Crystal form

Abstract

The present invention relates to novel crystalline forms of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride (HCl salt), pharmaceutical compositions thereof, methods for preparing or isolating such crystalline forms and compositions, and methods of using such crystalline forms and compositions in the treatment of various diseases or disorders mediated by motilin receptor activity.

Description

[Technical field]

[0001] The present invention relates to novel crystalline forms of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride (HCl salt), pharmaceutical compositions thereof, methods for preparing or isolating such crystalline forms and compositions, and methods of using such crystalline forms and compositions in the treatment of various diseases or disorders mediated by motilin receptor activity. [Background technology]

[0002] The compound (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide is disclosed in WO2010 / 098145 (Patent Document 1) as a motilin receptor agonist, which is useful for the treatment of disease states mediated by motilin receptor activity, particularly motilin receptor agonist activity, such as gastroesophageal reflux disease; functional gastrointestinal disorders; irritable bowel syndrome; constipation; pseudo-intestinal obstruction; paralytic ileus after surgery or other procedures; vomiting; gastric stasis or hypomotility caused by various diseases such as diabetes and / or administration of drugs, or in patients undergoing enteral nutrition therapy; Crohn's disease; colitis; cachexia associated with progressive diseases such as cancer and / or its treatment; and other disorders such as incontinence (see Patent Document 1 and Non-Patent Documents 1-4).

[0003] The previously known method for preparing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide described in Patent Document 1 merely produces a white solid. A general description of the pharma- ceutically acceptable salt of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide of the present application is disclosed, and Patent Document 1 discloses and claims the free base of the compound of the present invention. However, no crystalline form of the compound, nor any salt thereof, has actually been described or synthesized in the prior art. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2010 / 098145 [Non-patent literature]

[0005] [Non-Patent Document 1] Perdikis G et al., Am J Surg, 1994, 167, 186-192 [Non-Patent Document 2] Sanger GJ et al., Nat Rev Gastroenterol Hepatol, 2016, 13, 38-48 [Non-Patent Document 3] Sharma SS et al., Dig Dis Sci, 1995, 40, 2446-2449 [Non-Patent Document 4] Logo WE et al., Dis Colon Rectum, 1993, 36, 696-708 [Non-Patent Document 5] Byrn SR et al., Solid-State Chemistry of Drugs 2nd ed., pp 3-43 and 461-503, 1999, Indiana, SSCI, Inc. [Non-Patent Document 6] Lieberman HA et al., Pharmaceutical Dosage Forms: Tablets, Vol. 1, 2nd ed., pp 1-73, 1989, New York, Marcel Dekker, Inc. Summary of the Invention [Problem to be solved by the invention]

[0006] As is well known to those skilled in the art, finding or producing crystals, crystalline forms, or salt forms is a desirable goal in pharmaceutical development from various standpoints, including pharmaceutical formulation and preparation (see, Non-Patent Document 5 and Non-Patent Document 6). Despite the many advantages associated with crystal and salt forms, the development of stable crystal forms and / or salts is not always feasible.

[0007] Along these lines, considerable efforts have been made to find or prepare crystals or crystalline forms of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide, which was disclosed by RaQualia Pharmaceutical Co., Ltd. in 2010 (WO2010 / 098145). For example, esters such as ethyl acetate (EtOAc), alcohols such as methanol, ethanol, and isopropyl alcohol, nitriles such as acetonitrile (MeCN), ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), and cyclopentyl methyl ether (CPME), cyclic ethers such as 2-methyltetrahydrofuran (2-MeTHF) and tetrahydropyran, ketones such as acetone and methyl ethyl ketone (MEK), and halogenated hydrocarbons such as dichloromethane and chloroform have all been used as recrystallization solvents, but all of them have failed.

[0008] Furthermore, even contract research companies specializing in crystallization services have tried intensively but have failed to obtain a crystalline form, including mixtures of ethyl acetate, acetonitrile, tetrahydrofuran (THF), diisopropyl ether, CPME, toluene, ethyl acetate / heptane, ethyl acetate / MTBE, toluene / heptane, and ethyl acetate / CPME as recrystallization solvents, all of which have failed.

[0009] Despite these extensive efforts, a pharma- ceutically suitable crystalline form of the free base compound has not been identified to date, and the free base compound has thus far only been available in an amorphous state (hereinafter "free base amorphous").

[0010] Initial attempts by RaQualia Pharmaceuticals, Inc. to obtain pharma- ceutical suitable crystalline forms involved the addition of acidic counterions such as hydrochloric acid, tartaric acid, citric acid, malic acid, succinic acid, phosphoric acid, benzoic acid, benzenesulfonic acid, ethanesulfonic acid, lactic acid, naphthalene-2-sulfonic acid, pamoic acid, and sulfuric acid to various solvent systems as salt screens, but failed to obtain a pharma-ceutical suitable crystalline salt form of the compound.

[0011] Through thorough and careful research, the inventors of the present invention have finally succeeded in finding the preparation conditions of crystals which can provide the desired pharma- ceutically suitable crystalline form of the compound as a hydrochloride, i.e., (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A (hereinafter referred to as “hydrochloride crystalline form A”).

[0012] Additionally, a contract research organization with scientific expertise and technology to provide a full suite of drug discovery, development, and manufacturing solutions was unable to identify any polymorphs other than the hydrochloride crystalline form A in a preliminary polymorph screening. Additionally, a salt screening failed to yield another crystalline salt form that was more pharma- ceutical suitable than the hydrochloride crystalline form A. For example, although counterion selections and salt formation conditions were performed, most of the counterions did not yield filterable solids as disclosed in the reference examples of the present invention.

[0013] Furthermore, the present inventors evaluated the physical properties of the obtained hydrochloride crystals and found another novel hydrochloride crystal form, i.e., (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form B (hereinafter referred to as "hydrochloride crystal form B").

[0014] Of the obtained crystalline forms, the hydrochloride crystalline form A and the hydrochloride crystalline form B were less susceptible to the decrease in purity (decomposition) due to the influence of temperature and humidity, compared to the amorphous free base of the compound, and therefore it was found that the hydrochloride crystalline form A and the hydrochloride crystalline form B have very high storage stability against temperature and humidity. With regard to storage stability against light, the hydrochloride crystalline form A was more stable than the amorphous free base.

[0015] Further, as disclosed in the examples of the present invention, the present invention provides a method for preparing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A (HCl salt crystalline form A). The method includes mixing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide free base in ethyl acetate with hydrochloric acid to obtain a hydrochloride solid. The hydrochloride solid is dissolved in tetrahydrofuran containing less than 10% by volume of water with heating, to which ethyl acetate is added, optionally with the addition of seed crystals, and the mixture is stirred with heating to obtain hydrochloride salt crystalline form A. More preferably, the hydrochloride solid is dissolved in tetrahydrofuran containing 0.1-2.5% by volume of water at 60-70° C., ethyl acetate is added thereto, and optionally seed crystals are added, and the mixture is stirred at 60-70° C. to grow the hydrochloride crystalline form A. The precipitate is filtered and dried to obtain the hydrochloride crystalline form A. Those skilled in the art have never previously thought of such crystallization conditions.

[0016] The present invention aims to provide pharma- ceutically suitable crystalline forms of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride for use in pharmaceutical formulations, which are simply, economically and reproducibly prepared and have unexpectedly superior and consistent performance properties, e.g., filterability, ease of handling, easy purity control, stability, non-hygroscopicity, etc. It is also an object of the present invention to provide methods for the preparation of such crystalline forms, compositions containing such crystalline forms and uses.

