DETAILED DISCLOSURE OF THE INVENTION

[0040] 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. Examples of 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, carbamazepine/acetic acid, carbamazepine/1,3,5,7-adamantanetetracarboxylic acid, carbamazepine/benzoquinone, carbamazepine/butyric acid, carbamazepine/dimethyl sulfoxide (DMSO), carbamazepine/formamide, carbamazepine/formic acid, and carbamazepine/trimesic acid, which have been characterized by various techniques and exhibit physical properties different from the parent pharmaceutical ingredient as a direct result of hydrogen bonding interaction. These crystalline assemblies can afford improved drug solubility, dissolution rate, stability and bioavailability, for example.

[0041] In one aspect, 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.

[0042] In another aspect, 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. Thus, according to this method, the formation of homosynthons for the purpose of disrupting the intermolecular interactions between pharmaceutical moieties can be carried out.

[0043] In still another aspect, 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.

[0044] In each of the three aspects of the methods described above, 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. In addition, 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.

[0045] 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.

[0046] By way of example, the external functionalities of ibuprofen are an isopropyl group and a carboxylic acid, as shown in FIG. 1.

[0047] Using the methods of the subject invention, it has been determined that this interaction can be disrupted by co-crystallization with an aromatic amine, as shown in FIG. 2. Specifically, by using diamines, 2:1 multiple-component phases of ibuprofen have been prepared, as shown in FIG. 3, as well as other phases exemplified herein. Therefore, the methods of the subject invention can be used to identify complementary chemical functionalities and produce multiple-component phase compositions for a variety of pharmaceuticals, including those pharmaceutical compounds with structures very different those of ibuprofen, flurbiprofen, and aspirin, which are shown in FIGS. 13A-13C, respectively.

[0048] As used herein, the term “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. Examples of 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. Preferably, 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.

[0049] The terms “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. As used herein, 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, 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. 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.

[0050] As used herein, 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.

[0051] 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. Optionally, 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. For example, Remington's Pharmaceutical Science (Martin EW [1995] Easton Pa., Mack Publishing Company, 19^th ed.) describes formulations that can be used in connection with the subject invention. 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. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the subject invention can include other agents conventional in the art having regard to the type of formulation in question.

[0052] In terms of superstructure, 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.

[0053] 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.

[0054] In the context of organic and pharmaceutical solids, 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. These 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).

[0055] 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.

[0056] 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.

[0057] The following pages describe examples of multiple-component crystalline phases that have been characterized using single crystal X-ray crystallography and structure-sensitive analytical techniques: FT-IR, XRPD, DSC, TGA. They represent prototypal examples of the invention as they are all based upon pharmaceutical molecules that are inherently predisposed to form supramolecular synthons with other complementary functional groups. They were chosen for study because of well-known limitations in their solubility/bioavailibility. In each example, the nature of the pure phase is discussed and it is sustained by a supramolecular homosynthon (self-complementary functionalities). 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.

EXAMPLE 1

Multi-Component Crystal of Acetaminophen: Acetominophen/4,4′-Bipyridine/Water (1:1:1 Stoichiometry)

[0058] 50 mg (0.3307 mmol) acetaminophen and 52 mg (0.3329 mmol) 4,4′-bipyridine were dissolved in hot water and allowed to stand. Slow evaporation yielded colorless needles of a 1:1:1 acetaminophen/4,4′-bipyridine/water co-crystal, as shown in FIG. 4B.

[0059] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₃₆H₄₄N₂O₄, M=339.84, triclinic, space group P{overscore (I)}; a=7.0534(8), b=9.5955(12), c=19.3649(2) Å, a=86.326(2), β=80.291(2), γ=88.880(2)°, U=1308.1(3) ų, T=200(2) K, Z=2, μ(Mo-Kα)=0.090 mm⁻¹, D_c=1.294 Mg/m³, λ=0.71073 ų, F(000)=537, 2θ_max=25.02°; 6289 reflections measured, 4481 unique (R_int=0.0261). Final residuals for 344 parameters were R₁=0.0751, wR₂=0.2082 for I>2σ((I), and R₁=0.1119, wR₂=0.2377 for all 4481 data.

