US20030224006A1 - Multiple-component solid phases containing at least one active pharmaceutical ingredient - Google Patents

Multiple-component solid phases containing at least one active pharmaceutical ingredient Download PDF

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Publication number
US20030224006A1
US20030224006A1 US10/378,956 US37895603A US2003224006A1 US 20030224006 A1 US20030224006 A1 US 20030224006A1 US 37895603 A US37895603 A US 37895603A US 2003224006 A1 US2003224006 A1 US 2003224006A1
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US
United States
Prior art keywords
phase composition
carbamazepine
component
active pharmaceutical
pharmaceutical ingredient
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.)
Abandoned
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US10/378,956
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English (en)
Inventor
Michael Zaworotko
Brian Moulton
Nair Rodriguez-Hornedo
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 Michigan System
University of South Florida St Petersburg
Original Assignee
Individual
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
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27789020&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20030224006(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US10/378,956 priority Critical patent/US20030224006A1/en
Assigned to UNIVERSITY OF SOUTH FLORIDA, REGENTS OF THE UNIVERSITY OF MICHIGAN reassignment UNIVERSITY OF SOUTH FLORIDA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MOULTON, BRIAN, RODRIGUEZ-HORNEDO, NAIR, ZAWOROTKO, MICHAEL J.
Priority to JP2006552403A priority patent/JP4923182B2/ja
Priority to PCT/US2003/027772 priority patent/WO2004078161A1/en
Priority to CA2513746A priority patent/CA2513746C/en
Priority to EP03754445A priority patent/EP1608339B8/en
Priority to AU2003272270A priority patent/AU2003272270A1/en
Priority to AT03754445T priority patent/ATE550022T1/de
Priority to HK06106215.0A priority patent/HK1083770B/en
Priority to US10/660,202 priority patent/US7927613B2/en
Publication of US20030224006A1 publication Critical patent/US20030224006A1/en
Priority to US10/541,216 priority patent/US8362062B2/en
Priority to PCT/US2003/041273 priority patent/WO2004061433A1/en
Priority to US10/747,742 priority patent/US7790905B2/en
Priority to US10/551,014 priority patent/US20060223794A1/en
Priority to US10/926,842 priority patent/US7446107B2/en
Priority to US12/234,420 priority patent/US20090088443A1/en
Priority to US12/792,415 priority patent/US20100311701A1/en
Priority to US14/179,862 priority patent/US10633344B2/en
Priority to US15/639,223 priority patent/US20170362182A1/en
Priority to US16/270,981 priority patent/US20190169130A1/en
Abandoned legal-status Critical Current

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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/26—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a double bond between positions 10 and 11
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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    • A61K31/33—Heterocyclic compounds
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom

Definitions

  • Crystal engineering (Schmidt, G. M. J. Pure Appl. Chem., 1971, 27:647-678; Desiraju, G. R. Crystal Engineering: the Design of Organic Solids, 1989, Elsevier: Amsterdam) is predicated on the assumption that crystals are de facto examples of self-assembly, i.e. crystals are comprised from a series of molecular recognition events or supramolecular synthons (Desiraju, G. R. Angew. Chem., Int. Ed. Engl., 1995, 34:2311-2327). It also offers a more realizable goal than crystal structure prediction since it relies on design and allows for careful selection of substrates, i.e.
  • the prototypal molecules used in crystal engineering contain exofunctional molecular recognition sites and they can be complementary with themselves (self-assembly) (Boucher, E. et al., J. Org. Chem., 1995, 60:1408-1412) or with other molecules (modular self-assembly) (Zaworotko, M. J. Chem. Soc. Rev., 1994, 23:283-288; Sharma, C. V. K. and M. J. Zaworotko Chem. Commun., 1996, 2655-2656).
  • most pharmaceutical molecules also contain exterior molecular recognition sites and, although this makes them susceptible to polymorphism and solvate formation, it also makes them attractive candidates for crystal engineering studies.
  • the Food and Drug Administration's strict purity requirements effectively mean that a particular crystalline phase of a drug must be selected and that its composition must be established. This has typically meant that a consistent X-ray powder diffraction (XPD) pattern is required (Federal Drug Administration Fed. Regist., 1997, 62:62893-62894).
  • XPD X-ray powder diffraction
  • the need to ensure that processing produces both purity and ease of processing is problematic because many drug molecules are prone to form multiple phases, and crystal size and morphology can vary for a given phase.
  • the commercial and public image costs of not ensuring that processing is reliable and reproducible is at best very high, as demonstrated by the recent pull back and reformulation of NORVIR by ABBOTT LABORATORIES).
  • the subject invention relates to the application of the concepts of crystal engineering towards the design of new pharmaceutical phases that contain more than one molecular component.
  • the subject invention concerns multiple-component solids having at least one active pharmaceutical ingredient.
