MULTICOMPONENT CRYSTAL FORMULATIONS

Abstract

A multicomponent crystal (or co-crystal) comprising a first active pharmaceutical ingredient and a second active pharmaceutical ingredient. The multicomponent crystal is formed/sustained by non-covalent interactions between the nitrogen-containing heterocycle alpha-substituted with an amino group of the first active pharmaceutical ingredient and a carboxylic acid group of the second active pharmaceutical ingredient, suitably as well as other further non-covalent interactions with other H-bond forming groups. The multicomponent crystal may provide an improved multidrug dosage form comprising lamotrigine and valproic acid as the first and second active pharmaceutical ingredients, respectively. A pharmaceutical composition comprising a therapeutically effective amount of the multicomponent crystal and a pharmaceutically acceptable excipient, and a method of forming the multicomponent crystal, are also provided.

Claims

1. A multicomponent crystal of a first active pharmaceutical ingredient and a second active pharmaceutical ingredient; wherein the first active pharmaceutical ingredient comprises a nitrogen-containing heterocycle substituted with an amino group; wherein the second active pharmaceutical ingredient comprises a carboxylic acid group; and wherein the nitrogen-containing heterocycle substituted with an amino group of the first active pharmaceutical ingredient interacts with the carboxylic acid of the second active pharmaceutical ingredient, in the multicomponent crystal.

2. The multicomponent crystal according to claim 1, wherein the first active pharmaceutical ingredient and/or the second active pharmaceutical ingredient form non-covalent interactions with other H-bond forming groups of the components of the multicomponent crystal.

3. The multicomponent crystal according to claim 1, wherein the nitrogen-containing heterocycle substituted with an amino group of the first active pharmaceutical ingredient has the structure (I): ##STR00007## wherein R.sup.1 and R.sup.2 are each independently selected from H, a C.sub.1-C.sub.8 alkyl, a C.sub.1-C.sub.8 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups; wherein n=0, 1, 2 or 3; wherein X, Y and each Z are independently selected from N or C atoms; wherein said N atoms are optionally substituted with a C.sub.1-C.sub.8 alkyl, a C.sub.1-C.sub.8 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, which are optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups; and wherein said C atoms are optionally substituted with C.sub.1-C.sub.8 alkyl, a C.sub.1-C.sub.8 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups, or wherein said C atoms are optionally substituted with NR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are each independently selected from H, a C.sub.1-C.sub.4 alkyl, a C.sub.1-C.sub.4 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups.

4. The multicomponent crystal according to claim 1, wherein the nitrogen-containing heterocycle substituted with an amino group of the first active pharmaceutical ingredient has the structure (II): ##STR00008## wherein R.sup.1 and R.sup.2 are each independently selected from H, a C.sub.1-C.sub.8 alkyl, a C.sub.1-C.sub.8 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups; wherein R.sup.3 and R.sup.4 are each independently selected from H, NR.sup.5R.sup.6, C.sub.1-C.sub.8 alkyl, a C.sub.1-C.sub.8 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups; wherein R.sup.5 and R.sup.6 are each independently selected from H, a C.sub.1-C.sub.4 alkyl, a C.sub.1-C.sub.4 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups.

5. The multicomponent crystal according to claim 1, wherein the second active pharmaceutical ingredient has the ##STR00009## structure (V): wherein X is H or a negative charge; and wherein R.sup.7 is selected from C.sub.1-C.sub.10 alkyl, a C.sub.1-C.sub.10 alkenyl, an aryl group, an alkylaryl group, a heteroaryl group or an alkylheteroaryl group, optionally substituted with one or more of C.sub.1-C.sub.4 alkoxy, hydroxy, amino, carboxylic acid, ester, amide, halogen, CF.sub.3, CHF.sub.2 or CH.sub.2F groups.

6. The multicomponent crystal according to claim 1, wherein the first active pharmaceutical ingredient is selected from lamotrigine, 4-aminopyridine, cytosine, thymine, 5-fluorocytosine, dihydralazine, endralazine, hydralazine, pipofezine, minaprine, cadralazine or cefozopran.