[0060] 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 π-π interactions between the phenyl groups of the acetaminophen moieties.

[0061] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 57.77° C. (endotherm); m.p.=58-60° C. (MEL-TEMP); (acetaminophen m.p.=169° C., 4,4′-bipyridine m.p.=111-114° C.).

EXAMPLE 2

Multi-Component Crystal of Phenytoin: Phenytoin/Pyridone (1:1 Stoichiometry)

[0062] 28 mg (0.1109 mmol) phenytoin and 11 mg (0.1156 mmol) 4-hydroxypyridone were dissolved in 2 mL acetone and 1 mL ethanol with heating and stirring. Slow evaporation yielded colorless needles of a 1:1 phenytoin/pyridone co-crystal, as shown in FIG. 5B.

[0063] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₂₀H₁₇N₃O₃, M=347.37, monoclinic P2_I/c; a=16.6583(19), b=8.8478(10), c=11.9546(14) Å, β=96.618(2)°, U=1750.2(3) ų, T=200(2) K, Z=4, μ(Mo-Kα)=0.091 mm⁻¹, D_c=1.318 Mg/m³, λ=0.71073 ų, F(000)=728, 2θ_max=56.600; 10605 reflections measured, 4154 unique (R_int=0.0313). Final residuals for 247 parameters were R₁=0.0560, wR₂=0.1356 for I>2σ(I), and R₁=0.0816, wR₂=0.1559 for all 4154 data.

[0064] 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.

[0065] 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.

[0066] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 233.390 C (endotherm) and 271.330 C (endotherm); m.p.=231-2330 C (MEL-TEMP); (phenytoin m.p.=295° C., pyridone m.p.=148° C.).

[0067] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), a 29.09% weight loss starting at 192.80° C., 48.72% weight loss starting at 238.27° C., and 18.38% loss starting at 260.17° C. followed by complete decomposition.

[0068] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kα (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. In all cases of recrystallization and solid state reaction, experimental (calculated): 5.2 (5.3); 11.1 (11.3); 15.1 (15.2); 16.2 (16.4); 16.7 (17.0); 17.8 (17.9); 19.4 (19.4); 19.8 (19.7); 20.3 (20.1); 21.2 (21.4); 23.3 (23.7); 26.1 (26.4); 26.4 (26.6); 27.3 (27.6); 29.5 (29.9).

EXAMPLE 3

Multi-Component Crystal of Aspirin (Acetylsalicylic Acid): Aspirin/4,4′-bipyidine (2:1 Stoichiometry)

[0069] 50 mg (0.2775 mmol) aspirin and 22 mg (0.1388 mmol) 4,4′-bipyridine were dissolved in 4 mL hexane. 8 mL ether was added to the solution and allowed to stand for one hour, yielding colorless needles of a 2:1-aspirin/4,4′-bipyridine co-crystal, as shown in FIG. 6D. Alternatively, aspirin/4,4′-bipyridine (2:1 stoichiometry) can be made by grinding the solid ingredients in a pestle and mortar.

[0070] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₂₈H₂₄N₂O₈, M=516.49, orthorhombic Pbcn; a=28.831(3), b=11.3861(12), c=8.4144(9) Å, U=2762.2(5) ų, T=173(2) K, Z=4, μ(Mo-Kα)=0.092 mm, Dc=1.242 Mg/m³, λ=0.71073 ų, F(000)=1080, 2θ_max=25.020; 12431 reflections measured, 2433 unique (R_int=0.0419). Final residuals for 202 parameters were R₁=0.0419, wR₂=0.1358 for I>2σ((I), and R₁=0.0541, wR₂=0.1482 for all 2433 data.

[0071] 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. In addition to the dominant hydrogen bonding interaction of the heterodimer, π-π stacking of the bipyridine and phenyl groups of the aspirin and hydrophobic interactions contribute to the overall packing interactions.

[0072] 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.

[0073] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 95.14° C. (endotherm); m.p.=91-96° C. (MEL-TEMP); (aspirin m.p.=1345° C., 4,4′-bipyridine m.p.=111-114° C.).

[0074] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), weight loss of 9% starting at 22.62° C., 49.06% weight loss starting at 102.97° C. followed by complete decomposition starting at 209.37° C.