[0017] That is, the present invention provides the following: [1] The peaks in 2-theta are 14.7 and 17.5 ( o ) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0018] [1-1] Peaks at 2-theta are 14.7, 17.5, and 22.3 ( o ) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0019] [2] Peaks in 2-theta are 4.0, 7.9, 14.7, 17.5, and 22.3 ( o ) (where each peak is within + / - 0.2(o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0020] [2-1] Peaks in 2-theta are 4.0, 7.9, 13.6, 14.7, 15.7, 16.7, 17.5, 22.3, 25.5, 27.1, and 31.7 ( o ) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0021] [3] The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2] and [2-1], further characterized by differential scanning calorimetry (DSC) showing an endothermic event at 254°C (wherein this temperature has an error range of + / - 1°C);

[0022] [4] 3327, 2926, 1707, 1668, 1616, and 700 cm -1 (where each peak is within + / - 2 cm -1The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1] and [3], further characterized by an infrared (IR) spectrum (KBr) exhibiting an absorbance band at 100 nm (with error bars of 100 nm);

[0023] [4-1] 4047, 3971, 3327, 2926, 2758, 2712, 2621, 2523, 2490, 2401, 2120, 1952, 1898, 1707, 1668, 1616, 1460, 1385, 1358, 1306, 1250, 1223, 1119, 1061, 1051, 990, 953, 912, 745, 700, 631, 561, and 494 cm -1 (where each peak is within + / - 2 cm -1 The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1] and [3], further characterized by an infrared (IR) spectrum (KBr) exhibiting an absorbance band at 100 nm (with error bars of 100 nm);

[0024] [5] The peaks in 2-theta are 19.8 and 21.6 ( o ) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0025] [5-1] The peaks in 2-theta are 17.9, 19.8, and 21.6 ( o) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0026] [6] Peaks in 2-theta are 4.0, 7.9, 15.7, 17.9, 19.8, and 21.6 ( o ) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0027] [6-1] Peaks in 2-theta are 4.0, 7.9, 15.7, 17.9, 19.8, 21.6, 25.5, and 31.7 ( o ) (where each peak is within + / - 0.2( o (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, having an error range of 0.05;

[0028] [7] The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B according to any one of [5], [5-1], [6] and [6-1], further characterized by differential scanning calorimetry (DSC) showing an endothermic event at 258°C (wherein this temperature has an error range of + / - 1°C);

[0029] [8] A pharmaceutical composition comprising the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form according to any one of [1], [1-1], [2], [2-1], [3], [4], [4-1], [5], [5-1], [6], [6-1], and [7], together with one or more pharma- ceutically acceptable carriers or excipients;

[0030] [9] The pharmaceutical composition according to [8], which is in a dosage form for oral, parenteral, topical, rectal, vaginal, ocular or aural administration;

[0031]

[10] The pharmaceutical composition according to [9], wherein the dosage form is selected from the group consisting of tablets, soft capsules, hard capsules, lozenges, films, ovules, sprays, patches, suspensions, solutions, syrups, elixirs, modified release formulations, lotions, creams, ointments, gels, drops, foams, wafers, implants, microemulsions, injections, dry powders, and suppositories;

[0032]

[11] A pharmaceutical composition comprising the step of using the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form according to any one of [1], [1-1], [2], [2-1], [3], [4], [4-1], [5], [5-1], [6], [6-1] and [7] together with one or more pharma- ceutically acceptable carriers or excipients;

[0033]

[12] The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form according to any one of [1], [1-1], [2], [2-1], [3], [4], [4-1], [5], [5-1], [6], [6-1], and [7] for use as a medicament;

[0034]

[13] Use of the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form according to any one of [1], [1-1], [2], [2-1], [3], [4], [4-1], [5], [5-1], [6], [6-1], and [7], or the pharmaceutical composition according to any one of [8] to

[11] , in the preparation of a medicament for the curative, palliative or prophylactic treatment of a pathology mediated by motilin receptor activity;

[0035]

[14] A method for treating a condition mediated by motilin receptor activity, comprising administering to an animal, including a human, in need of such treatment an effective amount of the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form according to any one of [1], [1-1], [2], [2-1], [3], [4], [4-1], [5], [5-1], [6], [6-1], and [7], or the pharmaceutical composition according to any one of [8] to

[11] ;

[0036]

[15] A method for preparing the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4] and [4-1], comprising adding hydrochloric acid in a first organic solvent to a solution of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide in a second organic solvent; Preferably, the first organic solvent is water, ethyl acetate, water / EtOH, dioxane, DMF, ether, acetone, ethanol, methanol, or THF; Preferably, the second organic solvent is water, ethyl acetate, water / EtOH, dioxane, ethanol, methanol, ether, acetone, DMF, THF, or t-butyl methyl ether; More preferably, the first organic solvent is water, ethyl acetate, water / EtOH, dioxane, ethanol, or THF; More preferably, the second organic solvent is ethyl acetate, THF, or t-butyl methyl ether;

[0037]

[16] A method for preparing the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4] and [4-1], comprising exposing a (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride solid to tetrahydrofuran containing less than 10% by volume of water while heating;

[0038]

[17] A method for preparing the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4], and [4-1], comprising the steps of adding a (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride solid to 0.01-5% (v / v) aqueous tetrahydrofuran at 50-80° C., and adding ethyl acetate at 50-80° C.;

[0039]

[18] A method for preparing the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4], and [4-1], comprising the steps of heating a (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride solid in ethyl acetate at a temperature in the range of 50 to 80° C. and cooling to room temperature;

[0040] [18-1] A method for preparing the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4], and [4-1], comprising the steps of heating a (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride solid in ethyl acetate at a temperature in the range of 50 to 80° C., and cooling to room temperature; preferably, the temperature range is 60 to 80° C.;

[0041]

[19] A method for preparing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4] and [4-1], comprising a step of stirring (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B in an organic solvent to convert it to the hydrochloride crystalline form A at room temperature to 100° C.;

[0042]

[20] A method for preparing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to

[19] , comprising stirring (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, wherein the organic solvent is ethyl acetate or THF / ethyl acetate containing less than 1% by volume of water;

[0043]

[21] A method for preparing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4] and [4-1], comprising adding seed crystals of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride to obtain hydrochloride crystalline form A;

[0044]

[22] A process for preparing (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of [1], [1-1], [2], [2-1], [3], [4] and [4-1], comprising the step of crystallizing the crystalline form from a solvent; preferably, the solvent is water, ethyl acetate, water / EtOH, dioxane, DMF, ether, acetone, ethanol, methanol, or THF; more preferably, the solvent is ethyl acetate. Effect of the Invention

[0045] As mentioned above, in drug development from various aspects including drug formulation and manufacturing, it is an objective to find or prepare crystals or crystalline forms having unexpectedly excellent physicochemical properties. Surprisingly, it has been found that this objective has been achieved by the present invention, which provides (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A. Prior to the present invention, despite extensive efforts by those skilled in the art, no pharma- ceutically suitable crystalline form of said compound had ever been identified.

[0046] The crystalline forms of the present invention have significant and unexpected advantages over the white solid disclosed in the prior art WO2010 / 098145: the hydrochloride crystalline form A has been found to be more stable than the solid disclosed in the prior art WO2010 / 098145.

[0047] Furthermore, it has been found that the hydrochloride salt crystalline form A of the present invention is amenable to large scale synthesis. They have acceptable solid-state properties for the development of solid dosage forms. [Brief description of the drawings]

[0048] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A. [Diagram 2] FIG. 2 shows the differential scanning calorimetry (DSC) of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A. [Diagram 3]FIG. 3 shows the infrared (IR) spectrum of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form A. [Figure 4] FIG. 4 shows the X-ray powder diffraction (XRPD) pattern of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B. [Diagram 5] FIG. 5 shows the differential scanning calorimetry (DSC) of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B. [Figure 6] FIG. 6 shows the infrared (IR) spectrum of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form B. [Figure 7] 7 shows the photostability of the amorphous solid of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride (hereinafter referred to as "hydrochloride amorphous"). Data (% area) of the decomposition products are expressed as a percentage of the initial value of the initial sample of the hydrochloride amorphous. [Figure 8] 8 shows the photostability of the amorphous solid (free base amorphous) of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide free base. Data (% area) of decomposition products are expressed as a percentage of the initial value of the initial sample of free base amorphous. [Figure 9]9 shows the photostability of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A. Data (% area) of decomposition products are expressed as a percentage of the initial value of the initial sample of hydrochloride crystalline form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] Thus, the present invention provides peaks in 2-theta of 4.0, 7.9, 14.7, 17.5, and 22.3 ( o ); more specifically, the peaks in 2-theta are 4.0, 7.9, 13.6, 14.7, 15.7, 16.7, 17.5, 22.3, 25.5, 27.1, and 31.7 ( o ) (where each peak is within + / - 0.2( o The present invention provides crystalline (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-Kα radiation, having an error range of 0.05% (within the ...

[0050] Accordingly, the present invention provides crystalline (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline Form A as described above, which is further characterized by Differential Scanning Calorimetry (DSC) showing an endothermic event at 254° C. (wherein this temperature has an error range of + / − 1° C.).

