EP1631260A2 - Pharmazeutische kokristallzusammensetzungen aus arzneistoffen wie carbamazepin, celecoxib, olanzapin, itraconazol, topiramat, modafinil, 5-fluoruracil, hydrochlorothazid, acetaminophen, aspirin, flurbiprofen, phenytoin und ibuprofen - Google Patents

Pharmazeutische kokristallzusammensetzungen aus arzneistoffen wie carbamazepin, celecoxib, olanzapin, itraconazol, topiramat, modafinil, 5-fluoruracil, hydrochlorothazid, acetaminophen, aspirin, flurbiprofen, phenytoin und ibuprofen

Info

Publication number
EP1631260A2
EP1631260A2 EP04715190A EP04715190A EP1631260A2 EP 1631260 A2 EP1631260 A2 EP 1631260A2 EP 04715190 A EP04715190 A EP 04715190A EP 04715190 A EP04715190 A EP 04715190A EP 1631260 A2 EP1631260 A2 EP 1631260A2
Authority
EP
European Patent Office
Prior art keywords
crystal
acid
degrees
ray diffraction
diffraction pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04715190A
Other languages
English (en)
French (fr)
Inventor
Örn ALMARSSON
Magali Bourghol Hickey
Matthew Peterson
Brian Moulton
Nair Rodriguez-Hornedo
Michael J. Zaworotko
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of South Florida
University of Michigan
Transform Pharmaceuticals Inc
Original Assignee
University of South Florida
University of Michigan
Transform Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2003/006662 external-priority patent/WO2003074474A2/en
Priority claimed from US10/449,307 external-priority patent/US7078526B2/en
Priority claimed from PCT/US2003/019574 external-priority patent/WO2004000284A1/en
Priority claimed from PCT/US2003/027772 external-priority patent/WO2004078161A1/en
Priority claimed from US10/660,202 external-priority patent/US7927613B2/en
Priority claimed from PCT/US2003/041273 external-priority patent/WO2004061433A1/en
Application filed by University of South Florida, University of Michigan, Transform Pharmaceuticals Inc filed Critical University of South Florida
Publication of EP1631260A2 publication Critical patent/EP1631260A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present mvention relates to co-crystal API-containing compositions, pharmaceutical compositions comprising such APIs, and methods for preparing the same.
  • APIs Active pharmaceutical ingredients (API or APIs (plural)) in pharmaceutical compositions can be prepared in a variety of different forms. Such APIs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such APIs can also be prepared to have different physical forms. For example, the APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.
  • APIs that have improved properties, in particular, as oral formulations. Specifically, it is desirable to identify improved forms of APIs that exhibit significantly improved properties including increased aqueous solubility and stability. Further, it is desirable to improve the processability, or preparation of pharmaceutical formulations. For example, needle-like crystal forms or habits of APIs can cause aggregation, even in compositions where the API is mixed with other substances, such that a non- uniform mixture is obtained. It is also desirable to increase or decrease the dissolution rate of API-containing pharmaceutical compositions in water, increase or decrease the bioavailability of orally-administered compositions, and provide a more rapid or more delayed onset to therapeutic effect.
  • APIs can be obtained which improve the properties of APIs as compared to such APIs in a non-co-crystalline slate (free acid, free base, zwitter ions, salts, etc.).
  • the present invention provides a co-crystal pharmaceutical composition
  • a co-crystal pharmaceutical composition comprising an API compound and a co-crystal former, such that the API and co- crystal former are capable of co-crystallizing from a solid or solution phase under crystallization conditions.
  • Another aspect of the present invention provides a process for the production of a pharmaceutical composition, which process comprises:
  • an API which has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine;
  • a co-crystal former which has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine;
  • a further aspect of the present invention provides a process for the production of a pharmaceutical composition, which comprises:
  • the present invention provides a process for the production of a pharmaceutical composition, which comprises:
  • the present invention provides a process for modulating the solubility of an API, which process comprises:
  • the present invention provides a process for modulating the dissolution of an API, whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased or decreased, which process comprises:
  • the present invention provides a process for modulating the bioavailability of an API, whereby the AUC is increased, the time to T max is reduced, the length of time the concentration of the API is above ' _ T max is increased, or C max is increased, which process comprises: (1) grinding, heating, co-subliming, co-melting, or contacting in solution the API with a co-crystal former under crystallization conditions, so as to form a co-crystal of the API and the co-crystal former; and
  • the present invention provides a process for improving the linearity of a dose response of an API, which process comprises:
  • the present invention provides a process for improving the stability of a pharmaceutical salt, which process comprises:
  • the present invention provides a process for making co-crystals of difficult to salt or unsaltable APIs, which process comprises:
  • the present invention provides a method for decreasing the hygroscopicity of an API, which method comprises: (1) grinding, heating, co-subliming, co-melting, or contacting in solution the API with a co-crystal former under crystallization conditions, so as to form a co-crystal of the API and the co-crystal former; and
  • the present invention provides a process for crystallizing an amorphous compound, which process comprises:
  • the present invention provides a process for reducing the form diversity of an API, which process comprises:
  • the present invention provides a process for modifying the morphology of an API, which process comprises:
  • the present invention provides a co-crystal composition
  • a co-crystal composition comprising a co-crystal, wherein said co-crystal comprises an API compound and a co-crystal former.
  • the co-crystal has an improved property as compared to the free form (including a free acid, free base, zwitter ion, hydrate, solvate, etc.) or a salt (which includes salt hydrates and solvates).
  • the improved property is selected from the group consisting of: increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, a crystalline form of a normally amorphous compound, a crystalline form of a difficult to salt or unsaltable compound, decreased form diversity, more desired morphology, or other property described herein.
  • Figs. I A-B PXRD diffractograms of a co-crystal comprising celecoxib and nicotinamide, with the background removed and as collected, respectively.
  • Fig. 2 DSC thermogram for a co-crystal comprising celecoxib and nicotinamide.
  • Fig. 3 TGA thermogram for a co-crystal comprising celecoxib and nicotinamide.
  • Fig. 4 Raman spectrum for a co-crystal comprising celecoxib and nicotinamide.
  • Figs. 5A-B PXRD diffractograms of a co-crystal comprising celecoxib and 18-crown-6, with the background removed and as collected, respectively.
  • Fig. 6 DSC thermogram for a co-crystal comprising celecoxib and 18-crown-6.
  • Fig. 7 TGA thermogram for a co-crystal comprising celecoxib and 18-crown-6.
  • Figs. 8A-B PXRD diffractograms of a co-crystal comprising topiramate and 18-crown-6, with the background removed and as collected, respectively.
  • Fig. 9 DSC thermogram for a co-crystal comprising topiramate and 18-crown-6.
  • Figs. 10A-B PXRD diffractograms of a co-crystal comprising olanzapine and nicotinamide (Form
  • Fig. 11 DSC thermogram for a co-crystal comprising olanzapine and nicotinamide (Form I).
  • Fig. 12 PXRD diffractogram of a co-crystal comprising olanzapine and nicotinamide (Form II).
  • Figs. 13A-B PXRD diffractograms of a co-crystal comprising olanzapine and nicotinamide (Form
  • Figs. 14A-D Packing diagrams and crystal structure of a co-crystal comprising olanzapine and nicotinamide (Form III).
  • Fig. 15 PXRD diffractogram of a co-crystal comprising c ⁇ -itraconazole and succinic acid.
  • Fig. 16 DSC thermogram for a co-crystal comprising c ⁇ -itraconazole and succinic acid.
  • Fig. 17 PXRD diffractogram of a co-crystal comprising c/s-itraconazole and fumaric acid.
  • Fig. 18 DSC thermogram for a co-crystal comprising CM-itraconazole and fumaric acid.
  • Fig. 19 PXRD diffractogram of a co-crystal comprising czAitraconazole and L-tartaric acid.
  • Fig. 20 DSC thermogram for a co-crystal comprising c ⁇ -itraconazole and L-tartaric acid.
  • Fig. 21 PXRD diffractogram of a co-crystal comprising cw-itraconazole and L-malic acid.
  • Fig. 22 DSC thermogram for a co-crystal comprising c/ ' s-itraconazole and L-malic acid.
  • Fig. 23 PXRD diffractogram of a co-crystal comprising cw-itraconazoleHCl and DL-tartaric acid.
  • Fig 24 DSC thermogram for a co-crystal comprising c ⁇ -itraconazoleHCl and DL-tartaric acid.
  • Fig. 26 DSC thermogram for a co-crystal comprising modafinil and malonic acid (Form I).
  • Fig. 27 Raman spectrum for a co-crystal comprising modafinil and malonic acid (Form I).
  • Fig. 28 PXRD diffractogram of a co-crystal comprising modafinil and malonic acid (Form II).
  • Figs. 29A-B PXRD diffractograms of a co-crystal comprising modafinil and glycolic acid, with the background removed and as collected, respectively.
  • Figs. 30A-B PXRD diffractograms of a co-crystal comprising modafinil and maleic acid, with the background removed and as collected, respectively.
  • Figs. 31 A-B PXRD diffractograms of a co-crystal comprising 5-fluorouracil and urea, with the background removed and as collected, respectively.
  • Fig. 32 DSC thermogram for a co-crystal comprising 5-ftuorouracil and urea.
  • Fig. 33 TGA thermogram for a co-crystal comprising 5-fluorouracil and urea.
  • Fig. 34 Raman spectrum for a co-crystal comprising 5-fluorouracil and urea.
  • Figs. 35 A-B PXRD diffractograms of a co-crystal comprising hydrochlorothiazide and nicotinic acid, with the background removed and as collected, respectively.
  • Figs. 37A-B PXRD diffractograms of a co-crystal comprising hydrochlorothiazide and piperazine, with the background removed and as collected, respectively.
  • Figs. 38A-B An acetaminophen 1-D polymeric chain and a co-crystal of acetaminophen and 4,4'- bipyridine, respectively.
  • Figures 40C and 40D show the supramolecular entity containing the synthon and corresponding co-crystal of aspirin and 4,4'-bipyridine, respectively.
  • FIGs. 41A-D Pure ibuprofen and the corresponding crystal structure are shown in Figures 41A and 4 IB, respectively.
  • Figures 41C and 41D show the supramolecular entity containing the synthon and corresponding co-crystal of ibuprofen and 4,4'-bipyridine, respectively.
  • FIGs. 2A-D Pure flurbiprofen and the corresponding crystal structure are shown in Figures 42A and 2B, respectively.
  • Figures 42C and 42D show the supramolecular synthon and corresponding co-crystal of flurbiprofen and 4,4'-bipyridine, respectively.
  • Figs. 43A-B The supramolecular entity containing the synthon and the corresponding co-crystal structure of flurbiprofen and trans- l,2-bis(4-pyridyl)ethylene, respectively.
  • Figs. 44A-B The crystal structure of pure carbamazepine and the co-crystal structure of carbamazepine and -phthalaldehyde, respectively.
  • Fig. 45 A packing diagram of the co-crystal structure of carbamazepine and nicotinamide.
  • Fig. 46 PXRD diffractogram of a co-crystal comprising carbamazepine and nicotinamide.
  • Fig. 47 DSC thermogram for a co-crystal comprising carbamazepine and nicotinamide.
  • Fig. 48 A packing diagram of the co-crystal structure of carbamazepine and saccharin.
  • Fig. 49 PXRD diffractogram of a co-crystal comprising carbamazepine and saccharin.
  • Fig. 50 DSC thermogram for a co-crystal comprising carbamazepine and saccharin.
  • Figs. 51 A-B The crystal structure of carbamazepine and the co-crystal structure of carbamazepine and 2,6-pyridinedicarboxylic acid, respectively.
  • Figs. 52A-B The crystal structure of carbamazepine and the co-crystal structure of carbamazepine and 5-nitroisophthalic acid, respectively.
  • Figs. 53 A-B The crystal structure of carbamazepine and the co-crystal structure of carbamazepine and 1,3,5,7-adamantanetetracarboxylic acid, respectively.
  • Figs. 54A-B The crystal structure of carbamazepine and the co-crystal structure of carbamazepme and benzoquinone, respectively.
  • Figs. 55A-B The crystal structure of carbamazepine and the co-crystal structure of carbamazepine and trimesic acid, respectively.
  • Fig. 56 PXRD diffractogram of a co-crystal comprising carbamazepine and trimesic acid.
  • Fig. 57 Dissolution profile for a co-crystal of celecoxib :nicotinamide vs. celecoxib free acid.
  • Fig. 58 Dissolution profile for co-crystals of itraconazole: succinic acid, itraconazle:tartaric acid and itraconazole:malic acid vs. itraconazole free base.
  • Fig. 61 Dissolution profile of several formulations of modafinil free form and modafinikmalonic acid (Form I).
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion, with the exception that, if specifically stated, the API may be a liquid at room temperature.
  • the co-crystals of the present invention comprise a co-crystal former H-bonded to an API.
  • the co- crystal former may be H-bonded directly to the API or may be H-bonded to an additional molecule which is bound to the API.
  • the additional molecule may be H-bonded to the API or bound ionically or covalently to the API.
  • the additional molecule could also be a different API.
  • Solvates of API compounds that do not further comprise a co-crystal former are not co-crystals according to the present invention.
  • the co-crystals may however, include one or more solvate molecules in the crystalline lattice. That is, solvates of co-crystals, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature, is included in the present invention, but crystalline material comprised of only one solid and one or more liquids (at room temperature) are not included in the present invention, with the previously noted exception of specifically stated liquid APIs.
  • the co-crystals may also be a co-crystal between a co-crystal former and a salt of an API, but the API and the co-crystal former of the present invention are constructed or bonded together through hydrogen bonds.
  • Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions.
  • hydrogen-bonding is the dominant interaction in the formation of the co-crystal, (and a required interaction according to the present invention) whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other. Hydrogen bonding can result in several different intermolecular configurations.
  • hydrogen bonds can result in the formation of dimers, linear chains, or cyclic structures. These configurations can further include extended (two-dimensional) hydrogen bond networks and isolated triads (Fig. 60).
  • An alternative embodiment provides for a co-crystal wherein the co-crystal former is a second API. In another embodiment, the co-crystal former is not an API. In another embodiment the co-crystal comprises two co-crystal formers.
  • the chemical and physical properties of an API in the form of a co-crystal may be compared to a reference compound that is the same API in a different form.
  • the reference compound may be specified as a free form, or more specifically, a free acid, free base, or zwitterion; a salt, or more specifically for example, an inorganic base addition salt such as sodium, potassium, lithium, calcium, magnesium, ammonium, aluminum salts or organic base addition salts, or an inorganic acid addition salts such as HBr, HCl, sulfuric, nitric, or phosphoric acid addition salts or an organic acid addition salt such as acetic, propionic, pyruvic, malanic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, methanesulfonic, ethanesulforic, stearic or lactic acid addition salt; an anhydrate or hydrate of a free form or salt, or more specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate, quadrahydrate, pentahydrate, sesquihydrate; or a solvate of a free form or salt.
  • the reference compound for an API in salt form co-crystallized with a co-crystal former can be the API salt form.
  • the reference compound for a free acid API co-crystallized with a co-crystal former can be the free acid API.
  • the reference compound may also be specified as crystalline or amorphous.
  • the co-crystals can include an acid addition salt or base addition salt of an API.
  • Acid addition salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as 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, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid,/?-chlorobenzenes
  • Base addition salts include, but are not limited to, inorganic bases such as sodium, potassium, lithium, ammonium, calcium and magnesium salts, and organic bases such as primary, secondary and tertiary amines (e.g. isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, and N-ethylpiperidine).
  • inorganic bases such as sodium, potassium, lithium, ammonium, calcium and magnesium salts
  • organic bases such as primary, secondary and tertiary amines (e.g. isopropylamine,
  • the ratio of API to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. For example, 1 :1, 1.5:1, 1 :1.5, 2:1 and 1 :2 ratios of API:co-crystal former are acceptable.
  • a co-crystal form of an API is particularly advantageous where the original API is insoluble or sparingly soluble in water.
  • the co-crystal properties conferred upon the API are also useful because the bioavailability of the API can be improved and the plasma concentration and/or serum concentration of the API can be improved. This is particularly advantageous for orally-administrable formulations.
  • the dose response of the API can be improved, for example by increasing the maximum attainable response and/or increasing the potency of the API by increasing the biological activity per dosing equivalent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a co-crystal of an API and a co-crystal former, such that the API and co-crystal former are capable of co-crystallizing from a solution phase under crystallization conditions or from the solid-state, for example, through grinding, heating, or through vapor transfer (e.g., co-sublimation).
  • the API has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine and a co-crystal former which has at least one functional group selected from ether, thioether,
  • co-crystals of the present invention are formed where the API and co-crystal former are bonded together through hydrogen bonds.
  • Other non-covalent interactions including pi-stacking and van der Waals interactions, may also be present.
  • the co-crystal former is selected from the co-crystal formers of Table I and Table II. In other embodiments, the co-crystal former of Table I is specified as a Class 1, Class 2, or Class 3 co-crystal former (see column labeled "class" Table I).
  • the difference in pK a value of the co-crystal former and the API is less than 2. In other embodiments, the difference in pK a values of the co- crystal former and API is less than 3, less than 4, less than 5, between 2 and 3, between 3 and 4, or between 4 and 5. Table I lists multiple pK a values for co-crystal formers having multiple functionalities. It is readily apparent to one skilled in the art the particular functional group corresponding to a particular pK a value.
  • the particular functional group of a co-crystal former interacting with the API is specified (see for example Table I, columns labeled “Functionality” and “Molecular Structure” and the column of Table II labeled "Co- Crystal Former Functional Group”).
  • the functional group of the API interacting with the co-crystal former functional group is specified (see, for example, Tables II and III).
  • the co-crystal comprises more than one co-crystal former.
  • two, three, four, five, or more co-crystal formers can be incorporated in a co-crystal with an API.
  • Co-crystals which comprise two or more co-crystal formers and an API are bound together via hydrogen bonds.
  • incorporated co- crystal formers are hydrogen bonded to the API molecules.
  • co- crystal formers are hydrogen bonded to either the API molecules or the incorporated co- crystal formers.
  • co-crystal formers can be contained in a single compartment, or kit, for ease in screening an API for potential co-crystal species.
  • the co-crystal kit can comprise 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or more of the co-crystal formers in Tables I and II.
  • the co-crystal formers are in solid form or in solution and in an array of individual reaction vials such that individual co-crystal formers can be tested with one or more APIs by one or more crystallization methods or multiple co-crystal formers can be easily tested against one or more compounds by one or more crystallization methods.
  • the crystallization methods include, but are not limited to, melt recrystallization, grinding, milling, standing, co-crystal formation from solution by evaporation, thermally driven crystallization from solution, co-crystal formation from solution by addition of anti-solvent, co-crystal formation from solution by vapor- diffusion, co-crystal formation from solution by drown-out, co-crystal formation from solution by any combination of the above mentioned techniques, co-crystal formation by co-sublimation, co-crystal formation by sublimation using a Knudsen cell apparatus, co- crystal formation by standing the desired components of the co-crystal in the presence of solvent vapor, co-crystal formation by slurry conversion of the desired components of the co-crystal in a solvent or mixtures of solvents, or co-crystal formation by any combination of the above techniques in the presence of additives, nucleates, crystallization enhancers, precipitants, chemical stabilizers, or anti-oxidants.
  • kits can be used alone or as part of larger crystallization experiments.
  • kits can be constructed as single co-crystal former single well kits, single co- crystal former multi-well kits, multi-co-crystal former single well kits, or multi-co-crystal former multi-well kits.
  • High-throughput crystallization e.g., the CrystalMaxTM platform
  • Multi-well plates e.g., 96 wells, 384 wells, 1536 wells, etc.
  • the API is selected from an API of Table IV or elsewhere herein.
  • co-crystals can comprise such APIs in free form (i.e. free acid, free base, zwitter ion), salts, solvates, hydrates, or the like.
  • the API can either be of the form listed in Table IV or its corresponding free form, or of another form that is not listed.
  • Table IV includes the CAS number, chemical name, or a PCT or patent reference (each incorporated herein in their entireties).
  • the functional group of the particular API interacting with the co-crystal former is specified.
  • a specific functional group of a co-crystal former, a specific co-crystal former, or a specified functional group or a specific co-crystal former interacting with the particular API may also be specified. It is noted that for Table II, the co-crystal former, and optionally the specific functionality, and each of the listed corresponding interacting groups are included as individual species of the present invention. Thus, each specific combination of a co-crystal former and one of the interacting groups in the same row may be specified as a species of the present invention. The same is true for other combinations as discussed in the Tables and elsewhere herein.
  • the co-crystal comprises an API wherein the API forms a dimeric primary amide structure via hydrogen bonds with an R 2 2 (8) motif.
  • the dimeric primary amide structure further comprises one, two, three, or four hydrogen bond donors.
  • the dimeric primary amide structure further comprises one or two hydrogen bond acceptors.
  • the dimeric primary amide structure further comprises a combination of hydrogen bond donors and acceptors.
  • the dimeric primary amide structure can further comprise one hydrogen bond donor and one hydrogen bond acceptor, one hydrogen bond donor and two hydrogen bond acceptors, two hydrogen bond donors and one hydrogen bond acceptor, two hydrogen bond donors and two hydrogen bond acceptors, or three hydrogen bond donors and one hydrogen bond acceptor.
  • Two non- limiting examples of APIs which form a dimeric primary amide co-crystal structure include modafinil and carbamazepine.
  • APIs which include a primary amide functional group include, but are not limited to, arotinolol, atenolol, carpipramine, cefotetan, cefsulodin, docapromine, darifenacin, exalamide, fidarestat, frovatriptan, silodosin, levetiracetam, MEN- 10700, mizoribine, oxiracetam, piracetam, protirelin, TRH, ribavirm, valrecemide, temozolomide, tiazofurin, antiPARP-2, levovirin, N- benzyloxycarbonyl glycinamide, and UCB-34714.
  • each process according to the invention there is a need to contact the API with the co-crystal former. This may involve grinding or milling the two solids together or melting one or both components and allowing them to recrystallize.
  • the use of a granulating liquid may improve or may impede co-crystal formation.
  • Non-limiting examples of tools useful for the formation of co-crystals may include, for example, an extruder or a mortar and pestle.
  • contacting the API with the co-crystal former may also involve either solubilizing the API and adding the co-crystal former, or solubilizing the co-crystal former and adding the API. Crystallization conditions are applied to the API and co-crystal former.
  • This may entail altering a property of the solution, such as pH or temperature and may require concentration of the solute, usually by removal of the solvent, typically by drying the solution. Solvent removal results in the concentration of both API and co-crystal former increasing over time so as to facilitate crystallization. For example, evaporation, cooling, co-sublimation, or the addition of an antisolvent may be used to crystallize co-crystals. In another embodiment, a slurry comprising an API and a co-crystal former is used to form co-crystals. Once the solid phase comprising any crystals is formed, this may be tested as described herein.
