Patent Description:
The present invention also relates to process for manufacturing a solid composition according to the invention comprising a step of mixing a <NUM>,<NUM>,<NUM>-oxadiazole derivative comprising exactly two monocyclic tertiary amine groups with citric acid and/or saccharin; and to the solid formulation obtainable from the process.

The present invention also relates to a method for increasing the physical stability of a <NUM>,<NUM>,<NUM>-oxadiazole derivative comprising exactly two monocyclic tertiary amine groups, comprising a step of mixing the <NUM>,<NUM>,<NUM>-oxadiazole derivative with citric acid and/or saccharin.

Cardiometabolic diseases are among the most common causes of death in the world. They account for <NUM>% of all deaths before cancer and chronic respiratory diseases, and effect more than <NUM> million people. It is predicted that it will cause more than <NUM> million deaths in <NUM>, compared to <NUM> million in <NUM>. It is estimated that in the United States, one in four adults is affected, whereas in Europe it affects <NUM>% of adults.

A widespread cardiometabolic disorder is type <NUM> diabetes, or non-insulin-dependent diabetes. This diabetes is the most common form since it affects about <NUM>% of people with diabetes. This disease affects all age groups but its frequency increases with age. For example, the incidence of the disease is <NUM>% in the United States beyond <NUM> years; and over <NUM> years in France. At the global level, the incidence of diabetes among adults increased from <NUM>% in <NUM> to <NUM>% in <NUM>. The mortality directly associated with diabetes is estimated at <NUM> million deaths per year. In addition, recent studies have shown that diabetes is associated, in <NUM>% of cases, with the appearance of many other cardiometabolic risk factors such as hypertension, overweight and even obesity, and dyslipidaemia. The search for treatment for type <NUM> diabetes thus remains today a major challenge.

It is known that GLP-<NUM> peptide receptor is involved in cardiovascular diseases and eating disorders such as diabetes, obesity or anorexia. Moreover, the GLP-<NUM> receptor is also involved directly and indirectly in brain disorders, especially neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, psychiatric disorders such as schizophrenia and mood disorders. Thus, <CIT>) discloses <NUM>,<NUM>,<NUM>-oxadiazole derivatives for preventing and/or treating a disease in which GLP-<NUM> receptor participates or mediates which may be useful in the treatment of diabetes.

However, the disclosed <NUM>,<NUM>,<NUM>-oxadiazole derivatives are not convenient for widespread medical use as they present in the form of oils or deliquescent solids. Such physical forms are significant limitations for industrial manufacturing processes of drugs from these active ingredients because the oils or deliquescent solids are convenient neither for handling (transfer, mixing, cleaning) nor for quality control (e.g., in-line automated analyses), especially compared to homogeneous and stable liquids or powders. Storage between manufacture of the active ingredient and further manufacture of a pharmaceutical composition comprising it is also render more difficult with oils or deliquescent solids.

Therefore, it would be advantageous to obtain <NUM>,<NUM>,<NUM>-oxadiazole derivatives as disclosed in <CIT> in a more convenient physical form.

<CIT> discloses solid formulations of <NUM>,<NUM>,<NUM>-oxadiazole derivatives which can be present as citrate salts.

The Applicant carried out in-depth research in order to solve the technical problem of the physical stability of the <NUM>,<NUM>,<NUM>-oxadiazole derivatives. Especially, it was tried to take advantage of the presence of tertiary amine functions in the <NUM>,<NUM>,<NUM>-oxadiazole derivatives for manufacturing mono- or di-addition salts which may have to stabilized the intramolecular structure of the <NUM>,<NUM>,<NUM>-oxadiazole derivative. Disappointingly, contacting an organic or inorganic acid with the <NUM>,<NUM>,<NUM>-oxadiazole derivative lead in most cases to another sicky oil or to a hygroscopic solid which achieves quick deliquescence (as shown in the comparative Examples below). Therefore, it appeared that physically stable addition salts of the <NUM>,<NUM>,<NUM>-oxadiazole derivatives cannot be easily formed.

However, the Applicant surprisingly found that a solid formulation may be obtained by mixing citric acid and/or saccharin with an <NUM>,<NUM>,<NUM>-oxadiazole derivative comprising two monocyclic tertiary amine groups, and that the solid formulation manufactured thereby remained unexpectedly physically stable overtime.

The invention relates to a solid formulation comprising from about <NUM>% to about <NUM>% w/w of:
the compound of formula (A):
<CHM>
and.

According to one embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one specific embodiment, the molar ratio is about <NUM>.

