Cross-reference to Related Applications

[001] Priority is claimed to U.S. Application Ser. No. 61/445,573, filed 25 February 2011, the disclosure of which incorporated herein by reference.

Field of the invention

[002] The invention relates to new rebamipide complexes and new rebamipide cocrystats. In particular, the invention relates to a 1:1 rebamipide nicotinamide complex and a 1:1 rebamipide nicotinamide cocrystal. The invention also relates to a 1:1 rebamipide 2,4-dihydroxybenzpic acid complex and a 1:1 rebamipide 2,4-dihydroxybenzoic add cocrystal. The invention also relates to pharmaceutical compositions containing a rebamipide complex or cocrystal of the invention as well as methods of treatment using them.

Background

[003] Rebamipide, 2-(4-chlorobenxamfdo}-3-(2-oxo-1,2-dihydroquinolin-4-yi)prop anoic acid, shown beiow, is an agent that exhibits anti-inflammatory and antiulcer effects on the

gastrointestinal tract.

Rebamipide occurs as a white crystalline powder that is odourless and has a bitter taste, it is very slightly soluble in methanol and ethanol but is practically insoluble in water. Rebamipide is identified by CAS Registry Number: 90098-04-7. A method of preparation of rebamipide is described in JP-B- 63-35623.

[004] Rebamipide is known as an agent for improving both subjective and objective symptoms of diseases such as gastric uicer, duodenal ulcer, gastritis and other like diseases, it has also been disclosed that rebamipide Is useful in the treatment of various other diseases, for example, for the treatment of ulcerative colitis (cf., Kazuya Makiyama, "Study of the treatment of ulcerative colitis by enema therapy of rebamipide"}, for stomatitis (Japanese Patent No. 2839847), for accelerating salivation (WO/2005/01.183.1} and for inhibiting carcinogenesis of the digestive tract

{WO/1997/009045], Rebamipide is also known for having an increasing action of goblet ceil density in the eye, an increasing action of mucus in the eye and an increasing action of lacrimal fluid, and it is already known as an agent for treating dry eye {JP-A-9-301866}.

[005] Rebamipide is marketed by Otsuka Pharmaceutical Co., Ltd under the Mueosta ^® tradename, it is currently indicated for the treatment of gastric mucosal legions (erosions, bleeding, redness and edema} in acute gastritis and acute exacerbation of chronic gastritis. The typical dosage in adults is one 100 mg tablet three tiroes d3iiy.

[006] There is a need therefore to develop new forms of rebamipide that have improved dissolution, solubiiity and/or increased bioavailability. The rebamipide complexes and cocrysta!s of this invention answer such needs.

[007] Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient {API}, the salt and solid state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its harmacological properties, such as bioavailability, and to its development as a viable APi. Recently, crystalline forms of API's have been used to alter the phvsicocherofca! properties of a particular API. Each crystalline form of a drug candidate can have different solid state (physical and chemical) properties. The differences in physical properties exhibited by a novei solid form of an API {such as a cocrystai or polymorph of the original therapeutic compound) affect pharmaceutical parameters such as storage stability, compressibility and density {important in formulation and product manufacturing}, and solubiiity and dissolution rates (important factors in determining bioavailability). Because these practical physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form,, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.

[008] Obtaining crystalline forms of an API is extremely useful in drug development but is not necessarily predictable. It permits better characterization of the drug candidate's chemical and physical properties, (t is also possible to achieve desired properties of a particular APi by forming a cocrystai of the APi and a coformer. Crystalline forms often have better chemical and physical properties than the free base in its amorphous state. Such crystalline forms may, as with the cocrystai of the invention, possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a cocrystai, if achieved, may have different dissolution and solubiiity properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising a cocrystai of a given API may have superior properties over its existing drug formulations. They may also have better storage stability. [009] Another potentially important solid state property of an API is its dissolution rate in aqueous fkiid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.

[010] A cocry5tal of any APS is a new and distinct chemical composition of the API and the coforhierfs} and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer{s) individually, Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, amon other techniques. Cocrystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetrie analysis {TGA} and differential scanning calorimetry (DSC).