7. The multicomponent crystal according to claim 1, wherein the second active pharmaceutical ingredient is selected from valproic acid and/or a valproate salt, NSAIDs—including salicylate derivative NSAIDs, p-amino phenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs and fenamic acid derivative NSAIDs—non-selective cyclo-oxygenase (cox) inhibitors, selective cyclooxygenase 1 (cox 1) inhibitors, selective cyclooxygenase 2 (cox 2) inhibitors or an antibiotic such as oxacillin, ampicillin, amoxicillin, cephalexin, cephalotin, cephalosporin, p-amino-salicylic acid, ciprofloxacin, enrofloxacin, difloxacin or danofloxacin.

8. The multicomponent crystal according to claim 1, wherein the second active pharmaceutical ingredient is a pharmaceutically acceptable excipient.

9. The multicomponent crystal according to claim 8, wherein the second active pharmaceutical ingredient is benzoic acid.

10. The multicomponent crystal according to claim 1, wherein the molar ratio of the first active pharmaceutical ingredient to the second active pharmaceutical ingredient in the multicomponent crystal is 1:2.

11. The multicomponent crystal according to claim 1, wherein the interaction of the nitrogen-containing heterocycle substituted with an amino group of the first active pharmaceutical ingredient and the carboxylic acid group of the second active pharmaceutical ingredient comprises an R.sub.1.sup.2 (4) synthon.

12. The multicomponent crystal according to claim 1, wherein the interaction of the nitrogen-containing heterocycle substituted with an amino group of the first active pharmaceutical ingredient and the carboxylic acid group of the second active pharmaceutical ingredient comprises an R.sub.2.sup.2(8) synthon.

13. The multicomponent crystal according to claim 1, wherein the multicomponent crystal of this first aspect comprises a neutral form of at least one of the first or second active pharmaceutical ingredients.

14. The multicomponent crystal according to claim 1, comprising an ionic form and a neutral form of the first active pharmaceutical ingredient and an ionic form and a neutral form of the second active pharmaceutical ingredient; and wherein the first active pharmaceutical ingredient and the second active pharmaceutical ingredient are organic compounds.

15. The multicomponent crystal according to claim 1 in the form of a medicament.

16. The multicomponent crystal according to claim 1 in the form of a medicament useful in the treatment of epilepsy.

17. A method of preparing a multicomponent crystal comprising at least two active pharmaceutical ingredients, the method comprising the steps of: a) providing a first active pharmaceutical ingredient comprising a nitrogen-containing heterocycle substituted with an amino group; b) providing a second active pharmaceutical ingredient comprising a carboxylic acid; c) combining the first active pharmaceutical ingredient and the second active pharmaceutical ingredient; and d) crystallising the combination of the first active pharmaceutical ingredient and the second active pharmaceutical ingredient obtained from step c) to provide the multicomponent crystal.

18. A pharmaceutical composition comprising a therapeutically effective amount of a multicomponent crystal according to claim 1 and a pharmaceutically acceptable excipient.

19. The multicomponent crystal according to claim 1, wherein the first active pharmaceutical ingredient is lamotrigine and wherein the second active pharmaceutical ingredient is valproic acid.

Description

EXAMPLES

[0103] Materials and Methods

[0104] In the following description, the comparative example lamotrigine (single API) is termed “LAM” and the multicomponent crystal of lamotrigine and valproic acid is termed “LAMVAL”.

[0105] Lamotrigine and valproic acid (also termed “VAL” herein) were obtained from Baoji Guokang Bio-Technology Co. Ltd. and used without further purification. All other solvents and reagents were purchased from Sigma-Aldrich and used as received.

Example 1—Lamotrigine:Valproic Acid

[0106] Synthesis of lamotrigine:valproic acid (1:2) ionic cocrystal (LAMVAL): 256.09 mg of lamotrigine (1 mmol) and 1.82 ml of valproic acid (2 mmol) were placed in a mortar and pestle and manually ground for 5 minutes until a dry, fine white powder was produced. Synthesis was also attempted by ball milling the same reagents in Retsch MM400 shaker mill in a 15 mL steel vessel with one 15 mm steel ball at 25 hz for 15 min.

[0107] Slurry experiments were conducted by stirring 256.09 mg of lamotrigine (1 mmol) and 1.82 ml of valproic acid (2 mmol) in deionised water (10 ml) for 48 h. The product was recovered by filtration and dried in air.

[0108] Recrystallization was attempted by slow evaporating a solution of about 5 mg of the microcrystalline powder in 20 ml of ethanol in a vial and by slow cooling of a hot solution containing 5 mg of the microcrystalline powder in 20 ml of 1:1 isopropanol/methanol (vide infra).