The invention also relates to a process for manufacturing a solid composition according to the invention comprising a step of mixing at least one <NUM>,<NUM>,<NUM>-oxadiazole derivative as defined hereinabove with citric acid and/or saccharin, wherein the initial molar ratio between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative ranges from about <NUM> to about <NUM>; preferably ranges from about <NUM> to about <NUM>.

The invention also relates to a method for increasing the physical stability of the <NUM>,<NUM>,<NUM>-oxadiazole derivative as defined hereinabove, comprising a step of mixing the <NUM>,<NUM>,<NUM>-oxadiazole derivative with citric acid and/or saccharin, wherein the initial molar ratio between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative ranges from about <NUM> to about <NUM>; preferably ranges from about <NUM> to about <NUM>, and wherein no solvent is present during the mixing step. According to one embodiment, the mixing is stirring and/or grinding.

The invention also relates to a pharmaceutical composition comprising a solid formulation according to the invention and at least one pharmaceutically acceptable excipient. According to one embodiment, the at least one pharmaceutically acceptable excipient is free of citric acid and free of saccharin. The invention also relates to a solid formulation according to the invention or a pharmaceutical composition according to the invention for use as a medicament.

The invention also relates to a solid formulation according to the invention or a pharmaceutical composition according to the invention for use in the treatment and/or prevention of a disease in which GLP-<NUM> receptor participates or mediates, whereby the disease is selected from: metabolic disorders such as diabetes or obesity; diseases induced by or associated with metabolic disorders such as diabetic neuropathy, diabetic retinopathy, glaucoma, cataract, diabetic nephropathy or diabetic foot ulcer; cardiovascular diseases such as coronary artery diseases, stroke, heart failure, hypertensive heart disease or congenital heart disease; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, optic nerve degeneration and movement disorder, neuromuscular disorders or cognitive deficiency; and neurological or neuropsychiatric diseases such as epilepsy, schizophrenia, bipolar disorders, depression or pain.

The invention relates to a solid formulation, as defined by the claims, comprising:.

wherein the molar ratio in the solid formulation between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative is higher or equal to about <NUM>.

The invention also relates to a solid formulation obtainable by mixing:.

According to one embodiment, no solvent is present during the mixing step. In one embodiment, no substance other than <NUM>,<NUM>,<NUM>-oxadiazole derivative(s) and citric acid and/or saccharin is present during the mixing step.

According to the invention, the <NUM>,<NUM>,<NUM>-oxadiazole derivative is <NUM>-((<NUM>-((<NUM>-(<NUM>-(trifluoromethyl)phenyl)-<NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl)methyl)piperidin-<NUM>-yl)methyl)morpholine of formula (A) (hereafter "Compound A"):
<CHM>.

Compound A was named using ChemDraw® Professional <NUM> (PerkinElmer).

Citric acid or "<NUM>-Hydroxypropane-<NUM>,<NUM>,<NUM>-tricarboxylic acid" (C<NUM>H<NUM>O<NUM>, <NPL>]) of formula:
<CHM>
is a weak organic acid (pKa for acid groups of <NUM>, <NUM> and <NUM> at <NUM>) occurring naturally in citrus fruits.

Saccharin or "benzoic sulfimide" or "<NUM>,<NUM>-dioxo-<NUM>,<NUM>-benzothiazol-<NUM>-one" (C<NUM>H<NUM>NO<NUM>S, <NPL>]) of formula:
<CHM>
is a weak organic acid (pKa of <NUM> at <NUM>) manufactured with synthetic chemistry.

Any reference to "<NUM>,<NUM>,<NUM>-oxadiazole derivative", "citric acid" or "saccharin" in the present disclosure encompass any enantiomers and solvates thereof. Any reference to "<NUM>,<NUM>,<NUM>-oxadiazole derivative", "citric acid" or "saccharin" in the present disclosure encompass any salts thereof, preferably pharmaceutically acceptable salts thereof. Any reference to "a compound" (e.g., "a <NUM>,<NUM>,<NUM>-oxadiazole derivative") should be constructed as meaning "at least one compound" and thus encompasses any mixtures of two or more <NUM>,<NUM>,<NUM>-oxadiazole derivatives, enantiomers, solvates and/or salts thereof.