Summary of the Invention

[011] The invention relates to new rebamipide complexes and new rebamipide cocrystals. In particular, the invention relates to a 1:1 rebamipide nicotinamide complex, a 1:1 rebamipide nicotinamide cocrystai, a 1:1 rebamipide 2,4-dihydroxybenzoic acid complex, and a 1:1 rebamipide 2,4-dihydroxybenzoic acid cocrystai. The invention relates to pharmaceutical compositions containing a rebamipide complex or cocrystai of the invention and a pharmaceutically acceptable carrier, The rebamipide complexes and cocrystals may be used in the same way as rebamipide to treat or prevent disorders relating to gastric ulcer, duodenal ulcer, gastritis, ulcerative colitis, and stomatitis. The rebamipide complexes and cocrystals may also be used in the same way as rebamipide to accelerate salivation, to inhibit ca cinogenesis of the digestive tract, to increase action of goblet cei! density in the eye, to increase the action of mucus in the eye, to increase the action of lacrimal fluid, as weii as to treat dry eye.

Brief Description of Figures

[012] Fig. 1 shows an XRPD pattern for the 1 :1 rebamipide nicotinamide cocrystai.

[013] Fig. 2 shows a DSC trace for the 1:1 rebamipide nicotinamide cocrystai.

[014] Fig, 3 shows the ³ H WMR spectrum of the 1:1 rebamipide nicotinamide cocrystai.

[015] Fig. 4 shows the ¹³ C solid state NMR spectrum of rebamipide.

[016] Fig. 5 shows the ¹³ C solid state NMR spectrum of nicotinamide.

[017] Fig. 6 shows the ¹³ C solid state NMR spectrum of the 1:1 rebamipide nicotinamide cocrystai.

[018] Fig. 7 shows an XRPD pattern for the 1:3 rebamipide 2,4-dihydroxybenzoic acid cocrystai. [019] Fig, 8 shows a DSC trace for the 1:1 rebamipide 2,4-dihydroxybenzoie add cocrystal.

[020] Fig, 9 shows the ^l H NM spectrum of the 1:1 rebamipide 2,4-dihydroxybenzoic acid cocrystal

[021] Fig, 10 shows the ^U C so!id state fvlR spectrum of 2,4-dihydroxyberuoic acid.

[022] Fsg.li shows the ⁱ C solid state NMR spectrum of the 1:1 rebamipide 2,4-dihydroxybenzoic acid cocrystai.

Detailed Description

[023] The invention relates to improvements of the physiochemica! and/or the pharmaceutical properties of rebamipide. Disclosed herein are new rebamipide complexes and new rebamipide cocrystals. In particular, the invention relates to a 1:1 rebamipide nicotinamide complex, a 1:1 rebamipfde nicotinamide cocrystal a 1:1 rebamipide 2 4-dihydroxybemaic acid complex, and a 1:1 rebamiptde 2,4-dshydroxybenzoic acid cocrystai. The therapeutic uses of the rebamipide complexes and cocrystals of the invention are described below as we!i as therapeutic compositions containing them. The cocrystals and the methods used to characterize them are described below,

[024] Therapeutic Uses of Rebamipide Complexes and Cocrystals

[025] The invention further relates to the therapeutic use of the rebamipide complexes and cocrystals of the invention, a 1:1 rebamipide nicotinamide complex, a 1:1 rebamipide nicotinamide cocrystai, a 1:1 rebamipide 2,4-dihydroxy benzoic acid complex, and a 1:1 rebamipide 2,4- dihydroxybenzoic acid cocrystai, to treat or prevent disorders relating to gastric ulcer, duodenal ulcer, gastritis, ulcerative colitis, and stomatitis. The rebamipide complexes and cocrystals may also be used in the same way as rebamipide to accelerate salivation, to inhibit carcinogenesis of the digestive tract, to increase action of gobiet cell density in the eye, to increase the action of mucus in the eye, to increase the action of lacrimal fluid, as well as to treat dry eye. Accordingly, the invention relates to method of treating such a disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount of a rebamipide complex or cocrystai of the invention or of administering to a patient in need thereof a therapeutic composition containing a rebamipide complex or cocrystal of the invention,

[026] The term "treatment" or "treating" means any treatment of a condition or disorder in a mammal, including preventing or protecting against the condition or disorder, that is, causing the clinical symptoms not to develop; inhibiting the condition or disorder, that is, arresting or suppressing the development of clinical symptoms; and/or relieving the condition or disorder

(including the relief of discomfort associated with the condition or disorder), that is, causing the regression of clinical symptoms, !t will be understood by those skilled in the art that in human medicine, it is not always possib!e to distinguish between "preventing" and "suppressing" since the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events. Therefore, as used herein the term "prophylaxis" is intended as an element of "treatment" to encompass both "preventing" and "suppressing" the condition or disorder. The term "protection" is meant to include "prophylaxis."