EXAMPLE 4

Multi-Component Crystal of Ibuprofen: Ibuprofen/4,4′-Bipyridine (2:1 Stoichiometry)

[0075] 50 mg (0.242 mmol) racemic ibuprofen and 18 mg (0.0960 mmol) 4,4′-bipyridine were dissolved in 5 mL acetone. Slow evaporation of the solvent yielded colorless needles of a 2:1 ibuprofen/4,4′-bipyridine co-crystal, as shown in FIG. 7D.

[0076] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₃₆H₄₄N₂O₄, M=568.73, triclinic, space group P−1; a=5.759(3), b=11.683(6), c=24.705(11) Å, α=93.674(11), β=90.880(10), γ=104.045(7)°, U=1608.3(13) ų, T=200(2) K, Z=2, μ(Mo-Kα)=0.076 mm, D_c=1.174 Mg/m³, λ=0.71073 ų, F(000)=612, 2θ_max=23.29°; 5208 reflections measured, 3362 unique (R_int=0.0826). Final residuals for 399 parameters were R₁=0.0964, wR₂=0.2510 for I>2σ(I), and R₁=0.1775, wR₂=0.2987 for all 3362 data.

[0077] Crystal packing: 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.

[0078] 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.

[0079] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 64.85° C. (endotherm) and 118.79° C. (endotherm); m.p.=113-120° C. (MEL-TEMP); (ibuprofen m.p.=75-77° C., 4,4′-bipyridine m.p.=111-114° C.).

[0080] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 13.28% weight loss between room temperature and 100.02° C. immediately followed by complete decomposition.

[0081] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kα (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. XRPD derived from the single crystal data, experimental (calculated): 3.4 (3.6); 6.9 (7.2); 10.4 (10.8); 17.3 (17.5); 19.1 (19.7).

EXAMPLE 5

Multi-Component Crystal of Flurbiprofen: Flurbiprofen/4,4′-bipyridine (2:1 Stoichiometry)

[0082] 50 mg (0.2046 mmol) flurbiprofen and 15 mg (0.0960 mmol) 4,4′-bipyridine were dissolved in 3 mL acetone. Slow evaporation of the solvent yielded colorless needles of a 2:1 flurbiprofen/4,4′-bipyridine co-crystal, as shown in FIG. 8D.

[0083] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₄₀H₃₄F₂N₂O₄, M=644.69, monoclinic P2_I/n; a=5.860(4), b=47.49(3), c=5.928(4) Å, β=107.382 (8)°, U=1574.3(19) ų, T=200(2) K, Z=2, μ(Mo-Kα)=0.096 mm⁻¹, D_c=1.360 Mg/m³, λ=0.71073 ų, F(000)=676, 2θ_max=21.690; 4246 reflections measured, 1634 unique (R_int=0.0677). Final residuals for 226 parameters were R₁=0.0908, wR₂=0.2065 for I>2σ(I), and R₁=0.1084, wR₂=0.2209 for all 1634 data.

[0084] Crystal packing: 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.

[0085] 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.

[0086] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 162.470 C (endotherm); m.p.=155-160° C. (MEL-TEMP); (flurbiprofen m.p.=110-111° C., 4,4′-bipyridine m.p.=111-114° C.).

[0087] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 30.93% weight loss starting at 31.13° C. and a 46.26% weight loss starting at 168.74° C. followed by complete decomposition.

[0088] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kα (λ=1.540562), 30 kV, 15 mA), the powder data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. 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).

EXAMPLE 6

Multi-Component Crystal of Flurbiprofen: Flurbiprofen/trans-1,2-bis (4-pyridyl) ethylene (2:1 Stoichiometry)

[0089] 25 mg (0.1023 mmol) flurbiprofen and 10 mg (0.0548 mmol) trans-1,2-bis (4-pyridyl) ethylene were dissolved in 3 mL acetone. Slow evaporation of the solvent yielded colorless needles of a 2:1 flurbiprofen/1,2-bis (4-pyridyl) ethylene co-crystal, as shown in FIG. 9B.

