially as shown in Figure 4A.
• the tartaric acid salt of gaboxadol is characterized as exhibiting a weight loss, as determined by TGA, substantially similar to that shown in Figure 4B.
• forms of gaboxadol as described herein have a solubility greater than 5 micrograms/mL, such as greater than lO microgranis/niL, greater than 20 micrograms/mL, greater than 30 micrograms/mL, greater than 40 micrograms/mL, greater than 50 micrograms/mL, or greater than 100 micrograms/mL in a solution with a pH of about 1.
• Gaboxadol forms of the invention include, but are not limited to:
• a gaboxadol free base characterized by a powder X-ray diffraction pattern expressed in terms of 2-theta angles, and wherein the X-ray powder diffraction pattern comprises approximately the 2-theta angle values listed and illustrated in Figure IE herein;
• a tartaric acid salt of gaboxadol characterized by a powder X-ray diffraction pattern expressed in terms of 2-theta angles, and wherein the X-ray powder diffraction pattern comprises approximately the 2-theta angle values listed and illustrated in Figure 4E herein.
• compositions and dosage forms can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• Oral and parenteral pharmaceutical compositions and dosage forms are exemplary dosage forms.
• the oral dosage form is a solid dosage form, such as a tablet, a caplet, a hard gelatin capsule, a starch capsule, a hydroxypropyl methylcellulose (HPMC) capsule, or a soft elastic gelatin capsule.
• Other dosage forms include an intradermal dosage form, an intramuscular dosage form, a subcutaneous dosage form, and an intravenous dosage form.
• gaboxadol can be administered by controlled- or delayed-release means.
• Controlled-release pharmaceutical products generally have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
• the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of API substance being employed to cure or control the condition in a minimum amount of time.
• Controlled-release formulations generally include: 1) extended activity of the API; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total API; 5) reduction in local or systemic side effects; 6) minimization of API accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of API activity; and 10) improvement in speed of control of diseases or conditions.
• greater targeting of the liver and the sites of lipid particle generation could be an advantage of controlled release.
• Topical dosage forms of the invention include, but are not limited to, creams, lotions, ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, and other forms know to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia, PA (1985).
• viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity optionally greater than water are typically employed.
• Suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
• auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts
• suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, optionally in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as freon), or in a squeeze bottle.
• a pressurized volatile e.g., a gaseous propellant, such as freon
• Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, PA (1990).
• Parenteral dosage forms can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are optionally sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
• Transdermal and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, patches, sprays, aerosols, creams, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, or other forms know to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, PA (1990); and Introduction to Pharmaceutical Dosage
• Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes, as oral gels, or as buccal patches.
• transdermal dosage forms include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
• the amounts and specific type of active ingredient in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
• typical dosage forms of the invention comprise a gaboxadol form, for example a pharmaceutically acceptable salt or hydrate of gaboxadol in an amount of from about 1 mg to about 250 mg, from about 1 mg to 125 mg, or from about 1 mg to about 50 mg.
• the gaboxadol form for use in such a composition is gaboxadol free base, a gaboxadol monohydrate, a maleic acid salt of gaboxadol, or a tartaric acid salt of gaboxadol.
• a pharmaceutical composition comprising a gaboxadol form of the present invention is administered orally as needed in an amount of from about 0.1 mg to about 50 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, or from about 0.5 mg to about 30 mg.
• pharmaceutical compositions comprising a gaboxadol form of the present invention can be administered orally in amounts of about 20 or 30 mg. The dosage amounts can be administered in single or divided doses.
• the present invention is directed to compositions comprising a gaboxadol form as described herein and one or more diluents, carriers, and/or excipients suitable for the administration to a mammal for the treatment or prevention of one or more of the conditions described herein or for GABAA system malfunction-related conditions.
• Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
• Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein.
• excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, stabilizers, fillers, disintegrants, and lubricants. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
• oral dosage forms such as tablets or capsules may contain excipients not suited for use in parenteral dosage forms.
• compositions or dosage forms may contain one or more compounds that reduce or alter the rate by which the active ingredient will decompose.
• stabilizers include, but are not limited to, antioxidants, pH buffers, or salt buffers.
• the gaboxadol forms of the invention are reasonably considered to exhibit activity at the GABAA receptor.