  • pharmaceutical molecules that may be utilized as active pharmaceutical ingredients in the multiple-component solids of the subject invention include, but are not limited to, aspirin, one or more members of the profen series (e.g., ibuprofen and flurbiprofen), carbamazepine, phenytoin, and acetaminophen.
  • Multiple-component solids, such as multiple-component crystals, containing these pharmaceutical ingredients and complementary molecules hereafter referred to as “cocrystal formers” have been characterized by various techniques and can exhibit physical and/or chemical properties that are the same or different from the parent pharmaceutical ingredient as a direct result of alternative molecular recognition patterns. These novel crystalline assemblies can afford improved drug solubility, dissolution rate, stability and bioavailability.
  • the subject invention relates to the application of the concepts of crystal engineering towards the design of new pharmaceutical solid phases, such as multiple-component phases, using cocrystal formers that are complementary in the sense of supramolecular chemistry, i.e. they form supramolecular synthons with pharmaceutical molecules or ions.
  • the cocrystal formers can be, but are not limited to, solvent molecules, other drug molecules, GRAS compounds, or approved food additives.
  • Pharmaceutical molecules or ions are inherently predisposed for such crystal engineering studies since they already contain molecular recognition sites that bind selectively to biomolecules, and they are prone to supramolecular self-assembly.
  • Examples of the groups commonly found in active pharmaceutical ingredients, and which are capable of forming supramolecular synthons include, but are not limited to, acids, amides, aliphatic nitrogen bases, unsaturated aromatic nitrogen bases (e.g. pyridines, imidazoles), amines, alcohols, halogens, sulfones, nitro groups, S-heterocycles, N-heterocycles (saturated or unsaturated), and O-heterocycles.
  • Other examples include ethers, thioethers, thiols, esters, thioesters, thioketones, epoxides, acetonates, nitrils, oximes, and organohalides.
  • Some of these groups can form supramolecular synthons with identical groups in similar or different molecules and are termed homosynthons, e.g. acids and amides.
  • Other groups can form supramolecular synthons with different groups and are termed heterosynthons, e.g. acid/amide; pyridine/amide; alcohol/amine.
  • Heterosynthons are particularly suitable for formation of multiple-component crystals whereas homosynthons can sometimes form multiple-component crystals.
  • the subject invention concerns methods for identifying complementary chemical functionalities to form a desired supramolecular synthon, wherein the method comprises the steps of evaluating the structure of an active pharmaceutical ingredient (API), which can include determining its crystal structure; determining whether the API contains chemical functionalities capable of forming supramolecular synthons with itself; identifying from a plurality of chemical functionalities that are known to form a supramolecular synthon at least one chemical functionality that will form a further supramolecular synthon to the supramolecular synthon formed by the API, wherein the identified chemical functionality is not capable of disrupting non-covalent bonding within the supramolecular synthon formed by the supramolecular synthon formed by the API, and wherein the selected chemical functionality is capable of forming a noncovalent bond to the supramolecular synthon formed by the API; and identifying co-crystal formers having chemical functionalities that are complementary with the API.
  • API active pharmaceutical ingredient
  • the subject invention concerns methods for identifying complementary chemical functionalities to form a desired supramolecular synthon, wherein the method comprises the steps of evaluating the structure of an API, which can include determining its crystal structure; determining whether the API contains chemical functionalities capable of forming supramolecular synthons with itself; identifying from a plurality of chemical functionalities that are known to form supramolecular synthons at least one functionality that will form a supramolecular synthon with the API, wherein the identified chemical functionality is capable of disrupting non-covalent bonding within the supramolecular synthon formed by the API, and wherein the selected chemical functionality is capable of forming a noncovalent bond to a complementary chemical functionality on the API; and identifying co-crystal formers having chemical functionalities that are complementary with the API.
  • the formation of homosynthons for the purpose of disrupting the intermolecular interactions between pharmaceutical moieties can be carried out.
  • the subject invention concerns methods for identifying complementary chemical functionalities to form a desired supramolecular synthon, wherein the method comprises the steps of evaluating the structure of an API, which can include determining its crystal structure; determining whether the API contains chemical functionalities capable of forming supramolecular synthons with different molecules; identifying from a plurality of chemical functionalities that are known to form supramolecular synthons at least one functionality that will form a supramolecular synthon with the API, and wherein the selected chemical functionality is capable of forming a noncovalent bond to a complementary chemical functionality on the API; and identifying co-crystal formers having chemical functionalities that are complementary with the active pharmaceutical ingredient.
  • certain aspects of the subject invention can involve selecting a chemical functionality that is capable of disrupting the non-covalent bonding between identical functionalities (homosynthon) and form a non-covalent bond between different, yet complementary, functionalities (heterosynthon); selecting a plurality of molecular entities that comprise the complementary functionality (preferably GRAS compounds or approved food additives); identifying additional chemical features on the molecular entities that will not interfere with the formation of the desired supramolecular synthon and that will impart the desired physical properties to the target phase; and, optionally, preparing a new solid phase that is composed of the pharmaceutical moiety and the complementary molecular entity (such as a multiple-component phase or two component phase) by crystallization techniques comprising reactions in solvent, and/or solventless reactions, that afford crystalline materials.