According to one embodiment, the solid formulation comprises about <NUM>% w/w or more of <NUM>,<NUM>,<NUM>-oxadiazole derivative(s) and citric acid and/or saccharin (i.e., the total amount of <NUM>,<NUM>,<NUM>-oxadiazole derivative(s) and citric acid and/or saccharin represents at least about <NUM>% of the total weight of the solid composition). According to the invention, the solid formulation comprises a total amount of <NUM>,<NUM>,<NUM>-oxadiazole derivative and citric acid and/or saccharin ranging from about <NUM>% to about <NUM>% w/w, preferably ranging from about <NUM>% to <NUM>% w/w, more preferably ranging from about <NUM>% to <NUM>% w/w, furthermore preferably ranging from about <NUM>% to <NUM>% w/w, furthermore preferably ranging from about <NUM>% to <NUM>% w/w. In these embodiments, "w/w" means "in weight of the total weight of the solid formulation". In one embodiment, the solid formulation consists of <NUM>,<NUM>,<NUM>-oxadiazole derivative and citric acid and/or saccharin.

According to one embodiment, the solid formulation comprises a mono- or di-citrate salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative. In one embodiment, the solid formulation comprises a di-citrate salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative. According to one embodiment, the solid formulation comprises a mono- or di-saccharin salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative. In one embodiment, the solid formulation comprises a di-saccharin salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative. In one embodiment, the solid formulation comprises a mono-citrate and mono-saccharin salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative.

In one embodiment, the solid formulation comprises or consists of:.

According to the invention, the molar ratio in the solid formulation or the initial molar ratio between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative ranges from about <NUM> to about <NUM>. In one specific embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one further specific embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one further specific embodiment, the molar ratio is about <NUM>, about <NUM>, about <NUM> or about <NUM>. In one further specific embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one further specific embodiment, the molar ratio is about <NUM>.

According to one embodiment, the solid formulation keeps its physical stability (as defined hereinabove) for at least <NUM> days at <NUM> ± <NUM> and <NUM> ± <NUM>% humidity. In one embodiment, the solid formulation keeps its physical stability for at least <NUM> days. In one specific embodiment, the solid formulation keeps its physical stability for at least <NUM> weeks. In one further specific embodiment, the solid formulation keeps its physical stability for at least <NUM> weeks. In one further specific embodiment, the solid formulation keeps its physical stability for at least <NUM> weeks.

According to one embodiment, the specific surface area (BET) of the solid formulation is higher than the specific surface area of the citric acid and/or saccharin; when the citric acid and/or saccharin is not included in the solid formulation.

In one embodiment, the specific surface area (BET) of the solid formulation is higher than <NUM><NUM>/g; preferably higher than <NUM><NUM>/g; more preferably higher than <NUM><NUM>/g. In one specific embodiment, the specific surface area (BET) of the solid formulation is about <NUM><NUM>/g. In one specific embodiment, the specific surface area (BET) of the solid formulation is about <NUM><NUM>/g. In one specific embodiment, the specific surface area (BET) of the solid formulation is about <NUM><NUM>/g.

According to one embodiment, the solid formulation is not a pharmaceutical composition. In one embodiment, the solid formulation is not an oral formulation such as oral powder. In one embodiment, the solid formulation is not a solid formulation such as a solid tablet. In these embodiments, the solid formulation as such (per se) is not suitable to be directly administrated to a subject for therapeutic purposes, e.g., because it comprises a very high concentration of the therapeutic agent (namely, the <NUM>,<NUM>,<NUM>-oxadiazole derivative), which would cause toxicity or significant adverse effects or which would not lead to potent medical treatment. However, the solid formulation may be formulated in a pharmaceutical composition as a therapeutic agent for therapeutic purposes, typically in very low amounts, as described hereinafter.

The invention also relates to a citrate and/or saccharin salt of a <NUM>,<NUM>,<NUM>-oxadiazole derivative comprising exactly two monocyclic tertiary amine groups.

According to one embodiment, the salt is a mono- or di-citrate salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative, i.e., the <NUM>,<NUM>,<NUM>-oxadiazole derivative is ionized through at least one proton transfer from one citric acid to at least one of the tertiary amine groups. In one embodiment, the salt is a di-citrate salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative, i.e., the <NUM>,<NUM>,<NUM>-oxadiazole derivative is ionized through two proton transfer from one or two citric acid to both tertiary amine groups.

According to one embodiment, the salt is a mono- or di-saccharin salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative, i.e., the <NUM>,<NUM>,<NUM>-oxadiazole derivative is ionized through at least one proton transfer from one saccharin to at least one of the tertiary amine groups. In one embodiment, the salt is a di-saccharin salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative, i.e., the <NUM>,<NUM>,<NUM>-oxadiazole derivative is ionized through two proton transfer from two saccharin to both tertiary amine groups.