• Compositions of the invention are reasonably considered to be effective in the treatment of a number of illnesses and medical conditions, including, for example, sleep disorders.
• an effective amount of a composition of the invention is used for the treatment of sleeps disorders, for example.
• An effective amount of a composition of the invention is useful treating one or more of the following: difficulties in falling asleep, frequent nocturnal arousals, early morning awakening and/or a dissatisfaction with the intensity of sleep.
• an effective amount of a composition of the invention is particularly suitable for the treatment of elderly patients.
• the dose to be administered may depend on the patient's age and weight as well as the degree and nature of sleep disorder.
• a gaboxadol form as described herein and used according to this invention is administered in a dose of 0.5 mg to 50 mg per day.
• the administration may be intravenous, intramuscular, or oral, or a combination thereof.
• an effective amount of a composition of the invention is useful for treating insomnia.
• Insomnia may be characterised by one or more of the following symptoms: 1) difficulty falling asleep; 2) difficulty sleeping without interruption; and 3) waking up frequently, or very early, and having a feeling of being unrested.
• a method of treating a sleep disorder may in certain embodiments provide improved sleep induction. Alternatively, the method may provide improved sleep maintenance. In other embodiments, the method provides improved sleep architecture or provide an improved or substantially normal sleep pattern. Moreover, in additional embodiments, the compositions of the present invention can be administered to treat a sleep disorder without producing psychological or physical dependence to gaboxadol.
• compositions of the present invention can be used to treat, ameliorate, or prevent sleep-related breathing disorders.
• the method comprises, in certain embodiments, the administration of an effective dose of a composition of the present invention to a patient in need of such therapy, alone or in a combination with a glycine receptor antagonist.
• Sleep-related breathing disorders include, but are not limited to, obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.
• an effective amount of a composition of the invention is useful treating sleep apnea.
• Sleep apnea is described as a period when there is no airflow at the nose and mouth for ten seconds or more, which typically stops when the patient awakens abruptly.
• the dose to be administered may depend on the patient's age and weight as well as the degree and nature of the sleep apnea.
• a gaboxadol form as described herein and used according to this invention is administered in a dose of 0.5 mg to 50 mg per day.
• the administration may be intravenous, intramuscular, or oral, or a combination thereof.
• a particular patient demographic segment that is optionally treated includes elderly patients, for example, patients of fifty-five years of age or older. Of course, patients of all ages may be treated with the method of the present invention.
• Gaboxadol can be made using various methods known to those skilled in the art.
• European Patent Application Publication No. EP0000338 Application No. 78100191.2 discloses gaboxadol and a method of preparing it.
• other methods known to one of ordinary skill in the art may be used to prepare the active ingredient of gaboxadol.
• Forms of the invention including salts, polymorphs, hydrates, or solvates of gaboxadol may be prepared by reacting the gaboxadol with an appropriate acid, such as an organic or inorganic acid, including without limitation, oxalic acid, succinic acid, malic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, tartaric acid, maleic acid, malonic acid, adipic acid, and benzenesulfonic acid.
• an appropriate acid such as an organic or inorganic acid, including without limitation, oxalic acid, succinic acid, malic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, tartaric acid, maleic acid, malonic acid, adipic acid, and benzenesulfonic acid.
• an appropriate acid such as an organic or inorganic acid, including without limitation, oxalic acid, succinic acid, malic acid, hydrochloric acid, sulfuric
• a crystallization solvent in which the resulting form, e.g., salt, is only slightly soluble or not soluble.
• a crystallization solvent is used in which the desired salt is very soluble, and an anti-solvent (or a crystallization solvent in which the resulting salt is poorly soluble) is added to the solution.
• Other variants for salt formation or crystallization includes concentrating the salt solution (e.g., by heating, under reduced pressure if necessary, or by slowly evaporating the solvent, for example, at room temperature), or seeding with the addition of seed crystals, or setting up water activity required for hydrate formation.
• the present invention is directed to a method of preparing gaboxadol free base, said method comprising:
• Suitable salts of gaboxadol include acid addition salts, such as hydrochloride, hydrobromide, sulfonate, and the like.
• Suitable alcohols include C 1 -C 6 alcohols, such as methanol, ethanol, «-propanol, isopropanol, r ⁇ -butanol, and t-butanol, and the like.