[0051] The hydrochloride salt crystalline form A described above, which has peaks at 3327, 2926, 1707, 1668, 1616, and 700 cm -1;more details: 4047, 3971, 3327, 2926, 2758, 2712, 2621, 2523, 2490, 2401, 2120, 1952, 1898, 1707, 1668, 1616, 1460, 1385, 1358, 1306, 1250, 1223, 1119, 1061, 1051, 990, 953, 912, 745, 700, 631, 561, and 494 cm -1 (where each peak is within + / - 2 cm -1 The compound is further characterized by an infrared (IR) spectrum (KBr) which shows an absorbance band at 100 nm (with error bars of 0.05 nm).

[0052] In a further aspect, the present invention provides the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of the present invention for use as a medicament.

[0053] As a further aspect of the present invention, there is provided the use of the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of the present invention in the manufacture of a medicament for the curative, preventive or palliative treatment of any disease mediated by motilin receptor activity, in particular 1) gastrointestinal disorders, 2) diseases characterized by motilin receptor expression regions, and 3) diseases in which a lack of motilin secretion is involved.

[0054] The pathology may be selected from the group consisting of gastroesophageal reflux disease; functional dyspepsia; irritable bowel syndrome; constipation; pseudo-obstruction; paralytic ileus following surgery or other procedures; vomiting; gastric stasis or hypomotility caused by various diseases such as diabetes and / or administration of drugs, or in patients receiving enteral nutrition therapy; Crohn's disease; colitis; cachexia associated with progressive diseases such as cancer and / or its treatment; and other disorders such as incontinence.

[0055] In another aspect of the present invention, there is provided a method for the treatment of any disease mediated by motilin receptor activity, in particular the curative, preventive or palliative treatment of gastroesophageal reflux disease; functional gastrointestinal disorders; irritable bowel syndrome; constipation; pseudo-obstruction; paralytic ileus following surgery or other procedures; vomiting; gastric stasis or hypomotility caused by various diseases such as diabetes and / or administration of drugs or in patients receiving enteral nutrition therapy; Crohn's disease; colitis; cachexia associated with progressive diseases such as cancer and / or their treatment; and other disorders such as incontinence, comprising the administration of a therapeutically effective amount of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A and / or hydrochloride crystalline form B of the present invention to an animal, including a human, in need of such treatment.

[0056] The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of the present invention is useful for the general treatment of disease conditions mediated by motilin receptor activity.

[0057] The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A and / or hydrochloride crystalline form B of the present invention may also be useful for the treatment of disorders or conditions selected from the group consisting of gastroesophageal reflux disease; functional gastrointestinal disorders; irritable bowel syndrome; constipation; pseudo-intestinal obstruction; paralytic ileus following surgery or other procedures; vomiting; gastric stasis or hypomotility caused by various diseases such as diabetes and / or administration of drugs, or in patients undergoing enteral nutrition therapy; Crohn's disease; colitis; cachexia associated with progressive diseases such as cancer and / or its treatment; and other disorders such as incontinence.

[0058] A synthetic route for the preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide is described in WO2010 / 098145 and in the experimental section below.

[0059] (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A can be prepared by crystallization from a solution of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide in an organic solvent such as ethyl acetate by adding an ether such as diethyl ether or MTBE (t-butyl methyl ether) containing hydrochloric acid.

[0060] Organic solvents that can be used for crystallization of the hydrochloride salt crystalline form include carboxylic acid esters such as ethyl acetate and tetrahydrofuran. Preferred solvents that can be mixed with ethyl acetate include one or more solvents selected from water; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tert-butyl methyl ether, dioxane, and tetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, dichloromethane, chloroform, benzene, toluene, and xylene; ketones such as acetone and methyl ethyl ketone; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.

[0061] The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A and / or hydrochloride crystalline form B of the present invention can be administered alone or in combination with one or more other drugs (or any combination thereof). Generally, they are administered as a formulation with one or more pharma-ceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipient depends to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0062] Thus, as a further aspect of the present invention, there is provided a pharmaceutical composition comprising a (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form and one or more suitable excipients, which composition is suitable for the treatment of a condition mediated by motilin receptor activity.

[0063] As used herein, the term "hydrochloride crystalline form" includes hydrochloride crystalline form A and / or hydrochloride crystalline form B.

[0064] The weight purity of the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of the present invention is not limited, but preferably, the essentially pure crystalline form can be used in specific embodiments of the present invention.

[0065] For the avoidance of doubt, the term "essentially pure" as used herein means at least 90% purity by weight. More preferably, "essentially pure" means at least 95% purity by weight, and most preferably, at least 98% purity by weight. References herein to "treatment" include references to curative, palliative and prophylactic treatment. As used herein, the article "a" or "an" refers to both the singular and the plural of the object it refers to, unless otherwise indicated.

[0066] The term "animal" as used herein includes mammals or non-mammals. Examples of suitable mammals include, but are not limited to, humans, rodents, companion animals, livestock, and primates. Suitable rodents include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock include, but are not limited to, horses, goats, sheep, pigs, cows, llamas, and alpacas. Suitable primates include, but are not limited to, chimpanzees, lemurs, rhesus monkeys, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammals include birds, reptiles, amphibians, and fish. Examples of birds include, but are not limited to, chickens, turkeys, ducks, and geese. A preferred mammal is a human. For non-human animal administration, the term "pharmaceutical" as used herein may be interchanged with "veterinary."

[0067] Pharmaceutical compositions suitable for the delivery of the hydrochloride salt crystalline form of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995); Polymorphism: In the Pharmaceutical Industry by Rolf Hilfiker (John Wiley & Sons, 2006).

[0068] Oral route The hydrochloride salt crystalline forms of the present invention can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

[0069] Formulations suitable for oral administration include solid, semi-solid, and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particles, liquids, or powders; lozenges (e.g., containing a liquid fill); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches.

[0070] Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations are used as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), and typically may contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstitution from solids, such as sachets.

[0071] The hydrochloride salt crystalline forms of the present invention may also be used in fast dissolving, fast disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001).

[0072] For tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0073] Binders are generally used to provide adhesion to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, and anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as, for example, sodium lauryl sulfate and polysorbate 80, and glidants, such as, for example, silicon dioxide and talc. If present, the surface active agents may comprise from 0.2% to 5% by weight of the tablet, and the glidants may comprise from 0.2% to 1% by weight of the tablet.

[0074] Tablets also generally contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight of the tablet, preferably from 0.5% to 3% by weight. Other possible ingredients include antioxidants, colorants, flavors, preservatives, and taste-masking agents. Exemplary tablets contain up to about 80% drug, about 10% to about 90% by weight binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight disintegrant, and about 0.25% to about 10% by weight lubricant.

[0075] Tablet blends can be directly or by roller compression to form tablets. Alternatively, tablet blends or portions of blends can be wet-, dry- or melt-granulated, melt-congealed or extruded before tableting. The final formulation can include one or more layers, and can be coated or uncoated; it can also be encapsulated.

[0076] Tablet formulations are discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets, Vol. 1 (Marcel Dekker, New York, 1989); Larry L. Augsburger and Hoag W. Stephen, Pharmaceutical Dosage Forms: Tablets, Third Edition, Volume 2: Rational Design and Formulation (Informa Healthcare, published June 2008).

[0077] Consumable oral films for human or veterinary use are typically flexible water-soluble or water-swellable thin film dosage forms, which may be rapidly dissolving or mucoadhesive, and typically comprise a hydrochloride salt crystalline form according to the invention, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the formulation may perform more than one function.

[0078] Formulations of the hydrochloride crystalline form of the invention may be water soluble or water insoluble depending on the environmental conditions. Water soluble compounds may typically comprise from 1% to 80% by weight, more typically from 20% to 50% by weight of solute. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88% by weight of solute. Alternatively, the hydrochloride crystalline form of the invention may be in the form of multiparticulate beads.

[0079] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

[0080] Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, co-solvents (including, for example, oils), emollients, bulking agents, anti-foaming agents, surfactants and flavor masking agents.

[0081] Films of the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper.

[0082] This can be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuum processing.

[0083] Solid formulations for oral administration can be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0084] Suitable modified release formulations for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release techniques, such as high energy dispersions, osmotic particles, and coated particles, can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14, (2001). The use of chewing gum to achieve controlled release is described in WO00 / 35298.

[0085] Parenteral Administration The hydrochloride crystalline form of the present invention can also be administered directly into the bloodstream, into muscle, or into internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.Suitable devices for parenteral administration include needle (including, for example, microneedle) injectors, needle-free injectors and infusion techniques.