[0090] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₄₂H₃₆F₂N₂O₄, M=670.73, monoclinic P2_I/n; a=5.8697(9), b=47.357(7), c=6.3587(10) Å, β=109.492(3)°, U=1666.2(4) ų, T=200(2) K, Z=2, μ(Mo-Kα)=0.093 mm⁻¹, D_c=1.337 Mg/m³, λ=0.71073 ų, F(000)=704, 2θ_max=21.690, 6977 reflections measured, 2383 unique (R_int=0.0383). Final residuals for 238 parameters were R₁=0.0686, wR₂=0.1395 for I>2σ(I), and R=0.1403, wR₂=0.1709 for all 2383 data.

[0091] 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 π-π stacking and hydrophobic interactions of the bipyridine and phenyl groups of the flurbiprofen.

[0092] 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.

[0093] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 100.010 C, 125.590 C and 163.54° C. (endotherms); m.p. 153-158° C. (MEL-TEMP); (flurbiprofen m.p.=110-111° C., trans-1,2-bis (4-pyridyl) ethylene m.p.=150-153° C.).

[0094] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 91.79% weight loss starting at 133.180 C followed by complete decomposition.

[0095] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Ka (λ=1.540562), 30 kV, 15 mA), the powder data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. 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).

EXAMPLE 7

Multi-Component Crystal of Carbamazepine: Carbamazepine/p-Phthalaldehyde (1:1 Stoichiometry)

[0096] 25 mg (0.1058 mmol) carbamazepine and 7 mg (0.0521 mmol) p-phthalaldehyde were dissolved in approximately 3 mL methanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 carbamazepine/p-phthalaldehyde co-crystal, as shown in FIG. 10B.

[0097] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₃₈H₃₀N₄O₄, M=606.66, monoclinic C2/c; a=29.191(16), b=4.962(3), c=20.316(11) Å, β=92.105(8)°, U=2941(3) ų, T=200(2) K, Z=4, μ(Mo-Kα)=0.090 mm, D_c=1.370 Mg/m³, λ=0.71073 ų, F(OOO)=1272, 2θ_max=43.660, 3831 reflections measured, 1559 unique (R_int=0.0510). Final residuals for 268 parameters were R₁=0.0332, wR₂=0.0801 for I>2σ(I), and R₁=0.0403, wR₂=0.0831 for all 1559 data.

[0098] 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 π-π interactions between phenyl rings of the CBZ.

[0099] 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.

[0100] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 128.460 C (endotherm), m.p.=121-124° C. (MEL-TEMP), (carbamazepine m.p.=190.20 C, p-phthalaldehyde m.p.=116° C.).

[0101] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 17.66% weight loss starting at 30.330 C then a 17.57% weight loss starting at _100.14° C. followed by complete decomposition.

[0102] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Ka (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 30 to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. XRPD 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 (29.6); 29.4 (29.8).

EXAMPLE 8

Multi-Component Crystal of Carbamazepine: Carbamazepine/Nicotinamide (GRAs) (1:1 Stoichiometry)

[0103] 25 mg (0.1058 mmol) carbamazepine and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 carbamazepine/nicotinamide co-crystal, as shown in FIG. 11.

[0104] Using a separate method, 25 mg (0.1058 mmol) carbamazepine and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 carbamazepine/nicotinamide microcrystals (XPD).

[0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₂₁H₁₈N₄O₂, M=358.39, monoclinic P2_I/n; a=5.0961(8), b=17.595(3), c=19.647(3) Å, β=90.917(3)°, U=1761.5(5) ų, T=200(2) K, Z=4, μ(Mo-Kα)=0.090 mm⁻¹, D_c=1.351 Mg/m³, λ=0.71073 ų, F(000)=752, 2θ_max=56.600, 10919 reflections measured, 4041 unique (R_int=0.0514). Final residuals for 248 parameters were R₁=0.0732, wR₂=0.1268 for I>2σ(I), and R₁=0.1161, wR₂=0.1430 for all 4041 data.

[0106] 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 π-π interactions from the phenyl groups of the CBZ.

[0107] 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.

[0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49° C. (endotherm) and 59.05° C. (endotherm), m.p.=153-158° C. (MEL-TEMP), (carbamazepine m.p.=190.2° C., nicotinamide m.p.=150-160° C.).