  • co-crystals on a large and/or commercial scale may be successfully completed using one or more of the processes and techniques described herein.
  • crystallization of co-crystals from a solvent and grinding or milling are conceivable non-limiting processes.
  • co-crystals with stoichiometries of 1:1, 2:1, or 1 :2 can be produced by adding co-crystal former in an amount that is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100 times or more than the stoichiometric amount for a given co- crystal.
  • Such an excessive use of a co-crystal former to form a co-crystal can be employed in solution or when grinding an API and a co-crystal former to drive co-crystal formation.
  • the present invention provides for the use of an ionic liquid as a medium for the formation of a co-crystal, and can also be used to crystallize other forms in addition to co-crystals (e.g., salts, solvates, free acid, free base, zwitterions, etc.).
  • This medium is useful, for example, where the above methods do not work or are difficult or impossible to control.
  • ionic liquids useful in co-crystal formation are: l-butyl-3-methylimidazolium lactate, 1-ethyl- 3-methylimidazolium lactate, and 1-butylpyridinium hexafluorophosphate.
  • compositions in general are discussed in further detail below and may further comprise a pharmaceutically-acceptable diluent, excipient or carrier.
  • the present invention provides a process for the production of a pharmaceutical composition, which process comprises:
  • an API which has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine or of Table II or III;
  • a co-crystal former which has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O- heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine or of Table I, II, or III; (3) grinding, heating or contacting in solution the
  • the present invention provides a process for the production of a pharmaceutical composition, which comprises:
  • Assaying the solid phase for the presence of co-crystals of the API and the co- crystal former 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 co-crystals. This may be affected by comparing the spectra of the API, the crystal former and putative co-crystals in order to establish whether or not true co- crystals had been formed. Other techniques, used in an analogous fashion, include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solid state NMR spectroscopy, and Raman spectroscopy. Single crystal X-ray diffraction is especially useful in identifying co-crystal structures.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TGA solid state NMR spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • the present invention therefore provides a process of screening for co-crystal compounds, which comprises:
  • APIs and co-crystal formers of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, several APIs and co-crystal formers of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention including, for example, cis- and tr ⁇ s-isomers, R- and S-enantiomers, and (D)- and (L)-isomers.
  • Co-crystals of the present invention can include isomeric forms of either the API or the co-crystal former or both.
  • Isomeric forms of APIs and co-crystal formers include, but are not limited to, stereoisomers such as enantiomers and diastereomers.
  • a co-crystal can comprise a racemic API and/or co-crystal former.
  • a co-crystal can comprise an enantiomerically pure API and/or co-crystal former.
  • a co-crystal can comprise an API or a co-crystal former with an enantiomeric excess of about 50 percent, 55 percent, 60 percent, 65 percent, 70 percent, 75 percent, 80 percent, 85 percent, 90 percent, 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, greater than 99 percent, or any intermediate value.
  • stereoisomeric APIs include modafinil, cw-itraconazole, ibuprofen, and flurbiprofen.
  • stereoisomeric co-crystal formers include tartaric acid and malic acid.
  • Co-crystals comprising enantiomerically pure components (e.g., API or co-crystal former) can give rise to chemical and/or physical properties which are modulated with respect to those of the corresponding co-crystal comprising a racemic component.
  • the modafinil :malonic acid co-crystal from Example 10 comprises racemic modafinil.
  • Enantiomerically pure R-modafinil:malonic acid can conceivably be synthesized via the same or another method of the present invention and is therefore included in the scope of the invention.
  • enantiomerically pure S- modaf ⁇ nikmalonic acid can conceivably be synthesized via a method of the present invention and is therefore included in the scope of the invention.
  • a co-crystal comprising an enantiomerically pure component can give rise to a modulation of, for example, activity, bioavailability, or solubility, with respect to the corresponding co-crystal comprising a racemic component.
  • the co-crystal R-modafinil:malonic acid can have modulated properties as compared to the racemic modafinikmalonic acid co-crystal.
  • racemic co-crystal refers to a co-crystal which is comprised of an equimolar mixture of two enantiomers of the API, the co-crystal former, or both.
  • a co-crystal comprising a stereoisomeric API and a non-stereoisomeric co-crystal former is a "racemic co-crystal" when there is present an equimolar mixture of the API enantiomers.
  • a co-crystal comprising a non-stereoisomeric API and a stereoisomeric co-crystal former is a "racemic co-crystal" when there is present an equimolar mixture of the co-crystal former enantiomers.
  • a co-crystal comprising a stereoisomeric API and a stereoisomeric co-crystal former is a "racemic co-crystal" when there is present an equimolar mixture of the API enantiomers and of the co-crystal former enantiomers.
  • enantiomerically pure co- crystal refers to a co-crystal which is comprised of a stereoisomeric API or a stereoisomeric co-crystal former or both where the enantiomeric excess of the stereoisomeric species is greater than or equal to about 90 percent ee.
  • the present invention includes a pharmaceutical composition comprising a co-crystal with an enantiomerically pure API or co-crystal former wherein the bioavailability is modulated with respect to the racemic co-crystal.
  • the present invention includes a pharmaceutical composition comprising a co-crystal with an enantiomerically pure API or co-crystal former wherein the activity is modulated with respect to the racemic co-crystal.
  • the present invention includes a pharmaceutical composition comprising a co-crystal with an enantiomerically pure API or co-crystal former wherein the solubility is modulated with respect to the racemic co-crystal.
  • enantiomerically pure includes a composition which is substantially enantiomerically pure and includes, for example, a composition with greater than or equal to about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent enantiomeric excess.
  • the present invention provides a process for modulating the solubility of an API, which process comprises:
  • solubility of the API is modulated such that the aqueous solubility is increased.
  • Solubility of APIs may be measured by any conventional means such as chromatography (e.g., HPLC) or spectroscopic determination of the amount of API in a saturated solution of the API, such as UV-spectroscopy, IR-spectroscopy, Raman spectroscopy, quantitative mass spectroscopy, or gas chromatography.
  • the API may have low aqueous solubility.
  • low aqueous solubility in the present application refers to a compound having a solubility in water which is less than or equal to 10 mg/mL, when measured at 37 degrees C, and preferably less than or equal to 5 mg/mL or 1 mg/mL.
  • Low aqueous solubility can further be specifically defined as less than or equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100, 90, 80, 70, 60, 50, 40, 30, 20 micrograms/mL, or further 10, 5 or 1 micrograms/mL, or further 900, 800, 700, 600, 500, 400, 300, 200 150, 100 90, 80, 70, 60, 50, 40, 30, 20, or 10 ng/mL, or less than 10 ng/mL when measured at 37 degrees C.
  • Aqueous solubility can also be specified as less than 500, 400, 300, 200, 150, 100, 75, 50 or 25 mg/mL.
  • solubility can be increased 2, 3, 4, 5, 7, 10, 15, 20, 25, 50, 75, 100, 200, 300, 500, 750, 1000, 5000, or 10,000 times by making a co-crystal of the reference form (e.g., crystalline or amorphous free acid, free base or zwitter ion, hydrate or solvate), or a salt thereof.
  • aqueous solubility can be measured in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than water.
  • the pH of the solvent used may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or 14 or any pH in between successive values.
  • Examples of embodiments includes: co-crystal compositions with an aqueous solubility, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the reference form, co-crystal compositions with a solubility in SGF that is increased at least 5 fold over the reference form, co-crystal compositions with a solubility in SIF that is increased at least 5 fold over the reference form.
  • the dissolution profile of the API is modulated whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid or in simulated intestinal fluid, or in a solvent or plurality of solvents is increased.
  • Dissolution rate is the rate at which API solids dissolve in a dissolution medium.
  • the rate-limiting step in the absorption process is often the dissolution rate. Because of a limited residence time at the absorption site, APIs that are not dissolved before they are removed from intestinal absorption site are considered useless. Therefore, the rate of dissolution has a major impact on the performance of APIs that are poorly soluble. Because of this factor, the dissolution rate of APIs in solid dosage forms is an important, routine, quality control parameter used in the API manufacturing process.
  • Dissolution rate K S (C 3 -C)
  • K dissolution rate constant
  • S is the surface area
  • C s is the apparent solubility
  • C is the concentration of API in the dissolution medium.
  • C 3 -C is approximately equal to C s .
  • the dissolution rate of APIs may be measured by conventional means known in the art.
  • the increase in the dissolution rate of a co-crystal, as compared to the reference form (e.g., free form or salt), may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the reference form (e.g., free form or salt form) in the same solution.
  • Conditions under which the dissolution rate is measured is the same as discussed above
  • the increase in dissolution may be further specified by the time the composition remains supersaturated before reaching equilibrium solubility.
  • Examples of above embodiments include: co-crystal compositions with a dissolution rate in aqueous solution, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the reference form, co-crystal compositions with a dissolution rate in SGF that is increased at least 5 fold over the reference form, co-crystal compositions with a dissolution rate in SIF that is increased at least 5 fold over the reference form.
  • the methods of the present invention are used to make a pharmaceutical API formulation with greater solubility, dissolution, and bioavailability. Bioavailability can be improved via an increase in AUC, reduced time to T ma , (the time to reach peak blood serum levels), or increased C max ,.
  • the present invention can result in higher plasma concentrations of API when compared to the neutral form or salt alone (reference form).
  • AUC is the area under the plot of plasma concentration of API (not logarithm of the concentration) against time after API administration. The area is conveniently determined by the "trapezoidal rule": The data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed. When the last measured concentration (C Thread, at time t n ) is not zero, the AUC from t n to infinite time is estimated by C Cincinnati/k eI .
  • the AUC is of particular use in estimating bioavailability of APIs, and in estimating total clearance of APIs (Cl ⁇ ).
  • AUC F • D/Cl ⁇ , where F is the absolute bioavailability of the API.
  • the present invention provides a process for modulating the bioavailability of an API when administered in its normal and effective dose range as a co-crystal, whereby the AUC is increased, the time to T max is reduced, or C max is increased, as compared to a reference form, which process comprises:
  • Examples of the above embodiments include: co-crystal compositions with a time to T max that is reduced by at least 10% as compared to the reference form, co-crystal compositions with a time to T max that is reduced by at least 20% over the reference form, co-crystal compositions with a time to T max that is reduced by at least 40% over the reference form, co-crystal compositions with a time to T max that is reduced by at least 50% over the reference form, co-crystal compositions with a T max that is reduced by at least 60% over the reference form, co-crystal compositions with a T max that is reduced by at least 70% over the reference form, co-crystal compositions with a T ma that is reduced by at least 80% over the reference form, co-crystal compositions with a T max that is reduced by at least 90% over the reference form, co-crystal compositions with a C ma ⁇ that is increased by at least 20% over the reference form, co-crystal compositions with a C max that is increased by
  • the present invention provides a process for improving the dose response of an API, which process comprises:
  • Dose response is the quantitative relationship between the magnitude of response and the dose inducing the response and may be measured by conventional means known in the art.
  • the curve relating effect (as the dependent variable) to dose (as the independent variable) for an API-cell system is the "dose-response curve".
  • dose-response curve is the measured response to an API plotted against the dose of the API (mg/kg) given.
  • the dose response curve can also be a curve of AUC against the dose of the API given.
  • a co-crystal of the present mvention has an increased dose response curve or a more linear dose response curve than the corresponding reference compound.
  • the present invention provides a process for improving the stability of an API (as compared to a reference form such as its free form or a salt thereof), which process comprises:
  • compositions of the present invention including the API or active pharmaceutical ingredient (API) and formulations comprising the API, are suitably stable for pharmaceutical use.
  • the API or formulations thereof of the present invention are stable such that when stored at 30 degrees C for 2 years, less than 0.2 % of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, for the purpose of the present invention, it would be considered a single degradant. More preferably, when stored at 40 degrees C for 2 years, less than 0.2 % of any one degradant is formed.
  • the relative humidity (RH) may be specified as ambient (RH), 75 % (RH), or as any single integer between 1 to 99 %. Difficult to Salt or Unsaltable Compounds
  • the present invention provides a process for making co- crystals of unsaltable or difficult to salt APIs which process comprises:
  • Difficult to salt compounds include bases with a pKa less than 3 or acids with a pKa greater than 10.
  • Zwitter ions are also difficult to salt or unsaltable compounds according to the present invention.
  • the present invention provides a method for decreasing the hygroscopicity of an API, which method comprises:
  • An aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a co-crystal of an API that is less hygroscopic than amorphous or crystalline, free form or salt (including metal salts such as sodium, potassium, lithium, calcium, magnesium) or another reference compound.
  • Hygroscopicity can be assessed by dynamic vapor sorption analysis, in which 5-50 mg of the compound is suspended from a Cahn microbalance.
  • the compound being analyzed should be placed in a non- hygroscopic pan and its weight should be measured relative to an empty pan composed of identical material and having nearly identical size, shape, and weight. Ideally, platinum pans should be used.
  • the pans should be suspended in a chamber through which a gas, such as air or nitrogen, having a controlled and known percent relative humidity (%RH) is flowed until eqilibrium criteria are met.
  • a gas such as air or nitrogen
  • Typical equilibrium criteria include weight changes of less than 0.01 % over 3 minutes at constant humidity and temperature.
  • the relative humidity should be measured for samples dried under dry nitrogen to constant weight ( ⁇ 0.01 % change in 3 minutes) at 40 degrees C unless doing so would de-solvate or otherwise convert the material to an amorphous compound.
  • the hygroscopicity of a dried compound can be assessed by increasing the RH from 5 to 95 % in increments of 5 % RH and then decreasing the RH from 95 to 5 % in 5 % increments to generate a moisture sorption isotherm.
  • the sample weight should be allowed to equilibrate between each change in % RH. If the compound deliquesces or becomes amorphous above 75 % RH, but below 95 % RH, the experiment should be repeated with a fresh sample and the relative humidity range for the cycling should be narrowed to 5-75 % RH or 10-75 % RH, instead of 5-95 %RH.
  • Hygroscopicity can be defined using various parameters. For purposes of the present invention, a non-hygroscopic molecule should not gain or lose more than 1.0 %, or more preferably, 0.5 % weight at 25 degrees C when cycled between 10 and 75 % RH (relative humidity at 25 degrees C).
  • the non-hygroscopic molecule more preferably should not gain or lose more than 1.0 %, or more preferably, 0.5 % weight when cycled between 5 and 95 % RH at 25 degrees C, or more than 0.25 % of its weight between 10 and 75 % RH. Most preferably, a non-hygroscopic molecule will not gain or lose more than 0.25 % of its weight when cycled between 5 and 95 % RH.
  • hygroscopicity can be defined using the parameters of Callaghan et al., "Equilibrium moisture content ofpharmaceutical excipients", in Api Dev. Ind. Pharm., Vol. 8, pp. 335-369 (1982). Callaghan et al. classified the degree of hygroscopicity into four classes.
  • Class 1 Non-hygroscopic Essentially no moisture increases occur at relative humidities below 90 %.
  • Class 2 Slightly hygroscopic Essentially no moisture increases occur at relative humidities below 80%.
  • Class 3 Moderately hygroscopic Moisture content does not increase more than 5 % after storage for 1 week at relative humidities below 60 %.
  • Class 4 Very hygroscopic Moisture content increase may occur at relative humidities as low as 40 to 50 %.
  • hygroscopicity can be defined using the parameters of the European Pharmacopoeia Technical Guide (1999, p. 86) which has defined hygrospocity, based on the static method, after storage at 25 degrees C for 24 hours at 80 % RH:
  • Hygroscopic Increase in mass is less than 15 percent m/m and equal to or greater than 0.2 percent m/m.
  • Co-crystals of the present invention can be set forth as being in Class 1, Class 2, or Class 3, or as being Slightly hygroscopic, Hygroscopic, or Very Hygroscopic. Co- crystals of the present invention can also be set forth based on their ability to reduce hygroscopicity. Thus, preferred co-crystals of the present invention are less hygroscopic than a reference compound.
  • the reference compound can be specified as the API in free form (free acid, free base, hydrate, solvate, etc.) or salt (e.g., especially metal salts such as sodium, potassium, lithium, calcium, or magnesium).
  • co-crystals that do not gain or lose more than 1.0 % weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 1.0 % weight under the same conditions.
  • co-crystals that do not gain or lose more than 0.5 % weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 0.5 % or more than 1.0 % weight under the same conditions.
  • co-crystals that do not gain or lose more than 1.0 % weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 1.0 % weight under the same conditions.
  • co-crystals that do not gain or lose more than 0.5 % weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5 % or more than 1.0 % weight under the same conditions.
  • co-crystals that do not gain or lose more than 0.25 % weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5 % or more than 1.0 % weight under the same conditions.
  • co-crystals that have a hygroscopicity (according to Callaghan et al.) that is at least one class lower than the reference compound or at least two classes lower than the reference compound. Included are a Class 1 co-crystal of a Class 2 reference compound, a Class 2 co-crystal of a Class 3 reference compound, a Class 3 co-crystal of a Class 4 reference compound, a Class 1 co- crystal of a Class 3 reference compound, a Class 1 co-crystal of a Class 4 reference compound, or a Class 2 co-crystal of a Class 4 reference compound.
  • co-crystals that have a hygroscopicity (according to the European Pharmacopoeia Technical Guide) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • a slightly hygroscopic co-crystal of a hygroscopic reference compound a hygroscopic co-crystal of a very hygroscopic reference compound, a very hygroscopic co-crystal of a deliquescent reference compound, a slightly hygroscopic co-crystal of a very hygroscopic reference compound, a slightly hygroscopic co-crystal of a deliquescent reference compound, and a hygroscopic co-crystal of a deliquescent reference compound.
  • the present invention provides a process for crystallizing an amorphous compound, which process comprises: (1) grinding, heating, co-subliming, co-melting, or contacting in solution the API with a co-crystal former under crystallization conditions, so as to form a co-crystal of the API and the co-crystal former; and
  • An amorphous compound includes compounds that do not crystallize using routine methods in the art.
  • the present invention provides a process for reducing the form diversity of an API, which process comprises:
  • the number of forms of a co-crystal is compared to the number of forms of a reference compound (e.g. the free form or a salt of the API) that can be made using routine methods in the art.
  • a reference compound e.g. the free form or a salt of the API
  • the present invention provides a process for modifying the morphology of an API, which process comprises:
  • the co-crystal comprises or consists of a co-crystal former and a pharmaceutical wherein the interaction between the two, e.g., H-bonding, occurs between a functional group of Table III of an API with a corresponding interacting group of Table III.
  • the co-crystal comprises a co-crystal former of Table I or II and an API with a corresponding interacting group of Table III.
  • the co-crystal comprises an API from Table IV and a co-crystal former with a functional group of Table III.
  • the co-crystal is from Table I or II.
  • co-crystals having an H-bond acceptor on the first molecule and an H-bond donor on the second molecule are included in the present invention.
  • Table IV includes the CAS number, chemical name or a PCT or patent reference (each incorporated herein in their entireties). Thus, whether a particular API contains an H-bond donor, acceptor or both is readily apparent.
  • the co-crystal former and API each have only one H- bond donor/acceptor.
  • the molecular weight of the API is less than 2000, 1500, 1000, 750, 500, 350, 200, or 150 Daltons. In another embodiment, the molecular weight of the API is between 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, 900-1000, 1000-1200, 1200-1400, 1400-1600, 1600-1800, or 1800-2000. APIs with the above molecular weights may also be specifically excluded from the present invention.
  • the hydrogen bond donor moieties of a co-crystal can include, but are not limited to, any one, any two, any three, any four, or more of the following: amino-pyridine, primary amine, secondary amine, sulfonamide, primary amide, secondary amide, alcohol, and carboxylic acid.
  • the hydrogen bond acceptor moieties of a co-crystal can include, but are not limited to, any one, any two, any three, any four, or more of the following: amino-pyridine, primary amine, secondary amine, sulfonamide, primary amide, secondary amide, alcohol, carboxylic acid, carbonyl, cyano, dimethoxyphenyl, sulfonyl, aromatic nitrogen (6 membered ring), ether, chloride, organochloride, bromide, organobromide, and organoiodide. Hydrogen bonds are known to form many supramolecular structures including, but not limited to, a catemer, a dimer, a trimer, a t ⁇ tramer, or a higher order structure.
  • Tables V-XXI list specific hydrogen bond donor and acceptor moieties and their approximate interaction distances from the electromagnetic donor atom through the hydrogen atom to the electromagnetic acceptor atom.
  • Table V lists functional groups that are known to hydrogen bond with amino-pyridines. Amino-pyridines comprise two distinct sites of hydrogen bond donation/acceptance. Both the aromatic nitrogen atom (Npy) and the amine group (NH 2 ) can participate in hydrogen bonds. The ability of a given functional group to participate in a hydrogen bond as a donor or as an acceptor or both can be determined by inspection by those skilled in the art.
  • Tables V-XXI are taken from an analysis of solid-state structures as reported in the Cambridge Structural Database (CSD). These data include a number of hydrogen bonding interactions between many functional groups and their associated interaction distances.
  • peptides, proteins, nucleic acids or other biological APIs are excluded from the present invention.
  • all non- pharmaceutically acceptable co-crystal formers are excluded from the present invention.
  • organometalic APIs are excluded from the present invention.
  • a co-crystal former comprising any one or more of the functional groups of Table III may be specifically excluded from the present invention.
  • any one or more of the co-crystal formers of Table I or II may be specifically excluded from the present invention. Any APIs currently known in the art may also be specifically excluded from the present invention.
  • the API is not a salt, is not a non-metal salt, or is not a metal salt, e.g., sodium, potassium, lithium, calcium or magnesium.
  • the API is a salt, is a non-metal salt, or is a metal salt, e.g., sodium, potassium, lithium, calcium, magnesium.
  • the API does not contain a halogen. In one embodiment, the API does contain a halogen.
  • any one or more of the APIs of Table IV may be specifically excluded from the present invention.