  • the methods can further include at least one of the subsequent steps of determining the structure of the new solid phase formed; and analyzing the physical properties of the new solid phase.
  • the subject invention further concerns new solid phases identified or produced using the methods identified herein.
  • the subject invention further pertains to a multiple-component phase composition comprising a solid material (phase) that is sustained by intermolecular interactions between two or more independent molecular entities, in any stoichiometric ratio, wherein at least one of the independent molecular entities is a pharmaceutical entity.
  • the multiple-component phase composition can be, for example, a discrete supramolecular entity or a polymeric structure.
  • FIG. 1 shows the chemical structure of ibuprofen.
  • the external functionalities are an isopropyl group (encircled on the left, in cyan) and a carboxylic acid (encircled on the right, in magenta).
  • FIG. 2 shows a scheme with the synthon of pure ibuprofen on the left and the supramolecular entity containing the synthon on the right, demonstrating that pure phases of ibuprofen are sustained by carboxylic acid-carboxylic acid interactions.
  • FIG. 3 shows a scheme wherein the carboxylic acid-carboxylic acid interactions of ibuprofen are disrupted by co-crystallization with an aromatic amine. Specifically, by using diamines, 2:1 multiple-component phases are produced.
  • FIGS. 4 A-B show an acetaminophen 1-D polymeric chain and an acetaminophen/4,4′-bipyridine/water crystal, respectively.
  • Reported forms are monoclinic (P2 I /n) (Haisa, M. et al., Acta Crystallogr., Sect B, 1974, 30:2510) and orthorhombic (Pbca) (Haisa, M. et al., Acta Crystallogr., Sect B, 1976, 32:1283) polymorphs.
  • the monoclinic& polymorph forms lpleated sheets with all hydrogen bonding donors and acceptors interacting.
  • the orthorhombic polymorph forms form 1-D polymeric chains with all donors and acceptors interacting.
  • FIGS. 5 A- 5 B show pure phenytoin and a phenytoin/pyridone co-crystal, respectively.
  • Phenytoin has one known pure form (Carmerman, A. et al., Acta Crystallogr., Sect B, 1971, 27:2207).
  • the crystal structure reveals a two dimensional polymeric network formed by hydrogen bonds between both the carbonyl and 2° amine.
  • FIGS. 6 A- 6 D show supramolecular entities containing synthons and corresponding crystal structures of pure aspirin and aspirin/4,4′-bipyridine.
  • FIGS. 3A and 3B show the supramolecular entity containing the synthon of pure aspirin and corresponding crystal structure, respectively.
  • FIGS. 6C and 6D show the supramolecular entity containing the synthon and corresponding co-crystal of aspirin/4,4′-bipyridine, respectively.
  • the pure phase (Chiari, G.
  • FIGS. 7 A- 7 D show supramolecular entities containing synthons and corresponding crystal structures of pure ibuprofen [2-(4-isobutylphenyl) propionic acid] and ibuprofen/4,4′-bipyridine.
  • FIGS. 7A and 7B show the supramolecular entity containing the synthon of pure ibuprofen and corresponding crystal structure, respectively.
  • FIGS. 7C and 7D show the supramolecular entity containing the synthon of ibuprofen/4,4′-bipyridine and corresponding co-crystal, respectively.
  • the reported crystal structures of ibuprofen are racemic (McConnell, J. F. Cryst. Strucut.
  • FIGS. 8 A- 8 D show supramolecular entities containing synthons and corresponding crystal structures of pure flurbiprofen [2-(2-fluror-4-biphenyl) propionic acid] and flurbiprofen/4,4′-bipyridine.
  • FIGS. 8A and 8B show the supramolecular entity containing the synthon of pure flurbiprofen and corresponding crystal structure, respectively.
  • FIGS. 5C and 5D show the supramolecular synthon of flurbiprofen/4,4′-bipyridine and corresponding cocrystal, respectively.
  • Flurbiprofen has one reported pure form (Flippen, J. L. et al., Acta Crystallogr., Sect.
  • FIGS. 9A and 9B show the supramolecular entity containing the synthon of flurbiprofen/trans-1,2-bis(4-pyridyl)ethylene and the corresponding crystal structure, respectively.
  • FIGS. 10A and 10B show the crystal structures of pure carbamazepine and carbamazepine/p-phthalaldehyde, respectively.
  • Carbamazepine [5H-Dibenz(b, f) azepine-5-carboxamide] (CBZ) has been shown to exist in at least three anhydrous forms and two solvated forms (a dihydrate and an acetonate) (Himes, V. L. et al., Acta Crystallogr., 1981, 37:2242-2245; Lowes, M. M. J. et al., J. Pharm. Sci., 1987, 76:744-752; Reck, G. et al., Cryst. Res.