[0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43° C. followed by complete decomposition.

[0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kα (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4).

EXAMPLE 9

Multi-Component Crystal of Carbamazepine: Carbamazepine/saccharin (GRAs) (1:1 Stoichiometry)

[0111] 25 mg (0.1058 mmol) carbamazepine and 19 mg (0.1037 mmol) saccharin were dissolved in approximately 4 mL ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 carbamazepine/saccharin cocrystal, as shown in FIG. 12. Solubility measurements indicate that this multiple-component crystal of carbamazepine has improved solubility over previously known forms of carbamazepine (e.g., increased molar solubility and in aqueous solutions).

[0112] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C₂₂H₁₇N₃O₄S₁, M=419.45, triclinic P−1; a=7.5140(11), b=10.4538(15), c=12.6826(18) Å, a=83.642(2)°, β=85.697(2)°, γ=75.411(2) °, U=957.0(2) ų, T=200(2) K, Z=2, μ(Mo-Kα)=0.206 mm⁻¹, D_c=1.456 Mg/m³, k=0.71073 ų, F(000)=436, 2θ_max=56.200; 8426 reflections measured, 4372 unique (R₁.t 0.0305). Final residuals for 283 parameters were R₁=0.0458, wR₂=0.1142 for I>2σ(I), and R₁=0.0562, wR₂=0.1204 for all 4372 data.

[0113] 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.

[0114] 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.

[0115] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 75.310 C (endotherm) and 177.32° C. (endotherm), m.p.=148-155° C. (MEL-TEMP); (carbamazepine m.p.=190.20 C, saccharin m.p.=228.8° C.).

[0116] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 3.342% weight loss starting at 67.03° C. and a 55.09% weight loss starting at 118.71° C. followed by complete decomposition.

[0117] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kα (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3° to 40° 2θ in continuous scan mode using a step size of 0.02° 2θ and a scan speed of 2.0°/minute. 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).

EXAMPLE 10

Multi-Component Crystal of Carbamazepine: Carbamazepine/2,6-pyridinedicarboxylic Acid (2:3 Stoichiometry)

[0118] 36 mg (0.1524 mmol) carbamazepine and 26 mg (0.1556 mmol) 2,6-pyridinedicarboxylic acid were dissolved in approximately 2 mL ethanol. Slow evaporation of the solvent yielded clear needles of a 1:1 carbamazepine/2,6-pyridinedicarboxylic acid cocrystal, as shown in FIG. 14B.

[0119] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₂₂H₁₇N₃O₅, M=403.39, orthorhombic P2(1)2(1)2(1); a=7.2122, b=14.6491, c=17.5864 Å, α=90°, β=90°, γ=90°, V=1858.0(2) ų, T=100 K, Z=4, μ(MO-Kα)=0.104 mm, D_c=1.442 Mg/m³, λ=0.71073 ų, F(000)840, 2θ_max=28.3.116641 reflections measured, 4466 unique (R_int=0.093). Final residuals for 271 parameters were R₁=0.0425 and wR₂=0.0944 for I>2σ(I).

[0120] 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.

[0121] 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).

[0122] Melting Point: 214-216° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., 2,6-pyridinedicarboxylic acid m.p.=248-250° C.).

[0123] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 69% weight loss starting at 215° C. and a 17% weight loss starting at 392° followed by complete decomposition.

EXAMPLE 11

Multi-Component Crystal of Carbamazepine: Carbamazepine/5-nitroisophthalic Acid (1:1 Stoichiometry)

[0124] 40 mg (0.1693 mmol) carbamazepine and 30 mg (0.1421 mmol) 5-nitroisophthalic acid were dissolved in approximately 3 mL methanol or ethanol. Slow evaporation of the solvent yielded yellow needles of a 1:1 carbamazepine/5-nitroisophthalic acid co-crystal, as shown in FIG. 15B.