  • Any APIs currently known in the art may also be specifically excluded from the present invention.
  • nabumetone:2,3-naphthalenediol fluoxetine HCkbenzoic acid, fluoxetine HCLsuccinic acid, acetaminophe piperazine, acetaminophe theophylline, theophylline: salicylic acid, theophylline :p-hydiOxybenzoic acid, theophylline: sorbic acid, theophylline :l-hydroxy-2- naphthoic acid, theophylline :glycolic acid, theophylline:2,5-dihydroxybenzoic acid, theophylline xhloroacetic acid, bis(diphenylhydantoin):9-ethyladenine acetylacetone solvate, bis(diphenylhydantoin)
  • a pharmaceutical composition can be formulated to contain an API in co-crystal form as micronized or nano-sized particles. More specifically, another embodiment couples the processing of a pure API to a co-crystal form with the process of making a controlled particle size for manipulation into a pharmaceutical dosage form. This embodiment combines two processing steps into a single step via techniques such as, but not limited to, grinding, alloying, or sintering (i.e., heating a powder mix). The coupling of these processes overcomes a serious limitation of having to isolate and store the bulk drug that is required for a formulation, which in some cases can be difficult to isolate (e.g., amorphous, chemically or physically unstable).
  • Excipients employed in pharmaceutical compositions of the present invention can be solids, semi-solids, liquids or combinations thereof. Preferably, excipients are solids.
  • Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with an API or therapeutic agent.
  • a pharmaceutical composition of the invention contains a desired amount of API per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, or any other form reasonably adapted for such administration.
  • oral dosage forms that are discrete dose units each containing a predetermined amount of the API, such as tablets or capsules.
  • APIs with an inappropriate pH for transdermal patches can be co-crystallized with an appropriate co-crystal former, thereby adjusting its pH to an appropriate level for use as a transdermal patch.
  • an APIs pH level can be optimized for use in a transdermal patch via co-crystallization with an appropriate co-crystal former.
  • Non-limiting examples follow of excipients that can be used to prepare pharmaceutical compositions of the invention.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable carriers or diluents as excipients.
  • suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose (e.g., CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of alpha- and a
  • Such carriers or diluents constitute in total about 5% to about 99%, preferably about 10% to about 85%, and more preferably about 20% to about 80%, of the total weight of the composition.
  • the carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
  • Lactose, mannitol, dibasic sodium phosphate, and microcrystalline cellulose are preferred diluents. These diluents are chemically compatible with many co-crystals described herein.
  • the use of extragranular microcrystalline cellulose that is, microcrystalline cellulose added to a granulated composition
  • Lactose, especially lactose monohydrate is particularly preferred.
  • Lactose typically provides compositions having suitable release rates of co-crystals, stability, pre- compression flowability, and/or drying properties at a relatively low diluent cost. It provides a high density substrate that aids densification during granulation (where wet granulation is employed) and therefore improves blend flow properties and tablet properties.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations.
  • Suitable disintegrants include, but are not limited to, either individually or in combination, starches, including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g., NationalTM 1551 of National Starch and Chemical Company, NationalTM 1550, and ColorconTM 1500), clays (e.g., VeegumTM HV of R.T.
  • Vanderbilt celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and fragacanth gums.
  • Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to about 5%, of the total weight of the composition.
  • Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, preferably constitutes about 0.2% to about 10%, more preferably about 0.2% to about 7%, and still more preferably about 0.2% to about 5%, of the total weight of the composition. Croscarmellose sodium confers superior intragranular disintegration capabilities to granulated pharmaceutical compositions of the present invention.
  • Pharmaceutical compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations. Such binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
  • binding agents may also prevent or inhibit crystallization or recrystallization of a co-crsytal of the present invention once the salt has been dissolved in a solution.
  • Suitable binding agents and adhesives include, but are not limited to, either individually or in combination, acacia; fragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., KlucelTM of Aqualon); and ethylcellulose (e.g., EthocelTM of the Dow Chemical
  • binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, are preferably included in pharmaceutical compositions of the present invention.
  • Polyvinylpyrrolidones such as povidone K-30 are especially preferred.
  • Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer.
  • Polymeric binding agents can also be copolymers, such as block co-polymers that contain mixtures of ethylene oxide and propylene oxide units. Variation in these units' ratios in a given polymer affects properties and performance. Examples of block co-polymers with varying compositions of block units are Poloxamer 188 and Poloxamer 237 (BASF Corporation).
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients.
  • Such wetting agents are preferably selected to maintain the co-crystal in close association with water, a condition that is believed to improve bioavailability of the composition.
  • Such wetting agents can also be useful in solubilizing or increasing the solubility of co-crystals.
  • Non-limiting examples of surfactants that can be used as wetting agents in pharmaceutical compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and degrees Ctoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, poly
  • Sodium lauryl sulfate is a particularly preferred wetting agent.
  • Sodium lauryl sulfate if present, constitutes about 0.25% to about 7%, more preferably about 0.4% to about 4%, and still more preferably about 0.5% to about 2%, of the total weight of the pharmaceutical composition.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients.
  • suitable lubricants include, but are not limited to, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888 of Gattefosse); stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex of Abitec); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000 of the Dow Chemical Company); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • Such lubricants if present, constitute in total about 0. 1% to about 10%, preferably about
  • Magnesium stearate is a preferred lubricant used, for example, to reduce friction between the equipment and granulated mixture during compression of tablet formulations.
  • Suitable anti-adherents include, but are not limited to, talc, cornstarch, DL- leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a preferred anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend.
  • Talc if present, constitutes about 0.1% to about 10%, more preferably about 0.25% to about 5%, and still more preferably about 0.5% to about 2%, of the total weight of the pharmaceutical composition.
  • Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.
  • compositions of the invention can further comprise, for example, buffering agents.
  • one or more effervescent agents can be used as disintegrants and/or to enhance organoleptic properties of pharmaceutical compositions of the invention.
  • one or more effervescent agents are preferably present in a total amount of about 30% to about 75%, and preferably about 45% to about 70%, for example about 60%, by weight of the pharmaceutical composition.
  • an effervescent agent present in a solid dosage form in an amount less than that effective to promote disintegration of the dosage form, provides improved dispersion of the API in an aqueous medium.
  • the effervescent agent is effective to accelerate dispersion of the API from the dosage form in the gastrointestinal tract, thereby further enhancing absorption and rapid onset of therapeutic effect.
  • an effervescent agent is preferably present in an amount of about 1% to about 20%, more preferably about 2.5% to about 15%, and still more preferably about 5% to about 10%, by weight of the pharmaceutical composition.
  • an “effervescent agent” herein is an agent comprising one or more compounds which, acting together or individually, evolve a gas on contact with water.
  • the gas evolved is generally oxygen or, most commonly, carbon dioxide.
  • Preferred effervescent agents comprise an acid and a base that react in the presence of water to generate carbon dioxide gas.
  • the base comprises an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid comprises an aliphatic carboxylic acid.
  • Non-limiting examples of suitable bases as components of effervescent agents useful in the invention include carbonate salts (e.g., calcium carbonate), bicarbonate salts (e.g., sodium bicarbonate), sesquicarbonate salts, and mixtures thereof. Calcium carbonate is a preferred base.
  • Non-limiting examples of suitable acids as components of effervescent agents and/or solid organic acids useful in the invention include citric acid, tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid (as D-, L-, or DL-malic acid), maleic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof.
  • Citric acid is a preferred acid.
  • the weight ratio of the acid to the base is about 1 : 100 to about 100:1, more preferably about 1:50 to about 50:1, and still more preferably about 1 : 10 to about 10:1.
  • the ratio of the acid to the base is approximately stoichiometric.
  • Excipients which solubilize APIs typically have both hydrophilic and hydrophobic regions, or are preferably amphiphilic or have amphiphilic regions.
  • One type of amphiphilic or partially-amphiphilic excipient comprises an amphiphilic polymer or is an amphiphilic polymer.
  • a specific amphiphilic polymer is a polyalkylene glycol, which is commonly comprised of ethylene glycol and/or propylene glycol subunits.
  • Such polyalkylene glycols can be esterified at their termini by a carboxylic acid, ester, acid anhyride or other suitable moiety.
  • excipients examples include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol; e.g., poloxamer 237), polyalkyene glycolated esters of tocopherol (including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol polyethylene glycol- 1000 succinate), and macrogolglycerides (formed by alcoholysis of an oil and esterification of a polyalkylene glycol to produce a mixture of mono-, di- and tri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32 glycerides).
  • poloxamers symmetric block copolymers of ethylene glycol and propylene glycol
  • polyalkyene glycolated esters of tocopherol including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol
  • compositions of the present invention can comprise about 10 % to about 50 %, about 25 % to about 50 %, about 30 % to about 45 %, or about 30 % to about 35 % by weight of a co-crystal; about 10 % to about 50 %, about 25 % to about 50 %, about 30 % to about 45 %, or about 30 % to about 35 % by weight of an excipient which inhibits crystallization in aqueous solution, in simulated gastric fluid, or in simulated intestinal fluid; and about 5 % to about 50 %, about 10 % to about 40 %, about 15 % to about 35 %, or about 30 % to about 35 % by weight of a binding agent.
  • the weight ratio of the co-crystal to the excipient which inhibits crystallization to binding agent is about 1 to 1 to 1.
  • Solid dosage forms of the invention can be prepared by any suitable process, not limited to processes described herein.
  • An illustrative process comprises (a) a step of blending an API of the invention with one or more excipients to form a blend, and (b) a step of tableting or encapsulating the blend to form tablets or capsules, respectively.
  • solid dosage forms are prepared by a process comprising (a) a step of blending a co-crystal of the invention with one or more excipients to form a blend, (b) a step of granulating the blend to form a granulate, and (c) a step of tableting or encapsulating the blend to form tablets or capsules respectively.
  • Step (b) can be accomplished by any dry or wet granulation technique known in the art, but is preferably a dry granulation step.
  • a salt of the present invention is advantageously granulated to form particles of about 1 micrometer to about 100 micrometer, about 5 micrometer to about 50 micrometer, or about 10 micrometer to about 25 micrometer.
  • One or more diluents, one or more disintegrants and one or more binding agents are preferably added, for example in the blending step, a wetting agent can optionally be added, for example in the granulating step, and one or more disintegrants are preferably added after granulating but before tableting or encapsulating.
  • a lubricant is preferably added before tableting. Blending and granulating can be performed independently under low or high shear.
  • a process is preferably selected that forms a granulate that is uniform in API content, that readily disintegrates, that flows with sufficient ease so that weight variation can be reliably controlled during capsule filling or tableting, and that is dense enough in bulk so that a batch can be processed in the selected equipment and individual doses fit into the specified capsules or tablet dies.
  • solid dosage forms are prepared by a process that includes a spray drying step, wherein an API is suspended with one or more excipients in one or more sprayable liquids, preferably a non-protic (e.g., non-aqueous or nonalcoholic) sprayable liquid, and then is rapidly spray dried over a current of warm air.
  • a granulate or spray dried powder resulting from any of the above illustrative processes can be compressed or molded to prepare tablets or encapsulated to prepare capsules. Conventional tableting and encapsulation techniques known in the art can be employed. Where coated tablets are desired, conventional coating techniques are suitable.
  • Excipients for tablet compositions of the invention are preferably selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and still more preferably about 15 minutes or less, in a standard disintegration assay.
  • compositions can be administered by controlled-, sustained-, or delayed-release means.
  • Controlled-release pharmaceutical products 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 drug substance being employed to cure or control the condition in a minimum amount of time.
  • Controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions.
  • Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like.
  • controlled- release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
  • controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the co-crystals and compositions of the mvention.
  • Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl; each of which is incorporated herein by reference.
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, liydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • ion exchange materials can be used to prepare immobilized, adsorbed co-crystals and thus effect controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited to, Duolite® A568 and Duolite® AP143 (Rohm & Haas, Spring House, PA. USA).
  • One embodiment of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable co-crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphous form thereof, and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition or dosage form is formulated for controlled-release.
  • Specific dosage forms utilize an osmotic drug delivery system.
  • OROS® osmotic drug delivery system
  • This technology can readily be adapted for the delivery of compounds and compositions of the invention.
  • Various aspects of the technology are disclosed in U.S. Pat. Nos. 6,375,978 Bl; 6,368,626 Bl; 6,342,249 Bl; 6,333,050 B2; 6,287,295 Bl; 6,283,953 Bl; 6,270,787 Bl; 6,245,357 Bl; and 6,132,420; each of which is incorporated herein by reference.
  • OROS® that can be used to administer compounds and compositions of the invention
  • OROS® Push-PullTM Delayed Push-PullTM, Multi- Layer Push-PullTM, and Push-StickTM Systems, all of which are well known. See, e.g., http://www.alza.com.
  • Additional OROS® systems that can be used for the controlled oral delivery of compounds and compositions of the invention include OROS®-CT and L- OROS®. Id.; see also, Delivery Times, vol. II, issue II (Alza Corporation).
  • OROS® oral dosage forms are made by compressing a drag powder (e.g. co-crystal) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser).
  • a drag powder e.g. co-crystal
  • Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, Pa.: 2000).
  • the advantage of such dosage forms is that the delivery rate of the drug is not influenced by physiological or experimental conditions. Even a drug with a pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium.
  • OROS® drug delivery systems cannot be used to effectively deliver drugs with low water solubility. Id. at 234. Because co-crystals of this invention can be far more soluble in water than the API itself, they are well suited for osmotic-based delivery to patients. This invention does, however, encompass the incorporation of conventional crystalline API (e.g. pure API without co-crystal former), and non-salt isomers and isomeric mixtures thereof, into OROS® dosage forms.
  • conventional crystalline API e.g. pure API without co-crystal former
  • a specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow- promoting layer interposed between the inner surface of the wall and at least the external surface of the drug layer located within the cavity, wherein the drug layer comprises a co- crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphous form thereof. See U.S. Pat. No. 6,368,626, the entirety of which is incorporated herein by reference.
  • Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and tlie drug layer, wherein the active agent formulation comprises a co-crystal, or a solvate, hydrate, dehydrate, anhydrous, or amorphous form thereof. See U.S. Pat. No. 6,342,249, the entirety of which is incorporated herein by reference.
  • CrystalMaxTM comprises a sequence of automated, integrated high throughput robotic stations capable of rapid generation, identification and characterization of polymorphs, salts, and co-crystals of APIs and API candidates. Worksheet generation and combinatorial mixture design is carried out using proprietary design software ArchitectTM. Typically, an API or an API candidate is dispensed from an organic solvent into tubes and dried under a stream of nitrogen. Salts and/or co-crystal formers may also be dispensed and dried in the same fashion. Water and organic solvents may be combinatorially dispensed into the tubes using a multi-channel dispenser. Each tube in a 96-tube array is then sealed within 15 seconds of combinatorial dispensing to avoid solvent evaporation.
  • the mixtures are then rendered supersaturated by heating to 70 degrees C for 2 hours followed by a 1 degree C/minute cooling ramp to 5 degrees C.
  • Optical checks are then conducted to detect crystals and/or solid material. Once a solid has been identified in a tube, it is isolated through aspiration and drying. Raman spectra are then obtained on the solids and cluster classification of the spectral patterns is performed using proprietary software (InquireTM).
  • Co-crystals may be obtained by dissolving the separate components in a solvent and adding one to the other. The co-crystal may then precipitate or crystallize as the solvent mixture is evaporated slowly. The co-crystal may also be obtained by dissolving the two components in the same solvent or a mixture of solvents.
  • a co-crystal may be obtained by melting the two components together (i.e., co- melting) and allowing recrystallization to occur.
  • an anti-solvent may be added to facilitate crystallization.
  • a co-crystal may be obtained by melting the higher melting component on a glass slide and allowing it to recrystallize. The second component is then melted and is also allowed to recrystallize. The co-crystal may form as a separated phase/band in between the eutectic bands of the two original components.
  • a co-crystal may be obtained by mixing or grinding two components together in the solid state.
  • a co-crystal may be obtained by co-subliming a mixture of an API and a co- crystal former in the same sample cell as an intimate mixture either by heating, mixing or placing the mixture under vacuum.
  • a co-crystal may also be obtained by co-sublimation using a Kneudsen apparatus where the API and the co-crystal former are contained in separate sample cells, connected to a single cold finger, each of the sample cells is maintained at the same or different temperatures under a vaccum atmosphere in order to co-sublime the two components onto the cold-finger forming the desired co-crystal.
  • the purge gas used was dry nitrogen
  • the reference material was an empty aluminum pan that was crimped
  • the sample purge was 50 mL/minute.
  • DSC analysis of the sample was performed by placing ⁇ 2 mg of sample in an aluminum pan with a crimped pan closure.
  • the starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 300 degrees C. Unless otherwise indicated, all reported transitions are as stated +/- 1.0 degrees C.
  • TGA analysis of samples was performed using a Q500 Thermogravimetric Analyzer (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).
  • 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).
  • the purge gas used was dry nitrogen, the balance purge was 40 mL/minute N 2 , and the sample purge was 60 mL/minute N 2 .
  • TGA of the sample was performed by placing ⁇ 2 mg of sample in a platinum pan.
  • the starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 300 degrees C.
  • a powder X-ray diffraction pattern for the samples was 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 1.5406A; x-y stage was manual; collimator size was 0.3 or 0.8 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 or 0.8 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 2-40 or 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 degree due to differences in calibration, settings, and other variations from instrument to instrument and from operator to operator. Procedure for Raman Acquisition. Filtering and Binning
  • the sample was either left in the glass vial in which it was processed or an aliquot of the sample was transferred to a glass slide.
  • the glass vial or slide was positioned in the sample chamber.
  • the measurement was made using an AlmegaTM Dispersive Raman (AlmegaTM Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711- 4495) system fitted with a 785nm laser source.
  • the sample was manually brought into focus using the microscope portion of the apparatus with a lOx power objective (unless otherwise noted), thus directing the laser onto the surface of the sample.
  • the spectrum was acquired using the parameters outlined in Table XXII. (Exposure times and number of exposures may vary; changes to parameters will be indicated for each acquisition.)
  • Each spectrum in a set was filtered using a matched filter of feature size 25 to remove background signals, including glass contributions and sample fluorescence. This is particularly important as large background signal or fluorescence limit the ability to accurately pick and assign peak positions in the subsequent steps of the binning process.
  • Filtered spectra were binned using the peak pick and bin algorithm with the parameters given in Table XXIII.
  • the sorted cluster diagrams for each sample set and the corresponding cluster assignments for each spectral file were used to identify groups of samples with similar spectra, which was used to identify samples for secondary analyses.
  • Single crystal x-ray data were collected on a Bruker SMART-APEX CCD diffractometer (M. J. Zaworotko, Department of Chemistry, University of South Florida). Lattice parameters were determined from least squares analysis. Reflection data was integrated using the program SAINT. The structure was solved by direct methods and refined by full matrix least squares using the program SHELXTL (Sheldrick, G. M. SHELXTL, Release 5.03; Siemans Analytical X-ray Instruments Inc.: Madison, WI).
  • the co-crystals 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 Raman shift peaks listed herein or disclosed in a figure, or by single crystal x-ray diffraction data.
  • celecoxib icotinamide co-crystals were prepared. Celecoxib (100 mg, 0.26 mmol) and nicotinamide (32.0 mg, 0.26 mmol) were each dissolved in acetone (2 mL). The two solutions were mixed and the resulting mixture was allowed to evaporate slowly overnight. The precipitated solid was redissolved in acetone a second time and left to evaporate to dryness. The powder was collected and characterized. Detailed characterization of the celecoxib icotinamide co-crystal is listed in Table XXIV. Fig. 1A shows the PXRD diffractogram after subtraction of background noise. Fig. IB shows the raw PXRD data. Fig.
  • FIG. 2 shows a DSC thermogram of the celecoxib :nicotinamide co- crystal.
  • Fig. 3 shows a TGA thermogram of the celecoxib :nicotinamide co-crystal.
  • Fig. 4 shows a Raman spectrum of the celecoxib:nicotinamide co-crystal.
  • Co-crystals of topiramate and 18-crown-6 were prepared. To topiramate (100 mg, 0.29 mmol) dissolved in diethyl ether (5 mL) was added 18-crown-6 (78 mg, 0.29 mmol) in diethyl ether (5 mL). Upon addition of 18-crown-6, the solution became cloudy and was sonicated for 30 seconds. The solution was left standing for 1 hour and a colorless precipitate was observed. The precipitate was collected, washed with diethyl ether and dried to give a 1 :1 co-crystal of topiramate: 18-crown-6 as a colorless solid.
  • Fig. 8 A shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 8B shows the raw PXRD data.
  • Fig. 9 shows a DSC thermogram of the topiramate: 18-crown-6 co-crystal.
  • Co-crystals of olanzapine and nicotinamide were prepared.