[0109] Powder X-ray diffraction (PXRD): X-ray powder diffraction (XRPD) patterns were collected in Bragg-Brentano geometry on a PANalytical Empyrean diffractometer equipped with a sealed tube (Cu Kα.sub.12, λ=1.5418 Å) an 1D X'Celerator detector between 4 and 40° 2θ.

[0110] Variable temperature PXRD data were collected in Bragg-Brentano geometry on a X'Pert MPD Pro equipped with a Anton-Paar TK450 stage, a sealed tube (Cu Kα.sub.12, λ=1.5418 Å) and a 1 D X'Celerator detector in the 4-30° (2θ) range.

[0111] Single-crystal X-ray Diffraction: Single crystals were manually selected and mounted with Paratone® oil on a polymeric fibre. Data was collected at room temperature (298 K) as well as at 100 K on a Bruker Quest D8 diffractometer equipped with Mo sealed tube Tube (Mo-Kα radiation λ=0.71073 Å), a Photon II CPAD detector and Oxford Cryosystem Cryostreem 800. Data was integrated with the APEX program suite and empirically corrected for absorption correction. Structure solution was found through direct methods in SHELX through X-Seed. All heavy atoms were found on the electron density map and refined anisotropically against all F.sup.2.sub.obb. H atoms were constrained through the riding model in their position as determined by an analysis of the distances between heavy atoms.

[0112] Results and Discussion

[0113] Crystal Synthesis and Structure Analysis

[0114] The neat grinding described above of a 1:2 ratio of LAM and VAL in a ball mill affords a dry microcrystalline powder. PXRD reveals that the product is stable as a slurry in water. Recrystallization by slow evaporation from ethanol resulted in crystals of a lamotrigine ethanolate (CSD ref. code GEVYOY). Recrystallization by slow cooling from isopropanol/methanol, affords quality single crystals of the title multicomponent crystal: LAMVAL. The monoclinic P2,1n unit cell comprises two LAM and four VAL independent residues. PXRD confirms the identity between the bulk powder and the single crystal, as shown in FIG. 1 wherein the traces in order from the top show the PXRD data for lamotrigine; LAMVAL after stability test; LAMVAL after slurring in water; LAMVAL by ball mill; and calculated from LAMVAL single crystal data.

[0115] Since traditional X-ray diffraction cannot determine the hydrogen position in a reliable manner, the values of C—O distances were used to confirm that one LAM and one VAL species are ionised forming an ionic or salt multicomponent crystal. Crystals forms in which both components have mixed ionization state are rarely seen. LAMVAL may be considered to belong to a novel type of multicomponent crystal that could be represented as (aA)A*B.sup.−(bB).

[0116] FIG. 2 shows a graph set analysis of LAMVAL highlighting key intermolecular interactions. The supramolecular structure is rather complex and multiple motifs can be recognised. One VAL molecule forms a typical R.sub.2.sup.2(8) heterosynthon with the neutral LAM through the N2 donor. Another R.sub.2.sup.2(8) motif forms between the aminopyridine moiety of the neutral LAM and the aminopyridine moiety of the cationic LAM involving both the N4 donors, as shown in FIG. 2. Notably the triazine rings in the synthon lay on different planes. The carbonyl oxygen of a VAL stabilises the interaction by bridging the adjacent amine hydrogens: R.sub.3.sup.2(8). The same VAL also donates into a charged assisted H-bond with the valproate generating a R.sub.3.sup.2(10) motif. In the cation, the proton sits on the most basic nitrogen (N2) and a double, charge-assisted H-bond forms with the carboxylate anion: R.sub.1.sup.2(4) motif. Finally, the last VAL donates into the valproate (D), and bridges with an adjacent complex to guarantee 1D H-bonded structure along the b crystallographic direction (FIG. 2).

[0117] From a supramolecular point of view, the R.sub.1.sup.2 (4) motif is unusual. A CSD analysis revealed only another example of such motif (CSD ref. code VECVAD) out of 349 total entries containing aminopyridinium-carboxylate interactions (see methods). In all the other cases, the typical R.sub.2.sup.2(8) motif is present, which involves both the pyridinium and the amino functions.