In one embodiment, the salt is a mono-citrate and a mono-saccharin salt of the <NUM>,<NUM>,<NUM>-oxadiazole derivative, i.e., the <NUM>,<NUM>,<NUM>-oxadiazole derivative is ionized through one proton transfer from one citric acid and one proton transfer from one saccharin to both tertiary amine groups.

According to one embodiment, the salt is a pharmaceutically acceptable salt.

According to the invention, the <NUM>,<NUM>,<NUM>-oxadiazole derivative is Compound A, as described hereinabove.

The invention also relates to a process for manufacturing a solid composition according to the invention as described hereinabove, comprising a step of mixing a <NUM>,<NUM>,<NUM>-oxadiazole derivative comprising exactly two monocyclic tertiary amine groups with citric acid and/or saccharin,
wherein the initial molar ratio between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative is higher or equal to about <NUM>.

The invention also relates to a method for increasing the physical stability of a <NUM>,<NUM>,<NUM>-oxadiazole derivative comprising exactly two monocyclic tertiary amine groups, comprising a step of mixing the <NUM>,<NUM>,<NUM>-oxadiazole derivative with citric acid and/or saccharin,
wherein the initial molar ratio between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative is higher or equal to about <NUM>.

In accordance with the definition of "physical stability" provided hereinabove, in the invention an "improvement of the physical stability" or an "increase of the physical stability" of a substance refers to reduction (or suppression) of deliquescence of the substance and/or to reduction (or suppression) of hygroscopy - so that the substance remains is not deliquescent and/or absorbs less water; and/or to increase of the melting point of the substance - so that the substance becomes solid.

Reduction of deliquescence of a substance may possibly be characterized by a reduction of the hygroscopy of the substance. Hygroscopy may for example be measured by DVS (Dynamic Vapor Sorption), which measures the change in mass of a sample regarding the vapor pressure of a solvent.

Melting point of a substance may for example be measured by DSC (Differential Scanning Calorimetry) analysis, which measures the heat flow between the sample and a reference maintained both at the same temperature, or by a melting-point meter, a device where the sample can be observed when it is heated gradually in order to detect the melting point.

According to the invention, the initial molar ratio between the total amount of citric acid and/or saccharin and the amount of the <NUM>,<NUM>,<NUM>-oxadiazole derivative ranges from about <NUM> to about <NUM>. In one specific embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one further specific embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one further specific embodiment, the molar ratio is about <NUM>, about <NUM>, about <NUM> or about <NUM>. In one further specific embodiment, the molar ratio ranges from about <NUM> to about <NUM>. In one further specific embodiment, the molar ratio is about <NUM>.

According to one embodiment, the process or method comprises a first step of contacting the <NUM>,<NUM>,<NUM>-oxadiazole derivative with citric acid and/or saccharin followed by a second step of mixing the <NUM>,<NUM>,<NUM>-oxadiazole derivative and citric acid and/or saccharin.

According to one embodiment, the mixing is stirring. According to one embodiment, the mixing is grinding.

According to one embodiment, no solvent is present during the mixing step. In one embodiment, no substance other than <NUM>,<NUM>,<NUM>-oxadiazole derivative and citric acid and/or saccharin is present during the mixing step.

The invention also relates to a pharmaceutical composition comprising a solid formulation according to the invention as described hereinabove and at least one pharmaceutically acceptable excipient.

According to one embodiment, the solid formulation in the pharmaceutical composition is a therapeutic agent.

According to one embodiment, the pharmaceutical composition comprises the solid formulation in an amount ranging from about <NUM>% to about <NUM>% w/w, preferably ranging from about <NUM>% to about <NUM>% w/w, more preferably ranging from about <NUM>% to about <NUM>% w/w. In one embodiment, the pharmaceutical composition comprises the solid formulation in an amount ranging from about <NUM>% to about <NUM>% w/w, preferably ranging from about <NUM> to about <NUM>% w/w, more preferably ranging from about <NUM> to about <NUM>% w/w. In these embodiments, "w/w" means "in weight of the total weight of the pharmaceutical composition".

According to one embodiment, the at least one pharmaceutically acceptable excipient is free of citric acid. According to one embodiment, the at least one pharmaceutically acceptable excipient is free of saccharin. In one embodiment, the at least one pharmaceutically acceptable excipient is free of citric acid and free of saccharin, i.e., each pharmaceutically acceptable excipient which is comprised in the pharmaceutical composition does not itself comprise citric acid or saccharin.