  • a 9-block experiment was designed with 12 solvents.
  • a block is a receiving plate, which can be, for example, an industry standard 24 well, 96 well, 384 well, or 1536 well format, or a custom format.
  • 864 crystallization experiments with 10 co-crystal formers and 3 concentrations were carried out using the CrystalMaxTM platform.
  • Form I was obtained from mixtures containing 1:1 and 1:2 molar ratios of olanzapine:nicotinamide in 1,2- dichloroethane.
  • Form II was obtained from mixtures containing a 1 :2 molar ratio of olanzapine and nicotinamide in isopropyl acetate.
  • PXRD and DSC characterization of the olanzapine:nicotinamide co-crystals are listed in Table XXIV.
  • Fig. 10A shows the PXRD diffractogram of form I after subtraction of background noise.
  • Fig. 10B shows the raw PXRD data of form I.
  • Fig. 11 shows a DSC thermogram of the olanzapine :nicotinamide form I co-crystal.
  • Fig. 12 shows the PXRD diffractogram of olanzapinemicotinamide form II after subtraction of background noise.
  • Co-crystals of olanzapine and nicotinamide were prepared.
  • Olanzapine 40 microliters of 25 mg/mL stock solution in tetrahydrofuran
  • nicotinamide 37.6 microliters of 20 mg/mL stock solution in methanol
  • To the solid mixture was added isopropyl acetate (100 microliters) and the vial was sealed with an aluminum cap.
  • the suspension was then heated at 70 degrees C for two hours in order to dissolve all of the solid material.
  • the solution was then cooled to 5 degrees C and maintained at that temperature for 24 hours.
  • Fig. 13 A shows the PXRD diffractogram of form III after subtraction of background noise.
  • Fig. 13B shows the raw PXRD data of form III.
  • Figs. 14A-D show packing diagrams of the olanzapine:nicotinamide form III co-crystal.
  • the olanzapine :nicotinamide (Form III) co-crystal is made up of a ternary system containing olanzapine, nicotinamide, water and isopropyl acetate in the unit cell.
  • the co-crystal crystallizes in the monoclinic space group P2i/c and contains two olanzapine molecules, one nicotinamide molecule, 4 water molecules and one isopropyl acetate molecule in the asymmetric unit.
  • the packing diagram is made up of a two-dimensional hydrogen-bonded network with the water molecules connecting the olanzapine and nicotinamide moieties.
  • the packing diagram is also comprised of alternating olanzapine and nicotinamide layers connected through hydrogen bonding via the water and isopropyl acetate molecules, as shown in Figure 14B.
  • the olanzapine layer propagates along the b axis at c/4 and 3c/4.
  • the nicotinamide layer propagates along the b axis at c/2.
  • the top of Figure 14C illustrates the nicotinamide superstructure.
  • the nicotinamide molecules form dimers which hydrogen bond to chains of 4 water molecules.
  • the water chains terminate with isopropyl acetate molecules on each side.
  • a co-crystal of cw-itraconazole and succinic acid was prepared.
  • succinic acid (16.8 mg, 0.142 mmol) in tetrahydrofuran (THF) (0.50 mL) was added cis- itraconazole (100 mg, 0.142 mmol).
  • THF tetrahydrofuran
  • a clear solution formed with heating (60 degrees C) and stirring. Upon cooling to room temperature (25 degrees C), crystals began to form.
  • the solid was collected by filtration and washed with cold THF (2 mL).
  • the white solid was air-dried and placed in a glass vial.
  • the crystalline substance was found to be a succinic acid co-crystal of cz ' s-itraconazole.
  • the solid was characterized by PXRD and DSC.
  • Fig. 15 shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 16 shows a DSC thermogram
  • a co-crystal of czAitraconazole and fumaric acid was prepared.
  • To a blend of fumaric acid (8.40 mg, 0.072 mmol) and czAitraconazole (51.8 mg, 0.073 mmol) was added tetrahydrofuran (THF) (1.0 mL).
  • THF tetrahydrofuran
  • To the clear solution was added t-butyl methyl ether (1.0 mL).
  • a white solid formed immediately and was collected by filtration and washed with cold t-butyl methyl ether (2 mL). The white solid was air-dried and placed in a glass vial.
  • the crystalline substance was found to be a fumaric acid co-crystal of czAitraconazole.
  • the solid was characterized by PXRD and DSC.
  • Fig. 17 shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 18 shows a DSC thermogram of the co-crystal.
  • a co-crystal of czAitraconazole and L-tartaric acid was prepared.
  • L-tartaric acid (21.3 mg, 0.142 mmol) in tetrahydrofuran (THF) (0.50 mL) was added cis- itraconazole (100 mg, 0.142 mmol).
  • THF tetrahydrofuran
  • cis- itraconazole 100 mg, 0.142 mmol
  • a clear solution formed with heating (60 degrees C) and stirring. Upon cooling to room temperature (25 degrees C), crystals began to form.
  • the solid was collected by filtration and washed with cold THF (2 mL).
  • the white solid was air-dried and placed in a glass vial.
  • the crystalline substance was found to be an L- tartaric acid co-crystal of czAitraconazole.
  • the solid was characterized by PXRD and DSC.
  • Fig. 19 shows the PXRD diffractogram after
  • a co-crystal of czAitraconazole and L-malic acid was prepared.
  • L-malic acid (19.1 mg, 0.143 mmol) in tetrahydrofuran (THF) (0.50 mL) was added cis- itraconazole (100 mg, 0.142 mmol).
  • THF tetrahydrofuran
  • a clear solution formed with heating (60 degrees C) and stirring. Upon cooling to room temperature (25 degrees C), crystals began to form.
  • the solid was collected by filtration and washed with cold THF (2 mL).
  • the white solid was air-dried and placed in a glass vial.
  • the crystalline substance was found to be an L- malic acid co-crystal of czAitraconazole.
  • the solid was characterized by PXRD and DSC.
  • Fig. 21 shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 22 shows a DSC thermogram of the
  • a co-crystal of czAitraconazole hydrochloride and DL-tartaric acid was prepared.
  • a suspension of c/Aitraconazole freebase (20.1 g, 0.0285 mol) in absolute ethanol (100 mL) was added a solution of hydrochloric acid (1.56 g, 0.0428 mol) and DL-tartaric acid (2.99 g, 0.0171mol) in absolute ethanol (100 mL).
  • a clear solution formed with stirring and heating to reflux.
  • the hot solution was gravity filtered and allowed to cool to room temperature (25 degrees C). Upon cooling white crystals formed.
  • the solid was collected by filtration and washed with cold absolute ethanol (15 mL).
  • the white solid was dried in a vacuum oven overnight at 80 degrees C.
  • the crystalline substance was found to be a DL-tartaric acid co-crystal of ezAitraconazole hydrochloride.
  • the solid was characterized by PXRD and DSC.
  • Fig. 23 shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 24 shows a DSC thermogram of the co-crystal.
  • Co-crystals of modafinil and malonic acid were prepared. Using a 250 mg/ml modafinil-acetic acid solution, malonic acid was dissolved on a hotplate (about 67 degrees C) at a 1 :2 modafinil to malonic acid ratio. The mixture was dried under flowing nitrogen overnight. A powdery white solid was produced. After further drying for 1 day, acetic acid was removed (as determined by TGA) and the crystal structure of the modafinikmalonic acid (Form I) co-crystal, as determined by PXRD, remained the same. The modafinil :malonic acid (Form I) co-crystal was also prepared by grinding the API and co-crystal former together.
  • FIG. 26 shows a DSC thermogram of the modafinil :malonic acid Form I co-crystal.
  • Fig. 27 shows the Raman spectrum of the modafinil :malonic acid Form I co-crystal.
  • Fig. 27 comprises peaks, in order of decreasing intensity, of 1004, 222, 633, 265, 1032, 1183, 814, 1601, 490, 718, 767, 361, 917, 1104, 889, 412, 1225, 1251, 1398, 1442, 1731, 1298, 3065, and 2949 cm "1 .
  • Single crystal data of the modafinikmalonic acid Form I co-crystal were acquired and are reported below.
  • a polymorph of the modafinikmalonic acid Form I co-crystal was prepared in a vial. 11.4 mg of modafinil and 8.9 mg of malonic acid were dissolved in 2 mL of acetone. The solids dissolved at room temperature, and the vial was left open to evaporate the solvent in air. Large parallelogram shaped crystals formed on the walls and bottom of the vial.
  • the PXRD diffractogram of the large crystals showed modafinil :malonic acid co-crystals Form II, a polymorphic form of modafinil :malonic acid Form I.
  • Fig. 28 shows the PXRD diffractogram of the modafinil :malonic acid Form II co-crystal after subtraction of background noise.
  • Co-crystals of modafinil and glycolic acid were prepared. Modafinil (1 mg, 0.0037mmol) and glycolic acid (0.30 mg, 0.0037 mmol) were dissolved in acetone (400 microliters). The solution was allowed to evaporate to dryness and the resulting solid was characterized using PXRD.
  • PXRD data for the modafinil: glycolic acid co-crystal is listed in Table XXIV.
  • Fig. 29A shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 29B shows the raw PXRD data.
  • Co-crystals of modafinil and maleic acid were prepared. Using a 250 mg/ml modafinil-acetic acid solution, maleic acid was dissolved on a hotplate (about 67 degrees C) at a 2:1 modafinil to maleic ratio. The mixture was dried under flowing nitrogen overnight. A clear amorphous material remained. Solids began to grow after 2 days stored in a sealed vial at room temperature. The solid was collected and characterized as the modafinil :maleic acid co-crystal using PXRD. Fig. 30A shows the PXRD diffractogram after subtraction of background noise. Fig. 3 OB shows the raw PXRD data.
  • FIG. 32 shows a DSC thermogram of the 5-fluorouracil:urea co-crystal.
  • Fig. 33 shows a TGA thermogram of the 5-fluorouracil:urea co-crystal.
  • Fig. 34 shows a Raman spectrum of the 5-fluorouracil:urea co-crystal. Single crystal data of the 5-fluorouracil:urea co- crystal were acquired and are reported below.
  • Co-crystals of hydrochlorothiazide and nicotinic acid were prepared. Hydrochlorothiazide (12.2 mg, 0.041 mmol) and nicotinic acid (5 mg, 0.041 mmol) were dissolved in methanol (1 mL). The solution was then cooled to 5 degrees C and maintained at that temperature for 12 hours. A white solid precipitated and was collected and characterized as the hydrochlorothiazide:nicotinic acid co-crystal using PXRD.
  • Fig. 35A shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 35B shows the raw PXRD data.
  • Co-crystals of hydrochlorothiazide and 18-crown-6 were prepared. Hydrochlorothiazide (100 mg, 0.33 mmol) was dissolved in diethyl ether (15 mL) and was added to a solution of 18-crown-6 (87.2 mg, 0.33 mmol) in diethyl ether (15 mL). A white precipitate immediately began to form and was collected and characterized as the hydrochlorothiazide: 18-crown-6 co-crystal using PXRD.
  • Fig. 36A shows the PXRD diffractogram after subtraction of background noise.
  • Fig. 36B shows the raw PXRD data.
  • Crystal packing The co-crystals contain bilayered sheets in which water molecules act as a hydrogen bonded bridge between the network bipyridine moieties and the acetaminophen. Bipyridine guests are sustained by ⁇ - ⁇ stacking interactions between two network bipyridines. The layers stack via ⁇ - ⁇ interactions between the phenyl groups of the acetaminophen moieties.
  • Crystal packing The co-crystal is sustained by hydrogen bonding of adjacent phentoin molecules between the carbonyl and the amine closest to the tetrahedral carbon, and by hydrogen bonding between pyridone carbonyl functionalities and the amine not involved in phenytoin-phenytoin interactions.
  • the pyridone carbonyl also hydrogen bonds with adjacent pyridone molecules forming a one-dimensional network.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR), characteristic peaks for the co-crystal were identified as: 2° amine found at 3311cm "1 , carbonyl (ketone) found at 1711cm "1 , olephin peak found at 1390cm "1 .
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), a 29.09% weight loss starting at 192.80 degrees C, 48.72% weight loss starting at 238.27 degrees C, and 18.38% loss starting at 260.17 degrees C followed by complete decomposition.
  • the co-crystal contains the carboxylic acid-pyridine heterodimer that crystallizes in the Pbcn space group.
  • the structure is an inclusion compound containing disordered solvent in the channels.
  • ⁇ - ⁇ stacking of the bipyridine and phenyl groups of the aspirin and hydrophobic interactions contribute to the overall packing interactions.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR), characteristic (-COOH) peak at 1679 cm “1 was shifted up and less intense at 1694cm " , where as the lactone peak is shifted down slightly from 1750cm “1 to 1744cm “1 .
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), weight loss of 9% starting at 22.62 degrees C, 49.06% weight loss starting at 102.97 degrees C followed by complete decomposition starting at 209.37 degrees C.
  • Crystal packing The co-crystal contains ibuprofembipyridine heterodimers, sustained by two hydrogen bonded carboxylic acidpyridine supramolecular synthons, arranged in a herringbone motif that packs in the space group P-1.
  • the heterodimer is an extended version of the homodimer and packs to form a two-dimensional network sustained by ⁇ - ⁇ stacking of the bipyridine and phenyl groups of the ibuprofen and hydrophobic interactions from the ibuprofen tails.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), 13.28% weight loss between room temperature and 100.02 degrees C immediately followed by complete decomposition.
  • the co-crystal contains flurbiprofe bipyridine heterodimers, sustained by two hydrogen bonded carboxylic acidpyridine supramolecular synthon, arranged in a herringbone motif that packs in the space group P2j/n.
  • the heterodimer is an extended version of the homodimer and packs to form a two-dimensional network sustained by ⁇ - ⁇ stacking and hydrophobic interactions of the bipyridine and phenyl groups of the flurbiprofen.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), 30.93% weight loss starting at 31.13 degrees C and a 46.26% weight loss starting at 168.74 degrees C followed by complete decomposition.
  • the co-crystal contains flurbiprofen: 1 ,2-bis (4-pyridyl) ethylene heterodimers, sustained by two hydrogen bonded carboxylic acid-pyridine supramolecular synthons, arranged in a herringbone motif that packs in the space group P2]/n.
  • the heterodimer from 1,2-bis (4-pyridyl) ethylene further extends the homodimer relative to example 21 and packs to form a two-dimensional network sustained by ⁇ - ⁇ stacking and hydrophobic interactions of the bipyridine and phenyl groups of the flurbiprofen.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), 91.79% weight loss starting at 133.18 degrees C followed by complete decomposition.
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers that crystallize in the space group C2/c.
  • the 1° amines of the homodimer are bifurcated to the carbonyl of the/7-phthalaldehyde forming a chain with an adjacent homodimer.
  • the chains pack in a crinkled tape motif sustained by ⁇ - ⁇ interactions between phenyl rings of the carbamazepine.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), 17.66% weight loss starting at 30.33 degrees C then a 17.57% weight loss starting at 100.14 degrees C followed by complete decomposition.
  • PXRD derived from the single crystal data, experimental (calculated): 8.5 (8.7); 10.6 (10.8); 11.9 (12.1); 14.4 (14.7) 15.1 (15.2); 18.0 (18.1); 18.5 (18.2); 19.8 (18.7); 23.7 (24.0); 24.2 (24.2); 26.4 (26.7); 27.6 (27.9); 27.8 (28.2); 28.7 (29.1); 29.3
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers.
  • the 1° amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer.
  • the 1° amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer.
  • the dimers form chains with ⁇ - ⁇ interactions from the phenyl groups of the carbamazepine.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 degrees C followed by complete decomposition.
  • PXRD Showed analogous peaks to the simulated PXRD derived from the single crystal data.
  • carbamazepine saccharin co-crystals were also prepared via another method.
  • a 12-block experiment was designed with 12 solvents.
  • a block is a receiving plate, which can be an industry standard 96 well, 384 well, or 1536 well format, or a custom format.
  • 1152 crystallization experiments were carried out using the CrystalMaxTM platform.
  • the carbamazepine: saccharin co-crystal was obtained from a mixture of isopropyl acetate and heptane.
  • the resulting co-crystal was characterized by PXRD and DSC and these data are shown in Figures 49 and 50, respectively.
  • the co-crystal prepared from a mixture of isopropyl acetate and heptane may contain impurities such as carbamazepine in free form due to incomplete purification.
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers.
  • the 2° amines of the saccharin are hydrogen bonded to the carbonyl of the carbamazepine on each side forming a tetramer.
  • the crystal has a space group of P-1 with ⁇ - ⁇ interactions between the phenyl groups of the carbamazepine and the saccharin phenyl groups.
  • PXRD derived from the single crystal data, experimental (calculated): 6.9 (7.0); 12.2 (12.2); 13.6 (13.8); 14.0 (14.1); 14.1 (14.4); 15.3 (15.6); 15.9 (15.9); 18.1 (18.2); 18.7 (18.8); 20.2 (20.3); 21.3 (21.5); 23.7 (23.9); 26.3 (26.4); 28.3 (28.3).
  • Crystal packing Each hydrogen on the carbamazepine 1° amine is hydrogen bonded to a carbonyl group of a different 2,6-pyridinedicarboxylic acid moiety.
  • the carbonyl of the carbamazepine carboxamide is hydrogen bonded to two hydroxide groups of one 2,6-pyridinedicarboxylic acid moiety.
  • Crystal packing The co-crystals are sustained by hydrogen bonded carboxylic acid homodimers between the two 5-nitroisophthalic acid moieties and hydrogen bonded carboxy-amide heterodimers between the carbamazepine and 5-nitroisophthalic acid moiety. There is solvent hydrogen bonded to an additional N-H donor from the carbamazepine moiety.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA). 32.02% weight loss starting at 202 degrees C, a 12.12% weight loss starting at 224 degrees C and a 17.94% weight loss starting at 285 degrees C followed by complete decomposition.
  • PXRD Showed analogous peaks to the simulated PXRD derived from the single crystal data.
  • PXRD analysis experimental (calculated): 10.138 (10.283), 15.291 (15.607), 17.438 (17.791), 21.166 (21.685), 31.407 (31.738), 32.650 (32.729).
  • Crystal packing The co-crystals form a single 3D network of four tetrahedron, linked by square planes similar to the PtS topology. The crystals are sustained by hydrogen bonding.
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers. Each 1° amine on the carbamazepine is bifurcated to a carbonyl group of a benzoquinone moiety. The dimers form infinite chains.
  • Crystal packing The co-crystals are sustained by hydrogen bonded carboxylic acid homodimers between carbamazepine and trimesic acid moieties and hydrogen bonded carboxylic acid-amine heterodimers between two trimesic acid moieties arranged in a stacked ladder formation.
  • Thermogravimetric Analysis (TA Instruments 2950 Hi-Resolution TGA). 62.83%o weight loss starting at 253 degrees C and a 30.20% weight loss starting at 278 degrees C followed by complete decomposition.
  • PXRD analysis experimental 10.736, 12.087, 16.857, 24.857, 27.857.
  • DSC Two endothermic transitions at about 117 and 119 degrees C and a sharp endotherm at about 130 degrees C
  • TGA Decomposition beginning at about 150 degrees
  • TGA Decomposition above 200 degrees C with a 25% weight loss between about 190-
  • TGA Rapid decomposition beginning at about 135 degrees C and leveling off slightly after 200 degrees C
  • TGA 29.09 percent weight loss starting at about 193 degrees C, 48.72 percent weight loss starting at about 238 degrees C, 18.38 percent weight loss starting at about 260 degrees C
  • TGA 9 percent weight loss starting at about 23 degrees C, 49.06 percent weight loss starting at about 103 degrees C, decomposition starting at about 209 degrees C
  • PXRD 16.8, 17.1, 18.1, 19.0, 20.0, 21.3, 22.7, 25.0, 26.0, 26.1, 28.2, 29.1
  • TGA 30.93 percent weight loss starting at about 31 degrees C, 46.26 percent weight loss starting at about 169 degrees C
  • TGA 17.66 percent weight loss starting at about 30 degrees C, 17.57 percent weight loss starting at about 100 degrees C
  • TGA Decomposition beginning at about 150 degrees
  • TGA 3.342 percent weight loss starting at about 67 degrees C, 55.09 percent weight loss starting at about 119 degrees C
  • TGA 32.02 percent weight loss starting at about 202 degrees C, 12.12 percent weight loss starting at about 224 degrees C, 17.94 percent weight loss starting at about 285 degrees C
  • TGA 9 percent weight loss starting at about 189 degrees C, 52 percent weight loss starting at about 251 degrees C, 31 percent weight loss starting at about 374 degrees C
  • TGA 20.62 percent weight loss starting at about 168 degrees C, 78 percent weight loss starting at about 223 degrees C
  • TGA 62.83 percent weight loss starting at about 253 degrees C, 30.20 percent weight loss starting at about 278 degrees C
  • a co-crystal with a modulated dissolution profile has been prepared.
  • Celecoxib nicotinamide co-crystals were prepared via methods shown in Example 1. (See Fig. 57)
  • a co-crystal with a modulated dissolution profile has been prepared, cis- Itraconazole: succinic acid, cw-itraconazolei-tartaric acid and czAitraconazole:L-malic acid co-crystals were prepared via methods shown in Examples 5, 7 and 8. (See Fig. 58)
  • a co-crystal of an unsaltable or difficult to salt API has been prepared.
  • Celecoxib nicotinamide co-crystals were prepared via methods shown in Example 1.
  • Example 34
  • a co-crystal with an improved hygroscopicity profile has been prepared.
  • Celecoxib nicotinamide co-crystals were prepared via methods shown in Example 1. (See Fig. 59)
  • a co-crystal with reduced form diversity as compared to the API has been prepared.
  • Co-crystals of carbamazepine and saccharin have been prepared via method shown in Example 25.
  • the formulation of a modafinil :malonic acid form I co-crystal was completed using lactose.
  • Two mixtures, one of modafinil and lactose, and the second of modafinil :malonic acid co-crystal and lactose, were ground together in a mortar an pestle.
  • the mixtures targeted a 1 :1 weight ratio of modafinil to lactose.
  • 901.2 mg of modafinil and 901.6 mg of lactose were ground together.
  • 1221.6 mg of co-crystal and 871.4 mg of lactose were ground together.
  • the resulting powders were analyzed by PXRD and DSC.
  • the PXRD patterns and DSC thermograms of the mixtures showed virtually no change upon comparison with both individual components.
  • the DSC of the co-crystal mixture showed only the co-crystal melting peak at 113.6 degrees C with a heat of fusion of 75.9 J/g. This heat of fusion is 59.5 % of that found for the co-crystal alone (127.5 J/g). This result is consistent with a 58.4 % weight ratio of co-crystal in the mixture.
  • the DSC of the modafinil and lactose mixture had a melting point of 165.7 degrees C. This is slightly lower then the measured melting point of modafinil (168.7 degrees C).
  • the heat of fusion of the mixture (59.3 J/g) is 46.9 % that of the modafinil alone (126.6 J/g), which is consistent with the estimated value of 50 %.
  • Modafinil and the modafinikmalonic acid form I co-crystal were passed through a 38 micrometer sieve.
  • Gelatin capsules Size 0, B&B Pharmaceuticals, Lot # 15-01202
  • Dissolution studies were performed in a Vankel VK 7000 Benchsaver Dissolution Testing Apparatus with the VK750D heater/circulator set at 37 degrees C. At 0 minutes, the capsules were dropped into vessels containing 900 mL 0.01 M HCl and stirred by paddles.
  • Absorbance readings were taken using a Cary 50 Spectrophotometer (wavelength set at 260nm) at the following time points: 0, 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes. The absorbance values were compared to those of standards and the modafinil concentrations of the solutions were calculated.
  • Modafinil and the modafinil :malonic acid form I co-crystal were mixed with equivalent amounts of lactose (Spectrum, Lot QV0460) for approximately 5 minutes.
  • Gelatin capsules Size 0, B&B Pharmaceuticals, Lot # 15-01202 were filled with 400.2 mg modafinil and lactose (approximately 200 mg modafinil), or 561.0 mg modafinil :malonic acid form I co-crystal and lactose (approximately 200 mg modafinil).
  • HPMC capsules (Size 0, Shionogi, Lot # A312A6) were filled with 399.9 mg modafinil and lactose, 560.9 mg modafinikmalonic acid co-crystal and lactose, 199.9 mg modafinil, or 280.5 mg modafinil :malonic acid form I co-crystal.
  • the dissolution study was carried out as described above.
  • the modafinikmalonic acid form I co-crystal (from Example 10) was administered to dogs in a pharmacokinetic study.
  • Particles of modafinil :malonic acid co- crystal with a median particle size of about 16 micrometers were administered in the study.
  • micronized modafinil with a median particle size of about 2 micrometers was also administered in the study.
  • the AUC of the modafinil :malonic acid co-crystal was determined to be 40 to 60 percent higher than that of the pure modafinil.
  • Such a higher bioavailability illustrates the modulation of an important pharmacokinetic parameter due to an embodiment of the present invention.
  • a compilation of important pharmacokinetic parameters measured during the animal study are included in Table XXV.
  • the increased half-life and bioavailability of modafinil in the malonic acid form I co-crystal may be due to the presence of malonic acid. It is believed that the malonic acid may be inhibiting one or more pathways responsible for the metabolism or elimination of modafinil. It is noted that modafinil and malonic acid share a similar structure: each including two carbonyl or sulfonyl groups separated by a -CH 2 - and each molecule is terminated with a group that is capable of participation in a hydrogen bond with an enzyme. Such a mechanism may take place with other APIs or co-crystal formers of similar structure.
  • the stability of the modafinikmalonic acid form I co-crystal was measured at various temperatures and relative humidities over a four week period. No degradation was found to occur at 20 or 0 degrees C. At 60 degrees C, about 0.14 percent degradation per day was determined based on a simple exponential model. At 80 degrees C, about 8 percent degradation per day was determined. TABLE I