[0086] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably pH 3-9), although for some applications they may be more suitably formulated as sterile non-aqueous solutions or as a dry form for use with a suitable vehicle such as sterile, pyrogen-free water.

[0087] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, is readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0088] Formulations for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus, the hydrochloride salt crystalline form of the present invention can be formulated as a suspension or as a solid, semi-solid or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include semi-solids and suspensions containing drug-coated stents and drug-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres.

[0089] Topical administration The hydrochloride salt crystalline form of the present invention can also be administered topically, dermally (intradermally), or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sweat powders, finishes, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can also be incorporated (see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999)).

[0090] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection (e.g., Powderject™, Bioject™, etc.).Topical administration can also be accomplished using a patch, such as a transdermal iontophoretic patch.

[0091] Formulations for topical administration may be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.

[0092] The hydrochloride salt crystalline forms of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (alone, as a mixture in a dry blend with, for example, lactose, or as mixed component particles mixed with, for example, a phospholipid, such as phosphatidylcholine), as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to generate a fine mist) or nebulizer, or as nasal drops, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin.

[0093] The pressurized container, pump, spray, nebulizer, or inhaler contains a solution or suspension of the hydrochloride salt crystalline form of the invention in, for example, ethanol, aqueous ethanol, or a suitable substitute for the active ingredient, a propellant as a solvent, and an optional surfactant, for example, sorbitan trioleate, oleic acid, or oligolactic acid, for dispersing, solubilizing, or extending the release.

[0094] Before use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns).This can be achieved by any suitable comminuting method, such as vortex jet milling, fluid bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

[0095] Capsules (e.g., made of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the compound of the present invention, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol or magnesium stearate.Lactose can be anhydrous or in the form of monohydrate, preferably the latter.Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0096] Suitable solution formulations for use in electrohydrodynamic nebulizers to generate a fine mist may contain 1 μg to 20 mg of the compound of the invention per actuation, with actuation volumes varying from 1 μL to 100 μL. A typical formulation may contain the hydrochloride salt crystalline form of the invention, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

[0097] Suitable flavours, such as methanol and levomethanol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0098] Formulations for inhaled / intranasal administration can be formulated for immediate and / or modified release, for example using PLGA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed-release.

[0099] For dry powder inhalers and aerosols, the dosage unit is determined by a valve which delivers a metered amount. Units of the invention are typically adapted to administer a metered dose or "puff" containing between 1 μg and 20 mg of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form. The total daily dose typically ranges from 1 μg to 100 mg, which can be administered in a single dose or, more usually, as divided doses throughout the day.

[0100] Rectal / vaginal administration The hydrochloride salt crystalline forms of the present invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0101] Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release.

[0102] Ocular / Ear Administration The hydrochloride crystalline form of the present invention can also be administered directly to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic pH-adjusted sterile saline.Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g., absorbent gels, sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes.Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers such as gellan gum can be incorporated together with preservatives such as benzalkonium chloride.Such formulations can also be delivered by iontophoresis.

[0103] Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release.

[0104] Other techniques The hydrochloride salt crystalline forms of the present invention may be combined with soluble polymeric substances, such as cyclodextrin and suitable derivatives thereof, or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the above modes of administration. For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. The most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrins, examples of which can be found in WO91 / 11172, WO94 / 02518, WO98 / 55148, and Evrard, B. et al., Journal of Controlled Release 96 (3), pp. 403-410, 2004.

[0105] Dosage For treating or preventing conditions mediated by motilin receptor activity, suitable dosage levels of the hydrochloride crystalline form of the present invention are about 0.0001-1000 mg per day of active compound, preferably about 0.001-100 mg per day, more preferably about 0.005-50 mg per day, and most preferably about 1-50 mg per day. The compound may be administered on a dosing regimen of 1-4 times per day. However, in some cases, doses outside these limits may be used.

[0106] These dosages are based on an average human subject having a body weight of about 60 kg to 70 kg. A physician can readily determine dosages for subjects whose body weight is outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

[0107] The hydrochloride crystalline forms of the present invention can also be optionally combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly for the treatment of conditions mediated by motilin receptor activity. For example, the hydrochloride crystalline forms of the present invention as described above can be administered simultaneously, sequentially or separately in combination with one or more agents selected from the following:

[0108] opioid analgesics, such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, or pentazocine;

[0109] nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflucinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;

[0110] barbiturates, such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal, or thiopental;

[0111] benzodiazepines with sedative properties, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0112] Sedating H1 antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;

[0113] · Sedatives, such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

[0114] Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

[0115] NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®: a combination formulation of morphine and dextromethorphan), topiramate, neramexane, or perzinfotel, including NR2B antagonists, such as ifenprodil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[0116] Alpha adrenergic agonists, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;

[0117] Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline;

[0118] Anticonvulsants, such as carbamazepine, lamotrigine, topiramate, or valproate;

[0119] Tachykinin (NK) antagonists, specifically NK-3, NK-2, or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6,13-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0120] Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine, and ipratropium;

[0121] COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

[0122] Coal tar analgesics, specifically paracetamol;

[0123] Neuroleptics, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindol, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion®, or sarizotan;

[0124] Vanilloid receptor agonists (e.g., resiniferatoxin) or antagonists (e.g., capsazepine);

[0125] Transient receptor potential cation channel subtype (V1, V2, V3, V4, M8, A1) agonists or antagonists;

[0126] β-adrenergic agonists, e.g. propranolol;

[0127] Local anesthetics, e.g., mexiletine;

[0128] Corticosteroids, e.g. dexamethasone;

[0129] 5-HT receptor agonists or antagonists, in particular 5-HT1B / 1D agonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0130] · 5-HT2A receptor antagonists, for example, R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0131] Cholinergic (nicotinic) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), or nicotine;

[0132] Tramadol (registered trademark);

[0133] · PDEV inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7 -Propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyri 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0134] α-2-δ ligands, e.g., gabapentin, pregabalin, 3-methylgabapentin, (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1 -aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

[0135] ·Cannabinoids;

[0136] ·Metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

[0137] Serotonin reuptake inhibitors, such as sertraline, demethylsertraline, a metabolite of sertraline, fluoxetine, norfluoxetine (the desmethyl metabolite of fluoxetine), fluvoxamine, paroxetine, citalopram, desmethylcitalopram, a metabolite of citalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone;

[0138] noradrenaline (norepinephrine) reuptake inhibitors, for example maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, the metabolite of bupropion, hydroxybupropion, nomifensine, and viloxazine (Vivalan®), in particular selective noradrenaline reuptake inhibitors such as reboxetine, specifically (S,S)-reboxetine;

[0139] Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran, and imipramine;

[0140] Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-( 5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyl disulfide;

[0141] Acetylcholinesterase inhibitors, e.g. donepezil;

[0142] Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide, or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0143] Leukotriene B4 antagonists, such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870;

[0144] 5-lipoxygenase inhibitors, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

[0145] Sodium channel blockers, e.g., lidocaine;

[0146] Calcium channel blockers, e.g. ziconotide, zonisamide, mibefradil;

[0147] 5-HT3 antagonists, e.g., ondansetron; Chemotherapy drugs, such as oxaliplatin, 5-fluorouracil, leucovorin, paclitaxel; ·Calcitonin gene-related protein (CGRP) antagonists; Bradykinin (BK1 and BK2) antagonists; · Voltage-gated sodium-gated channel blockers (Nav1.3, Nav1.7, Nav1.8); Voltage-dependent calcium channel blockers (N-type, T-type); ·P2X (ionotropic ATP receptor) antagonists; · Acid-sensing ion channel (ASIC1a, ASIC3) antagonists; · Angiotensin AT2 antagonists; · Chemokine CCR2B receptor antagonists; · Cathepsin (B, S, K) inhibitors; Sigma-1 (σ-1) receptor agonists or antagonists;

[0148] and pharma-ceutically acceptable salts and solvates thereof.

[0149] Such combinations provide excellent therapeutic effects, including synergistic effects.

