DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

STABLE AMORPHOUS FORM OF DIPEPTIDYL PEPTIDASE-4
(DPP-4) ENZYME INHIBITOR

We, LEE PHARMA LIMITED,
A company incorporated under the companies act, 1956 having address at
Sy.No: 257 & 258/1; Door No: 11-6/56-C; Opp: IDPL Factory; Moosapet; Balanagar (Post);
Hyderabad, Telangana; 500037- India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:

Field Of The Invention
The present invention relates to stable amorphous form of pharmaceutically acceptable salt of a dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor.
The present invention specifically relates to stable amorphous form of pharmaceutically acceptable salts of Sitagliptin.
The present invention more specifically relates to stable amorphous form of Sitagliptin malate of Formula I.

The present invention also relates to solid dispersion/premix comprising amorphous Sitagliptin malate of Formula I and a pharmaceutically acceptable excipient.

The present invention further relates to a process for preparation of novel amorphous form of Sitagliptin malate of Formula I and pharmaceutical composition comprising Sitagliptin malate of Formula I and a pharmaceutically acceptable excipient.

Background Of The Invention
Sitagliptin phosphate is glucagen like peptide 1 metabolism modulator, hypoglycemic agent and dipeptidyl peptidase IV inhibitor. Sitagliptin phosphate is currently marketed in the United States under the trade name of JANUVIATM in its monohydrate form. JANUVIATM is indicated to improve glycemic control in patients with type2 diabetes mellitus. Its chemical name is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3,-a]pyrazine phosphate monohydrate and the molecular Formula is C16H15F6N5O.H3PO4.H2O with a molecular weight of 523.32. The structural Formula of Sitagliptin phosphate monohydrate is:

Sitagliptin base and its pharmaceutically acceptable acid addition salts have been described in U.S. Pat. No. 6,699,871. In particular, Example 7 of U.S. Pat. No. 6,699,871 discloses the preparation of Sitagliptin base and its hydrochloride salt.

Sitagliptin phosphate salt and different forms thereof have been disclosed in a number of references (i.e. U.S. Pat. No. 7,326,708, and U.S. Patent Application Nos. 20060287528, 20070021430 and 20070281941).

WO 05/072530 discloses several novel crystalline salts of sitagliptin, i.e. the hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid crystalline salts.

The hemifumarate salt of sitagliptin has been described by in J. Med. Chem. 2005, 48, 141-151.

WO 07/035198 relates to a crystalline anhydride form of the dodecylsulfate salt of sitagliptin. WO 08/000418 discloses the preparation of sitagliptin hydrochloride in amorphous form. In addition, WO 09/085990 describes other acid addition salts of sitagliptin, i.e. sitagliptin salts of di-p-tolyl-L-tartaric acid, phosphoric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid, and lactic acid.

US 8,389,724 B2 discloses different salts of Sitagliptin such as galactaratc, sitagliptin hydrochloride amorphous form, Sitagliptin citrate amorphous form, sitagliptin hemicitrate amorphous form, sitagliptin glycolate amorphous form, sitagliptin malate amorphous form. This patent also discloses a process for the preparation of sitagliptin malate amorphous form from alcohol solvents specifically isopropanol.

EP 2 586 782 B1 claims crystalline Sitagliptin malic acid salt and its preparation.

Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice. The amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.
An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient's bloodstream. The rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

It has been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Konno T., Chem. Pharm. Bull., 1990;38:2003-2007). For some therapeutic indications one bioavailability pattern may be favoured over another.

To the best of the inventors knowledge, stable amorphous form of Sitagliptin malate of Formula I has not been reported in the prior-art.

Although amorphous forms are more soluble than crystalline forms, they are usually associated with their own problems. One such problem is that amorphous forms are very often unstable and revert to a crystalline form after short periods. An unstable amorphous form such as this is therefore not suitable for pharmaceutical use, where it is essential to have a stable physical form of the compound.

Surprisingly, the inventors were able to develop an amorphous form of Sitagliptin malate of Formula I which is stable and does not revert to the crystalline form following prolonged storage.

Objective Of The Invention
The main objective of the present invention relates to stable amorphous form of pharmaceutically acceptable salt of a dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor.

Another objective of the present invention relates to stable amorphous form of Sitagliptin malate.