[0118] A CSD search of the multicomponent crystals that include LAM with carboxylic groups revealed that in 43 out of 48 cases LAM is protonated in the N2 position. In the remaining five cases (CSD ref. codes HUQIVA QIQHIJ QIQHOP WOKXUR GAVLEV), C—O bond distance analysis suggest that a partial charge transfer is present: the proton is reported either disordered over the nitrogen and oxygen positions or sitting half way. Such behaviour is consistent with the aforementioned idea of a continuum between neutral and ionised forms.

[0119] A visual inspection reveals that in all the structures with partial charge transfer, the R.sub.2.sup.2(8) is always isolated. On the contrary, in the structures reported as salts, the carboxylate is always involved in at least another H-bond: with carboxylic, amine or hydroxyl donors. Indeed, a CSD search revealed other 62 cases of the same charge-assisted synthon involving either three or four functional groups in structures containing α-aminopyridines, α-aminopyrazine, or α-aminotriazine with carboxylic acids.

[0120] These observations suggest that the ionic character of the synthons could be related to the presence of ancillary H-bond donors. Such behaviour is exemplified by two forms of LAM and acetic acid (AA). LIBXUR is an ionic multicomponent crystal of LAM and AA in a 1:3 ratio that shows the same synthon as LAMVAL. In the new LAMAA 1:1 salt, two independent ionic R.sub.2.sup.2(8) synthon are complemented by an H-bonded amine group each. In these cases, the difference in C—O distances 0.003(2), 0.001(2) and 0.045(2), suggest that the degree of ionization decreases with the H-bond donor distance: the 2.553(2), 2.752(2) and 2.912(2) respectively.

[0121] Such hypothesis was further confirmed computationally. The refinement of hydrogen positions in the four-molecular synthon of LIBXUR confirms that the ionic multicomponent crystal is the most stable form. On the contrary when the same refinement is performed on the isolated two-molecular R.sub.2.sup.2(8) synthon, the multicomponent crystal form is the favoured (FIG. 3). FIG. 3 shows the following—Top: molecular and supramolecular distances as measured by single crystal XRD data for LIBXUR (left) and LAMAA (right). Bottom: molecular and supramolecular distances as measured from the DFT refined model LIBXUR (left) and LAMAA (right).

[0122] Fourier-transform infrared spectroscopy (FTIR) was employed to investigate the mechanism behind the solid state changes in the powder material. FIG. 4 illustrates major peaks relating to presence of starting materials and demonstrated changes within the fingerprint region, suggestive of the formation of a new solid form. Of note, there is a shift of 1609 peak in LAM to 1638 in LAMVAL related to amine protons, a more pronounced peak at 1540 in LAMVAL, at 1444 slight peak change in LAMVAL, a new peak at 1058 in LAMVAL, 936 band missing in LAMVAL replaced by new band at 905-1005 and the increase of the 666 peak LAMVAL. All of these changes could be related to the formation of intermolecular H-bonds.

[0123] Survey of Cambridge Structural Database (CSD): The Cambridge Structural Database was searched through ConQuest (v. 1.23, 2018) and the retrieved entries were subsequently analysed with Mercury (v. 3.10.3, 2018). In all cases, the cut off distance for the interatomic interactions between H and O was set equal to the sum of vdW radii+0.3 Å. This precaution was justified by the possible errors associated with the H position.

[0124] Quantumechanical calculation: Computational studies were performed with GAUSSIAN 09. Model structures were created starting from the crystallographic data replacing the propyl groups on each valproic acid with H atoms. The coordinates of all the H and O atoms plus those of selected C and N were refined by M06-2X/6-31+G(d,p) level of theory.

[0125] Thermal Analysis: Thermogravimetric analysis (TGA) was performed using a TA Instruments TGA-Q50 on at a constant rate of 10° C./min from 25° C. to 350° C. under a flux of nitrogen of 50 ml/min. Differential Scanning Calorimetry (DSC) was carried out using sealed aluminium pans on a TA instruments DSC-Q2000 differential scanning calorimeter. Temperature calibrations were made using indium as the standard. An empty pan, sealed in the same way as the sample, was used as a reference. All the thermograms were run at a heating/cooling rate of 10° C./min under a nitrogen purge at a rate of 50 ml/min. FIG. 5 shows the TGA (top) and DSC (bottom) traces for LAMVAL.

[0126] Scanning Electron Microscopy (SEM): LAM and LAMVAL were separately placed onto carbon tape and coated with a thin layer of gold followed by analysis on a Joel CarryScope JCM-5700 scanning electron microscope. Micrographs were recorded at various magnifications using a beam voltage of 2.0 kV.