  • the primary intermolecular interaction in these crystal forms is the dimer formed between the carboxamide moieties of each CBZ molecule forming centrosymmetric dimers.
  • the anhydrous polymorphs are monoclinic, trigonal, and triclinic.
  • the polymorphs are enantiotropically related with the monoclinic form being the most thermodynamically stable at room temperature.
  • FIG. 11 shows the crystal structure of carbamazepine/nicotinamide (vitamin B3).
  • FIG. 12 shows the crystal structure of carbamazepine/saccharin, engineered using the carbamazepine/nicotinamide co-crystal as a model.
  • FIGS. 13 A- 13 C show the chemical structures of ibuprofen, flurbiprofen, and aspirin, respectively.
  • FIGS. 14A and 14B show the crystal structures of carbamazepine and carbamazepine/2,6-pyridinedicarboxylic acid, respectively.
  • FIGS. 15A and 15B show the crystal structures of carbamazepine and carbamazepine/5-nitroisophthalic acid, respectively.
  • FIGS. 16A and 16B show the crystal structures of carbamazepine and carbamazepine/acetic acid.
  • FIGS. 17A and 17B show the crystal structure of carbamazepine and carbamazepine/adamantanetetracarboxylic acid.
  • FIGS. 18A and 18B show the crystal structure of carbamazepine and carbamazepine/benzoquinone.
  • FIGS. 19A and 19B show the crystal structure of carbamazepine and carbamazepine/butyric acid.
  • FIGS. 20A and 20B show the crystal structure of carbamazepine and carbamazepine/DMSO.
  • FIGS. 21A and 21B show the crystal structure of carbamazepine and carbamazepine/formamide.
  • FIGS. 22A and 22B show the crystal structure of carbamazepine and carbamazepine/formic acid.
  • FIGS. 23A and 23B show the crystal structure of carbamazepine and carbamazepine/trimesic acid.
  • FIG. 24 shows an exemplified scheme for preparing multiple-component phase compositions of the subject invention.
  • the subject invention relates to the application of the concepts of crystal engineering towards the design of new multiple-component solid phases, such as multiple-component crystals, having at least one active pharmaceutical component.
  • multiple-component crystals of the subject invention include, but are not limited to, acetominophen/4,4′-bipyridine/water, phenytoini/pyridone, aspirin/4,4′-bipyridine, ibuprofen/4,4′-bipyridine, flurbiprofen/4,4′-bipyridine, flurbiprofen/trans-1,2-bis (4-pyridyl) ethylene, carbamazepine/p-phthalaldehyde, carbamazepine/nicotinamide (GRAs), carbamazepine/saccharin (GRAs), carbamazepine/2,6-pyridinedicarboxylic acid, carbamazepine/5-nitroisophthalic acid, carbamazepin
  • the subject invention concerns methods for identifying complementary chemical functionalities to form a desired supramolecular synthon, wherein the method comprises the steps of evaluating the structure of an active pharmaceutical ingredient (API), which can include determining its crystal structure; determining whether the API contains chemical functionalities capable of forming supramolecular synthons with itself; identifying from a plurality of chemical functionalities that are known to form a supramolecular synthon at least one chemical functionality that will form a further supramolecular synthon to the supramolecular synthon formed by the API, wherein the identified chemical functionality is not capable of disrupting non-covalent bonding within the supramolecular synthon formed by the supramolecular synthon formed by the API, and wherein the selected chemical functionality is capable of forming a noncovalent bond to the supramolecular synthon formed by the API; and identifying co-crystal formers having chemical functionalities that are complementary with the API.
  • API active pharmaceutical ingredient
  • the subject invention concerns methods for identifying complementary chemical functionalities to form a desired supramolecular synthon, wherein the method comprises the steps of evaluating the structure of an API, which can include determining its crystal structure; determining whether the API contains chemical functionalities capable of forming supramolecular synthons with itself; identifying from a plurality of chemical functionalities that are known to form supramolecular synthons at least one functionality that will form a supramolecular synthon with the API, wherein the identified chemical functionality is capable of disrupting non-covalent bonding within the supramolecular synthon formed by the API, and wherein the selected chemical functionality is capable of forming a noncovalent bond to a complementary chemical functionality on the API; and identifying co-crystal formers having chemical functionalities that are complementary with the API.
  • the formation of homosynthons for the purpose of disrupting the intermolecular interactions between pharmaceutical moieties can be carried out.
  • the subject invention concerns methods for identifying complementary chemical functionalities to form a desired supramolecular synthon, wherein the method comprises the steps of evaluating the structure of an API, which can include determining its crystal structure; determining whether the API contains chemical functionalities capable of forming supramolecular synthons with different molecules; identifying from a plurality of chemical functionalities that are known to form supramolecular synthons at least one functionality that will form a supramolecular synthon with the API, and wherein the selected chemical functionality is capable of forming a noncovalent bond to a complementary chemical functionality on the API; and identifying co-crystal formers having chemical functionalities that are complementary with the active pharmaceutical ingredient.