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP04715190A 2003-02-28 2004-02-26 Pharmazeutische kokristallzusammensetzungen aus arzneistoffen wie carbamazepin, celecoxib, olanzapin, itraconazol, topiramat, modafinil, 5-fluoruracil, hydrochlorothazid, acetaminophen, aspirin, flurbiprofen, phenytoin und ibuprofen Withdrawn EP1631260A2 (de)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US45121303P 2003-02-28 2003-02-28
PCT/US2003/006662 WO2003074474A2 (en) 2002-03-01 2003-03-03 Multiple-component solid phases containing at least one active pharmaceutical ingredient
US45602703P 2003-03-18 2003-03-18
US46396203P 2003-04-18 2003-04-18
US10/449,307 US7078526B2 (en) 2002-05-31 2003-05-30 CIS-itraconazole crystalline forms and related processes, pharmaceutical compositions and methods
PCT/US2003/019574 WO2004000284A1 (en) 2002-06-21 2003-06-20 Pharmaceutical compositions with improved dissolution
US10/601,092 US20050025791A1 (en) 2002-06-21 2003-06-20 Pharmaceutical compositions with improved dissolution
US48706403P 2003-07-11 2003-07-11
PCT/US2003/027772 WO2004078161A1 (en) 2003-02-28 2003-09-04 Pharmaceutical co-crystal compositions of drugs such as carbamazeptine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
US10/660,202 US7927613B2 (en) 2002-02-15 2003-09-11 Pharmaceutical co-crystal compositions
US50820803P 2003-10-02 2003-10-02
PCT/US2003/041273 WO2004061433A1 (en) 2002-12-30 2003-12-24 Pharmaceutical compositions with improved dissolution
US54275204P 2004-02-06 2004-02-06
PCT/US2004/006288 WO2004078163A2 (en) 2003-02-28 2004-02-26 Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen

Publications (1)

Publication Number Publication Date
EP1631260A2 true EP1631260A2 (de) 2006-03-08

Family

ID=56290526

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04715190A Withdrawn EP1631260A2 (de) 2003-02-28 2004-02-26 Pharmazeutische kokristallzusammensetzungen aus arzneistoffen wie carbamazepin, celecoxib, olanzapin, itraconazol, topiramat, modafinil, 5-fluoruracil, hydrochlorothazid, acetaminophen, aspirin, flurbiprofen, phenytoin und ibuprofen

Country Status (4)

Country Link
EP (1) EP1631260A2 (de)
JP (1) JP2007524596A (de)
CA (1) CA2514733A1 (de)
WO (1) WO2004078163A2 (de)

Families Citing this family (404)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10129714A1 (de) 2001-06-22 2003-01-02 Bayer Ag Topische Anwendung von Thiazolylamiden
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
CA2477923C (en) 2002-03-01 2021-02-23 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
AU2003243354A1 (en) * 2002-05-31 2003-12-19 Transform Pharmaceuticals, Inc. Novel conazole crystalline forms and related processes, pharmaceutical compositions and methods
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
EP1670753A4 (de) * 2003-09-04 2008-01-02 Cephalon Inc Modafinil-zusammensetzungen
US7507823B2 (en) 2004-05-06 2009-03-24 Bristol-Myers Squibb Company Process of making aripiprazole particles
EP1765379A4 (de) * 2004-06-17 2009-05-27 Transform Pharmaceuticals Inc Pharmazeutische ko-kristallzusammensetzungen und relevante anwendungsverfahren
DE102005014248A1 (de) 2005-03-30 2006-10-05 Aicuris Gmbh & Co. Kg Pharmazeutische Zubereitung von N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamid
US20100221327A1 (en) * 2005-06-15 2010-09-02 Elan Pharma International Limited Nanoparticulate azelnidipine formulations
US20070099237A1 (en) * 2005-10-31 2007-05-03 The Regents Of The University Of Michigan Reaction co-crystallization of molecular complexes or co-crystals
AR057882A1 (es) 2005-11-09 2007-12-26 Novartis Ag Compuestos de accion doble de bloqueadores del receptor de angiotensina e inhibidores de endopeptidasa neutra
ES2412357T3 (es) * 2005-12-08 2013-07-11 New Form Pharmaceuticals Inc. Cocristales de metronidazol
WO2008027557A2 (en) 2006-08-31 2008-03-06 Spherics, Inc. Topiramate compositions and methods of enhancing its bioavailability
US20080132419A1 (en) * 2006-10-04 2008-06-05 Nair Rodriguez-Hornedo Dissolution and precipitation of cocrystals with ionizable components
WO2008063284A2 (en) * 2006-10-10 2008-05-29 Janssen Pharmaceutica Nv Novel crystal of (s)-(+)-2-(2-chlorophenyl)-2-hydroxy-ethyl carbamate
EP1973528B1 (de) 2006-11-17 2012-11-07 Supernus Pharmaceuticals, Inc. Verzögert freigesetzte formulierungen aus topiramat
TW200901889A (en) 2007-02-09 2009-01-16 Basf Se Crystalline complexes of agriculturally active organic compounds
WO2008108639A1 (en) * 2007-03-08 2008-09-12 Avantium Holding B.V. Co-crystalline forms of carbamazepine
EP2167043A4 (de) 2007-06-06 2013-05-01 Univ South Florida Neutrazeutische co-kristall-zusammensetzungen
WO2009094155A1 (en) * 2008-01-22 2009-07-30 Thar Pharmaceuticals In vivo studies of crystalline forms of meloxicam
US7935817B2 (en) 2008-03-31 2011-05-03 Apotex Pharmachem Inc. Salt form and cocrystals of adefovir dipivoxil and processes for preparation thereof
US8003700B2 (en) * 2008-04-07 2011-08-23 Mutual Pharamaceutical Company, Inc. Colchicine solid complex; methods of making; and methods of use thereof
US8519002B2 (en) 2008-04-07 2013-08-27 Takeda Pharmaceuticals U.S.A., Inc. Colchicine solid complex; methods of making; and methods of use thereof
WO2009140466A2 (en) * 2008-05-14 2009-11-19 Dr. Reddy's Laboratories Ltd. Linezolid co-crystals
EP2123626A1 (de) 2008-05-21 2009-11-25 Laboratorios del Dr. Esteve S.A. Duloxetin-Kokristalle und Kokristallbildner für Schmerzbehandlung
WO2009152347A2 (en) * 2008-06-13 2009-12-17 Bionevia Pharmaceuticals Inc. Crystalline forms of zotepine hydrochloride
US8258155B2 (en) 2008-06-30 2012-09-04 Mutual Pharmaceutical Company, Inc. Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof
US8697735B2 (en) 2008-07-25 2014-04-15 Bionevia Pharmaceuticals, Inc. Solid forms of epalrestat
GB0813709D0 (en) * 2008-07-26 2008-09-03 Univ Dundee Method and product
WO2010017343A2 (en) * 2008-08-06 2010-02-11 Bionevia Pharmaceuticals, Inc. Flupirtine hydrochloride maleic acid cocrystal
ES2639019T3 (es) 2008-09-06 2017-10-25 Bionevia Pharmaceuticals Inc. Nuevo cocristal de colina de epalrestat
EP2177215A1 (de) * 2008-10-17 2010-04-21 Laboratorios Del. Dr. Esteve, S.A. Co-Kristalle von Tramadol und NSARs
EP2199274A1 (de) * 2008-12-16 2010-06-23 Laboratorios Del. Dr. Esteve, S.A. Kokristalle von Tramadol und Paracetamol
WO2010074753A1 (en) 2008-12-23 2010-07-01 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
WO2010085589A2 (en) 2009-01-22 2010-07-29 G&H Brands Llc Desensitizing drug product
KR20100091127A (ko) * 2009-02-09 2010-08-18 주식회사 한독약품 아데포비어 디피복실의 신규한 염 및 그의 제조방법
JP5558875B2 (ja) * 2009-03-19 2014-07-23 日本曹達株式会社 新規包接錯体、エポキシ樹脂組成物及び半導体封止用エポキシ樹脂組成物
US20110182850A1 (en) 2009-04-10 2011-07-28 Trixi Brandl Organic compounds and their uses
US8512690B2 (en) 2009-04-10 2013-08-20 Novartis Ag Derivatised proline containing peptide compounds as protease inhibitors
PE20120403A1 (es) 2009-05-15 2012-05-03 Novartis Ag Aril-piridinas como inhibidoras de sintasa de aldosterona
ES2430088T3 (es) 2009-05-15 2013-11-18 Novartis Ag Derivados de benzoxazolona como inhibidores de aldosterona sintasa
EP2432320A4 (de) * 2009-05-20 2013-03-06 Nutracryst Therapeutics Private Ltd Pharmazeutische quercetin-cokristalle
WO2010136474A2 (en) 2009-05-28 2010-12-02 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
UY32662A (es) 2009-05-28 2010-12-31 Novartis Ag Derivados amino-propionicos sustituidos como inhibidores de neprilisina
AR077490A1 (es) 2009-07-21 2011-08-31 Novartis Ag Composiciones farmaceuticas topicas para el tratamiento de una condicion hiperproliferativa de la piel
UY32799A (es) 2009-07-24 2011-02-28 Novartis Ag Derivados de oxazina y su uso en el tratamiento de trastornos neurológicos
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US20160016982A1 (en) 2009-07-31 2016-01-21 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
JP5852569B2 (ja) 2009-07-31 2016-02-03 タール ファーマシューティカルズ，インコーポレイテッド 結晶化方法および生物学的利用能
EP2281558A1 (de) * 2009-08-06 2011-02-09 Laboratorios Del. Dr. Esteve, S.A. Pharmazeutische Verbindungen von O-Desmethyltramadol und COX-Inhibitoren
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
AU2010283806A1 (en) 2009-08-12 2012-03-01 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
BR112012008061A2 (pt) 2009-08-20 2016-03-01 Novartis Ag compostos de oxima heterocíclica
KR20120050492A (ko) 2009-08-26 2012-05-18 노파르티스 아게 테트라-치환된 헤테로아릴 화합물 및 ｍｄｍ2 및/또는 ｍｄｍ4 조절제로서의 그의 용도
WO2011026917A1 (en) 2009-09-04 2011-03-10 Novartis Ag Heteroaryl compounds as kinase inhibitors
KR20120092586A (ko) 2009-09-04 2012-08-21 노파르티스 아게 증식성 질환의 치료에 유용한 비피리딘
CN102482265A (zh) 2009-09-04 2012-05-30 诺瓦提斯公司 用于治疗增殖性疾病的吡嗪基吡啶化合物
US20120165310A1 (en) 2009-09-10 2012-06-28 Novartis Ag Ether derivatives of bicyclic heteroaryls
JP2013504536A (ja) 2009-09-10 2013-02-07 ノバルティス アーゲー 癌の処置のためのｂｃｌ−２ファミリータンパク質阻害剤としてのスルホンアミド類
EP2325172A1 (de) * 2009-11-02 2011-05-25 Laboratorios Del. Dr. Esteve, S.A. Co-Kristalle von Celecoxib und L-prolin
EA201200651A1 (ru) 2009-11-04 2012-12-28 Новартис Аг Гетероциклические сульфонамидные производные, применимые в качестве ингибиторов мек
EP2993169B1 (de) 2009-11-17 2017-12-20 Novartis AG Aryl-pyridin derivate als aldosteron synthase hemmer
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors
EP2507234B1 (de) 2009-11-30 2014-03-12 Novartis AG Imidazolderivate als aldosteron-synthasehemmer
WO2011073316A1 (en) 2009-12-18 2011-06-23 Novartis Ag 4-aryl-butane-1,3-diamides
CN102762560A (zh) 2009-12-21 2012-10-31 诺瓦提斯公司 二取代的杂芳基-稠合的吡啶
US8530648B2 (en) 2009-12-21 2013-09-10 Novartis Ag Diaza-spiro[5.5]undecanes
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
EP2519515B1 (de) 2009-12-31 2013-11-06 Novartis AG Pyrazinderivate und ihre verwendung bei der behandlung von nervenerkrankungen
WO2011092293A2 (en) 2010-02-01 2011-08-04 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
EP2531510B1 (de) 2010-02-01 2014-07-23 Novartis AG Pyrazolo-[5,1b-]oxazol-derivate als crf-1-rezeptor-antagonisten
US8835444B2 (en) 2010-02-02 2014-09-16 Novartis Ag Cyclohexyl amide derivatives as CRF receptor antagonists
US8791100B2 (en) 2010-02-02 2014-07-29 Novartis Ag Aryl benzylamine compounds
US8399712B2 (en) * 2010-02-03 2013-03-19 Laurus Labs Private Limited Pterostilbene cocrystals
UY33236A (es) 2010-02-25 2011-09-30 Novartis Ag Inhibidores dimericos de las iap
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
AR082453A1 (es) 2010-04-21 2012-12-12 Novartis Ag Compuestos de furopiridina, composiciones farmaceuticas que los contienen y usos de los mismos
US8779146B2 (en) 2010-04-28 2014-07-15 Nuformix Limited Cilostazol cocrystals and compositions
US20130053381A1 (en) 2010-05-20 2013-02-28 Novartis Ag 2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl-sulfonamide derivatives
JP2013532149A (ja) 2010-06-17 2013-08-15 ノバルティス アーゲー ピペリジニル置換１，３−ジヒドロ−ベンゾイミダゾール−２−イリデンアミン誘導体
CN102947274A (zh) 2010-06-17 2013-02-27 诺瓦提斯公司 联苯基取代的1,3-二氢-苯并咪唑-2-亚基胺衍生物
UY33469A (es) 2010-06-29 2012-01-31 Irm Llc Y Novartis Ag Composiciones y metodos para modular la via de señalizacion de wnt
UA112517C2 (uk) 2010-07-06 2016-09-26 Новартіс Аг Тетрагідропіридопіримідинові похідні
KR101391041B1 (ko) 2010-07-13 2014-05-07 노파르티스 아게 옥사진 유도체, 및 신경계 장애의 치료에 있어서의 그의 용도
KR101491938B1 (ko) 2010-07-14 2015-02-10 노파르티스 아게 Ｉｐ 수용체 효능제 헤테로시클릭 화합물
MA34462B1 (fr) 2010-07-22 2013-08-01 Novartis Ag Composes de thiophene 2,3,5- trisubstitues et leurs utilisations
US9290485B2 (en) 2010-08-04 2016-03-22 Novartis Ag N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
PL2616465T3 (pl) 2010-09-13 2016-04-29 Novartis Ag Triazyno-oksadiazole
US8372845B2 (en) 2010-09-17 2013-02-12 Novartis Ag Pyrazine derivatives as enac blockers
ES2610360T3 (es) 2010-09-20 2017-04-27 Ironwood Pharmaceuticals, Inc. Compuestos de imidazotriazinona
KR20130120481A (ko) 2010-10-08 2013-11-04 노파르티스 아게 술파미드 ｎｓ3 억제제의 비타민 ｅ 제제
US20120101110A1 (en) 2010-10-26 2012-04-26 Sangamesh Badiger Diaza-spiro[5.5]undecanes
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
UY33794A (es) 2010-12-13 2012-07-31 Novartis Ag Inhibidores diméricos de las iap
WO2012080260A1 (en) 2010-12-13 2012-06-21 Novartis Ag Dimeric iap inhibitors
US20130274294A1 (en) 2010-12-20 2013-10-17 David Carcache 4-(Hetero)Aryl-Ethynyl-Octahydro-Indole-1-Esters
EP2655369A1 (de) 2010-12-20 2013-10-30 Irm Llc Zusammensetzungen und verfahren zur modulierung von farnesoid-x-rezeptoren
CU24152B1 (es) 2010-12-20 2016-02-29 Irm Llc 1,2 oxazol-8-azabiciclo[3,2,1]octano 8 il como moduladores de fxr
WO2012087520A1 (en) 2010-12-20 2012-06-28 Irm Llc Compositions and methods for modulating farnesoid x receptors
US20120165331A1 (en) 2010-12-22 2012-06-28 Sangamesh Badiger Di/tri-aza-spiro-C9-C11alkanes
MX347391B (es) 2011-01-04 2017-04-25 Novartis Ag Compuestos de indol o análogos de los mismos útiles para el tratamiento de degeneración macular relacionada con la edad (amd).
JP2014505688A (ja) 2011-01-12 2014-03-06 ノバルティス アーゲー オキサジン誘導体および神経障害の処置におけるその使用
CN103596569A (zh) 2011-01-13 2014-02-19 诺瓦提斯公司 用于治疗代谢障碍的bace-2抑制剂
MX336966B (es) 2011-01-13 2016-02-08 Novartis Ag Novedosos derivados y su uso en el tratamiento de transtornos neurologicos.
WO2012098501A1 (en) * 2011-01-21 2012-07-26 Ranbaxy Laboratories Limited Febuxostat co-crystals
EP2668159A1 (de) 2011-01-24 2013-12-04 Novartis AG 4-tolyl-ethynyl-octahydro-indol-1-ester-derivate
WO2012101064A1 (en) 2011-01-28 2012-08-02 Novartis Ag N-acyl pyrimidine biaryl compounds as protein kinase inhibitors
WO2012101063A1 (en) 2011-01-28 2012-08-02 Novartis Ag N-acyl pyridine biaryl compounds and their uses
WO2012101065A2 (en) 2011-01-28 2012-08-02 Novartis Ag Pyrimidine biaryl amine compounds and their uses
WO2012101066A1 (en) 2011-01-28 2012-08-02 Novartis Ag Pyridine biaryl amine compounds and their uses
PT2670753T (pt) 2011-01-31 2017-01-10 Novartis Ag Novos derivados heterocíclicos
WO2012104823A2 (en) 2011-02-04 2012-08-09 Novartis Ag Pyridopyrimidinone compounds in the treatment of neurodegenerative diseases
US20130324526A1 (en) 2011-02-10 2013-12-05 Novartis Ag [1,2,4] triazolo [4,3-b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
AU2012220572A1 (en) 2011-02-25 2013-08-29 Irm Llc Compounds and compositions as trk inhibitors
GB201103578D0 (en) 2011-03-02 2011-04-13 Sabrepharm Ltd Dipyridinium derivatives
CN103492390A (zh) 2011-03-08 2014-01-01 诺瓦提斯公司 氟苯基双环杂芳基化合物
JP2014508814A (ja) * 2011-03-24 2014-04-10 ユニバーシティ・オブ・サウス・フロリダ リチウム組成物
US8748435B2 (en) 2011-04-01 2014-06-10 Novartis Ag Pyrazolo pyrimidine derivatives
WO2012138648A1 (en) 2011-04-06 2012-10-11 Irm Llc Compositions and methods for modulating lpa receptors
US8614195B2 (en) 2011-04-14 2013-12-24 Novartis Ag Glycoside derivatives and uses thereof
KR20140019834A (ko) 2011-04-14 2014-02-17 노파르티스 아게 글리코시드 유도체 및 그의 용도
RS52982B (en) * 2011-04-28 2014-02-28 Zentiva, K.S. PHARMACEUTICAL ACCEPTIBLE CO-CRYSTALS OF N- [2- (7-METHOXY-1-NAPHTHYL) ACETAMIDE AND THEIR MAKING PROCEDURES
UY34072A (es) 2011-05-17 2013-01-03 Novartis Ag Derivados sustituidos de indol
AR086554A1 (es) 2011-05-27 2014-01-08 Novartis Ag Derivados de la piperidina 3-espirociclica como agonistas de receptores de la ghrelina
EP2721008B1 (de) 2011-06-20 2015-04-29 Novartis AG Hydroxy substituierte isochinolinone als p53 (mdm2 or mdm4) inhibitoren
WO2012175487A1 (en) 2011-06-20 2012-12-27 Novartis Ag Cyclohexyl isoquinolinone compounds
PL2729142T3 (pl) 2011-07-08 2018-10-31 Novartis Ag Sposób leczenia miażdżycy tętnic u osobników z wysokim poziomem triglicerydów
JP6047563B2 (ja) 2011-07-08 2016-12-21 ノバルティス アーゲー 新規トリフルオロメチル−オキサジアゾール誘導体および疾患の治療におけるその使用
EP2729466B1 (de) 2011-07-08 2015-08-19 Novartis AG Neuartige pyrrolopyrimidinderivate
US8846656B2 (en) 2011-07-22 2014-09-30 Novartis Ag Tetrahydropyrido-pyridine and tetrahydropyrido-pyrimidine compounds and use thereof as C5a receptor modulators
ES2551923T3 (es) 2011-07-27 2015-11-24 Novartis Ag Derivados de pirazolina y su uso como moduladores selectivos de receptores de andrógenos
UY34278A (es) 2011-08-25 2013-04-05 Novartis Ag Derivados novedosos de oxazina y su uso en el tratamiento de enfermedades
EP2751104B1 (de) 2011-09-01 2019-09-25 Novartis AG Verbindungen und zusammensetzungen als c-kit-kinasehemmer
CA2845791A1 (en) 2011-09-01 2013-03-07 Irm Llc Compounds and compositions as c-kit kinase inhibitors
UY34305A (es) 2011-09-01 2013-04-30 Novartis Ag Derivados de heterociclos bicíclicos para el tratamiento de la hipertensión arterial pulmonar
EA201490537A1 (ru) 2011-09-01 2014-07-30 АйАрЭм ЭлЭлСи СОЕДИНЕНИЯ И КОМПОЗИЦИИ В КАЧЕСТВЕ ИНГИБИТОРОВ КИНАЗЫ C-Kit
US20140206682A1 (en) 2011-09-01 2014-07-24 Novartis Pharmaceuticals Uk Limited Compounds and compositions as pdgfr kinase inhibitors
US9199981B2 (en) 2011-09-01 2015-12-01 Novartis Ag Compounds and compositions as C-kit kinase inhibitors
JO3192B1 (ar) 2011-09-06 2018-03-08 Novartis Ag مركب بنزوثيازولون
US9062045B2 (en) 2011-09-15 2015-06-23 Novartis Ag Triazolopyridine compounds
WO2013038378A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
WO2013038381A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine/pyrazine amide derivatives
US9034879B2 (en) 2011-09-16 2015-05-19 Novartis Ag Heterocyclic compounds for the treatment of CF
JP6165733B2 (ja) 2011-09-16 2017-07-19 ノバルティス アーゲー Ｎ−置換ヘテロシクリルカルボキサミド類
WO2013038373A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
TW201321353A (zh) 2011-10-08 2013-06-01 Novartis Ag 胺基甲酸酯／尿素衍生物
IN2014DN03206A (de) 2011-10-13 2015-05-22 Novartis Ag
TWI580442B (zh) 2011-10-19 2017-05-01 傑特大學 醫藥毫微懸浮物
EP2768813A1 (de) 2011-10-21 2014-08-27 Novartis AG Chinazolinderivate als pi3k-modulatoren
CN104039790B (zh) 2011-10-28 2016-04-13 诺华股份有限公司 嘌呤衍生物及它们在治疗疾病中的应用
WO2013076659A1 (en) 2011-11-25 2013-05-30 Nuformix Limited Aprepitant l-proline solvates - compositions and cocrystals
BR112014012815A8 (pt) 2011-11-28 2017-06-20 Novartis Ag derivados de trifluormetil-oxadiazol e uso dos mesmos no tratamento de doença
WO2013080141A1 (en) 2011-11-29 2013-06-06 Novartis Ag Pyrazolopyrrolidine compounds
PT2794600T (pt) 2011-12-22 2018-03-13 Novartis Ag Derivados de 2,3-di-hidro-benzo[1,4]oxazina e compostos relacionados como inibidores de fosfoinositídeo-3-cinase (pi3k) para o tratamento de, por exemplo, artrite reumatoide
WO2013093850A1 (en) 2011-12-22 2013-06-27 Novartis Ag Quinoline derivatives
EP2802583A1 (de) 2012-01-13 2014-11-19 Novartis AG Anellierte piperidine als ip-rezeptoragonisten zur behandlung von pulmonaler arterieller hypertonie (pah) und verwandten erkrankungen
US20140357641A1 (en) 2012-01-13 2014-12-04 Novartis Ag IP receptor agonist heterocyclic compounds
EP2802581A1 (de) 2012-01-13 2014-11-19 Novartis AG 7,8-dihydropyrido-[3,4, b-]pyrazine als ip-rezeptoragonisten zur behandlung von pulmonaler arterieller hypertonie (pah) und zugehörigen erkrankungen
US8937069B2 (en) 2012-01-13 2015-01-20 Novartis Ag Substituted pyrrolo[2,3-B]pyrazine compounds and their use
EP2802585A1 (de) 2012-01-13 2014-11-19 Novartis AG Kondensierte piperidine als ip-rezeptoragonisten zur behandlung von pah und verwandten erkrankungen
UY34591A (es) 2012-01-26 2013-09-02 Novartis Ag Compuestos de imidazopirrolidinona
WO2013111108A1 (en) 2012-01-27 2013-08-01 Novartis Ag 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors
EP2807156A1 (de) 2012-01-27 2014-12-03 Novartis AG Aminopyridinderivate als plasma-kallikrein-inhibitoren
UY34646A (es) 2012-03-02 2013-10-31 Novartis Ag Compuestos de espirohidantoína y su uso como moduladores selectivos del receptor de andrógenos
EP2828262A4 (de) 2012-03-19 2015-09-23 Forum Pharmaceuticals Inc Imidazotriazinonverbindungen
PE20150724A1 (es) 2012-04-27 2015-05-17 Novartis Ag Inhibidores de dgat1 de eter ciclico de cabeza de puente
WO2013163508A1 (en) 2012-04-27 2013-10-31 Novartis Ag Tetrahydropyran dgat1 inhibitors
SG11201405810UA (en) 2012-05-03 2014-11-27 Novartis Ag L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists
TW201348199A (zh) 2012-05-04 2013-12-01 Novartis Ag 補體路徑調節劑及其用途
UY34807A (es) 2012-05-16 2013-12-31 Novartis Ag Derivados monocíclicos de heteroarilcicloalquil- diamina
US9365576B2 (en) 2012-05-24 2016-06-14 Novartis Ag Pyrrolopyrrolidinone compounds
JP2015518895A (ja) 2012-06-06 2015-07-06 アイアールエム・リミテッド・ライアビリティ・カンパニーＩｒｍ，Ｌｌｃ Ｅｇｆｒ活性を調節するための化合物および組成物
JO3300B1 (ar) 2012-06-06 2018-09-16 Novartis Ag مركبات وتركيبات لتعديل نشاط egfr
CA2876539A1 (en) * 2012-06-15 2013-12-19 Basf Se Multicomponent crystals comprising dasatinib and selected co-crystal formers
WO2013192345A1 (en) 2012-06-20 2013-12-27 Novartis Ag Complement pathway modulators and uses thereof
EP2864313A1 (de) 2012-06-22 2015-04-29 Basf Se Mehrkomponentenkristalle mit imatinib-mesilat und ausgewählte co-kristall-former
EP2867227B1 (de) 2012-06-28 2018-11-21 Novartis AG Modulatoren des komplementweges und verwendungen davon
JP6209605B2 (ja) 2012-06-28 2017-10-04 ノバルティス アーゲー ピロリジン誘導体、および補体経路調節因子としてのその使用
CN105121429B (zh) 2012-06-28 2017-12-12 诺华股份有限公司 补体途径调节剂和其用途
CN104583193A (zh) 2012-06-28 2015-04-29 诺华股份有限公司 吡咯烷衍生物及其作为补体途径调节剂的用途
JP6154897B2 (ja) 2012-06-28 2017-06-28 ノバルティス アーゲー ピロリジン誘導体、および補体経路調節因子としてのその使用
WO2014002054A1 (en) 2012-06-28 2014-01-03 Novartis Ag Pyrrolidine derivatives and their use as complement pathway modulators
KR20150036481A (ko) 2012-07-12 2015-04-07 노파르티스 아게 보체 경로 조절제 및 그의 용도
US9034874B2 (en) 2012-07-20 2015-05-19 Novartis Ag Carbamate/urea derivatives
KR101303803B1 (ko) 2012-08-02 2013-09-04 순천향대학교 산학협력단 반용매법에 의한 카바마제핀-사카린 공결정의 제조 방법 및 제조된 공결정을 포함하는 조성물
JP6236083B2 (ja) 2012-08-13 2017-11-22 ノバルティス ティーアゲズントハイト アーゲー 脾臓チロシンキナーゼ（ｓｙｋ）の阻害剤としての二環式ヘテロアリールシクロアルキルジアミン誘導体
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
HUE033655T2 (en) 2012-08-30 2017-12-28 Novartis Ag Benzothiazolone Compounds with Beta-2-Adrenoceptor Effects
WO2014033631A1 (en) 2012-08-31 2014-03-06 Novartis Ag N-(3-pyridyl) biarylamides as kinase inhibitors
ES2671478T3 (es) 2012-08-31 2018-06-06 Novartis Ag Derivados de 2'-etinil nucleósidos para el tratamiento de infecciones virales
WO2014033630A1 (en) 2012-08-31 2014-03-06 Novartis Ag Novel aminothiazole carboxamides as kinase inhibitors
EA028093B1 (ru) 2012-09-07 2017-10-31 Новартис Аг Индолкарбоксамидные производные и их применение
MX2015003535A (es) 2012-09-19 2015-07-14 Novartis Ag Dihidro-pirrolidino-pirimidinas como inhibidoras de cinasa.
US20150216867A1 (en) 2012-09-25 2015-08-06 Novartis Ag Compounds for use in gastric complication
WO2014052619A1 (en) 2012-09-27 2014-04-03 Irm Llc Piperidine derivatives and compositions as modulators of gpr119 activity
JP2015532277A (ja) 2012-09-29 2015-11-09 ノバルティス アーゲー 環状ペプチドおよび医薬としてのその使用
ES2644758T3 (es) 2012-10-16 2017-11-30 Tolero Pharmaceuticals, Inc. Moduladores de PKM2 y métodos para su uso
US20150284364A1 (en) 2012-11-07 2015-10-08 Nicole Bieri Substituted indole derivatives
US9296733B2 (en) * 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
EP2920177A1 (de) 2012-11-19 2015-09-23 Novartis AG Verbindungen und zusammensetzungen zur behandlung von parasitenerkrankungen
RS56720B1 (sr) 2012-11-19 2018-03-30 Novartis Ag Jedinjenja i kompozicije za lečenje parazitskih oboljenja
US20140205566A1 (en) 2012-11-30 2014-07-24 Novartis Ag Cyclic nucleuoside derivatives and uses thereof
MX363437B (es) 2012-12-13 2019-03-22 Novartis Ag Pirimido-4,5-b]-quinolina-4,5 (3h,10h)-dionas como supresoras de mutacion sin sentido.