Yet another objective of the present invention is to provide highly pure and stable amorphous form of Sitagliptin malate substantially free of crystalline forms.

Still another objective of the present invention is to provide a stable solid dispersion/premix comprising amorphous Sitagliptin malate and a pharmaceutically acceptable excipient.

Still another objective of the present invention is to provide a process for the preparation of stable amorphous form of Sitagliptin malate.

Still another objective of the present invention is to provide a process for the preparation of stable solid dispersion/premix comprising amorphous Sitagliptin malate and a pharmaceutically acceptable excipient.

Summary Of The Invention

Accordingly, the present invention provides stable amorphous form of pharmaceutically acceptable salt of a dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor.
In another aspect, the present invention provides stable amorphous form of Sitagliptin malate of Formula I.

In yet another aspect, the present invention preferably provides stable amorphous form of Sitagliptin malate monohydrate.

In yet another aspect, the present invention preferably provides highly pure and stable amorphous form of Sitagliptin malate substantially free of crystalline forms.

In yet another aspect, the present invention provides stable amorphous form of Sitagliptin malate monohydrate characterized by X-ray powder diffraction pattern.

In yet another aspect, the present invention provides stable amorphous form of Sitagliptin malate monohydrate further characterized by DSC.

In yet another aspect, the present invention provides stable amorphous form of Sitagliptin malate monohydrate further characterized by TGA.

In yet another aspect, the present invention provides a process for the preparation of stable amorphous form of Sitagliptin malate which comprises the steps of:
i) providing Sitagliptin free base in a mixture of solvents ,
ii) adding malic acid to the solution obtained in step (i) and
iii) isolating amorphous Sitagliptin malate.

In yet another aspect, the present invention provides a process for the preparation of stable amorphous form of Sitagliptin malate which comprises the steps of:
i) providing Sitagliptin free base in a mixture of solvents,
ii) adding the solution obtained in step (i) to malic acid and
iii) isolating amorphous Sitagliptin malate.

In yet another aspect, the present invention provides a process for the preparation of stable amorphous form of Sitagliptin malate which comprises the steps of:
i) providing a solution of Sitagliptin free base and malic acid in a suitable solvent,
ii) adding a suitable anti-solvent and
iii) isolating amorphous Sitagliptin malate.

In yet another aspect, the present invention provides stable amorphous form of Sitagliptin Malate premix having enhanced stability and dissolution properties and process for preparation thereof.

In yet another aspect, the present invention provides a process for the preparation of stable amorphous form of Sitagliptin Malate by solid dispersion method along with pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides pharmaceutical composition comprising stable amorphous form of Sitagliptin Malate and a pharmaceutically acceptable excipient, having improved physiochemical characteristics that assist in the effective bioavailability of Sitagliptin.

Brief Description of Drawings

Fig.1: Represents X-ray powder diffraction pattern of stable amorphous form of Sitagliptin Malate.
Fig.2: Represents Differential Scanning Calorimetry (DSC) thermogram of stable amorphous form of Sitagliptin Malate.
Fig 3: Represents Thermogravimetric Analysis (TGA) of stable amorphous form of Sitagliptin Malate.

Detailed Description Of The Invention
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

In an embodiment, the present invention provides stable amorphous form of Sitagliptin malate.

In another embodiment, the present invention provides stable amorphous form of Sitagliptin malate monohydrate characterized by X-ray powder diffraction pattern as depicted in Figure 1.
In another embodiment, the present invention provides stable amorphous form of Sitagliptin malate monohydrate characterized by DSC as depicted in Figure 2.

In another embodiment, the present invention provides stable amorphous form of Sitagliptin malate monohydrate characterized by TGA as depicted in Figure 3.

In yet another embodiment, the starting material Sitagliptin free base used in the present invention is prepared by any procedures disclosed in the prior-art or any of the known Forms of Sitagliptin free base or its pharmaceutically acceptable salts.

The stable amorphous form of Sitagliptin malate can be prepared by dissolving any of the known forms of Sitagliptin malate by providing a solution of Sitagliptin malate which can be obtained any known methods or by providing a solution of free base in a solvent and adding malic acid to the solution and isolating stable amorphous form of Sitagliptin malate.

In yet another embodiment, solvents used in the present invention are selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and/or mixtures thereof, preferably the solvent is alcoholic solvent and more preferably methanol.