[0125] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₄₇H₄₀N₆O₁₆, M=944.85, monoclinic C2/c; a=34.355(8), b=5.3795(13), c-23.654(6) Å, α=90°, β=93.952(6)°, γ=900, V=4361.2(18)ų, T=200(2) K, Z=4, μ(MO-Kα)=0.110 mm⁻¹, D_c=1.439 Mg/m³, λ=0.71073 ų, F(000)1968, 2θ_max=26.43°. 11581 reflections measured, 4459 unique (R_int=0.0611). Final residuals for 311 parameters were R₁=0.0725, wR₂=0.1801 for I>2σ(I), and R₁=0.1441, wR₂=0.1204 for all 4459 data.

[0126] 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.

[0127] 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).

[0128] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 190.51° C. (endotherm). m.p.=NA (decomposes at 197-200° C.) (MEL-TEMP). (carbamazepine m.p.=191192° C., 5-nitroisophthalic acid m.p.=260-261° C.).

[0129] Thennogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 32.02% weight loss starting at 2020, a 12.12% weight loss starting at 224° and a 17.94% weight loss starting at 285° followed by complete decomposition.

[0130] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using CuKa (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.022 and a scan speed of 2.0/min. 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).

EXAMPLE 12

Multi-Component Crystal of Carbamazepine: Carbamazepine/acetic Acid (1:1 Stoichiometry)

[0131] 25 mg (0.1058 mmol) carbamazepine was dissolved in approximately 2 mL acetic acid. Slow evaporation of the solvent yielded yellow needles of a 1:1 carbamazepine/acetic acid co-crystal, as shown in FIG. 16B.

[0132] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₁₇H₁₆N₂O₃, M=296.32, monoclinic P2(1)/c; a=5.1206(4), b=15.7136(13), c=18.4986(15) Å, α=90°, β=96.5460(10)°, γ=900, V1478.8(2)ų, T=100(2) K, Z=4, μ(MO-Kα)=0.093 mm⁻¹, D_c=1.331 Mg/m³, λ=0.71073 ų, F(000)624, 2θ_max=28.4°. 12951 reflections measured, 3529 unique (R_int=0.076). Final residuals for 203 parameters were R₁=0.0492, wR₂=0.1335 for I>2σ(I).

[0133] 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.

[0134] 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).

[0135] Melting Point: 187° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., acetic acid m.p.=16.6° C.).

[0136] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 20.62% weight loss starting at 104° and a 77.05% weight loss starting at 2000 followed by complete decomposition.

EXAMPLE 13

Multi-Component Crystal of Carbamazepine: Carbamazepine/13,5,7-adamantanetetracarboxylic Acid (1:1 Stoichiometry)

[0137] 15 mg (0.1524 mmol) carbamazepine and 20 mg (0.1556 mmol) 1,3,5,7-adamantanetetracarboxylic acid were dissolved in approximately 1 mL methanol or 1 mL ethanol. Slow evaporation of the solvent yields clear plates of a 2:1 carbamazepine/1,3,5,7-adamantanetetracarboxylic acid co-crystal, as shown in FIG. 17B.

[0138] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₄₄H₄₀N₂O₁₀, M=784.80, monoclinicC2/c; a=18.388(4), b=12.682(3), c=16.429(3) Å, β=100.491(6)°, V=3767.1(14) ų, T=100(2) K, Z=4, μ(MO-Kα)=0.099 mm⁻¹, D_c=1.384 Mg/m³, λ=0.71073 ų, F(000)1648, 2θ_max=28.20°. 16499 reflections measured, 4481 unique (Rint=0.⁰⁵²). Final residuals for 263 parameters were R₁=0.0433 and wR₂=0.0913 for I>2σ(I).

[0139] 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.

[0140] 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).

[0141] Melting Point: (MEL-TEMP). 258-260° C. (carbamazepine m.p.=191-192° C., adamantanetetracarboxylic acid m.p.=>390° C.).

[0142] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 9% weight loss starting at 189° C., a 52% weight loss starting at 251° C. and a 31% weight loss starting at 374° C. followed by complete decomposition.

EXAMPLE 14

Multi-Component Crystal of Carbamazepine: Carbamazepine/benzoquinone (1:1 Stoichiometry)

[0143] 25 mg (0.1058 mmol) carbamazepine and 11 mg (0.1018 mmol) benzoquinone was dissolved in 2 mL methanol or THF. Slow evaporation of the solvent produced an average yield of yellow crystals of a 1:1 carbamazepine/benzoquinone co-crystal, as shown in FIG. 18B.