The invention also relates to a solid formulation or to a pharmaceutical composition according to the invention as described hereinabove for use as a medicament.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of a disease in which GLP-<NUM> receptor participates or mediates.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of a disease wherein a GLP-<NUM> receptor participates or mediates as disclosed in <CIT>).

In one embodiment, the disease wherein a GLP-<NUM> receptor participates or mediates is selected from obesity, anorexia, lipid dysfunction, diabetes, hyperinsulinism and metabolic syndrome. In one embodiment, the disease wherein GLP-<NUM> receptor participates or mediates is obesity. In another embodiment, the disease wherein GLP-<NUM> receptor participates or mediates is diabetes. In one embodiment, diabetes is type <NUM> Mellitus diabetes.

In one embodiment, the disease wherein a GLP-<NUM> receptor participates or mediates is selected from diseases induced by or associated with obesity, anorexia, lipid dysfunction, diabetes, hyperinsulinism and metabolic syndrome ("GLP-<NUM>-related disease"). In one embodiment, the disease is induced by or associated with diabetes ("diabetes-related disease"), such as diabetic neuropathy, diabetic retinopathy, glaucoma, cataract, diabetic nephropathy or diabetic foot ulcer.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of eating disorders. In one embodiment, the eating disorder is selected from obesity, anorexia, lipid dysfunction, diabetes, hyperinsulinism and metabolic syndrome.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of metabolic disorders such as diabetes or obesity. In one embodiment, the metabolic disorder is selected from diabetes and obesity.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of cardiovascular diseases. In one embodiment, the cardiovascular disease is selected from coronary artery diseases, stroke, heart failure, hypertensive heart disease and congenital heart disease.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of neurodegenerative diseases. In one embodiment, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, optic nerve degeneration and movement disorder, neuromuscular disorders and cognitive deficiency.

According to one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and/or prevention of neurological or neuropsychiatric diseases. In one embodiment, the neurological or neuropsychiatric disease is selected from epilepsy, schizophrenia, bipolar disorders, depression and pain.

The invention thus also relates to methods of treatment and/or prevention of diseases, comprising the administration of a therapeutically effective amount of a solid formulation or pharmaceutical composition according to the invention, as described hereinabove, to a subject in need thereof. The invention thus also relates to the use of a solid formulation or pharmaceutical composition according to the invention, as described hereinabove, in the manufacture of a medicament.

The invention also relates to a non-therapeutic method of prevention of weight gain in a subject, comprising a step of administration to said subject of a solid formulation or pharmaceutical composition according to the invention, as described hereinabove. According to one embodiment, prevention of weight gain is prevention of fat gain.

The invention also relates to a non-therapeutic method of control of weight gain in a subject, comprising a step of administration to said subject of a solid formulation or pharmaceutical composition according to the invention, as described hereinabove. According to one embodiment, control of weight gain is control of fat gain.

The invention also relates to a non-therapeutic method of stimulation of weight loss in a subject, comprising a step of administration to said subject of a solid formulation or pharmaceutical composition according to the invention, as described hereinabove. According to one embodiment, stimulation of weight loss is stimulation of fat loss.

Compound A was synthetized according to methods known in the art. <NUM>C-NMR (CDCl<NUM>): δ <NUM> (CH2pip), <NUM> (CH2pip), <NUM> (CH), <NUM> (CH2pip), <NUM> (CH<NUM>Npip), <NUM> (2CH<NUM>Nmorph), <NUM> (CH<NUM>Npip), <NUM> (CH2morph), <NUM> (2CH<NUM>Omorph), <NUM> (q, CF<NUM>), <NUM> (q, C) <NUM> (2CH), <NUM> (2CH), <NUM> (q, C)<NUM> (C(N)=N), <NUM> (C(O)=N). <NUM>H-NMR (CDCl<NUM>): δ <NUM>-<NUM> (m, <NUM>, <NUM>/2CH2pip), <NUM>-<NUM> (m, <NUM>, <NUM>/2CH2pip, CH2pip), <NUM>-<NUM> (m, <NUM>, <NUM>/<NUM> CH<NUM>Npip, CH), <NUM>-<NUM> (m, <NUM>, CH2morph, <NUM>/<NUM> CH<NUM>Npip), <NUM>-<NUM> (m, <NUM>, 2CH<NUM>Nmorph), <NUM> (d, <NUM>, <NUM>/<NUM> CH<NUM>Npip), <NUM> (d, <NUM>, <NUM>/2CH<NUM>Npip), <NUM>-<NUM> (m, <NUM>, 2CH<NUM>Omorph), <NUM> (q, <NUM>, CH2pip), <NUM> (d, <NUM>, 2CHAr), <NUM> (d, <NUM>, 2CHAr). Rf: <NUM> (thin layer chromatography (TLC) on silica plate (silica gel <NUM> F254 Merck on aluminum foil of <NUM> thickness) with eluent: dichloromethane/methanol (<NUM>/<NUM>), reveled by UV and KMnO<NUM> solution).