  • the methods can further comprise preparing a multiple-component solid phase composition composed of the API and at least one of the identified co-crystal formers.
  • the identified co-crystal former can be, for example, a different API, a GRAS compound, a food additive, a low toxicity organic, or a metalorganic complex.
  • Various methods can be utilized for preparing the multiple-component solid phase composition, such as crystallization from solution, cooling the melt, sublimation and grinding.
  • the methods of the subject invention can further comprise either or both of the following steps: determining the structure of the new multiple-component solid phase composition, and analyzing the physical and/or chemical properties of the new multiple-component solid phase composition.
  • the subject invention further concerns new solid phases identified or produced using the methods identified herein.
  • the subject invention further pertains to a multiple-component phase composition comprising a solid material (phase) that is sustained by intermolecular interactions between two or more independent molecular entities, in any stoichiometric ratio, wherein at least one of the independent molecular entities is a pharmaceutical entity.
  • the multiple-component phase composition of the subject invention can be, for example, a discrete supramolecular entity or a polymeric structure.
  • the multiple-component phase compositions of the subject invention can have properties, such as melting point, solubility, dissolution rate, stability, and/or bioavailability, which are different from the pharmaceutical compound, or compounds, upon which they are based.
  • the external functionalities of ibuprofen are an isopropyl group and a carboxylic acid, as shown in FIG. 1.
  • multiple-component phase refers to any solid material (phase) that is sustained by intermolecular interactions between at least two independent molecular entities, in any stoichiometric ratio, wherein at least one of the independent molecular entities is a pharmaceutical entity.
  • intermolecular interactions include, but are not limited to one or more of the following: hydrogen bonding (weak and/or strong), dipole interactions (induced and/or non-induced), stacking interactions, hydrophobic interactions, and other inter-static interactions.
  • Each independent molecular entity can be a discrete supramolecular entity or polymeric structure, for example.
  • one or more of the independent molecular entities comprises a molecule of a “GRAS” compound, that is, a compound “Generally Regarded as Safe by the Food and Drug Administration (FDA)”. More preferably, the GRAS compound is a non-pharmaceutical entity.
  • pharmaceutical entity “pharmaceutical moiety”, “pharmaceutical component”, “pharmaceutical molecule”, and “active pharmaceutical ingredient (API)”, and grammatical variations thereof, are used interchangeably herein to refer to any biologically active moiety having a therapeutic effect on a human or animal suffering from a given pathological condition, when administered in a given concentration. Therefore, pharmaceutical entities useful as the active pharmaceutical ingredients in the multiple phase solids of the subject invention can be administered to a human or animal, which may or may not be suffering from a pathological condition, and the pharmaceutical entity can have a prophylactic effect, a palliative effect, and/or be a curative intervention.
  • these pharmaceutical entities are intended to include pharmaceutically acceptable salts of a given pharmaceutical entity that retain all or a portion of their pharmaceutical activity.
  • Pharmaceutical molecules or ions are inherently predisposed for such crystal engineering studies since they already contain molecular recognition sites that bind selectively to biomolecules, and they are prone to supramolecular self-assembly.
  • Examples of the groups commonly found in active pharmaceutical ingredients, and which are capable of forming supramolecular synthons include, but are not limited to, acids, amides, aliphatic nitrogen bases, unsaturated aromatic nitrogen bases (e.g.
  • pyridines imidazoles
  • amines amines
  • alcohols halogens
  • sulfones nitro groups
  • S-heterocycles N-heterocycles (saturated or unsaturated)
  • O-heterocycles Other examples include ethers, thioethers, thiols, esters, thioesters, thioketones, epoxides, acetonates, nitrils, oximes, and organohalides.
  • ethers include ethers, thioethers, thiols, esters, thioesters, thioketones, epoxides, acetonates, nitrils, oximes, and organohalides.
  • Some of these groups can form supramolecular synthons with identical groups in similar or different molecules and are termed homosynthons, e.g., acids and amides.
  • Other groups can form supramolecular synthons with different groups and are termed heterosynthons, e.g., acid/amide; pyridine/amide; alcohol/amine.
  • Heterosynthons are particularly suitable for formation of multiple-component crystals whereas homosynthons can sometimes form multiple-component crystals.
  • the term “supramolecular synthon” refers to the sum of the components of a multi-component non-covalent interaction, wherein the non-covalent interaction contributes to the formation of a discrete supramolecular entity or polymeric structure, wherein each component is a chemical functionality.
  • a supramolecular synthon can be a dimer, trimer, or n-mer, for example.
  • the multiple-component phase compositions can be formulated according to known methods for preparing pharmaceutically useful compositions. Such pharmaceutical compositions can be adapted for various forms of administration, such as oral, parenteral, nasal, topical, transdermal, etc.
  • the multiple-component phase solids of the subject invention can be made into solutions or amorphous compounds, as injections, pills, or inhalants, for example.