[0144] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₂₁H₁₆N₂O₃, M=344.36, monoclinic P2(1)/c; a=10.3335(18), b=27.611(5), c=4.9960(9) Å, β=102.275(3)°, T=100(2) K, Z=3, Dc=1.232 Mg/m³, μ(MO-Kα)=0.084 mm⁻¹, λ=0.71073 ų, F(000)540, 2θ_max=28.24°. 8392 reflections measured, 3223 unique (R_int=0.1136). Final residuals for 199 parameters were R₁=0.0545 and wR₂=0.1358 for I>2σ(I), and R₁=0.0659 and all 3223 data.

[0145] 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.

[0146] 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).

[0147] Melting Point: 170° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., benzoquinone m.p.=115.7° C.).

[0148] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 20.62% weight loss starting at 1680 and a 78% weight loss starting at 223° followed by complete decompositon.

EXAMPLE 15

Multi-Component Crystal of Carbamazepine: Carbamazepine/butyric acid (1:1 Stoichiometry)

[0149] 10 mg (0.0423 mmol) carbamazepine was dissolved in approximately 1 mL butyric acid. Slow evaporation of the solvent mixture produced an average yield of yellow/brown crystals of a 1:1 carbamazepine/butyric acid co-crystal, as shown in FIG. 19B.

[0150] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₁₉H₂ON₂O₃, M=324.37, triclinic P−1; a=9.1567, b=10.1745, c=10.5116 Å, α=72.850°, β=70.288°, γ=67.2690, V=832.17 ų, T=100° K, Z=2, μ(MO-Kα)0.088 mm⁻¹, D_c=1.290 Mg/m³, λ=0.71073 ų F(000)344, 2θ_max=28.28°. 5315 reflections measured, 3686 unique (R_int=0.0552). Final residuals for 217 parameters were R₁=0.0499, wR₂=0.1137 for I>2σ(1), and R₁=0.0678, wR₂=0.1213 for all 3686 data.

[0151] 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.

[0152] 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).

[0153] Melting Point: 63-64° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., butyric acid m.p.=-94° C.).

[0154] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA).16% weight loss starting at 540, a 16% weight loss starting at 134° and a 49% weight loss starting at 1740 followed by complete decomposition.

EXAMPLE 16

Multi-Component Crystal of Carbamazepine: Carbamazepine/DMSO (1:1 Stoichiometry)

[0155] 25 mg (0.1058 mmol) carbamazepine was dissolved in approximately 1.5 mL DMSO. Slow evaporation of the solvent yielded colorless plates of a 1:1 carbamazepine/DMSO co-crystal, as shown in FIG. 20B.

[0156] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₃₄H₃₆N₄O₄S₂, M=628.79, triclinic P-1; a-7.3254(19), b=8.889(2), c=12.208(3) Å, α94.840(5)°, β=94.926(5)°, γ=100.048(5)°, V=775.8(3)ų, T=200(2) K, Z=2, μ(MO-Kα)=0.216 mm⁻¹, D_c=1.320 Mg/m³, k=0.71073 ų, F(000)320, 2θ_max=28.3°. 4648 reflections measured, 3390 unique (R_int=0.0459). Final residuals for 209 parameters were R₁=0.0929, wR₂=0.3043 for I>2σ(I).

[0157] 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 π-π interactions from the tricyclic azepine ring system groups of the CBZ.

[0158] 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).

[0159] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 100° C., 193° C. (endotherms). m.p.=189° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., DMSO m.p.=18.45° C.)

[0160] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 26% weight loss starting at 1020, a 64% weight loss starting at 2120 followed by complete decomposition.

EXAMPLE 17

Multi-Component Crystal of Carbamazepine: Carbamazepine/formamide (1:1 Stoichiometry)

[0161] 10 mg (0.0423 mmol) carbamazepine was dissolved in a mixture of approximately 1 mL formamide/1 mL THF or 1 mL formamide/1 mL methanol. Slow evaporation of the solvent mixture produced an average yield of clear needles of a 1:1 carbamazepine/formamide co-crystal, as shown in FIG. 21B.