In yet another embodiment, anti-solvents used in the present invention are selected from a group comprising of cyclic and non-cyclic linear or branched chain hydrocarbon, preferably, pentane, hexane, heptane, octane, cyclohexane, methylcyclohexane, chloronaphthalene, orthodichlorbenzene, toluene, ethylbenzene, isopropylbenzene, diethylbenzene and mixtures thereof, more preferably, the antisolvent is hexane or cyclohexane or heptane.

According to the present invention isolation of stable amorphous Sitagliptin malate from the reaction mixture is carried out by commonly employed methods for producing amorphous form such as the solvent crystallization method, partial removal of the solvent from the solution, sonication, solvent/anti solvent method, slurry, cooling, seeding, filtration, distillation, decanting, vacuum drying, spray drying, freeze drying, Agitated thin film drying, (ATFD); lyophilization method, grinding (mixed grinding) method, supercritical fluid method; lyophilization method, fusion method or any other methods known in the art.

The amorphous Sitagliptin malate obtained by the process disclosed herein is stable, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The stable amorphous Sitagliptin malate obtained by the process disclosed herein is also suitable for formulating into different dosage forms.

Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA):
Stable amorphous Sitagliptin malate monohydrate shows an endothermic peak at about 156ºC followed by a peak at 183.28 ºC. Figure 2 gives a typical DSC profile of Stable amorphous Sitagliptin malate monohydrate of the present invention. The endothermic phenomenon represents water loss and subsequent melting of the compound. Water loss is clearly demonstrated by the thermogravimetric analysis profile in figure 3. Thermogravimetric analysis shows that the compound appears as a monohydrate, as the water loss is 2.981% in a temperature range from 130 to 150°C, a value which totally fits the theoretical value of 3.2 %.

The premix of the present invention is prepared by combining Sitagliptin malate salt with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties wherein the premixing agent is selected from a pharmaceutically acceptable excipient.

In another embodiment, the pharmaceutically acceptable excipient is selected from the group consisting of polyvinylpyrrolidone (also called povidone or PVP), polyvinyl alcohol, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, hypromellose phthalate (HPMCP), lactose monohydrate, polyvinyl acetate, maltodextrins, cyclodextrins, gelatins, sugars, water soluble and water insoluble polymers and combinations comprising one or more of the foregoing hydrophilic carriers.

In another embodiment, the polymers used in the present invention are selected from N-vinyl lactams, such as homopolymers or copolymers of N-vinyl pyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate); cellulose esters or cellulose ethers, such as alkylcelluloses (e.g., methylcellulose or ethylcellulose), hydroxyalkylcelluloses (e.g., hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose), and cellulose phthalates or succinates (e.g., cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or hydroxypropylmethylcellulose acetate succinate); high molecular polyalkylene oxides, such as polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide; polyacrylates or polymethacrylates, such as methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates); polyacrylamides; vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid, and partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"); polyvinyl alcohol; oligo- or polysaccharides, such as carrageenans, galactomannans, and xanthan gum; polyhydroxyalkylacrylates; polyhydroxyalkyl-methacrylates; copolymers of methyl methacrylate and acrylic acid; polyethylene glycols (PEGs); graft copolymers of polyethylene glycol/polyvinyl caprolactam/polyvinyl acetate, or any mixture or combination thereof. In some cases, sugar alcohols can be used in addition to, or in lieu of polymers.

Non-limiting examples of preferred polymers for the invention include polyvinylpyrrolidone (PVP) K17, PVP K25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, HPMC P 55, Ethocel 4, Ethocel 7, Ethocel 10, Ethocel 14, Ethocel 20, copovidone (vinylpyrrolidone-vinyl acetate copolymer 60/40), polyvinyl acetate, methacrylate/methacrylic acid copolymer (Eudragit) L100-55, Eudragit L100, Eudragit S100, polyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, Soluplus, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407.

The spray drying method and the grinding method can both be performed by following common procedures. When the spray drying method is used, a stabilized and homogeneous amorphous form can be obtained with good reproducibility, and is advantageous for the production and supply of substances maintained at a certain quality as medicaments. Moreover, when the grinding method is used, grain refinement can be actively performed along with the amorphization, and is advantageous for bioavailability. For the grinding method, a mixed grinding method, in which the compound is ground with a solid polymer (solid base) or the like, can be used. Furthermore, methods for producing a solid dispersion in which a poorly-soluble drug and a water-soluble polymer base are processed without heating by a mixed grinding method (mechanochemical method) such as mixed grinding by a ball mill or roll mixing to amorphize the poorly soluble drug may also be included.