Pharmaceutical Compositions Containing the Rebamipide Complexes and Cocrystals

[028] The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a rebamipide complex or cocrystai according to the invention and a

pharmaceutically acceptable carrier (also known as a pharmaceutically acceptable excipient). As mentioned above, these pharmaceutical compositions are therapeutically useful to treat or prevent disorders such as those discussed above.

[029] A pharmaceutical composition of the invention may be in any pharmaceutical form which contains a rebamipide complex or cocrystai according to the invention. The pharmaceutics! composition may be, for example, a tablet, capsule, liquid suspension, injectable, topical, or transdermal. Liquid pharmaceutical compositions may be prepared comprising a rebamipide complex of the invention. The pharmaceutical compositions generally contain, for example, about 1% to about 99% by weight of a rebamipide complex or cocrystai of the invention and, for example, 99% to 1% by weight of at least one suitable pharmaceutical excipient. In one embodiment, the composition may be between about 5% and about 75% by weight of a rebamipide complex or cocrysta! of the invention with the rest being at least one suitable pharmaceutical excipient or at least one other adjuvant, as discussed below.

[030] A "therapeutically effective amount of a tebamipide complex or cocrystai according to the invention" is that which correlates to about 50 - about ISO rog of rebamipide itself. As discussed above, rebamipide is marketed b Otsuka Pharmaceutical Co,, Ltd under the Mucosts* tradename. It is currently prescribed for the treatment of gastric mucosal legions (erosions, bleeding, redness and edema) in acute gastritis and acute exacerbation of chronic gastritis. The typical dosage in adults is one 100 mg tablet three times daily.

[0313 The actual amount required for treatment of any particular condition or disorder or any particular patient may depend upon a variety of factors including, for example, the disease state being treated and its severity; the specific pharmaceutical composition employed; the sge, body weight, genera! health, sex and diet of the patient; the mode of administration; the time of administration; the route of administration; and the rate of excretion of rebamipide; the duration of the treatment; any drugs used in combination or coincidental with the specific compound employed; and other such factors well known in the medical arts. These factors are discussed In Goodman and Oilman's "The Pharmacological Basis of Therapeutics", Tenth Edition, A, Oilman, J. Hardman and L Ltmbird, eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference.

[032] Depending on the type of pharmaceutical composition, the pharmaceutically acceptable carrier may be chosen from any one or a combination of carriers known in the art. The choice of pharmaceutically acceptable carrier depends upon the pharmaceutical form and the desired method of administration to be used. For a pharmaceutical composition of the invention, that is one having a rebamipide cocrystal of the invention, a carrier should be chosen that maintains the crystalline form. In other words, the carrier should not substantially alter the rebamipide cocrystal. Nor should the carrier be otherwise incompatible with the rebamipide cocrystal used, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other companentfs) of the pharmaceutical composition.

[033] The pharmaceutical compositions of the invention may be prepared by methods know in the pharmaceuticai formulation art, for example, see Remington's Pharmaceutical Sciences, 18th Ed (Mack Publishing Company, Easton, Pa,, 1990}, which is incorporated herein by reference. In a solid dosage form, a rebamipide complex or cocrystal of the invention may be admixed with at least one pharmaceutically acceptable exripient such as, for example, sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitoi, and silicic acid, {b} binders, such as, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, {c} humectants, such as, for example, glycerol, d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, afginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, such as, for example, paraffin, (f) absorption accelerators, such as, for example, quaternary ammonium compounds, (gj wetting agents, such as, for example, cetyi alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, such as, for example, kaolin and bentonite, and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium iaury! sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[034] Pharmaceutically acceptable adjuvants known in the pharmaceutical formulation art may also be used in the pharmaceutical compositions of the invention.. These include, but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be ensured b inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanof, phenol, sorbic acid, and the like, it may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, if desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants,, and the tike, such as, for example, citric acid, sorbitan monolaurate, triethanoiamine oleate, butyiated hydroxytoiuene, etc.