[0150] Combination medications and kits: One embodiment of the present invention is the combination of the hydrochloride crystalline form of the present invention with a drug for a disease different from that of the hydrochloride crystalline form of the present invention. The "combination" of the present invention can exist as a "fix combination" or a "kit of parts combination". A "fixed combination" is defined as a combination in which (i) at least one drug for a disease different from the hydrochloride crystalline form of the present invention; and (ii) the hydrochloride crystalline form is present in one unit. A "kit of parts combination" is defined as a combination in which (i) at least one drug for a disease different from the hydrochloride crystalline form of the present invention; and (ii) the hydrochloride crystalline form is present in multiple units. The components of the "kit of parts combination" can be administered simultaneously, sequentially, or separately. The molar ratio of the hydrochloride crystalline form to the drug for a disease different from the hydrochloride crystalline form of the present invention used according to the present invention is in the range of 1:100 to 100:1, for example, 1:50 to 50:1, or 1:20 to 20:1, or 1:10 to 10:1. The two drugs can be administered separately in the same ratio.

[0151] The present invention extends to combinations comprising (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline forms and one or more therapeutic agents (e.g., those described above) for simultaneous, separate or sequential use in the curative, preventive or palliative treatment of pathologies mediated by motilin receptor activity.

[0152] Working Example The present invention will be described in more detail below with reference to examples, but the technical scope of the present invention is not limited thereto. Those skilled in the art can make various modifications within the technical scope of the present invention. The following examples are for reference only.

[0153] analysis

[0154] X-ray Powder Diffraction (XRPD) XRPD analysis is performed using a Riraku RINT-TTR or Riraku MiniFlex600 X-ray powder diffractometer using Cu-Kα radiation. Using a variable temperature sample holder attachment, it is also possible to measure samples under high / low temperature conditions. The instrument is equipped with a fine focus X-ray tube. The tube voltage and amperage were set at 50 kV and 300 mA (RINT-TTR) or 40 kV and 15 mA (MiniFlex600). The divergence, scattering, and receiving slits were set at 0.5, 1.0, and 1.5 mm, respectively. o , 0.5 o , and 0.15 mm (RINT-TTR), or 1.25 o , 13.0 mm (Open), and 13.0 mm (Open) (MiniFlex600). Diffracted radiation is detected by a NaI scintillation detector (RINT-TTR) or a D / teX Ultra (MiniFlex600). o )2-Theta to 4 o / min(RINT-TTR) or 20 o A theta-2theta continuous scan at 1000 nm / min (MiniFlex600) is used. A silicon standard is analyzed to check the alignment of the machine. Data is collected and analyzed using a Rigaku X-ray system. Samples are placed in an aluminum sample holder that rotates during data acquisition and aligned for analysis.

[0155] Thermogravimetry / differential thermal analysis (TG / DTA) TG / DTA is performed using a Seiko 6200R system. Samples are placed in aluminum TG / DTA pans. Each sample is heated at a rate of 5°C / min under nitrogen purge to a final temperature of 300°C. Indium metal is used as the calibration standard. Values ​​given are rounded and should be considered approximate.

[0156] Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) is performed using a Mettler Toledo DSC822. Samples are placed into aluminum DSC pans and the weights are accurately recorded. The pans are covered with lids containing a pinhole and then the lids are sealed. Each sample is heated at a rate of 5°C / min under a nitrogen purge to a final temperature of 280°C. Indium metal is used as the calibration standard. Values ​​given are rounded and should be considered approximate.

[0157] FT-IR spectroscopy Infrared spectra are acquired on a Shimadzu IRPrestage-21 (FT-IR) spectrophotometer equipped with an air-cooled high-energy ceramic light source, a germanium-coated potassium bromide (KBr) plate for the mid-infrared beam splitter, and a highly sensitive pyroelectric infrared detector (DLATGS). The measurements are performed using the diffuse reflectance method with a diffuse reflectance accessory DRS-8000. The sample powder is mixed with a small amount of KBr powder on a sample plate with a diameter of 6 mm and a depth of 1.5 mm. Each spectrum is captured by a 4 cm -1 Represents 40 additional scans collected at a spectral resolution of 100 nm. A background data set is acquired by filling with KBr powder. Wavelength calibration is performed using polystyrene. Values ​​given are rounded and should be considered as estimates.

[0158] Hygroscopicity Testing by Dynamic Vapor Sorption Analysis (DVS) Hygroscopicity tests are performed using a surface measurement system DVS-1. Samples are placed on a microbalance in the instrument and the weight change during adsorption is monitored at 25 °C. One program consists of a sorption scan from 0 to 90% relative humidity (RH) in 5% RH increments, with the sample equilibrated for 360 min or until equilibrium is reached at each step.

[0159] nuclear magnetic resonance (NMR) NMR data were measured at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA 300 spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvents unless otherwise stated, and data are given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Conventional abbreviations used are s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc.

[0160] High performance liquid chromatography (HPLC) measurement HPLC data is obtained on a Waters Alliance 2695 HPLC system equipped with a 2996 PDA detector using the following conditions: Column: XBridge Phenyl (3.5 μm, 4.6 × 150 mm), Eluent: acetonitrile / 0.3% perchloric acid = 35:65, Detection: UV at 215 nm; Flow rate: 1 mL / min, and Column temperature: 40°C. Data processing is performed using Empower 3 software supplied by Waters.

[0161] Room temperature means 15 to 35° C., but is not limited to this range as long as the purpose is achieved. The chemical symbols have the usual meanings: M (mole per liter), L (liter), mL (milliliter), g (gram), mg (milligram), mol (mole), and mmol (millimole).

[0162] Throughout this application, the following abbreviations are used with the following meanings: CPME (cyclopentyl methyl ether), EtOAc (ethyl acetate), EtOH (ethanol), MeCN (acetonitrile), MEK (methyl ethyl ketone), MeOH (methanol), 2-MeTHF (2-methyltetrahydrofuran), MTBE (t-butyl methyl ether), THF (tetrahydrofuran), DMF (N,N-dimethylformamide).

[0163] For other tests, the crystalline forms of the present invention can be distinguished by polarized light microscopy (PLM), scanning electron microscopy (SEM), hot stage optical microscopy, electron crystallography, single crystal X-ray diffraction, quantitative analysis, particle size analysis (PSA) (e.g., particle size, particle size distribution (PSD), and particle shape), specific surface area (SSA) analysis, surface energy analysis (e.g., inverse gas chromatography or IGC), dissolution testing, or a combination of these techniques.

[0164] Example 1 [Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide] This compound is synthesized according to the conventional process described in Example 1 of WO2010 / 098145.

[0165] Example 2 [Preparation of amorphous solid of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride (amorphous HCl salt)] (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide (50 mg, 97 μmol) obtained according to the method of Example 1 is dissolved in ethyl acetate (0.75 mL) and 4N hydrochloric acid in ethyl acetate (32 μL, 126 μmol) is added thereto. After adding t-butyl methyl ether (2.0 mL) to the mixture, the precipitated solid is collected by suction to obtain the hydrochloride salt as a white powder (46 mg, 83 μmol, 85% yield). Another batch (38 mg, 69 μmol) is prepared in the same manner, and the combined white powder (84 mg, 152 μmol) is completely dissolved in dichloromethane (5 mL). After evaporating off the solvent, the resulting solid was dried at room temperature under reduced pressure to give an amorphous solid of the hydrochloride salt (73 mg, 132 μmol, recovery 87%).

[0166] Example 3 [Preparation of R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form A (HCl salt crystal form A)] Preparation method 1: 4N HCl in ethyl acetate (2.25 mL, 8.9 mmol) is added to (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide (3.83 g, 7.41 mmol) obtained according to the method of Example 1, and dissolved in ethyl acetate (30 mL) at 0° C. and the volatiles removed in vacuo to give (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride as a gum. The gum is dissolved in ethyl acetate (60 mL) with heating, and the mixture is cooled to room temperature to give a colorless suspended solid. The mixture is stirred overnight at 40° C. under nitrogen to give a yogurt-like solid. The volatiles are removed in vacuo to give a colorless solid (4.04 g, 7.30 mmol) as a partially crystalline hydrochloride salt. Add ethyl acetate (5 mL) to the hydrochloride partial crystals (186 mg) in 2% aqueous tetrahydrofuran (5 mL) and add the above hydrochloride partial crystals as a seed crystal. Stir the mixture gently for about 5 minutes at room temperature, then stir the mixture at 60°C overnight. Filter the precipitate, wash with ethyl acetate, and dry in vacuum at 50°C to obtain a solid (175 mg) as hydrochloride crystal form A.

[0167] In this specification, the symbols "α", "θ", "δ" and "ν" may be written as "alpha", "theta", "delta" and "nu".