Mechanochemical refers to a phenomenon in which mechanical energy (compression, shearing and friction) causes changes in the physicochemical property of a substance, and it is thought that with this method, various factors such as mechanical operation-induced lattice defects, lattice mismatches and increases in specific surface area and surface energy would improve the activity of a solid substance to promote the amorphization of a drug as well as the dispersion of the amorphized drug in a carrier.

For the fusion method, there is a method of obtaining a solid dispersion by using melting point depression of a drug and a water-soluble polymer carrier to heat and melt both substances, then cooling, solidifying and grinding the melted substances [Chem. Pharm. Bull, 9, 866 (1961)], and there is a method of obtaining a solid dispersion by heat dissolving a drug in a water-soluble polymer with a relatively low melting point, then cooling, solidifying and grinding the mixture [Int. J. Pharm, 47, 51 (1988)].

In a preferred embodiment, the present invention provides a pharmaceutical composition containing said premix along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, lubricants and or anti-adherents. The premix can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

The term "stable" relates to a compound which after storage for up to 2 weeks, more suitably up to 4 weeks, still more suitably up to 12 weeks, or at least 12 weeks and especially up to 6 months, particularly at least 6 months at 25ºC and 60% relative humidity, 40ºC and 75% relative humidity or at 50ºC and ambient humidity, when protected from moisture is at least 95% chemically identical to the starting sample and retains an amorphous form.

Suitably, a stable compound will be at least 96% and more suitably at least 97% chemically identical to the starting sample and which retains an amorphous form after storage for up to 12 weeks, more suitably at least 12 weeks, protected from moisture at 25ºC and 60% relative humidity, 40ºC and 75% relative humidity or at 50ºC and ambient humidity.

In particular, a stable compound may be at least 95%, at least 96%, at least 97% or even at least 98% chemically identical to the starting sample and which retains an amorphous form after storage for up to 6 months, especially at least 6 months, at 25ºC and 60% relative humidity or at 40ºC and 75% relative humidity when protected from moisture.

In some cases, the stable compound may be at least 99% chemically identical to the starting sample and which retains an amorphous form after storage for up to 6 months, especially at least 6 months, at 25ºC and 60% relative humidity when protected from moisture.

Chemical identity to the starting material may be determined using high performance liquid chromatography (HPLC).

The term "solid dispersion" refers to a solid product comprising a polymeric matrix and a drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles, for instance clusters, or in crystalline particles. In certain embodiments, a solid dispersion is in any of the following forms, or any combination thereof: a) a simple eutectic mixture, b) a solid solution (continuous, discontinuous, substitutional, interstitial, amorphous), c) a glass solution, and d) an amorphous precipitation in a crystalline carrier. In certain embodiments, certain more complex combinations can be encountered, i.e. in the same sample some molecules are present in clusters while some are molecularly dispersed.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

Amorphous Sitagliptin malate prepared in accordance with the present invention contains less than about 0.5%, of the corresponding impurities as characterized by a chiral HPLC (high performance liquid chromatography) chromatogram obtained from a mixture comprising the desired compound and one or more of the said impurities, preferably less than about 0.1%.

The percentage herein refers to weight percent obtained from the area-% of the peaks representing the impurities. Sitagliptin malate is substantially free of other process-related impurities.

Amorphous Sitagliptin malate prepared in accordance with the present invention has residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia; the recommended amount is less than 5000 ppm for methanol, ethyl acetate and acetone; less than 800 ppm for toluene, dichloromethane, dimethylformamide and diisopropyl ether. Preferably, the amount is less than about 5000 ppm residual organic solvent, preferably, more preferably less than about 2000 ppm residual organic solvent, most preferably, less than about 700 ppm.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. The present invention is exemplified by the following examples, which are provided for illustration only and should not be construed to limit the scope of the invention.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

Examples
Example 1:
Ethanol (40.0ml) and Sitagliptin base (10.0g, 0.024Mol) were taken into 250.0ml RB flask. L-(-)-Malic acid (3.4g, 0.025Mol) was added at 25-35°C. The mixture was allowed to stir for 1.0hr and solvent was distilled off completely under vacuum at below 50oC and the mass was degassed for 20-30min under vacuum at below 50 °C. The product was unloaded and characterised as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 99.65%; Chiral purity by HPLC: 99.97%, S-isomer: 0.03%; XRD: Amorphous form.