WO2014093606A1 (en) 2012-12-13 2014-06-19 Novartis Ag Pyridone derivatives and uses thereof in the treatment of tuberculosis
EP2935249B1 (de) 2012-12-19 2018-12-12 Novartis AG Autotaxinhemmer
MX2015007940A (es) 2012-12-19 2016-03-11 Novartis Ag Compuestos tricíclicos como inhibidores de cftr.
BR112015014292A2 (pt) 2012-12-19 2017-07-11 Novartis Ag compostos tricíclicos para inibição do canal de cftr
US20150336960A1 (en) 2012-12-19 2015-11-26 Novartis Ag Aryl-substituted fused bicyclic pyridazine compounds
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
WO2014115080A1 (en) 2013-01-22 2014-07-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
EP2956455B1 (de) 2013-02-13 2017-05-17 Novartis AG Als ip-rezeptor-agonisten wirkende heterocyclische verbindungen
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
AU2014222362B2 (en) 2013-02-28 2016-07-21 Novartis Ag Formulation comprising benzothiazolone compound
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9475806B2 (en) 2013-03-14 2016-10-25 Novartis Ag Complement factor B inhibitors and uses there of
UY35400A (es) 2013-03-15 2014-10-31 Novartis Ag Compuestos y composiciones para el tratamiento de enfermedades parasitarias
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
WO2014151729A1 (en) 2013-03-15 2014-09-25 Irm Llc Compounds and compositions for the treatment of parasitic diseases
WO2014160649A1 (en) 2013-03-29 2014-10-02 Novartis Ag Hydroxamic acid derivatives as lpxc inhibitors for the treatment of bacterial infections
WO2014167528A1 (en) 2013-04-11 2014-10-16 Novartis Ag Spiropyrazolopyridine derivatives and uses thereof for the treatment of viral infections
WO2014178040A1 (en) 2013-04-29 2014-11-06 Mapi Pharma Ltd. Co-crystals of dapagliflozin
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
US8975417B2 (en) 2013-05-27 2015-03-10 Novartis Ag Pyrazolopyrrolidine derivatives and their use in the treatment of disease
EA029312B1 (ru) 2013-05-27 2018-03-30 Новартис Аг Производные имидазопирролидинона и их применение при лечении заболеваний
ES2656471T3 (es) 2013-05-28 2018-02-27 Novartis Ag Derivados de pirazolo-pirrolidin-4-ona como inhibidores de BET y su uso en el tratamiento de enfermedades
AU2014272700B2 (en) 2013-05-28 2016-12-01 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
JO3425B1 (ar) 2013-07-15 2019-10-20 Novartis Ag مشتقات البابيريدينيل-اندول واستخدامها كعامل متمم لمثبطات b
US20160168119A1 (en) 2013-07-18 2016-06-16 Novartis Ag Autotaxin inhibitors
PE20160521A1 (es) 2013-07-18 2016-05-20 Novartis Ag Inhibidores de autotaxina que comprenden un nucleo ciclico de anillo heteroaromatico-bencil-amida
CN105636953B (zh) 2013-07-31 2018-01-02 诺华股份有限公司 1,4‑二取代的哒嗪衍生物及其用于治疗与smn缺乏相关的病症的用途
EP3060563B1 (de) 2013-10-25 2018-05-02 Novartis AG Ringkondensierte bicyclische pyridylderivate als fgfr4-inhibitoren
CN105849090A (zh) 2013-10-30 2016-08-10 诺华股份有限公司 2-苄基-苯并咪唑补体因子b抑制剂及其用途
WO2015066413A1 (en) 2013-11-01 2015-05-07 Novartis Ag Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections
CN105658646B (zh) 2013-11-01 2018-11-27 诺华股份有限公司 作为激酶抑制剂的氨基杂芳基苯甲酰胺
AU2014346476B2 (en) * 2013-11-11 2019-01-24 Collaborative Medicinal Development, Llc Metal complexes and methods of treatment
US9550796B2 (en) 2013-11-21 2017-01-24 Novartis Ag Pyrrolopyrrolone derivatives and their use as BET inhibitors
US9512084B2 (en) 2013-11-29 2016-12-06 Novartis Ag Amino pyrimidine derivatives
CN105899526A (zh) 2013-12-17 2016-08-24 诺华股份有限公司 细胞毒性肽和其缀合物
MA39186A1 (fr) 2013-12-19 2017-11-30 Novartis Ag Dérivés de [1,2,4]triazolo[1,5-a]pyrimidine utilisés comme inhibiteurs du protéasome des protozoaires pour le traitement de maladies parasitaires comme la leishmaniose
BR112016011170B1 (pt) 2013-12-20 2023-01-10 Novartis Ag Derivados de ácido heteroaril butanóico, seus usos, combinação e composição farmacêutica
WO2015102929A1 (en) 2013-12-30 2015-07-09 Novartis Ag Tricyclic sulfonamide derivatives
CU24441B1 (es) 2014-03-24 2019-09-04 Novartis Ag Compuestos orgánicos de monobactam para el tratamiento de infecciones bacterianas
US9255093B2 (en) 2014-04-17 2016-02-09 Novartis Ag Polycyclic HERG activators
ES2687393T3 (es) 2014-04-22 2018-10-25 Novartis Ag Derivados del ácido hidroxámico de isoxazolina como inhibidores de LpxC
EP3134397A1 (de) 2014-04-24 2017-03-01 Novartis AG Aminopyrazinderivate als phosphatidylinositol-3-kinasehemmer
BR112016023967A2 (pt) 2014-04-24 2017-08-15 Novartis Ag derivados de pirazina como inibidores de fosfatidilinositol 3-cinase
WO2015162558A1 (en) 2014-04-24 2015-10-29 Novartis Ag Autotaxin inhibitors
EP3134396B1 (de) 2014-04-24 2019-09-18 Novartis AG Aminopyridinderivate als phosphatidylinositol-3-kinase-hemmer
WO2015175487A1 (en) 2014-05-13 2015-11-19 Novartis Ag Compounds and compositions for inducing chondrogenesis
US20170088545A1 (en) 2014-05-14 2017-03-30 Novartis Ag Carboxamide inhibitors
TW201623288A (zh) 2014-05-14 2016-07-01 諾華公司 甲醯胺衍生物
TW201946921A (zh) 2014-05-14 2019-12-16 瑞士商諾華公司 甲醯胺衍生物
WO2015173659A2 (en) 2014-05-14 2015-11-19 Novartis Ag Carboxamide derivatives
CA2945077A1 (en) 2014-05-28 2015-12-03 Novartis Ag Novel pyrazolo pyrimidine derivatives and their use as malt1 inhibitors
US9884862B2 (en) 2014-06-03 2018-02-06 Novartis Ag Pyridopyrimidinedione derivatives
WO2015186062A1 (en) 2014-06-03 2015-12-10 Novartis Ag PYRIMIDO[4,5-b]QUINOLINE-4,5(3H,10H)-DIONE DERIVATIVES
AU2015270125B2 (en) 2014-06-03 2017-10-19 Novartis Ag Naphthyridinedione derivatives
BR112016028835A2 (pt) 2014-06-13 2017-10-24 Novartis Ag derivados de auristatina e conjugados dos mesmos
TW201625584A (zh) 2014-07-02 2016-07-16 諾華公司 茚滿及吲哚啉衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
TW201625601A (zh) 2014-07-02 2016-07-16 諾華公司 噻吩－２－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
TW201625586A (zh) 2014-07-02 2016-07-16 諾華公司 環己烯－１－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
EP3177593A1 (de) 2014-08-06 2017-06-14 Novartis AG Chinolon-derivate als antibakterielle mittel
JP6646044B2 (ja) 2014-09-12 2020-02-14 ノバルティス アーゲー キナーゼ阻害剤としての化合物および組成物
JP6636014B2 (ja) 2014-09-12 2020-01-29 ノバルティス アーゲー Ｒａｆキナーゼ阻害剤としての化合物および組成物
UY36294A (es) 2014-09-12 2016-04-29 Novartis Ag Compuestos y composiciones como inhibidores de quinasa
WO2016049266A1 (en) * 2014-09-24 2016-03-31 Pain Therapeutics, Inc. 4:3 naltrexone: 5-methyl-2-furaldehyde cocrystal
PL3200786T3 (pl) 2014-10-03 2020-03-31 Novartis Ag Zastosowanie pochodnych pirydylowych o skondensowanym układzie bicyklicznym jako inhibitorów fgfr4
WO2016079669A1 (en) 2014-11-19 2016-05-26 Novartis Ag Labeled amino pyrimidine derivatives
WO2016088082A1 (en) 2014-12-05 2016-06-09 Novartis Ag Amidomethyl-biaryl derivatives complement factor d inhibitors and uses thereof
CN107001295B (zh) 2014-12-16 2021-02-02 诺华股份有限公司 作为LpxC抑制剂的异噁唑异羟肟酸化合物
EP3237418B1 (de) 2014-12-23 2019-01-30 Novartis AG Triazolopyrimidinverbindungen und verwendungen davon
BR112017016817A2 (pt) 2015-03-25 2018-04-03 Novartis Ag derivados heterocíclicos formilados como inibidores de fgfr4
ES2876974T3 (es) 2015-04-07 2021-11-15 Novartis Ag Combinación de terapia con receptor de antígeno quimérico y derivados de amino pirimidina
US10351576B2 (en) 2015-04-30 2019-07-16 Novartis Ag Fused tricyclic pyrazole derivatives useful for farnesoid X receptors
EP3310813A1 (de) 2015-06-17 2018-04-25 Novartis AG Antikörper-wirkstoff-konjugate
KR20180018800A (ko) * 2015-06-19 2018-02-21 신-낫 프로덕츠 엔터프라이즈 엘엘씨 카보플라틴 계 공-결정의 약제학적 조성물 및 이의 용도
CN107847521A (zh) * 2015-06-25 2018-03-27 新纳特产品公司 药物共晶组合物及其用途
CA2999268A1 (en) 2015-09-24 2017-03-30 Pain Therapeutics, Inc. Cocrystals of naloxone and naltrexone
GB2543550A (en) 2015-10-21 2017-04-26 Hox Therapeutics Ltd Peptides
SG11201803480WA (en) 2015-11-13 2018-05-30 Novartis Ag Novel pyrazolo pyrimidine derivatives
DK3380465T3 (da) 2015-11-26 2020-10-26 Novartis Ag Diaminopyridinderivativer
CN105399664A (zh) * 2015-12-11 2016-03-16 吉林大学珠海学院 以2,5-二羟基苯甲酸为前驱体的去铁酮药物共晶及其制备方法
CN105541701A (zh) * 2015-12-11 2016-05-04 吉林大学珠海学院 以顺丁烯二酸为前驱体的去铁酮药物共晶及其制备方法
CN105399665A (zh) * 2015-12-11 2016-03-16 吉林大学珠海学院 以对羟基苯甲酸为前驱体的去铁酮药物共晶及其制备方法
HUP1500618A2 (en) 2015-12-16 2017-06-28 Druggability Tech Ip Holdco Ltd Complexes of celecoxib and its salts and derivatives, process for the preparation thereof and pharmaceutical composition containing them
RU2018126349A (ru) 2015-12-18 2020-01-20 Новартис Аг Индановые производные и их применение в качестве активаторов растворимой гуанилатциклазы
WO2017103824A1 (en) 2015-12-18 2017-06-22 Novartis Ag Tricyclic compounds and compositions as kinase inhibitors
EP3405468A1 (de) 2016-01-21 2018-11-28 Novartis AG Verbindungen und zusammensetzungen zur behandlung von kryptosporidiose
US9845325B2 (en) 2016-02-19 2017-12-19 Novartis Ag Tetracyclic pyridone compounds as antivirals
ES2831832T3 (es) 2016-03-01 2021-06-09 Novartis Ag Compuestos de indol ciano-sustituidos y usos de los mismos como inhibidores de LSD1
US10858366B2 (en) 2016-03-08 2020-12-08 Novartis Ag Tricyclic compounds useful to treat orthomyxovirus infections
CN109311885A (zh) 2016-03-24 2019-02-05 诺华股份有限公司 炔基核苷类似物作为人类鼻病毒的抑制剂
WO2017175185A1 (en) 2016-04-08 2017-10-12 Novartis Ag Heteroaryl butanoic acid derivatives as lta4h inhibitors
WO2017208070A1 (en) 2016-05-31 2017-12-07 Grünenthal GmbH Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis
WO2017216685A1 (en) 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2017216686A1 (en) 2016-06-16 2017-12-21 Novartis Ag 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals
ES2798424T3 (es) 2016-06-20 2020-12-11 Novartis Ag Compuestos de triazolopiridina y usos de estos
ES2975263T3 (es) 2016-06-20 2024-07-04 Novartis Ag Formas cristalinas de un compuesto triazolopirimidínico
EP3472166A1 (de) 2016-06-20 2019-04-24 Novartis AG Imidazopyrimidinverbindungen zur behandlung von krebs
CN106432136B (zh) * 2016-06-30 2018-12-25 中国药科大学 一种氢氯噻嗪和阿替洛尔共无定型系统及其制备方法
TWI712598B (zh) 2016-07-20 2020-12-11 瑞士商諾華公司 胺基吡啶衍生物及其作為選擇性alk-2抑制劑之用途
TW201811766A (zh) 2016-08-29 2018-04-01 瑞士商諾華公司 N-(吡啶-2-基)吡啶-磺醯胺衍生物及其用於疾病治療之用途
JOP20170169A1 (ar) 2016-08-29 2019-01-30 Novartis Ag مركبات بيريدازين ثلاثية الحلقة مندمجة تفيد في علاج العدوى بفيروس أورثوميكسو
EP4059934A1 (de) 2016-09-09 2022-09-21 Novartis AG Verbindungen und zusammensetzungen als inhibitoren der endosomalen toll-like-rezeptoren
TW201811788A (zh) 2016-09-09 2018-04-01 瑞士商諾華公司 作為抗病毒劑之多環吡啶酮化合物
JOP20190053A1 (ar) 2016-09-23 2019-03-21 Novartis Ag مركبات أزا إندازول للاستخدام في إصابات الأوتار و/ أو الرباط
AR109688A1 (es) 2016-09-23 2019-01-16 Novartis Ag Compuestos de indazol para uso en lesiones de tendones y/o ligamentos
JOP20190061A1 (ar) 2016-09-28 2019-03-26 Novartis Ag مثبطات بيتا-لاكتاماز
WO2018073753A1 (en) 2016-10-18 2018-04-26 Novartis Ag Fused tetracyclic pyridone compounds as antivirals
TW201821076A (zh) 2016-11-10 2018-06-16 瑞士商諾華公司 Bmp增強劑
EP3576744A1 (de) 2017-02-01 2019-12-11 Medivir Aktiebolag Therapeutische anwendungen von malt1-hemmern
JP2020511486A (ja) 2017-03-24 2020-04-16 ノバルティス アーゲー イソオキサゾールカルボキサミド化合物及びその使用
AR111419A1 (es) 2017-04-27 2019-07-10 Novartis Ag Compuestos fusionados de indazol piridona como antivirales
UY37718A (es) 2017-05-05 2018-11-30 Novartis Ag 2-quinolinonas triciclicas como agentes antibacteriales
UY37774A (es) 2017-06-19 2019-01-31 Novartis Ag Compuestos 5-cianoindol sustituidos y usos de los mismos
WO2019087162A1 (en) 2017-11-06 2019-05-09 Novartis Ag Polycyclic herg activators
WO2019087163A1 (en) 2017-11-06 2019-05-09 Novartis Ag Polycyclic herg activators
CN111315749A (zh) 2017-11-17 2020-06-19 诺华股份有限公司 新颖的二氢异噁唑化合物及其在治疗乙型肝炎中的用途
EP3713927B1 (de) 2017-11-24 2021-12-15 Novartis AG Pyridinonderivate und deren verwendung als selektive alk-2-inhibitoren
US11234977B2 (en) 2017-12-20 2022-02-01 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
CA3085745A1 (en) 2017-12-21 2019-06-27 Kyorin Pharmaceutical Co., Ltd. An agent for treating nocturnal pollakiuria
UY38072A (es) 2018-02-07 2019-10-01 Novartis Ag Compuestos derivados de éster butanoico sustituido con bisfenilo como inhibidores de nep, composiciones y combinaciones de los mismos
JP7348663B2 (ja) * 2018-02-23 2023-09-21 センター フォー インテリジェント リサーチ イン クリスタル エンジニアリング，エセ．エレ． ユビキノールの共結晶及びそれらを含む組成物
UA126253C2 (uk) 2018-02-28 2022-09-07 Новартіс Аг ПОХІДНІ 10-(ДИ(ФЕНІЛ)МЕТИЛ)-4-ГІДРОКСИ-8,9,9а,10-ТЕТРАГІДРО-7H-ПІРОЛО[1',2':4,5]ПІРАЗИНО[1,2-b]ПІРИДАЗИН-3,5-ДІОНУ ЯК ІНГІБІТОРИ РЕПЛІКАЦІЇ ОРТОМІКСОВІРУСУ ДЛЯ ЛІКУВАННЯ ГРИПУ
US20200407365A1 (en) 2018-02-28 2020-12-31 Novartis Ag Indole-2-carbonyl compounds and their use for the treatment of hepatitis b
JP7440101B2 (ja) 2018-05-22 2024-02-28 ジェイエス・イノメッド・ホールディングス・リミテッド キナーゼ阻害剤としてのヘテロ環式化合物、ヘテロ環式化合物を含む組成物、及びそれらを使用する方法
MA52977A (fr) 2018-06-19 2021-04-28 Novartis Ag Composés de cyanotriazole et leurs utilisations
GB201811825D0 (en) 2018-07-19 2018-09-05 Benevolentai Bio Ltd Organic compounds
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
PT3837256T (pt) 2018-08-17 2023-05-23 Novartis Ag Compostos e composições de ureia como inibidores de smarca2/brm-atpase
GB201813791D0 (en) 2018-08-23 2018-10-10 Benevolental Bio Ltd Organic compounds
KR102672512B1 (ko) 2018-09-12 2024-06-10 노파르티스 아게 항바이러스 피리도피라진디온 화합물
EP3853212A1 (de) 2018-09-21 2021-07-28 Novartis AG Isoxazolcarboxamidverbindungen und deren verwendungen
TW202028208A (zh) 2018-10-09 2020-08-01 瑞士商諾華公司 N-(4-氟-3-(6-(3-甲基吡啶-2-基)-[1,2,4]三唑并[1,5-a]嘧啶-2-基)苯基)-2,4-二甲基㗁唑-5-甲醯胺固體形式
US20220033407A1 (en) 2018-12-18 2022-02-03 Novartis Ag N-(pyridin-2-ylsulfonyl)cyclopropanecarboxamide Derivatives and their Use in the Treatment of Disease
EP3908279B1 (de) 2019-01-11 2024-08-28 Novartis AG Lta4a-hemmer zur behandlung oder vorbeugung von hidradenitis suppurativa
WO2020150626A1 (en) 2019-01-18 2020-07-23 Biogen Ma Inc. Imidazo[1,2-a]pyridinyl derivatives as irak4 inhibitors
WO2020154581A1 (en) * 2019-01-24 2020-07-30 Assia Chemical Industries Ltd Solid state forms of fedovapagon-salicyclic acid co-crystal
CA3133460A1 (en) 2019-03-22 2020-10-01 Sumitomo Dainippon Pharma Oncology, Inc. Compositions comprising pkm2 modulators and methods of treatment using the same
BR112021024668A2 (pt) 2019-06-10 2022-05-31 Novartis Ag Derivado de piridina e pirazina para o tratamento de fc, dpoc e bronquiectasia
WO2020263980A1 (en) 2019-06-27 2020-12-30 Biogen Ma Inc. Imidazo[1,2-a]pyridinyl derivatives and their use in the treatment of disease
KR20220042132A (ko) 2019-06-27 2022-04-04 바이오젠 엠에이 인코포레이티드 2h-이미다졸 유도체 및 질환 치료에서 그의 용도
JP2022539208A (ja) 2019-07-03 2022-09-07 スミトモ ファーマ オンコロジー， インコーポレイテッド チロシンキナーゼ非受容体１（ｔｎｋ１）阻害剤およびその使用
WO2021038426A1 (en) 2019-08-28 2021-03-04 Novartis Ag Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease
TW202122078A (zh) 2019-09-06 2021-06-16 瑞士商諾華公司 使用lta4h抑制劑治療肝臟疾病之方法
AU2020353055B2 (en) 2019-09-26 2024-03-07 Gilead Sciences, Inc. Antiviral pyrazolopyridinone compounds
JP2021054781A (ja) * 2019-09-26 2021-04-08 デボン エルエス，リミテッド 共結晶形エフィナコナゾール、及びその製造方法
IL293530A (en) 2019-12-18 2022-08-01 Novartis Ag Derivatives of 3-(5-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione and their uses
MX2022008931A (es) 2020-01-22 2022-10-18 Benevolentai Bio Ltd Composiciones farmaceuticas y sus usos.
AU2021210187A1 (en) 2020-01-22 2022-07-21 Benevolentai Bio Limited Pharmaceutical compositions and their uses
EP3884938A1 (de) 2020-03-25 2021-09-29 ArtemiFlow GmbH 1,2,4-trioxan-verbindungen und zusammensetzungen damit zur verwendung in der behandlung von covid-19
CA3176727A1 (en) 2020-04-20 2021-10-28 Novartis Ag Antiviral 1,3-di-oxo-indene compounds
US20210323947A1 (en) 2020-04-20 2021-10-21 Novartis Ag Antiviral 1,3-di-oxo-indene compounds
CN113582927B (zh) * 2020-04-30 2023-07-04 苏州恩华生物医药科技有限公司 塞来昔布与普瑞巴林共无定型物及其制备方法
IL298109A (en) 2020-05-13 2023-01-01 Chdi Foundation Inc htt modulators for the treatment of Huntington's disease
WO2021253180A1 (en) 2020-06-15 2021-12-23 Novartis Ag Methyl (r) -2- (fluoromethyl) -5-oxo-4-phenyl-4, 5, 6, 7-tetrahydro-1h-cyclopenta [b] pyridine-3-carboxylate and methyl (r) -2- (fluoromethyl) -5-oxo-4-phenyl-1, 4, 5, 7-tetrahydrofuro [3, 4-b] pyridine-3-carboxylate as cav1.2 activators
TW202214652A (zh) 2020-06-16 2022-04-16 瑞士商諾華公司 甲基２－甲基－５－側氧基－１，４，５，７－四氫呋喃并〔３，４－ｂ〕吡啶－３－甲酸酯化合物作為ＣＡＶ１、２活化劑
IL300953A (en) 2020-09-17 2023-04-01 Novartis Ag Compounds and Preparations as SPPL2A Inhibitors
CN112552189A (zh) * 2020-11-10 2021-03-26 中国海洋大学 一种盐酸金刚烷胺与白藜芦醇的药物共晶及其制备方法
CN112521292B (zh) * 2020-12-18 2022-02-11 深圳市萱嘉生物科技有限公司 一种甜菜碱与有机酸的共晶及其制备方法、应用
CA3203011A1 (en) 2020-12-22 2022-06-30 Emily Anne Peterson 2h-indazole derivatives as irak4 inhibitors and their use in the treatment of disease
WO2022140425A1 (en) 2020-12-22 2022-06-30 Biogen Ma Inc. Imidazo[1,2-a]pyridine derivatives as irak4 inhibitors and their use in the treatment of disease
EP4274832A1 (de) 2021-01-07 2023-11-15 Biogen MA Inc. Tyk2-inhibitoren
WO2022195355A1 (en) 2021-03-15 2022-09-22 Novartis Ag Benzisoxazole derivatives and uses thereof
UY39671A (es) 2021-03-15 2022-10-31 Novartis Ag Derivados de pirazolopiridina y sus usos.
AR125196A1 (es) 2021-03-26 2023-06-21 Novartis Ag Derivados de ciclobutilo 1,3-sustituidos y sus usos
WO2022217248A1 (en) 2021-04-10 2022-10-13 Sunovion Pharmaceuticals Inc. Substituted sulfonamide-chroman compounds, and pharmaceutical compositions, and methods of use thereof
US20240150330A1 (en) 2021-04-10 2024-05-09 Sunovion Pharmaceuticals Inc. Chromans and benzofurans as 5-ht1a and taar1 agonists
US11932630B2 (en) 2021-04-16 2024-03-19 Novartis Ag Heteroaryl aminopropanol derivatives
WO2022234287A1 (en) 2021-05-06 2022-11-10 Benevolentai Bio Limited Imidazopyridazine derivatives useful as trk inhibitors
EP4347596A1 (de) 2021-05-26 2024-04-10 Novartis AG Triazolo-pyrimidin-analoga zur behandlung von erkrankungen im zusammenhang mit der hemmung des werner-syndroms recq-helikase (wrn)
TW202306570A (zh) 2021-06-03 2023-02-16 瑞士商諾華公司 3-(5-氧基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途
US12005134B2 (en) 2021-06-30 2024-06-11 Abe Pharmaceutical Composition for stimulating facial hair growth and methods of manufacturing a composition for stimulating facial hair growth
WO2023275796A1 (en) 2021-07-01 2023-01-05 Novartis Ag Heterocyclic derivatives as sphingosine-1-phosphate 3 inhibitors
US20240360082A1 (en) 2021-07-22 2024-10-31 Novartis Ag Substituted pyridone compounds useful to treat orthomyxovirus infections
AU2022348905A1 (en) 2021-09-23 2024-04-11 Sumitomo Pharma America, Inc. Methods of treating metabolic disorders
CN113845438B (zh) * 2021-10-12 2023-02-21 河北大学 一种对乙酰氨基酚-吡拉西坦药物共晶及其制备方法
AR127698A1 (es) 2021-11-23 2024-02-21 Novartis Ag Derivados de naftiridinona para el tratamiento de una enfermedad o un trastorno
CN114031515B (zh) * 2021-11-29 2022-10-21 河北大学 一种对乙酰氨基酚-布洛芬药物共晶及其制备方法
EP4448533A1 (de) 2021-12-13 2024-10-23 Novartis AG <sup2/>? <sub2/>?v?pyridin-3-carboxylatverbindungen als ca1,2-aktivatoren
WO2023139534A1 (en) 2022-01-24 2023-07-27 Novartis Ag Spirocyclic piperidinyl derivatives as complement factor b inhibitors and uses thereof
CN114644669A (zh) * 2022-03-10 2022-06-21 华润紫竹药业有限公司 一种黄体酮共晶体的制备方法及其应用
AR128931A1 (es) 2022-04-01 2024-06-26 Novartis Ag Inhibidores del factor b del complemento y usos de los mismos
CN114835657A (zh) * 2022-06-10 2022-08-02 大连工业大学 一种基于离子液体调控乙水杨胺-糖精共晶多晶型的方法
WO2024006493A1 (en) 2022-07-01 2024-01-04 Biogen Ma Inc. Tyk2 inhibitors
US20240067627A1 (en) 2022-08-03 2024-02-29 Novartis Ag Nlrp3 inflammasome inhibitors
TW202417450A (zh) 2022-10-12 2024-05-01 瑞士商諾華公司 三環化合物及其用途
WO2024105553A1 (en) 2022-11-16 2024-05-23 Novartis Ag Bicyclic heterocycles and their use as wrn inhibitors
US20240197715A1 (en) 2022-11-18 2024-06-20 Novartis Ag Pharmaceutical combinations and uses thereof
WO2024118488A1 (en) 2022-11-28 2024-06-06 Sumitomo Pharma America, Inc. 2-phenylmorpholine and 2-phenyl(thio)morpholine compounds and uses thereof
CN116162053A (zh) * 2023-01-10 2023-05-26 山东省分析测试中心 一种格列齐特-哌嗪共晶及其制备方法
WO2024176131A1 (en) 2023-02-23 2024-08-29 Novartis Ag Tead- and kras g12d-inhibitor combinations for treating cancer
WO2024176130A1 (en) 2023-02-23 2024-08-29 Novartis Ag Tead- and her2-inhibitor combinations for treating cancer
WO2024211696A1 (en) 2023-04-07 2024-10-10 Biogen Ma Inc. 1h-pyrrolo[2,3-b]pyridin-4-yl]-2-oxopyrrolidine-3-carbonitrile derivatives as tyrosine kinase 2 (tyk2) inhibitors for the treatment of inflammatory diseases
WO2024218275A1 (en) * 2023-04-20 2024-10-24 Institut Gustave Roussy Liquid and solid compositions of imipridone derivatives
CN118078830A (zh) * 2024-03-13 2024-05-28 海南海和制药有限公司 一种含有氟尿嘧啶的药物组合物的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8500862D0 (en) * 1985-01-14 1985-02-20 Tate & Lyle Plc Composition
UA74539C2 (en) * 1999-12-08 2006-01-16 Pharmacia Corp Crystalline polymorphous forms of celecoxib (variants), a method for the preparation thereof (variants), a pharmaceutical composition (variants)
AU784572B2 (en) * 1999-12-08 2006-05-04 Pharmacia Corporation Solid-state form of celecoxib having enhanced bioavailability
MXPA02006660A (es) * 2000-01-07 2002-12-13 Transform Pharmaceuticals Inc Formacion, identificacion y analisis de diversas formas solidas de alto rendimiento.
WO2003033462A2 (en) * 2001-10-15 2003-04-24 The Regents Of The University Of Michigan Systems and methods for the generation of crystalline polymorphs
CA2477923C (en) * 2002-03-01 2021-02-23 University Of South Florida Multiple-component solid phases containing at least one active pharmaceutical ingredient
ATE550022T1 (de) * 2003-02-28 2012-04-15 Mcneil Ppc Inc Pharmazeutische mischkristalle von celecoxib- nicotinamid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004078163A2 *