[0168] 1H-NMR (CDCl3) delta: 9.81-9.47 (1H, br), 7.55 (1H, dd, J=8.1, 3.6Hz), 7.30-7.14 (5H, m), 7.07-6.85 (3H, m), 4.92-4.83 (1H, m), 4.78-4.69 (1H, m), 4.47-4.26 (1H, m), 3.95-3.82 (1H, m), 3.72-3.57 (1H, m), 3.51-3.41 (1H, m), 3.18-2.55 (7H, m), 2.46-1.58 (10H, m), 1.35 (3H, s), 1.33 (3H, s). MS (ESI) m / z: 517 (M+H) + .

[0169] Crystallinity by XRPD: Hydrochloride crystalline form A (Figure 1). 2-theta 4.0, 7.9, 14.7, 17.5, and 22.3 ( o ) major peaks. More specifically, 2-theta 4.0, 7.9, 13.6, 14.7, 15.7, 16.7, 17.5, 22.3, 25.5, 27.1, and 31.7 ( o ). Each peak has a ±0.2( o ) error.

[0170] Melting point (DSC onset): (Figure 2). The endothermic peak shows an onset temperature of 254°C and a peak temperature of 257°C. Each temperature has an error of + / - 1°C.

[0171] IR (KBr): (Figure 3). 3327, 2926, 1707, 1668, 1616, and 700 cm -1 absorption bands at 4047, 3971, 3327, 2926, 2758, 2712, 2621, 2523, 2490, 2401, 2120, 1952, 1898, 1707, 1668, 1616, 1460, 1385, 1358, 1306, 1250, 1223, 1119, 1061, 1051, 990, 953, 912, 745, 700, 631, 561, and 494 cm -1 Each peak has an absorption band at + / - 2cm -1 There is an error.

[0172] Elemental analysis, C 31 H 41 Calculated for ClN4O3: C, 67.3; H, 7.5; Cl, ​​6.4; N, 10.1. Found: C, 66.8; H, 7.5; Cl, ​​6.4; N, 10.0.

[0173] Example 4 [Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form A (HCl salt crystal form A)] Preparation method 2: Amorphous solid (HCl salt amorphous) (40.5 g, 73.1 mmol) of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride obtained according to the method of Example 2 is added in small portions to 2% aqueous tetrahydrofuran (102 mL), and then 2% aqueous tetrahydrofuran (204 mL) is added to obtain a clear solution at 60° C. Ethyl acetate (400 mL) is added to the solution, and the resulting mixture is stirred at 60° C. for 5 minutes. Seed crystals (hydrochloride crystalline form A (20 mg) prepared by Preparation Method 1 in Example 3) are added to the mixture, which is then stirred at 50° C. for 1 hour, then at 40° C. for 1 hour, and at room temperature overnight. The precipitate is filtered, washed with ethyl acetate, and dried in a vacuum oven at 50° C. for 6 hours to obtain (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A (37.7 g, 68.2 mmol, 93% recovery) as a solid. Therefore, to obtain the hydrochloride salt crystalline form A, which is useful as a pharma- ceutically acceptable salt, the procedure described in Example 4 is preferred. This procedure can be carried out not only with the solvents used in the above examples, but also with MTBE, a solution of hydrochloric acid in dioxane, water / EtOH, or other solvents. In the XRPD, melting point (DSC onset) and IR (KBr) the same signals are observed as those described in Example 3, Preparation 1.

[0174] Example 5 [Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form A (HCl salt crystal form A)] Large scale (1 kg scale): 1.2 kg of hydrochloride crystalline form A is prepared from (R)-tert-butyl 3-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamoyl)piperidine-1-carboxylate (1.5 kg, 2.5 mol) obtained according to the conventional method described in Example 1 of WO2010 / 098145 by heating in ethyl acetate at 70° C. and using concentrated hydrochloric acid (217 mL, 1.04 eq.).

[0175] Example 6 [Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystal form B (HCl salt crystal form B)] (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide (9.8 g, 18 mmol) obtained according to the method of Example 1 is heated to 60° C. in THF (250 mL, 25 vol) and deionized water (1 mL) and further deionized water (3.2 mL) is added in portions until the solid is completely dissolved. Ethyl acetate (150 mL, 15 vol) is added dropwise at 60° C. over 30 min. After the addition of about 50 mL of ethyl acetate, a white solid appears. The mixture is stirred at 60° C. for 17 h, then cooled to room temperature at a rate of 5° C. every 30 min and stirred at 5° C. for 1 h. The solid is filtered, washed with anhydrous ethyl acetate (2 x 10 mL) and dried in a vacuum oven at 50 °C for 3 hours to give (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B (5.8 g, 10 mmol, 59% recovery) as a solid.

[0176] Crystallinity by XRPD: Hydrochloride crystalline form B (Figure 4). 2-theta 4.0, 7.9, 15.7, 17.9, 19.8, and 21.6 ( o ) major peaks. More specifically, 2-theta 4.0, 7.9, 15.7, 17.9, 19.8, 21.6, 25.5, and 31.7 ( o ). Each peak has a ±0.2( o ) error. Melting point (DSC onset): (Figure 5). The endothermic peak shows an onset temperature of 258°C and a peak temperature of 260°C. Each temperature has an error of + / - 1°C.

[0177] IR (KBr): (Figure 6). 3327, 2926, 1707, 1670, 1616, and 700 cm -1absorption bands at 4049, 3971, 3327, 2926, 2758, 2712, 2621, 2523, 2490, 2401, 2120, 1952, 1898, 1707, 1670, 1616, 1458, 1385, 1356, 1306, 1254, 1221, 1117, 1059, 989, 955, 910, 750, 700, 631, 563, 544, 519, and 494 cm -1 Absorption bands at each peak. + / - 2cm -1 There is an error.

[0178] When the hydrochloride crystalline form A obtained according to the method of Example 3, 4, or 5 contains hydrochloride crystalline form B, when a suspension of hydrochloride crystalline form A and hydrochloride crystalline form B in ethyl acetate is stirred with a stir bar at room temperature or at 60° C. for 6 days, hydrochloride crystalline form B is completely converted to hydrochloride crystalline form A and only hydrochloride crystalline form A is obtained. No significant conversion of hydrochloride form A to hydrochloride form B was observed in ethyl acetate and / or THF-water-ethyl acetate (1:0.04:3) mixtures at 60° C., and seeding of hydrochloride solutions in THF-water with hydrochloride form B at 5, 25, and 60° C. did not result in the appearance of hydrochloride form B.

[0179] Example 7 [Moisture absorption test] Hygroscopicity testing was performed using Dynamic Vapor Sorption (DVS) analysis. Table 1 below shows the weight gain percentage of the hydrochloride crystalline form A, the hydrochloride crystalline form B, the hydrochloride amorphous and the free base amorphous disclosed in the prior art WO2010 / 098145. The hydrochloride crystalline form A and the hydrochloride crystalline form B absorb less than 3.4% and 8.6% by weight of water, respectively, at 25° C. and 90% relative humidity (RH). On the other hand, the hydrochloride amorphous and the free base amorphous absorb 20.5% and 17.9% by weight of water, respectively, at 25° C. and 90% relative humidity (RH). Thus, the hydrochloride amorphous and the free base amorphous are much more hygroscopic than the hydrochloride crystalline form A and the hydrochloride crystalline form B.

[0180] [Table 1]

[0181] Example 8 [Stability test] Solid stability tests are performed using Nagano Science thermo-hygrostats LH-20-11M, LH-21-11M, LTL-200D3CJ-14 or LTX-01. Samples are placed in the thermo-hygrostats and exposed to 25°C / 60%RH, 40°C / 75%RH, and / or measured under light irradiation such as D65 lamp or xenon lamp. The crystal form, thermal behavior, purity, and / or weight change of the samples after exposure or irradiation are evaluated by XRPD, TG / DTA or DSC, HPLC, and microbalance, respectively.

[0182] In solid-state stability studies under accelerated conditions at 40°C / 75% RH, samples taken 26 and 50 days after exposure showed that for the hydrochloride crystalline form A, no other degradation products were observed after 50 days of storage, except for the degradant in the initial sample (day 0). However, for the hydrochloride amorphous and free base amorphous, one product (retention time 9.6 min) and four products (retention times 3.7, 9.6, 13.1 and 21.3, respectively) were observed after 50 days of storage, with the survival rates decreasing to 97.0% and 97.2%, respectively. The hydrochloride salt crystalline form A is found to be more stable compared to the hydrochloride salt amorphous and the free base amorphous disclosed in the prior art WO2010 / 098145.