[035] Solid dosage forms as described above may be prepared with coatings and sftelis, such ss enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Non-limiting examples of embedded compositions that may be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned extipients.

[036] Suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxyiated isasteary! alcohols, polyoxyethylene sorbitol and -sorbitan esters, microcrystailine cellulose, aluminum metahydroxide, bentortite, agar-agar and tragacanth, or mixtures of these substances, and the like. Liquid dosage forms may be aqueous, may contain a pharmaceutically acceptable solvent as well as traditional liquid dosage form excipients known in the art which include, but are not limited to, buffering agents, flavorants, sweetening agents, preservatives, and stabilizing agents.

[037] Compositions for rectal administrations are, for example, suppositories that may be prepared by mixing a rebamipide complex or cocrystai of the invention with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethy!eneglycol or a suppository wax, which may be solid a ordinary temperatures but may be liquid at body temperature and, therefore, melt while in a suitable body cavity and release the active component therein.

[038] Because the crystalline form of a rebamipide cocrystai may be maintained during preparation, solid dosage forms are preferred for the pharmaceutical composition of the invention. Solid dosage forms for oral administration, which includes capsules, tablets, pills, powders, and granules, may be used. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable exeipient {also known as a pharmaceutically acceptable carrier). A rebamipide complex and cocrystai according to the invention may also be used as to formulate liquid or injectable pharmaceutical compositions. Administration of a rebamipide compound or cocrystai in pure form or in an appropriate pharmaceutical composition may be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration may be, for example, orally, bucca!ly, nasally, parenteraily (intravenous, intramuscular, or subcutaneous), topically, transdermal^, mtravaginaiiy, intravesicaily, intrasystemicaliy, or rectaliy, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, such as, for example, in unit dosage forms suitable for simple administration of precise dosages. One route of administration may be oral administration, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the musculoskeletal condition to he treated-

Examples

[039] The following analytical methods were used to characterize the rebamipide cocrystals of the invention

[040] X-ray powder diffraction: X-ray powder diffraction patterns for the samples were acquired on a Bruke 08 diffract ometer using CuKct radiation (40kV, 40mA), Θ-2Θ goniometer, V4 receiving slits, a Ge monochromatar and a Lynxeye detector. The instrument is performance checked using a certified Corundum standard (NiST 1976J. The data were collected over an angular range of 2° to 42° 2Θ using a step size of 0.05* 2Θ and a step time of 0,5 seconds. Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding.

Approximately, 35 mg of the sample was gently packed into a cavity cut into polished, zero background (510} silicon wafer. Ail sam les were analysed using Diffrac Plus EVA vll.0.0.2 or V13.0.0.2,

[841] Thermal analysis ^• Differential Scanning Calorimetry (DSC); DSC data was collected on a TA instruments Q2000 equipped with a 50 position autosampier. The calibration for thermal capacity was carried out using sapphire and the calibration for the energy and temperature was carried out using certified indium. Typically 0,8-1.2mg of each sample, in a pin-holed aluminium pan, was heated at IQT/min from 25*C to 350"€. A purge of dry nitrogen at 50 ml/mtn was maintained over the sample. The instrument control software was Advantage for Q. series v2,S.0.392 and Thermal Advantage v4,8,3, Ai! data analysis was performed Using Universal Analysis v4.3A software,

[042] Solution Proton NSVtR; ^H-NMR spectra were recorded on a Bruker 400 MHz spectrometer equipped with an auto-sampler and controlled by a D X400 console. The samples were dissolved in o'6- DMSO for analysis. The data was aquired using ICO -NM v4.0.4 (build i) running with Topspin vl3 (patch level 8) using the standard Bruker loaded experiments.

[043] ¾_ Solid State NMB' The spectra were obtained using a Varian VNMRS spectrometer operating at 100.56 MHz and a 4 mm {rotor o.d.) magic-angle spinning probe. They were recorded using cross polarisation with acquisition conditions appropriate to the sample. The spectral referencing was with respect to neat, externa! tetramethylsilaoe {by setting the high-frequency line from adamantane to 38.5 ppm). [044] Example 1. 1:1 Rekamspide Nicotinamide Cocrystal

[045] 1.1 Preparation of a 1:1 Rebamipide Nicotinamide Cocrystal

[046] Rebamipide (100 rng) was weighed into 3 glass vial. 1.5 mi of a saturated solution of nicotinamide in nitromethane was added and the vial sealed. The resulting slurry was placed in a shaker and matured for 5 days (RT to SO °C on an 8 hour cycle, heating to 50 "C for 4 hours and then cooling to RT for a further 4 hours). The product was then filtered under vacuum and dried in a vacuum oven at 50 X overnight.