[0127] Intrinsic solubility study: Compacts of LAM and LAMVAL containing equivalent amounts of LAM were made by compacting 100 mg LAM and 220 mg of LAMVAL in an 8 mm punch and die set for 3 minutes using a hydraulic press with a compaction force of 5 tonnes. These compacts were each coated with paraffin wax, leaving one surface exposed and secured to the bottom of the dissolution apparatus with excess paraffin wax. Intrinsic solubility was determined using a 900 ml well filled with 900 ml of degassed, deionised water (or 0.1 M HCl solution) on a Pharma Test USP type II system. The solution had been previously equilibrated at 37° C. and the paddle speed was set to 100 rpm after adding the samples. Aliquots of media were withdrawn at 5, 10, 15, 20 30 and 60 minutes (or 0.25, 0.5, 1, 3, 6, 12 and 24 hours), filtered through 0.45 μm PTFE filters and tested via a UV spectrometer in triplicate.

[0128] Spectrometry: Infrared analysis was performed on a Perkin-Elmer Spectrum 100 FT-IR spectrometer equipped with a solid-state ATR stage. UV-Vis absorbance measurements were carried on a Cary 60 UV-Vis spectrometer using 1 ml quartz cuvettes. Calibration curves were obtained by linear regression from a set of absorbance measurements from solutions on lamotrigine of known concentration preformed in triplicate.

[0129] Tensile stress test: Tensile strength analysis for lamotrigine and LAMVAL was conducted on tablets produced from 100 mg of milled powder (25 hz, 15 m) across a range of compaction forces using a 6 mm, flat-faced punch and die, using a Gamblen R-series tablet press. Hardness testing was performed immediately after tableting using a Pharma Test hardness tester. Each compaction force was tested in triplicate. Tensile strength was calculated according to the Equation 1 where F is the load required to fracture the tablet, D the table diameter and H the tablet height:

Tensile strength=2F/πDH  Equation 1:

[0130] Stability testing: Accelerated stability testing was conducted by taking 100 mg of powdered sample and placing it into a humidity chamber under 75% relative humidity at 40° C. for 14 days. The samples were analysed before and after testing by PXRD, FT-IR, DSC and TGA.

[0131] Physicochemical Characterization

[0132] Thermogravimetric analysis shows that LAMVAL is thermally stable up to around 100° C. Differential scanning calorimetry and variable temperature PXRD reveals that the material undergoes an enantiotropic transition above 75° C. (see FIG. 6). FIG. 6 shows the variable temperature PXRD for LAMVAL.

[0133] LAMVAL powder remains crystalline at 45° C. at 75% relative humidity for two weeks (see FIG. 1, second line from the top), and FT-IR and DSC (FIG. 7) show no sign of product degradation. FIG. 7 shows DSC (top) and FTIR (bottom) before and after accelerated stability testing.

[0134] Pharmaceutical Characterization

[0135] Scanning electron microscopy shows that a polycrystalline powder of LAMVAL is formed by clusters of smaller prisms whereas LAM forms large, smooth crystals (see FIG. 8). FIG. 8 shows SEM images of LAMVAL (left) and Lamotrigine (Right). It is well-known that crystal morphology can affect the mechanical properties of a material. The tensile strength was measured for the two materials.

[0136] Tablets of LAM and LAMVAL were prepared by compressing the polycrystalline powders at different pressure. Tablets of LAM obtained with a compaction weight lower than 400 kg were too brittle to enable hardness testing. Tablets of LAMVAL obtained in the same conditions demonstrate superior tableting properties with significantly greater tensile strength across a range of compaction forces (FIG. 9). FIG. 9 shows a comparison of physicochemical properties LAMVAL (circular data points) and pure Lamotrigine (square data points): top—tensile strength; middle—dissolution rate in PBS buffer (pH=7.4); bottom—dissolution rate in 0.1 M HCl solution (pH=1.2). In the bottom graph, the error bars are smaller than the data points.

[0137] Direct compression is the preferred method of tablet processing and enables this formulation to fit into continuous manufacturing processes, an area of particular interest for industry. Materials that show poor tabletting properties can be formulated with excipients that act as binders. Although effective, such procedures increase the size of the dosage form, a particular concern for multidrug formulations such as this. The improved mechanical properties of LAMVAL suggest that tablets could be manufactured with minimal use of excipients, which would increase the tablet size.