[0183] Example 9 [Photostability test] The photostable samples were placed in a Nagano Science LTL-200D3CJ-14. The samples were placed in a chamber and stored under conditions of 25°C / 60%RH, and irradiated with a D65 lamp at 4000 lux. The hydrochloride crystalline form A, hydrochloride amorphous, and free base amorphous samples stored under these conditions for 13, 26, and 50 days were analyzed by HPLC.

[0184] Figures 7, 8, and 9 show data on degradation products excluding existing products of the initial sample (Day 0), i.e., peaks that clearly appear on the HPLC chart after storing the initial sample under light irradiation. Relative retention time (RRT) indicates the ratio of the retention time (RT) of the target peak to the retention time (RT) of the main peak. If a peak appears at the same RRT for at least two consecutive storage periods of 13, 26, and 50 days, the peak is recognized as a decomposition product. As shown in FIG. 7, for the amorphous hydrochloride salt, after storage periods of 13, 26, and 50 days, respectively, two, five, and five peaks were generated due to decomposition products caused by irradiation with light. As shown in FIG. 8, for the free base amorphous, two, four, and four peaks were generated due to decomposition products caused by irradiation with light after storage periods of 13, 26, and 50 days, respectively. As shown in FIG. 9, the hydrochloride crystalline form A does not produce any decomposition products upon irradiation with light.

[0185] Example 10 [Solubility test] 5 mg of each hydrochloride crystalline form A was weighed into a vial, and 20 μL of each of buffer solutions (pH 1.06, 2.98, 4.44, 7.34, 7.40, 9.22) and WFI (water for injection) were added to the vial. The mixtures were shaken with a vortex mixer and allowed to stand for 15 minutes, but no insoluble matter was observed. The mixtures remained clear solutions even after standing for 2 days. The hydrochloride salt crystalline form A exhibits good solubility (>250 mg / mL) in all buffer solutions.

[0186] Example 11 [Chiral Analysis] High performance liquid chromatography (HPLC) measurement HPLC data is obtained on a Waters Alliance 2695 HPLC system equipped with a 2996 PDA detector using the following conditions: Column: DAICEL CHIRALPAK IC (5 μm, 4.6 × 250 mm), Eluent: n-hexane / ethanol / diethylamine = 87 / 13 / 0.1 (v / v / v), Detection: UV at 254 nm; Flow rate: 1 mL / min, and Column temperature: 40°C. Data processing is performed using Empower 3 software supplied by Waters. In the present invention, the hydrochloride crystalline form A and the hydrochloride crystalline form B exhibit favorable stability and the above-mentioned utility.

[0187] Example 12 [Static electricity induction test] Considering that highly electrostatically conductive substances are generally difficult to handle under pharmaceutical technology conditions, especially under the pharmacological conditions of conventional industrial crude drugs, and are not easy to realize as drugs with uniform content, the electrostatic conductivity of the crystals tested in the present invention shows favorable results that indicate the above-mentioned practicality. The test is performed by a conventional method.

[0188] Example 13 [In vitro pharmacological assay] The motilin receptor agonist activity is identified by a reporter gene assay using cells expressing the motilin receptor and a reporter gene. The dose-response curve of the assay sample is plotted and calculated to determine the agonist activity (EC50). The hydrochloride salt crystalline form A demonstrated high potency consistent with earlier samples.

[0189] In summary, Form A and Form B are significantly less hygroscopic, and Form A is more inhibited from decomposing by light compared to amorphous and amorphous free base. Form A has demonstrated storage stability. No significant changes have been observed in the appearance, XRPD, IR(KBr), melting point (DSC onset) and potency of Form A during the storage period.

[0190] Reference example 1 [General procedure for the preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide salt]: A solution of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide (approximately 25 mg) in EtOH, THF, MTBE, MeCN, MEK, or EtOAc is equilibrated at elevated temperature (50°C-70°C) for approximately 5 minutes before the addition of counterion solution. A counterion solution such as MeCN, EtOH, MEK, THF, DMSO, dioxane, and / or water is added in an amount equivalent to 1.05 molar equivalents of each mixture, and the resulting mixture is then cooled slowly to ambient temperature at 20°C / hr and equilibrated overnight. Any precipitate is isolated by vacuum filtration and dried overnight under vacuum at ambient temperature.

[0191] Reference example 1(a) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide benzenesulfonate The test for salt formation with benzenesulfonic acid is carried out by the general procedure described above using the compound in MeCN and a solution of benzenesulfonic acid in MeCN. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0192] When a solution of this compound in EtOAc and benzenesulfonic acid in MeCN is used for salt formation with benzenesulfonic acid by the general procedure above, an oil is obtained but no solid.

[0193] Reference example 1(b) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide citrate The test for salt formation with citric acid is carried out by the general procedure described above using the compound in MeCN and a solution of citric acid in MeCN. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0194] When a solution of the compound in EtOAc and citric acid in EtOH is used for salt formation with citric acid according to the general procedure above, an oil is obtained but no solid.

[0195] Reference example 1(c) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide L-malate The test for salt formation with L-malic acid is carried out by the general procedure described above using the compound in MeCN and a solution of L-malic acid in MeCN. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0196] When a solution of said compound in EtOAc and L-malic acid in EtOH is used for salt formation with L-malic acid by the general procedure above, an oil is obtained but no solid.

[0197] Reference example 1(d) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide L-tartrate Salt formation with L-tartaric acid is tested by the general procedure described above using the compound in MeCN and L-tartaric acid in EtOH. After addition of counterion, the mixture is clear. After evaporating the solution to dryness, XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0198] Reference example 1(e) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide p-toluenesulfonate Testing for salt formation with p-toluenesulfonic acid salt is carried out by the general procedure described above using the compound in EtOAc and a solution of p-toluenesulfonic acid in MeCN. After addition of the counterion, the mixture is clear. After evaporating the solution to dryness, XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0199] Reference example 1(f) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide naphthalene-2-sulfonate Testing for salt formation with naphthalene-2-sulfonic acid salt is carried out using the above general procedure with the compound in MeCN and a solution of naphthalene-2-sulfonic acid in MeCN. After addition of the counterion, the mixture is clear. After evaporating the solution to dryness, evaluation by XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0200] Reference example 1(g) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide sulfate The salt formation with sulfuric acid is tested by the general procedure described above using the compound in MTBE and sulfuric acid in EtOH. After the addition of the counterion, the mixture is clear. The solution is evaporated to dryness to give an oil but no solid.

[0201] Reference example 1(h) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide ethanesulfonate The test for salt formation with ethanesulfonic acid is carried out by the general procedure described above using the compound in MEK and a solution of ethanesulfonic acid in MEK. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0202] Using EtOH instead of MEK for salt formation with ethanesulfonic acid gives an oil but not a solid.

[0203] Reference example 1(i) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide methanesulfonate (mesylate salt) The salt formation test with methanesulfonic acid is carried out by the general procedure described above using the compound in MeCN and a solution of methanesulfonic acid in MeCN. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0204] On the other hand, when a solution of the compound in MTBE and methanesulfonic acid in MeCN is used for salt formation with methanesulfonic acid according to the general procedure described above, the mixture is clear after the addition of the counterion, and after evaporating the solution to dryness, it is found by XRPD analysis that the mesylate salt is crystalline.

[0205] However, when tested by the same method as in the hygroscopicity test described in Example 7, the water adsorption amount of the mesylate crystals was 3.7% by weight at 60% RH and 16.9% by weight at 90% RH.

[0206] Using a method similar to the chiral analysis in Example 11, the mesylate crystals show the presence of a mixture of R,S- and R,R-isomers (79:21). The sample after isothermal stress is then analyzed, and the chiral purity is 93% (R,S- and R,R-isomers (93:7) are present). However, when the R,R-isomer is spiked into both the pre-isothermal stress and post-isothermal stress samples, the retention times do not match those of the R,R-isomer. The cause of this discrepancy is unknown, but possible reasons for the change in retention time include peak splitting, decomposition, and retention time shifts.

[0207] Therefore, the mesylate crystals are not practical as a pharma- ceutical acceptable salt.