• a suitable base includes diethylamine, triethylamine, diisopropalyethylamine, and the like.
• the ratio of water to the C 1 -C 6 alcohol of the first solution can vary.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1 :10 to about 10:1.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1:5 to about 5:1, of about 1:4 to about 4:1, of about 1 :3 to about 3 : 1 , of about 1 :2 to about 2: 1 , or of about 1 : 1 to about 1:1.
• the ratio of water to the C 1 -C 6 alcohol of the second solution can vary.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1:10 to about 10:1.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1:5 to about 5:1, of about 1:4 to about 4:1, of about 1:3 to about 3:1, of about 1:2 to about 2:1, or of about 1:1 to about
• the ratio of base to gaboxadol salt may vary. In certain embodiments, for example, the ratio of gaboxadol salt to base is from about 1:10 to about 10:1. In other embodiments, the ratio of gaboxadol salt to base is from about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1 :2 to about 2:1, or about 1 :1 to about 1:1. In a further embodiment, the ratio of gaboxadol salt to base is about 1.4: 1.
• the method of preparing a gaboxadol free base comprises adding to a first solution comprising gaboxadol HCl, water, and ethanol, a second solution comprising triethylamine, water, and ethanol.
• a precipitate begins to form.
• the third solution can be stored at room temperature or can be stored at a temperature below room temperature, for example, at about 0 0 C to about 20 °C, for example, about 5 °C, for a period of time to allow further accumulation of the precipitate.
• the third solution is placed at about 5 0 C for 1 to about 4 hours, for example, about 2 hours.
• the precipitate is then collected and dried in a vacuum oven, for example for about 3 days, to provide the gaboxadol free base.
• the present invention is directed to a method of preparing a gaboxadol monohydrate, said method comprising:
• Suitable salts of gaboxadol include acid addition salts, such as hydrochloride, hydrobromide, sulfonate, and the like.
• Suitable C 1 -C 6 alcohols include methanol, ethanol, ⁇ z-propanol, isopropanol, «-butanol, and t-butanol, and the like.
• a suitable base includes diethylamine, triethylamine, diisopropalyethylamine, and the like.
• the ratio of water to the C 1 -C 6 alcohol of the first solution can vary.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1 :10 to about 10:1.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1:5 to about 5:1, of about 1:4 to about 4:1, of about 1 :3 to about 3 : 1 , of about 1 :2 to about 2: 1 , or of about 1 : 1 to about 1:1.
• the ratio of water to the C 1 -C 6 alcohol of the second solution can vary.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1:10 to about 10:1.
• the first solution comprises water and a C 1 -C 6 alcohol in a ratio of about 1:5 to about 5:1, of about 1:4 to about 4:1, of about 1:3 to about 3:1, of about 1 :2 to about 2:1, or of about 1:1 to about 1:1.
• the ratio of base to gaboxadol salt may vary. In certain embodiments, for example, the ratio of gaboxadol salt to base is from about 1:10 to about 10:1. In other embodiments, the ratio of gaboxadol salt to base is from about 1 :5 to about 5:1, about 1 :4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1:1 to about 1:1. In a further embodiment, the ratio of gaboxadol salt to base is about 1.4: 1.
• the method of preparing a gaboxadol monohydrate comprises adding to a first solution comprising gaboxadol HCl, water, and ethanol, a second solution comprising triethylamine, water, and ethanol. Upon addition of the second solution to the first solution, thereby forming the third solution, a precipitate begins to form.
• the third solution can be stored at room temperature or can be stored at a temperature below room temperature, for example, at about 0 0 C to about 20 °C, for example, about 5 °C, for a period of time to allow further precipitation of the gaboxadol monohydrate.
• the third solution is placed at about 5 °C for 1 to about 4 hours, for example, about 2 hours.
• the precipitated gaboxadol monohydrate is then collected using standard procedures, such as vacuum filtration.
• the present invention provides a method of preparing a gaboxadol salt, said method comprises:
• salt forming compound which has at least one functional group selected from amine, amide, pyridine, imidazole, indole, pyrrolidine, carbonyl, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methylthio;
• the present invention provides a method of preparing a pharmaceutical composition, said method comprises:
• gaboxadol salt comprising the gaboxadol and the salt forming compound.