[047] 1,2 XRPD Characterisation of a 1:1 Rebamipide Nicotinamide Cocrysta!

[048] The experimental XRPO pattern of the 1:1 rebamipide nicotinamide cocrystal Is shown in Fig. 1. Table 1 itsts the angles "2Θ ± 0.2°28, and d-spscing of the peaks identified in the experimental XRPO pattern of Fig, 1. The entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal. f or example, the cocrysta! may be characterised by at least three peaks or at least five peaks selected from the peaks at 5.2, 9.5, 10.4, 11.5, 13.6, 16.0, 20.9 and 21.5 "28 ± 0.2 ^α 2θ as well as by an XRPO pattern substantially similar to Fig, 1,

[049] 1·3 DSC of 1:1 Rebamipide Nicotinamide Cocrystai

{0503 The differential scanning calorimetry (DSC) trace, Fig, 2, shows an eodotherm with an onset temperature of 205.5 °C and a peak maximum of 208.1 T.

[051] I- ⁴ *H NiVf Spectrwm of a ttt Rebamipide Nicotinamide Cocrystai

Ϊ0523 The ^* H UMH spectrum of the 1:1 rebamipide nicotinamide cocrystai, shown in Fig.3, dispiays the following peaks: ¹ H HMR {400MH-, d6-DMSO) δ; 13.07 {IN}, 11.66 U.HI.. 9.04 {1H), 8.93 {1H),

8.71 (1H), 8.22 f1H), 8,17 {1H), 7.83 (3H), 7,62 (1H), 7, 54 (4H), 7.27 (2H} _; 6.45 {1H}, 4.75 {1H), 3.4S

{1H} and 3.24 {1H}.. The peak at 6.45 ppm corresponds to one CH proton of rebamipide. Comparison of the integration of this peak with that at 8.71 ppm, which corresponds to one proton on the aromatic ring of nicotinamide, indicates that the cocrysta! has an APhcoformer stoichiometry of 1:1. [0533 1.5 C Solid State NMR Analysis of the 1:1 ebamipide Nicotinamide Coerysta!

0S4j The ^a3 C solid state NMR spectrum of rebamipide is shown in Fig. 4. A series of test measurements was carried out that showed that the pure rebamipSde sample reiaxed in such a way that a 10 s recycle delay was appropriate for this compound. When it was attempted to obtain the l ⁱ C spectra of a pure sample of nicotinamide under these same acquisition conditions it was found that the nicotinamide gave no signal. It was necessary to increase the recyc!e delay time to 600 s in order to obtain the spectrum: of nicotinamide (Fig. 5).

JOSS] The ^1J C spectrum obtained for the 1:1 rebamipide nicotinamide coerysta! is shown in Fig, 6, Table 2 lists the characteristic shifts, ppirs +/- 0.5 ppm, observed in the experimental ¹³ C NMR spectrum of Fig. 6, It can be seen that the 1:1 rebamipide nicotinamide coerysta! spectrum is significantly different to those of the pure rebamipide or nicotinamide. A recycle delay of 60 s was found to be necessary to obtain the spectrum of the cocrystal. A series of test measurements showed that this delay was appropriate for all the lines in the spectrum. The fact that there is a common, sample wide {hi Tj relaxation behaviour suggests that the the two components are strongly interacting and are present in the same crystal.

[0563 Example 2. 1:1 Rebamipide 2, ~0illiy roiiy benzoic AcM Cocrystal

fOS7] 2.1 Preparation of a 1:1 Rebamipide 2,4-DihydroKyben2oic Acid Cocrystal

[058] Rebamipide (200mg) and 2,4-dlhydroxybenzbic acid (S3 mg) were weighed into a glass vial.