[0138] Measurements of intrinsic dissolution show that the ionic multicomponent crystal LAMVAL dissolves significantly (×2) faster than pure LAM (see FIG. 9). In PBS buffer, at pH 7.4, the ionic multicomponent crystal affords a concentration of lamotrigine 20% higher than the pure base. In physiological acidic conditions (pH 1.2 M) LAMVAL affords a 33% increase in lamotrigine concentration.

[0139] Lamotrigine is a BCS class II drug, whose bioavailability is limited by poor solubility. Attempts at crystal engineering have been reported that aimed to find forms that are more soluble. In those cases, the formation of neutral adducts resulted in a material less soluble than LAM. On the contrary, LAMVAL produced a higher dissolution rate in in vitro physiological conditions, which could translate into increased bioavailability, without the need for excipients and therefore avoiding an increase in the size of the dosage form.

CONCLUSIONS

[0140] A stable ionic multicomponent crystal of LAM and VAL has been obtained either mechano-chemically or from solution in a reliable manner. The physicochemical properties such as dissolution rate and tabletability are significantly higher than those of LAM alone. Most importantly, the 1:2 stoichiometry appears to improve the pharmacokinetics of the APIs making LAMVAL an ideal candidate for a marketable multidrug dosage form.

[0141] The LAMVAL structure is sustained by a complex set of supramolecular motifs that include a four-component ionic synthon between the pyridinium a carboxylate and two ancillary carboxylic acids.

Example 2—Lamotrigine:Benzoic Acid

[0142] Synthesis of lamotriginium:benzoate:benzoic acid ionic cocrystal: 25.6 mg of lamotrigine (0.1 mmol) and 24.4 mg of benzoic acid (0.2 mmol) in were dissolved in a 20 ml solution of 1:1 isopropanol/methanol by heating and recrystallization was attempted by slow cooling.

[0143] Single-crystal X-ray Diffraction: X-ray diffraction data was collected and analysed as described above for Example 1, apart from data here being collected at room temperature and 150 K on the Bruker Quest D8 diffractometer, to provide the crystal structure shown in FIG. 10 and discussed below.

[0144] Results: FIG. 10 displays graph-set analysis of the ionic cocrystal of Example 2. One benzoic acid cation forms a R.sub.2.sup.2(8) heterosynthon with the aminopyridinum group in lamotrigine resulting in proton transfer from benzoic acid to lamotrigine. The proton is located on the most basic nitrogen (N2) as seen previously. Another neutral benzoic acid donates into the benzoate (D) to stabilise this charged interaction.

Example 3—Lamotrigine:Benzoate:Isopropanol

[0145] Synthesis of lamotriginium:benzoate:isopropanol: 25.6 mg of lamotrigine (0.1 mmol) and 12.2 mg of benzoic acid (0.1 mmol) and excess acetic acid (1 ml) were dissolved in a 20 ml solution of 1:1 isopropanol/methanol by heating and recrystallization was attempted by slow cooling.

[0146] Single-crystal X-ray Diffraction: The crystal structure shown in FIG. 11 and discussed below was obtained for this Example 3 as described above for Example 2.

[0147] Results: FIG. 11 displays graph-set analysis of the ionic cocrystal of Example 3. As in Example 2, one benzoic acid cation forms a R.sub.2.sup.2(8) heterosynthon with the aminopyridinum group in lamotrigine resulting in proton transfer from benzoic acid to lamotrigine. The proton is located on the most basic nitrogen (N2) as described previously. However, this time the charge transfer is stabilised by isopropanol.

Example 4—Melaminium:Acetate:Acetic Acid Hydrate Cocrystal

[0148] Synthesis of Melaminium:acetate:acetic acid hydrate cocrystal: 12.6 mg of melamine (0.1 mmol) and excess acetic acid (1 ml) were dissolved in a 20 ml solution of 1:1 isopropanol/methanol by heating and recrystallization was attempted by slow cooling.

[0149] Single-crystalX-ray Diffraction: The crystal structure shown in FIG. 12 and discussed below was obtained for this Example 4 as described above for Example 2.

[0150] Results: FIG. 12 displays graph-set analysis of the ionic cocrystal of Example 4. Here, one acetic acid cation forms a R.sub.2.sup.2(8) heterosynthon with the aminopyridinum group in melamine resulting in proton transfer from acetic acid to melamine. The proton is located on the most basic nitrogen. Another neutral acetic acid in addition to a water molecule donates into the acetate (D) to stabilise this charged interaction.