• the gaboxadol salt is then isolated. Under certain circumstances, the gaboxadol salt is then incorporated into a pharmaceutical composition.
• the grinding can be performed manually or mechanically.
• the grinding can be performed for various amounts of time. Suitable times include but are not limited to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, and 60 minutes.
• gaboxadol and maleic acid are ground together with the addition of a small amount, e.g., 1-10 drops, of a suitable solvent.
• suitable solvents include acetone, hexanes, ethanol, ethyl acetate, mixtures thereof, and the like.
• gaboxadol and tartaric acid are ground together with the addition of a small amount, e.g., 1-10 drops, of a suitable solvent.
• suitable solvents include acetone, hexanes, ehtanol, ethyl acetate, mixtures thereof, and the like.
• Assaying for the presence of gaboxadol forms may be carried out by conventional methods known in the art. For example, it is convenient and routine to use powder X-ray diffraction techniques to assess the presence of the salts. This may be effected by comparing the spectra of the gaboxadol, the salt forming compound, and the putative salts in order to establish whether or not true salts have been formed. Other techniques, used in an analogous fashion, include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Raman spectroscopy. Single crystal X-ray diffraction is especially useful in identifying salt structures.
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• Raman spectroscopy Raman spectroscopy
• the present invention therefore provides a method of screening for gaboxadol salts, said method comprises:
• the gaboxadol forms of the invention include, but are not limited to: [00126] 1) a gaboxadol free base prepared by crystallizing gaboxadol free base from a solution of gaboxadol HCl, ethanol, and water by the addition of a base, such as triethylamine, wherein the gaboxadol free base is characterized by a powder X-ray diffraction pattern expressed in terms of 2-theta angles, and wherein the X-ray powder diffraction pattern comprises approximately the 2-theta angle values listed and illustrated in Figure IE herein;
• a gaboxadol monohydrate prepared from a solution of gaboxadol HCl, ethanol, and water by the addition of a base, such as triethylamine, wherein the gaboxadol free base is characterized by a powder X-ray diffraction pattern expressed in terms of 2-theta angles, and wherein the X-ray powder diffraction pattern comprises approximately the 2-theta angle values listed and illustrated in Figure 3 C herein; and
• Thermogravimetic analysis of each sample was performed using a Q500 Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which uses as its control software Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ⁇ 2001 TA Instruments-Water LLC), with the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0.0.78 build 78.1; an TGA.DLL version 1.0.0.78 build 78.1. hi addition, the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E; Build 3.1.0.40 ( ⁇ 1991-2001 TA Instruments-Water LLC).
• thermogravimetric analysis comprised transferring an aliquot of a sample into a platinum sample pan (Pan part # 952019.906; (TA Instruments, New Castle, DE USA)). The pan was placed on the loading platform and was then automatically loaded into the Q500 Thermogravimetric Analyzer using the control software. Thermograms were obtained by individually heating the sample at 10°C/minute across a temperature range (generally from 25 0 C to 300°C) under flowing dry nitrogen (compressed nitrogen, grade 4.8 (BOC Gases, Murray Hill, NJ USA)), with a sample purge flow rate of 60 mL/minute and a balance purge flow rate of 40 mL/minute. Thermal transitions (e.g., weight changes) were viewed and analyzed using the analysis software provided with the instrument.
• DSC analysis of each sample was performed using a QlOOO Differential Scanning Calorimeter (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ⁇ 2001 TA Instruments- Water LLC), with the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0.0.78 build 78.1; an TGA.DLL version 1.0.0.78 build 78.1.
• the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E; Build 3.1.0.40 ( ⁇ 2001 TA Instruments-Water LLC).
• Dry nitrogen compressed nitrogen, grade 4.8 (BOC Gases, Murray Hill, NJ USA) was used as a sample purge gas and was set at a flow rate of 50 mL/minute. Thermal transitions were viewed and analyzed using the analysis software provided with the instrument.
• All X-ray powder diffraction patters were obtained using a D/Max Rapid X-ray Diffractometer (Rigaku/MSC, The Woodlands, TX, U.S.A.) equipped with a copper source (Cu/K ⁇ 1.5406 A), manual x-y stage, and 0.3 mm collimator.
• a sample was loaded into a 0.3 mm quartz capillary tube (Charles Supper Company, Natick, MA, U.S.A.) by sectioning off the closed end of the tube and tapping the small, open end of the capillary tube into a bed of the powdered sample or into the sediment of a slurried sample.