All others reactants and all solvents were purchased from commercial providers. All reactants and solvents used were reagent grade.

In a round bottom flask, to a solution of A in anhydrous Et<NUM>O (<NUM>/mmol) under argon atmosphere, the acid was added dropwise, as a pure liquid or in anhydrous Et<NUM>O (<NUM>/mmol) solution. The mixture was allowed to stand for <NUM>. The product was then isolated by evaporation of the solvent and was dried under vacuum.

The reaction between A and acetic acid was performed with <NUM> equivalents of the acid. After drying under vacuum a sticky oil was obtained.

The reaction between A and hydrobromic acid was performed with <NUM> equivalents of the acid. After drying under vacuum a deliquescent solid was obtained.

The reaction between A and hydrochloric acid was performed with a significant excess of the acid. After drying under vacuum a deliquescent solid was obtained.

The reaction between A and methanesulfonic acid was performed several times, with <NUM>, <NUM>, <NUM> and <NUM> equivalents of the acid.

After drying under vacuum a sticky oil was obtained, except for the product formed with <NUM> equivalent which was instead a deliquescent solid.

The reaction between A and sulfuric acid was performed with <NUM> equivalents of the acid. After drying under vacuum a sticky oil was obtained.

Mechanochemistry may be used for efficiently manufacture salts of organic compounds from solid acids or bases. It is a solvent-free process comprising a mixing step such as a grinding step. Grinding step may carried out either by net grinding or "Liquid Assisted Grinding (LAG)" where a very small amount of solvent is added in order to increase the molecular mobility. This aims in accelerating and/or completing the reaction.

In the present case, net grinding was used because Compound A is an oil so that molecular mobility was likely to be sufficient. Two different net grinding procedures were used:.

The reaction between A and citric acid was performed with <NUM> equivalents of the acid. After grinding, a white powder was obtained ("A-2CA", shown on <FIG>).

The reaction between A and citric acid was also performed with <NUM> equivalent of the acid. After grinding, a sticky oil was obtained ("A-1CA").

The reaction between A and fumaric acid was performed two times, with <NUM> or <NUM> equivalents of the acid. In both cases, a sticky oil was obtained.

The reaction between A and saccharin was performed two times, with <NUM> or <NUM> equivalents of the acid. When only one equivalent of saccharin was used, a sticky oil was obtained. On the other hand, with two equivalents a white powder was obtained ("A-2SA", shown on <FIG>).

The reaction between A, saccharin and citric acid was performed with <NUM> equivalent of each of the acids. After grinding, a white powder was obtained ("A-1CA-1SA", shown on <FIG>).

The reaction between A and sodium bicarbonate was performed two times, with <NUM> or <NUM> equivalents of the acid. In both cases, a sticky oil was obtained.

The reaction between A and succinic acid was performed two times, with <NUM> or <NUM> equivalents of the acid. In both cases, a sticky oil was obtained.

NMR Spectra were recorded on a JEOL JNM EX-<NUM><NUM> or JEOL JNM-ECZ <NUM>. Samples were prepared in deuterated DMSO at room temperature in standard quartz tubes (<NUM>). The spectra were analysed with Delta program.

Specific surface area was measured by Nitrogen adsorption-desorption analyses at <NUM> with a volumetric adsorption analyser (Micromeritics 3Flex physisorption apparatus). The Brunauer-Emmet-Teller (BET) method was applied in the <NUM>-<NUM> P /P0 range to calculate the specific surface area.

X-Ray powder diffraction (PXRD) data were collected on a Panalytical X'Pert Pro diffractometer (Bragg-Brentano geometry, X'Celerator detector), using Cu Kα radiation (λ = <NUM>Å) at <NUM> kV and <NUM> mA. Each sample was analysed between <NUM> and <NUM>° in 2θ.

Pictures of the samples were taken with a SEM microscope Jeol JSM-6010LV with a SEI detector.