[0151] The present invention demonstrates that the use of high-order synthons can provide ionic multicomponent crystals between heterocycle-amine and carboxylic acids groups in different APIs to enable the preparation of multidrug dosage forms with improved drug properties.

[0152] In summary, the present invention provides a multicomponent crystal (or co-crystal) comprising a first active pharmaceutical ingredient and a second active pharmaceutical ingredient. The multicomponent crystal is formed/sustained by non-covalent interactions between the nitrogen-containing heterocycle alpha-substituted with an amino group of the first active pharmaceutical ingredient and a carboxylic acid group of the second active pharmaceutical ingredient, suitably as well as other further non-covalent interactions with other H-bond forming groups. The multicomponent crystal may provide an improved multidrug dosage form comprising lamotrigine and valproic acid as the first and second active pharmaceutical ingredients, respectively. A pharmaceutical composition comprising a therapeutically effective amount of the multicomponent crystal and a pharmaceutically acceptable excipient is also provided.

[0153] As used herein, the term “alkyl” means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, and sec-butyl groups.

[0154] As used herein, the term “cycloalkyl” means a cyclic saturated hydrocarbon group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0155] As used herein, the term “aryl” means a carbocyclic aromatic system.

[0156] As used herein, the term “heteroaryl” means a cyclic aromatic system comprising at least one carbon atom and at least one heteroatom, for example at least one nitrogen atom.

[0157] As used herein, the term “halogen” or “halo” means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred.

[0158] “Pharmaceutically acceptable salt” means a salt such as those described in standard texts on salt formation, see for example: P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/WNey-VCH, 2002), or S. M. Berge, et al., “Pharmaceutical Salts” (1977) Journal of Pharmaceutical Sciences, 66, 1-19. Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as C.sub.1-C.sub.4alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids, which may or may not in themselves be pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.

[0159] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.

[0160] “Pharmaceutically acceptable solvate” means a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates, such as hydrates, exist when the drug substance incorporates solvent such as water, in the crystal lattice in either stoichiometric or non-stoichiometric amounts. Drug substances are routinely screened for the existence of hydrates since these may be encountered at any stage of the drug manufacturing process or upon storage of the drug substance or dosage form. Solvates are described in S. Byrn et al., Pharmaceutical Research, 1995. 12(7): p. 954-954, and Water-Insoluble Drug Formulation, 2<nd>ed. R. Liu, CRC Press, page 553, which are incorporated herein by reference.

[0161] “Therapy”, “treatment” and “treating” include both preventative and curative treatment of a condition, disease or disorder. It also includes slowing, interrupting, controlling or stopping the progression of a condition, disease or disorder. It also includes preventing, curing, slowing, interrupting, controlling or stopping the symptoms of a condition, disease or disorder.

[0162] Although a few preferred embodiments have been shown and described, it will be appreciated by those skilled in the art that various changes and modifications might be made without departing from the scope of the invention, as defined in the appended claims.

[0163] Throughout this specification, the term “comprising” or “comprises” means including the component(s) specified but not to the exclusion of the presence of other components. The term “consisting essentially of” or “consists essentially of” means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effect of the invention. Typically, when referring to compositions, a composition consisting essentially of a set of components will comprise less than 5% by weight, typically less than 3% by weight, more typically less than 1% by weight of non-specified components.

[0164] The term “consisting of” or “consists of” means including the components specified but excluding addition of other components.

[0165] Whenever appropriate, depending upon the context, the use of the term “comprises” or “comprising” may also be taken to encompass or include the meaning “consists essentially of” or “consisting essentially of”, and may also be taken to include the meaning “consists of” or “consisting of”.

[0166] The optional features set out herein may be used either individually or in combination with each other where appropriate and particularly in the combinations as set out in the accompanying claims. The optional features for each aspect or exemplary embodiment of the invention as set out herein are also to be read as applicable to any other aspect or exemplary embodiments of the invention, where appropriate. In other words, the skilled person reading this specification should consider the optional features for each exemplary embodiment of the invention as interchangeable and combinable between different exemplary embodiments.

[0167] Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0168] All of the features disclosed in this specification (including any accompanying claims, and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

[0169] Each feature disclosed in this specification (including any accompanying claims, and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0170] The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.