Nitromethane (2.0 ml) was added and the vial sealed. The resulting slurry was placed in a shaker and matured for 5 days (RT to 50 °C on an 8 hour cycle, heatin to 50 °C for 4 hours and then cooiing to RT for 3 further 4 hours), The product was then filtered under vacuum and dried in a vacuum oven at SO ^a C overnight,

[059] 2.2 XRPD Characterisation of a 1:1 Rebamipide 2,4-Dihydroxyberii!eie Add Cocrystai 10601 The experimental XRPD pattern of the 1:1. rebamipide 2,4-dihydroxybenzoic acid cocrystai is shown in Fig. 7. Table 3 lists the angies "20 ± 0.2 ^* 20, and d-spacing of the peaks identified in the experimentat XRPO pattern of Fig. 7. The entire list of peaks, or a subset thereof, may be suff icient to characterize the cocrystai. For example, the cocrystai may be characterised by at least three peaks or by at ieast five peaks selected from the peaks at 6.9, 11.5, 13.9, 14.5, 15.4, 6.6, 17,3 and 18.4 "29 ± 0.2 ^* 28 as well as by an XRPD pattern substantially similar to Fig. 7.

[0δ1| 2 DSC of 1:1 Rebamipide 2,4-Dihydi xybenzoic Acid Cocrysta!

[OBI] The differential scanning calorimetry (DSC) trace, Fig. 8, shows an endotherm with an onset temperature of 243.7 °C and a peak maximum of 244,2 °C.

[063] 2,4 *H NMR Spectrum of a 1;1 Rebamipide 2,4-Oihydroxybenzoic Add Cocrysta!

[064] The Ή MR spectrum of the 1:1 rebamipide 2,4-dihydroxyfaenzoic acid cocrystal, shown in Fig.9, displays the following peaks: ^X H HMR (400ΜΗζ, d6-DMSO) 6: 13.20 .(1H), 11.66 (1H), 10,36 (1H), 8.93 (1H), 7.S3 (3H), 7.56 (4H), 7.27 (2H), 6,45 (1H), 6,34 (1H), 6-27 (1H), 4.75 ( 1H), 3.48 (1H) and 3.24 (1H). The peak at 6.45 ppm in the ^S H NMR spectrum corresponds to one CH proton of rebamipide. Comparison of the integration of this peak, with that at 6.2? ppm, which corresponds to one proton on the aromatic ring of 2,4-dihydroxybenzoic acid, indicates that the cocrysta! has an APkcofarrrier stoic loraetry of 1:1.

[065] 2,5 ⁿ Sofid State NMR Analysis of this 1:1 Rebarriipide a dmydroxyberijioic Add Cocrysta i

0663 The ^{J "} C solid state NMR spectrum of rebamipide is shown in Fig. 4. A series of test measurements was carried out that showed that the pure rebamipide sample relaxed in such a way that a 10 s recycle delay was appropriate for this compound. When it was attempted to obtain the C spectra of a pure sample of 2,4-dihydroxybenzoic acid under these same acquisition conditions it: was found that the 2,4-dihydroxybenzoic acid gave no signal, it was necessary to increase the recycle delay time to 90 s in orde to obtain the spectrum of 2,4-dihydroxybenzoic acid (Fig, 10).

The "c spectrum obtained for the 1:1 rebamipide 2,4~dihydroxybenzoic acid cocrystat is shown in Fig. 11. Table 4 lists the characteristic shifts, ppm +/- 0.5 ppm, observed in the experimental ¹³ C NMR spectrum of Fig. 11. A recycle deiay of 10 s was found to be necessary to obtain the spectrum of the cocrystai. The cocrystai does display the same relaxation behaviour as the pure APS., however It cars be seen that the 1:1 rebamipide 2,4-dihydroxybenzoic acid cocrystai spectrum is significantly different to those of the pure rebamipide or 2,4-dihydroxybenzoic acid, A series of test measurements showed that this recycle delay was appropriate for ail the lines in the 1:1 rebamipide 2,4-dihydroxybenzoic acid cocrystai spectrum, it can, therefore, be seen the 2,4-dihydroxybenzoic acid in the 1:1 rebamipide 2,4-dihyriroxybenzoic acid complex displayed much faster relaxation behaviour than when it was in its pure form. The single sample-wide relaxation behaviour of the 1:1 rebamipide 2,4- dihydroxybenzoie acid cocrystai, together with the significant changes in the ¹³ C N R spectrum, suggests that the two components interact and are present in the same crystal.