  • the pharmaceutical compositions can include a pharmaceutically acceptable carrier or diluent. Formulations are described in a number of sources which are well known and readily available to those skilled in the art.
  • Formulations suitable for administration include, for example, aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unitdose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powder, granules, or tablets of the multiple-component phase compositions of the subject invention, for example.
  • the formulations of the subject invention can include other agents conventional in the art having regard to the type of formulation in question.
  • three general types of compounds generated by interaction of a pharmaceutical molecule with another molecule include: (1) multiple-component compounds, in which superstructure is generated by two or more molecules, both of which are integral components of the network and complementary; (2) clathrate inclusion compounds, in which the compounds' superstructure is generated by self-assembly of one or more molecules and a guest molecules is enclosed within the superstructure; and (3) porous inclusion compounds, in which the superstructure is open framework in nature.
  • the subject invention concerns multiple-component compositions, and it is demonstrated herein that the concepts of crystal engineering and supramolecular synthons can be applied to prepare a wide range of novel pharmaceutical materials that are based on rational design. Therefore, the multiple-component compounds of the subject invention can be generated in such a fashion that they have desirable composition, structure and properties. More specifically, an issue that is particularly relevant to pharmaceutical compositions of matter and processing is addressed by the subject invention: the diversity of compositions, superstructures and solubilities that can be generated when drug molecules form multiple-component phases with complementary molecules.
  • multiple-component phases involving the following drugs are exemplified herein: aspirin, acetaminophen, ibuprofen (and related compounds), phenytoin and carbamazepine and appropriate molecular additives.
  • These novel phases include both “model multiple-component phases” that illustrate the concept of crystal engineering and multiple-component phases that incorporate pharmaceuticals with “GRAS” compounds, that is, compounds “Generally Regarded as Safe by the FDA”, and/or food additives.
  • the subject invention addresses these issues by demonstrating that crystal engineering offers a paradigm for the supramolecular synthesis (Chang, Y. L. et al, J. Am. Chem. Soc., 1993, 115:5991-6000) of a wide range of new multiple-component phases that have predetermined compositions and, in some instances, predetermined topology.
  • Such an ability to build hierarchical structures from molecular or supramolecular modules facilitates precise control of structure and function of solid phases.
  • multiple-component phases have the following advantages over single component phases and traditional multiple-component phases (solid dispersions): high thermodynamic stability (thereby reducing problems associated with solid phase transformations), modified bioavailability (finely tunable solubility and delivery), and enhanced processability (crystal morphology, mechanical properties, hygroscopicity).
  • the subject invention has the following implications from a scientific perspective: (a) protocols are now available for the rational design of a new generation of pharmaceutical phases that contain at least two components that are sustained by supramolecular synthons; (b) correlation of structure and function of the new pharmaceutical phases via characterization of structure, crystal energy, solubility, dissolution rate, and stability is now possible; and (c) a new range of novel phases for the treatment of pathological conditions in humans and animals are available.
  • the subject invention extends the state-of-the-art in at least three ways: (1) by generating a rational, supramolecular strategy for the design of novel, multiple-component crystalline phases; (2) by extending this strategy to pharmaceutical phases; and (3) by using this strategy to control the delivery properties and stability of pharmaceutical compounds.
  • the multiple-component phases prepared confirm the ability to persistently and rationally disrupt the homosynthon by judicious choice of a second molecular component that is predisposed to form a supramolecular heterosynthon. That these new solid phases will have different solubility profiles-than their pure phases is to be expected. Examples designated as GRAS are those in which second a component that is “Generally Regarded as Safe by the FDA” was used.
  • 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 7E-a 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 cocrystal were identified as: 2° amine found at 3311 cm ⁇ 1 , carbonyl (ketone) found at 1711 cm ⁇ 1 , olephin peak found at 1390 cm ⁇ 1 .
  • XRPD Showed analogous peaks to the simulated XRPD derived from the single crystal data.
  • Crystal packing 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 1694 cm ⁇ 1 , where as the lactone peak is shifted down slightly from 1750 cm ⁇ 1 to 1744 cm ⁇ 1 .
  • the co-crystal contains ibuprofen/bipyridine 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 n-n stacking of the bipyridine and phenyl groups of the ibuprofen and hydrophobic interactions from the ibuprofen tails.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). Analysis observed stretching of aromatic C—H at 2899 cm ⁇ 1 ; N—H bending and scissoring at 1886 cm ⁇ 1 ; C ⁇ O stretching at 1679 cm ⁇ 1 ; C—H out-of-plane bending for both 4,4′-bipyridine and ibuprofen at 808 cm ⁇ 1 and 628 cm ⁇ 1 .
  • the co-crystal contains flurbiprofen/bipyridine heterodimers, sustained by two hydrogen bonded carboxylic acidpyridine supramolecular synthon, arranged in a herringbone motif that packs in the space group P2 I /n.