[0162] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₁₆H₁₅N₃O₂, M=281.31, triclinic P-1; a—5.1077(11), b=16.057(3), c=17.752(4) Å, α=73.711(3)°, β=89.350(3)°, γ=88.636(3)°, V=1397.1(5) ų, T=100° K, Z=4, μ(MO-Kα)=0.091 mm⁻¹, D_c=1.337 Mg/m³, λ=0.71073 ų, F(000)592, 2θ_max=28.33°. 11132 reflections measured, 6272 unique (R_int=0.1916). Final residuals for 379 parameters were R₁=0.0766 and wR₂=0.1633 for I>2σ(I).

[0163] 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.

[0164] 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).

[0165] Melting Point: 142-144° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., formamide m.p.=-94° C.).

[0166] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 27% weight loss starting at 1380, a 67% weight loss starting at 195° followed by complete decomposition.

EXAMPLE 18

Multi-Component Crystal of Carbamazepine: Carbamazepine/formic Acid (1:1 Stoichiometry)

[0167] 40 mg (0.1693 mmol) carbamazepine was dissolved in approximately 2 mL formic acid. Slow evaporation of the solvent yielded off-white starbursts of a 1:1 carbamazepine/formic acid co-crystal, as shown in FIG. 22B.

[0168] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₁₆H₁₄N₂O₃, M=282.29, monoclinic P2_I/c; a=5.2031(9), b=14.741(2), c=17.882(3) Å, α=90°, β=98.132(3)°, γ=900, V=1357.7(4)ų, T=100 K, Z=4, μ(MO-Kα)=0.097 mm¹, D_c=1.381 Mg/m³, k=0.71073 ų, F(000)592, 2θ_max=28.3. 9402 reflections measured, 3191 unique (R_int=0.111). Final residuals for 190 parameters were R₁=0.0533 and wR₂=0.1268 for I>2σ(I).

[0169] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxylic acid-amineheterodimers arranged in centrosymmetric tetramers.

[0170] 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).

[0171] Melting Point: 187° C. (MEL-TEMP). (carbamazepine m.p.=191-192° C., formic acid m.p.=8.4° C.).

[0172] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 14.60% weight loss starting at 123° and a 68.91% weight loss starting at 1960 followed by complete decomposition.

EXAMPLE 19

Multi-Component Crystal of Carbamazepine: Carbamazepine/trimesic Acid (1:1 Stoichiometry)

[0173] 36 mg (0.1524 mmol) carbamazepine and 31 mg (0.1475 mmol) trimesic acid were dissolved in a solvent mixture of approximately 2 mL methanol and 2 mL dichloromethane. Slow evaporation of the solvent mixture yielded white starbursts of a 1:1 carbamazepine/trimesic acid co-crystal, as shown in FIG. 23B.

[0174] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C₂₄H₁₈N₂O₇, M=446.26, monoclinic C2/c; a=32.5312(50), b=5.2697(8), c=24.1594(37) Å, α=90°, β=98.191(3)°, γ=900, V=4099.39(37) ų, T=-173 K, Z=8, μ(MO-Kα)=0.110 mm⁻¹, D_c=1.439 Mg/m³, k=0.71073 ų, F(000)1968, 2θ_max=26.43°. 11581 reflections measured, 4459 unique (R_int=0.0611). Final residuals for 2777 parameters were R₁=0.1563, wR₂=0.1887 for I>2((I), and R₁=0.1441, wR₂=0.1204 for all 3601 data.

[0175] 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.

[0176] 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).

[0177] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 273° C. (endotherm). m.p.=NA, decomposes at 278° C. (MEL-TEMP). (carbamazepine m.p.=191192° C., trimesic acid m.p.=380° C.)

[0178] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 62.83% weight loss starting at 2530 and a 30.20% weight loss starting at 2780 followed by complete decomposition.

[0179] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using CuKα (λ=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.022 and a scan speed of 2.0/min. XRPD analysis experimental: 10.736, 12.087, 16.857, 24.857, 27.857.

[0180] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0181] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.