In a <NUM> Eppendorf tube, A (<NUM>, <NUM> mmol, <NUM> eq), citric acid (<NUM>, <NUM> mmol, <NUM> eq), two of <NUM> and five of <NUM> stainless steel grinding balls were added. The Eppendorf was then placed in a grinding machine (Retsch Mixer Mill <NUM>), equipped with two grinding jars. The dry grinding was then performed for <NUM> at <NUM>. Similar results were obtained by decreasing grinding time to <NUM>. In order to improve the stirring, the reaction mixture was placed in a mortar and was manually ground with a pestle until A-2CA as a white powder was obtained.

<NUM>H NMR of A-2CA showed a spectrum similar to a superposition of the spectra of A and citric acid. Therefore, the molecular structure of A and citric acid have been maintained and no deterioration of the reactants has been observed.

<NUM>C NMR of A-2CA showed no significant shift for the carbon atoms near the nitrogen atoms (tertiary amines) in comparison with A. Thus, it cannot be assessed from RMN whether a salt has been formed.

A-2CA was left to the air at room temperature (<NUM> ± <NUM>) with normal humidity (relative humidity <NUM> ± <NUM>%) for <NUM> days.

No liquid phase appeared over this period, A-2CA solid composition is thus physically stable.

After <NUM> days, A-2CA powder particles became slightly stickier, the solid composition may thus be moderately hygroscopic.

The diffractograms of A-2CA and citric acid are shown on <FIG>. Citric acid is detected in A-2CA as both diffractogram present the same peak patterns. The diffractogram of A-2CA additionally shows the presence of an amorphous phase.

The specific surface area of a A-2CA sample was measured by BET analysis as:
BET surface A-2CA = <NUM><NUM>/g.

Many SEM pictures of a A-2CA sample were recorded, a representative example being shown on <FIG>. SEM pictures may be useful in order to characterize the particle size distribution in the solid formulation.

In a <NUM> Eppendorf tube, A (<NUM>, <NUM> mmol, <NUM> eq), saccharin (<NUM>, <NUM> mmol, <NUM> eq), two of <NUM> and five of <NUM> stainless steel grinding balls were added. The Eppendorf was then placed in the grinding machine (Retsch Mixer Mill <NUM>), equipped with two grinding jars. The dry grinding was then performed from <NUM> to <NUM> at <NUM> to afford A-2SA as a white powder.

It was found that the grinding time did not affect the results. The following analyses were performed on the solid formulation obtained after <NUM> of grinding.

<NUM>H NMR of A-2SA showed a spectrum similar to a superposition of the spectra of A and saccharin. Therefore, the molecular structure of A and saccharin have been maintained and no deterioration of the reactants has been observed.

<NUM>C NMR of A-2SA showed no significant shift for the carbon atoms near the nitrogen atoms (tertiary amines) in comparison with A. Thus, it cannot be assessed from RMN whether a salt has been formed.

A-2SA was left to the air at room temperature (<NUM> ± <NUM>) with normal humidity (relative humidity <NUM> ± <NUM>%) for <NUM> days.

No liquid phase appeared over this period, A-2SA solid composition is thus physically stable.

After <NUM> days, A-2SA powder particles became slightly stickier, the solid composition may thus be moderately hygroscopic.

For comparison purpose it was relevant to observe the effect of grinding on saccharin. Commercial saccharin was grinded for <NUM> at <NUM> and was compared to a non-grinded powder from the same batch of commercial saccharin.

The diffraction pattern (PXRD) of saccharin before and after grinding were obtained and compared: they are identical. Therefore, grinding does not lead to amorphization of saccharin under the experimental conditions.

Moreover, Scanning Electron Microscopy (SEM) pictures of saccharin before and after grinding confirmed that the crystal structure of grinded saccharin does not change, although it has smaller particles than commercial saccharin.

The diffractograms of A-2SA and saccharin are shown on <FIG>. As for A-2CA, saccharin is detected in A-2SA as both diffractogram present the same peak patterns. The diffractogram of A-2SA additionally shows the presence of an amorphous phase.

For comparison purpose, it was relevant to observe the effect of grinding on saccharin. Commercial saccharin was grinded for <NUM> at <NUM> and was compared to a non-grinded powder from the same batch of commercial saccharin.

The specific surface area of the two saccharin samples was measured by BET analysis as:.

This experiment evidence that no significant change is observed regarding the specific surface area (BET) of saccharin after grinding, with only a moderate decrease (about -<NUM>%).

The specific surface area of a A-2SA sample was measured by BET analysis as:
BET surface A-2SA = <NUM><NUM>/g.