[0208] Reference example 1(j) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hippurate (hippurate salt) The salt formation test with hippuric acid is carried out by the general procedure described above using the compound in MeCN and a solution of hippuric acid in EtOH. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0209] When the compound in MEK and a solution of hippuric acid in MEK are used to form a salt with hippuric acid according to the general procedure described above, the mixture is clear after the addition of counter ions. After evaporating the solution to dryness, it is found by XRPD analysis that the hippuric acid salt is crystalline.

[0210] However, in a method similar to the hygroscopicity test described in Example 7, the water adsorption amount of the hippurate crystals was 16.0% by weight at 90% RH, and partial deliquescence was observed. XRPD analysis of the material after the hygroscopic test gives an amorphous material. 1 H-NMR analysis shows that the amount of MEK is reduced to 1.6 wt %. The formation of amorphous material after DVS analysis and the concomitant loss of MEK are consistent with hippurate being a MEK solvate.

[0211] Thus, hippurate crystals are not practical as a pharma- ceutically acceptable salt.

[0212] Reference example 1(k) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride (HCl salt) The test for salt formation with hydrochloric acid is carried out by the general procedure described above using the compound in MeCN and a solution of hydrochloric acid in water / EtOH. After the addition of counter ion, the mixture is clear. After evaporating the solution to dryness, it is evaluated by XRPD analysis that an amorphous material is obtained. No salt crystals are obtained.

[0213] When a solution of the compound in MeCN and hydrochloric acid in dioxane is used for salt formation with hydrochloric acid according to the general procedure described above, the mixture is clear after the addition of the counterion. After evaporating the solution to dryness, evaluation by XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0214] Reference example 1(l) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide phosphate The salt formation with phosphoric acid is tested by the general procedure described above using the compound in MeCN and a solution of phosphoric acid in EtOH. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0215] When a solution of the compound in EtOAc and phosphoric acid in EtOH is used for salt formation with phosphoric acid according to the general procedure above, an oil is obtained but no solid.

[0216] The oil was then dissolved in MeCN and MTBE was added. The solution became slightly cloudy and a filterable solid was obtained, but it was not possible to isolate a sufficient amount for analysis.

[0217] Reference example 1(m) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide D-gluconate Salt formation with D-gluconic acid is tested using the compound in MTBE and a solution of D-gluconic acid in dioxane / water (volume ratio 4:1) according to the general procedure described above. After addition of the counterion, the mixture becomes two layers. After evaporating the solution to dryness, evaluation by XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0218] Reference example 1(n) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide 1-hydroxy-2-naphthoate The salt formation with 1-hydroxy-2-naphthoic acid is tested by the general procedure described above using the compound in MEK and a solution of 1-hydroxy-2-naphthoic acid in MEK. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0219] Reference example 1(o) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide L-pyroglutamate Salt formation with L-pyroglutamic acid is tested by the general procedure described above using a solution of the compound in EtOAc and L-pyroglutamic acid in EtOH. After addition of counter ion, the mixture is clear. After evaporating the solution to dryness, XRPD analysis shows that an amorphous material is obtained. No salt crystals are obtained.

[0220] Reference example 1(p) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide L-lactate The salt formation test with L-lactic acid is carried out by the general procedure described above using a solution of the above compound in MeCN and a solution of L-lactic acid in MeCN. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0221] When a solution of the above compound in EtOAc and L-lactic acid in EtOH are used to form a salt with L-lactic acid according to the general procedure above, after the addition of the counterion, the mixture becomes two layers. After evaporating the solution to dryness, an oil is obtained but no solid is obtained.

[0222] Reference example 1(q) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide glutarate The salt formation with glutaric acid is tested by the general procedure described above using a solution of the above compound in MEK and a solution of glutaric acid in MEK. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0223] Reference example 1(r) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide pamoate salt The salt formation test with pamoic acid is carried out by the general procedure described above using the compound in EtOAc and a solution of pamoic acid in DMSO. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0224] Reference example 1(s) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide nicotinate The salt formation test with nicotinic acid is carried out by the general procedure described above using the compound in MEK and nicotinic acid in DMSO solution. After adding counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

[0225] Reference example 1(t) Preparation of (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide sebacate The test for salt formation with sebacic acid is carried out by the general procedure described above using the compound in THF and a solution of sebacic acid in THF. After the addition of the counterion, the mixture is clear. After evaporating the solution to dryness, an oil is obtained, but no solid is obtained.

Claims

1. The peaks in 2-theta are 14.7 and 17.5 ( o ) (where each peak is + / - 0.2( o (R)—N—((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, containing an error bar of 0.05%.

2. The peaks in 2-theta were 4.0, 7.9, 14.7, 17.5, and 22.3 ( o ) (where each peak is + / - 0.2( o (R)—N—((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, containing an error bar of 0.05%.

3. 2. The (R)—N—((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of claim 1, further characterized by differential scanning calorimetry (DSC) showing an endothermic event at 254°C (wherein this temperature has an error margin of + / - 1°C).

4. 3327, 2926, 1707, 1668, 1616, and 700 cm -1 (where each peak is + / - 2 cm -1 2. The (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of claim 1, further characterized by an infrared (IR) spectrum (KBr) exhibiting an absorbance band at 100 nm (with an error bar of 0.05).

5. The peaks in 2-theta are 19.8 and 21.6 ( o ) (where each peak is within + / - 0.2( o (R)—N—((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, containing an error bar of 0.05%.

6. The peaks in 2-theta were 4.0, 7.9, 15.7, 17.9, 19.8, and 21.6 ( o ) (where each peak is + / - 0.2( o (R)—N—((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with Cu-K alpha (Cu-Kα) radiation, containing an error bar of 0.05%.

7. 6. The (R)—N—((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B of claim 5, further characterized by differential scanning calorimetry (DSC) showing an endothermic event at 258° C. (wherein this temperature has an error margin of + / −1° C.).

8. 8. A pharmaceutical composition comprising the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form according to any one of claims 1 to 7, together with one or more pharmaceutically acceptable carriers or excipients.

9. 9. The pharmaceutical composition of claim 8, in a dosage form for oral, parenteral, topical, rectal, vaginal, ocular or otic administration.

10. 10. The pharmaceutical composition of claim 9, wherein the dosage form is selected from the group consisting of tablets, soft capsules, hard capsules, trozenges, films, ovules, sprays, patches, suspensions, solutions, syrups, elixirs, modified release formulations, lotions, creams, ointments, gels, drops, foams, wafers, implants, microemulsions, injections, dry powders, and suppositories.

11. 8. A pharmaceutical composition comprising the use of the (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form of any one of claims 1 to 7 together with one or more pharmaceutically acceptable carriers or excipients.

12. The (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form according to any one of claims 1 to 7 for use as a medicament.

13. Use of the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form of any one of claims 1 to 7 in the preparation of a medicament for the curative, palliative or prophylactic treatment of a pathology mediated by motilin receptor activity.

14. Use of the pharmaceutical composition of claim 8 in the preparation of a medicament for the curative, palliative or prophylactic treatment of a pathology mediated by motilin receptor activity.

15. 5. A process for preparing the (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A of any one of claims 1 to 4, comprising the step of adding hydrochloric acid in a first organic solvent to a solution of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide in a second organic solvent.

16. 5. A process for preparing (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of claims 1 to 4, comprising exposing (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride solid to heating in tetrahydrofuran containing less than 10% by volume of water.

17. 5. A process for preparing the (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of claims 1 to 4, comprising the steps of adding a solid (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride to tetrahydrofuran containing 0.01 to 5% (v / v) water at 50 to 80°C, and then adding ethyl acetate at 50 to 80°C.

18. 5. A process for preparing the (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of claims 1 to 4, comprising the steps of heating (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride solid in ethyl acetate at a temperature in the range of 50 to 80°C, and cooling to room temperature.

19. 5. A process for preparing (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of claims 1 to 4, comprising the step of converting (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B into the hydrochloride crystalline form A by stirring in an organic solvent at room temperature to 100°C.

20. 20. A method for preparing (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to claim 19, comprising stirring (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form B, wherein the organic solvent is ethyl acetate or THF / ethyl acetate containing less than 1% water by volume.

21. 5. A process for preparing the (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of claims 1 to 4, comprising the step of adding seed crystals of (R)—N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride to obtain the hydrochloride crystalline form A.

22. A process for preparing the (R)-N-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)piperidine-3-carboxamide hydrochloride crystalline form A according to any one of claims 1 to 4, comprising the step of crystallizing the crystalline form from a solvent.

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