  • the heterodimer is an extended version of the homodimer and packs to form a two-dimensional network sustained by n-n stacking and hydrophobic interactions of the bipyridine and phenyl groups of the flurbiprofen.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR), aromatic C—H stretching at 3057 cm ⁇ 1 and 2981 cm ⁇ 1 ; N—H bending and scissoring at 1886 cm ⁇ 1 ; C ⁇ O stretching at 1690 cm ⁇ 1 ; C ⁇ C and C ⁇ N ring stretching at 1418 cm ⁇ 1 .
  • XRPD derived from the single crystal data experimental (calculated): 16.8 (16.8); 17.1 (17.5); 18.1 (18.4); 19.0 (19.0); 20.0 (20.4); 21.3 (21.7); 22.7 (23.0); 25.0 (25.6); 26.0 (26.1); 26.0 (26.6); 26.1 (27.5); 28.2 (28.7); 29.1 (29.7).
  • Crystal packing 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 I /n.
  • the heterodimer from 1,2-bis (4-pyridyl) ethylene further extends the homodimer relative to example 5 and packs to form a two-dimensional network sustained by ⁇ - ⁇ stacking and hydrophobic interactions of the bipyridine and phenyl groups of the flurbiprofen.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR), aromatic C—H stretching at 2927 cm ⁇ 1 and 2850 cm ⁇ 1 ; N—H bending and scissoring at 1875 cm ⁇ 1 ; C ⁇ O stretching at 1707 cm ⁇ 1 ; C ⁇ C and C ⁇ N ring stretching at 1483 cm ⁇ 1 .
  • XRPD derived from the single crystal data, experimental (calculated): 3.6 (3.7); 17.3 (17.7); 18.1 (18.6); 18.4 (18.6); 19.1 (19.3); 22.3 (22.5); 23.8 (23.9); 25.9 (26.4); 28.1 (28.5).
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers that crystallize in the space group C2/c.
  • the 10 amines of the homodimer are bifurcated to the carbonyl of the p-phthalaldehyde forming a chain with an adjacent homodimer.
  • the chains pack in a crinkled tape motif sustained by ⁇ - ⁇ interactions between phenyl rings of the CBZ.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). The 10 amine unsymmetrical and symmetrical stretching was shifted down to 3418 cm ⁇ 1 ; aliphatic aldehyde and 10 amide C ⁇ O stretching was shifted up to 1690 cm ⁇ 1 ; N—H in-plane bending at 1669 cm ⁇ 1 ; C—H aldehyde stretching at 2861 cm ⁇ 1 and H—C ⁇ O bending at 1391 cm ⁇ 1 .
  • 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 CBZ.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm ⁇ 1 and 3388 cm ⁇ 1 accounting for 10 amines; 1° amide C ⁇ O stretching at 1690 cm ⁇ 1 ; N—H in-plane bending at 1614 cm ⁇ 1 ; C—C stretching shifted down to 1579 cm ⁇ 1 ; aromatic H's from 800 cm ⁇ 1 to 500 cm ⁇ 1 are present.
  • XRPD Showed analogous peaks to the simulated XRPD derived from the single crystal data.
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers.
  • the 2° amines of the saccharin are hydrogen bonded to the carbonyl of the CBZ on each side forming a tetramer.
  • the crystal has a space group of P-i with n-g interactions between the phenyl groups of the CBZ and the saccharin phenyl groups.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts up to 3495 cm1 accounting for 10 amines; C ⁇ O aliphatic stretching was shifted up to 1726 cm ⁇ 1 ; N—H in-plane bending at 1649 cm; C ⁇ C stretching shifted down to 1561 cm ⁇ 1 ; (O ⁇ S ⁇ O) sulfonyl peak at 1330 cm ⁇ 1 C—N aliphatic stretching 1175 cm ⁇ 1 .
  • XRPD 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 CBZ 1° amine is hydrogen bonded to a carbonyl group of a different 2,6-pyridinedicarboxylic acid moiety.
  • the carbonyl of the CBZ carboxamide is hydrogen bonded to two hydroxide groups of one 2,6-pyridinedicarboxylic acid moitey.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3439 cm ⁇ 1 , (N—H stretch, 1° amine, CBZ); 1734 cm ⁇ 1 , (C ⁇ O); 1649 cm ⁇ 1 , (C ⁇ C).
  • 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.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3470 cm ⁇ 1 , (N—H stretch, 10 amine, CBZ); 3178 cm ⁇ 1 , (C—H stretch, alkene); 1688 cm ⁇ 1 , (C ⁇ O); 1602 cm ⁇ 1 , (C ⁇ C).
  • XRPD Showed analogous peaks to the simulated XRPD derived from the single crystal data.
  • XRPD 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-crystal is sustained by hydrogen bonded carboxamidecarboxylic heterodimers.