A significant change was observed regarding the specific surface area (BET) of saccharin mixed with A-2SA which is three times higher than the one of saccharin alone (about +<NUM>%), following the same grinding procedure.

Therefore, the presence of A in the solid formulation modify significantly the specific surface area of the solid, thereby evidencing an interaction between the two compounds of the solid formulation. The solid formulation is thus not a mere admixture.

Many SEM pictures of a A-2SA sample were recorded, a representative example being shown on <FIG>.

In a grinding jar, A (<NUM>, <NUM> mmol, <NUM> eq), citric acid (<NUM>, <NUM> mmol, <NUM> eq), saccharin (<NUM>, <NUM> mmol, <NUM> eq) and a grinding ball made of agate were added. The jar was then placed in the grinding machine (Retsch Mixer Mill <NUM>), equipped with another grinding jars. The dry grinding was performed for <NUM> at <NUM> to afford A-1CA-1SA as a white solid.

<NUM>H NMR of A-1CA-1SA showed a spectrum similar to a superposition of the spectra of A and citric acid and saccharin. Therefore, the molecular structure of A, citric acid and saccharin has been maintained and no deterioration of the reactants has been observed.

<NUM>C NMR of A-1CA-1SA showed no significant shift for the carbon atoms near the nitrogen atoms (tertiary amines) in comparison with A. Thus, it cannot be assessed from RMN whether a salt has been formed.

A-1CA-1SA was left to the air at room temperature (<NUM> ± <NUM>) with normal humidity (relative humidity <NUM> ± <NUM>%) for <NUM> days.

No liquid phase appeared over this period, A-1CA-1SA solid composition is thus physically stable.

The diffractograms of A-1CA-1SA, citric acid and saccharin are shown on <FIG>. As for A-2CA and A-2SA, citric acid and saccharin are detected in A-1CA-1SA as both diffractogram present the same peak patterns. The diffractogram of A-1CA-1SA additionally shows the presence of an amorphous phase.

The specific surface area of A-1CA-1SA sample was measured by BET analysis as:
BET surface A-1CA-1SA = <NUM><NUM>/g.

Many SEM pictures of a A-1CA-1SA sample were recorded, a representative example being shown on <FIG>.

Due to the presence of two tertiary amine functions in the <NUM>,<NUM>,<NUM>-oxadiazole derivative A, the manufacture of mono- or di-addition salts have been considered in order to obtain a physically stable form of the active ingredient.

The results of the in-depth formulation study carried out by the Applicant (Example <NUM>) can be summarized as shown in Table <NUM> below.

With most of the acids, used as liquids or solids in various relative amounts to A, led to the formation of either sticky oil or deliquescent (hygroscopic) compounds. Therefore, it appeared that physically stable addition salts of compound A cannot be easily obtained.

However, the use of specific acids being citric acid and/or saccharin has unexpectedly led to a stable solid formulation of compound A. It was also found that citric acid and/or saccharin had to be used in an amount of at least two equivalents in order to achieve the stabilization effect: when only one equivalent of citric acid or saccharin is added to compound A, then the resulting mixture is a sticky oil.

Analytical studies (Example <NUM>) have confirmed that the solid formulation according to the invention is physically stable.

It was also evidenced that the main structure of compound A in a solid formulation according to the invention is not affected, so that it can reasonably be expected that its biological activity will be comparable with the one of "free" compound A.

Significant surface specific area increase observed for A-2SA further shows that the solid composition is not a mere admixture but that A and saccharin have a chemical interaction within the solid formulation.

Without wishing to be bound by any theory, the Applicant believes that compound A might be associated with citric acid and/or saccharin by means of non-covalent bonds ("weak" bonds), e.g., hydrogen bonds or Van der Waals interactions. In that case, the solid formulation would then be a multi-component complex wherein A and citric acid and/or saccharin are weakly associated without actual proton transfer, although with sufficient interaction to increase significantly the physical stability of compound A.

Claim 1:
A solid formulation comprising from about <NUM>% to about <NUM>% w/w of:
- an <NUM>,<NUM>,<NUM>-oxadiazole derivative of formula (A)
<CHM>
and
- citric acid and/or saccharin,
wherein the molar ratio in said solid formulation between the total amount of citric acid and/or saccharin and the amount of said <NUM>,<NUM>,<NUM>-oxadiazole derivative ranges from about <NUM> to about <NUM>;
wherein "about" preceding a figure means plus or less <NUM>% of the value of said figure; and
wherein "solid" means that the melting point of said formulation at atmospheric pressure is higher than <NUM>.