Also Published As

Publication number Publication date
JP2007524596A (ja) 2007-08-30
CA2514733A1 (en) 2004-09-16
WO2004078163A2 (en) 2004-09-16
WO2004078163A3 (en) 2005-01-20

Similar Documents

Publication Publication Date Title
EP1631260A2 (de) Pharmazeutische kokristallzusammensetzungen aus arzneistoffen wie carbamazepin, celecoxib, olanzapin, itraconazol, topiramat, modafinil, 5-fluoruracil, hydrochlorothazid, acetaminophen, aspirin, flurbiprofen, phenytoin und ibuprofen
JP4923182B2 (ja) セレコキシブ及びニコチンアミド共結晶並びにこの共結晶を含む医薬組成物
US20070026078A1 (en) Pharmaceutical co-crystal compositions
US20070059356A1 (en) Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
US20100311701A1 (en) Pharmaceutical Co-Crystal Compositions
US7803786B2 (en) Pharmaceutical co-crystal compositions and related methods of use
EP1755388B1 (de) Mischkristalle sowie sie enthaltende pharmazeutische zusammensetzungen
US8436029B2 (en) Pharmaceutical forms, and methods of making and using the same
US7566805B2 (en) Modafinil compositions
CA2534664C (en) Modafinil compositions
US8809586B2 (en) Modafinil compositions
US20060287392A1 (en) Gabapentin compositions
EP2292213A1 (de) Armodafinil Polymorph enthaltende Zusammensetzungen
IL199140A (en) Modafinil preparations
ALMARSSON et al. Patent 2514733 Summary
ZA200602736B (en) Modafinil compositions

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050922

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1085137

Country of ref document: HK

17Q First examination report despatched

Effective date: 20110124

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110804

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1085137

Country of ref document: HK