  • the second 1° amine hydrogen from each CBZ joins 2 heterodimers side by side forming a tetramer.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3462 cm ⁇ 1 , (N—H stretch, 1° amine, CBZ); 1699 cm ⁇ 1 , (C ⁇ O); 1629 cm ⁇ 1 , (C ⁇ C, CBZ); 1419 cm ⁇ 1 , (COOH, acetic acid).
  • 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.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3431 cm, (N—H stretch, 1I amine, CBZ); 3123 cm ⁇ 1 , (C—H stretch, alkene); 1723 cm ⁇ 1 , (C ⁇ O); 1649 cm, (C ⁇ C).
  • Crystal packing The co-crystals contain hydrogen bonded carboxamide homodimers. Each 1° amine on the CBZ is bifurcated to a carbonyl group of a benzoquinone moiety. The dimers form infinite chains.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3420 cm ⁇ 1 , (N—H stretch, 1° amine, CBZ); 2750 cm ⁇ 1 , (aldehyde stretch); 1672 cm ⁇ 1 , (C ⁇ O); 1637 cm ⁇ 1 , (C ⁇ C, CBZ).
  • Crystal packing The co-crystals are sustained by hydrogen bonded carboxamide-carboxylic heterodimers between the carbamazepine moieties and the butyric acid moieties.
  • the second 1° amine hydrogen from each CBZ joins 2 heterodimers side by side forming a tetramer.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3486 cm ⁇ 1 , (N—H stretch, 1° amine, CBZ); 3307 cm ⁇ 1 , (C—H stretch, alkene); 1684 cm ⁇ 1 , (C ⁇ O); 1540 cm ⁇ 1 , (C ⁇ C).
  • Crystal packing The co-crystals are sustained by the hydrogen bonded carboxamide homosynthon.
  • the 1° amines are hydrogen bonded to the sulfoxide of the DMSO on each side of the homosynthon.
  • the crystal is stabilized by ⁇ - ⁇ interactions from the tricyclic azepine ring system groups of the CBZ.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3369 cm ⁇ 1 (N—H stretch, 1° amine, CBZ); 1665 cm ⁇ 1 (C ⁇ O stretching); 1481 cm ⁇ 1 (C ⁇ C).
  • Crystal packing The co-crystals are sustained by hydrogen bonded carboxamide homodimers between two carbamazepine moieties and carboxylic acid homodimers between two formamide moieties. Infinite chains are formed by the homodimers linked side by side, with every other set of CBZ molecules attached on the sides of the chain but not bonded to form a dimer.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3392 cm ⁇ 1 , (N—H stretch, 11 amine, CBZ); 2875 cm ⁇ 1 , (C—H stretch, alkene); 1653 cm ⁇ 1 , (C ⁇ O); 1590 cm ⁇ 1 , (C ⁇ C).
  • Crystal packing The co-crystals are sustained by hydrogen bonded carboxylic acid-amineheterodimers arranged in centrosymmetric tetramers.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3439 cm ⁇ 1 , (1° amine stretch,CBZ); 3026 cm ⁇ 1 (C—H stretch, CBZ); 1692 cm ⁇ 1 , (1° amide, C ⁇ O stretch).
  • 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.
  • Infrared Spectroscopy (Nicolet Avatar 320 FTIR). 3486 cm ⁇ 1 (N—H stretch, 1° amine, CBZ); 1688 cm ⁇ 1 (C ⁇ O, 1° amide stretch, CBZ); 1602 cm ⁇ 1 (C ⁇ C, CBZ).
  • XRPD analysis experimental 10.736, 12.087, 16.857, 24.857, 27.857.

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US12180179B2 (en) 2014-05-27 2024-12-31 R.J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
WO2015183801A1 (en) 2014-05-27 2015-12-03 R. J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
US10865192B2 (en) 2014-05-27 2020-12-15 R.J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
EP3871515A1 (en) 2014-05-27 2021-09-01 R. J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
US11136305B2 (en) 2014-05-27 2021-10-05 R.J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
US12077518B2 (en) 2014-05-27 2024-09-03 R.J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
CN108473596A (zh) * 2015-11-15 2018-08-31 西北大学 基于环糊精的多孔材料内的药物的摄取
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EP4338735A2 (en) 2015-11-25 2024-03-20 R. J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
EP4635478A2 (en) 2017-09-05 2025-10-22 R. J. Reynolds Tobacco Company Nicotine salts, co-crystals, and salt co-crystal complexes
WO2019049049A1 (en) 2017-09-05 2019-03-14 R. J. Reynolds Tobacco Company SALTS, CO-CRYSTALS, AND CO-CRYSTAL COMPLEXES OF NICOTINE SALTS

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JP4906233B2 (ja) 2012-03-28
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CA2477923A1 (en) 2003-09-12
CA2477923C (en) 2021-02-23
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AU2003213719A8 (en) 2003-09-16
US20170362182A1 (en) 2017-12-21
JP2010180239A (ja) 2010-08-19
US20190169130A1 (en) 2019-06-06
US20140162989A1 (en) 2014-06-12
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