• the precipitate can be amorphous or crystalline.
• the loaded capillary tube was mounted in a holder that was placed and fitted into the x-y stage.
• a diffractogram was acquired using control software (RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0 ( ⁇ 1999 Rigaku Co.)) under ambient conditions at a power setting of 46 kV at 40 mA in transmission mode, while oscillating about the omega-axis from 0-5 degrees at 1 degree/second, and spinning about the phi-axis over 360 degrees at 2 degrees/second.
• the exposure time was 15 minutes unless otherwise specified.
• the diffractogram obtained was integrated of 2-theta from 2-60 degrees and chi (1 segment) from 0-36 degrees at a step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display software (RINT Rapid display software, version 1.18 (Rigaku/MSC)) provided by Rigaku with the instrument.
• the dark counts value was set to 8 as per the system calibration by Rigaku. No normalization or omega, chi or phi offsets were used for the integration.
• Powder X-ray diffraction (PXRD) diffractograms were obtained using a D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.), which uses as its control software RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0 (1999 Rigaku Co.).
• RINT Rapid Control Software Rigaku Rapid/XRD, version 1.0.0 (1999 Rigaku Co.
• analysis software used were RINT Rapid display software, version 1.18 (Rigaku/MSC), and JADE XRD Pattern Processing, versions 5.0 and 6.0 ((1995-2002, Materials Data, Inc.).
• the acquisition parameters were as follows: source was Cu with a K line at 1.5406 A; x-y stage was manual; collimator size was 0.3 mm; capillary tube (Charles Supper Company, Natick, MA, U.S.A.) was 0.3 mm ID; reflection mode was used; the power to the X-ray tube was 46 kV; the current to the X- ray tube was 40 mA; the omega-axis was oscillating in a range of 0-5 degrees at a speed of 1 degree/minute; the phi-axis was spinning at an angle of 360 degrees at a speed of 2 degrees/second; 0.3 mm collimator; the collection time was 60 minutes; the temperature was room temperature; and the heater was not used.
• the sample was presented to the X-ray source in a boron rich glass capillary.
• the analysis parameters were as follows: the integration 2-theta range was 2-60 degrees; the integration chi range was 0-360 degrees; the number of chi segments was 1; the step size used was 0.02; the integration utility was cylint; normalization was used; dark counts were 8; omega offset was 180; and chi and phi offsets were 0.
• the relative intensity of peaks in a diffractogram is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. Further, the angles of each peak can vary by about +/- 0.1 degrees, preferably +/- 0.05. The entire pattern or most of the pattern peaks may also shift by about +/- 0.1 degrees to about +/- 0.2 degrees due to differences in calibration, settings, and other variations from instrument to instrument and from operator to operator. All reported PXRD peaks in the Figures, Examples, and elsewhere herein are reported with an error of about ⁇ 0.1 degrees 2-theta.
• IR spectra were obtained using NexusTM 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495 and were analyzed with Control and Analysis software: OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004.
• the gaboxadol forms of the present invention can be characterized, e.g., by the TGA or DSC data or by any one, any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, or any single integer number of PXRD 2-theta angle peaks, or by single crystal x-ray diffraction data.
• Gaboxadol Free Base (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol)
• Gaboxadol Maleate (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-olium maleate)
• Gaboxadol and maleic acid were ground together for 20 minutes. A drop of acetone was added to the solids before grinding was initiated. The solid mixture was then characterized using DSC, TGA, IR, Raman, and PXRD results of which are shown in Figures 2A, 2B, 2C, 2D, and 2E, respectively. The product was found to contain excess starting materials as well as a maleic acid salt of gaboxadol.
• Gaboxadol Monohydrate (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol monohydrate)
• Gaboxadol Tartrate (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-olium tartrate)
• Gaboxadol and dl-tartaric acid were ground together for 20 minutes. A drop of acetone was added to the solids before grinding was initiated. The solid mixture was then characterized using DSC, TGA, IR, Raman, and PXRD, the results of which are shown in Figures 4A, 4B, 4C, 4D, and 4E, respectively. The product was found to contain excess starting materials as well as a dl-tartaric acid salt of gaboxadol.

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