Example 2:
Take Methanol and Acetone (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distill off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 99.51%; Chiral purity by HPLC: 99.97%, S-isomer: 0.03%; XRD: Amorphous form.

Example 3:
Take Acetonitrile (30.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distill off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 99.66%; Chiral purity by HPLC: 99.94%, S-isomer: 0.06%, XRD: Amorphous form.

Example 4:
Take Methanol and Ethyl acetate (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distil off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 99.68%; Chiral purity by HPLC: 99.98%, S-isomer: 0.02%; XRD: Amorphous form.

Example 5:
Take Methanol and Acetonitrile (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 5250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distil off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 99.79%; Chiral purity by HPLC: 99.96%, S-isomer: 0.04%, XRD: Amorphous form.

Example 6:
Take Acetone (20.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distil off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 98.90%; Chiral purity by HPLC: 99.94%, S-isomer: 0.06%, XRD: Amorphous form.

Example 7:
Take Methanol + Methylteritiarybutylether (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distil off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 13.0g, Yield: 97.7%).
Purity by HPLC: 99.75%; Chiral purity by HPLC: 99.96%, S-isomer: 0.04%; XRD: Amorphous form.

Example 8:
Take Methanol and Isopropyl ether (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distil off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 12.0g, Yield: 90.2%).
Purity by HPLC: 99.70%; Chiral purity by HPLC: 99.97%, S-isomer: 0.03%; XRD: Amorphous form.

Example 9:
Take Methanol and THF (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distill off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 11.0g, Yield: 82.72%).
Purity by HPLC: 99.74%; Chiral purity by HPLC: 99.96%, S-isomer: 0.04%; XRD: Amorphous form.

Example 10:
Take Methanol and n-hexane (20.0ml+5.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distill off solvent completely under vacuum at below 50°C and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 12.0g, Yield: 90.2%).
Purity by HPLC: 99.75%; Chiral purity by HPLC: 99.94%, S-isomer: 0.06%; XRD: Amorphous form.

Example 11:
Take Methanol (20.0ml) and Sitagliptin base (10.0g, 0.024Mol) into 250.0ml RB flask, add L-(-)-Malic acid (3.4g, 0.025Mol) at 25-35°C. The mixture was allowed to stir for 1.0hr and distill off solvent completely under vacuum at below 50oC and degas the mass for 20-30min under vacuum at below 50°C. Unload the product as Sitagliptin Malate amorphous form (Dry: 12.0g, Yield: 90.2%).
Purity by HPLC: 99.88%; Chiral purity by HPLC: 99.98%, S-isomer: 0.02%; XRD: Amorphous form.

,CLAIMS:We Claim:
1. Stable amorphous form of dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor or a pharmaceutically acceptable salt.

2. Stable amorphous form of pharmaceutically acceptable salt as claimed in Claim 1 is Sitagliptin malate of Formula I.

wherein the stable amorphous form is highly pure and substantially free of crystalline forms.

3. Stable amorphous form of Sitagliptin malate monohydrate characterized by X-ray powder diffraction pattern as shown in Fig. 1.

4. Stable amorphous form of Sitagliptin malate monohydrate characterized by differential Scanning Calorimetry (DSC) thermogram having an endothermic peak at about 156ºC followed by a peak at 183.28 ºC as shown in Fig. 2.

5. Stable amorphous form of Sitagliptin malate monohydrate characterized by thermogravimetric Analysis (TGA) as the water loss is 2.981% in a temperature range from 130 to 150°C, a value which totally fits the theoretical value of 3.2 % as shown in Fig. 3.

6. Process for the preparation of stable amorphous form of Sitagliptin malate which comprises the steps of:
i) providing Sitagliptin free base in a mixture of solvents ,
ii) adding malic acid to the solution obtained in step (i), and
iii) isolating amorphous Sitagliptin malate.

7. Process for the preparation of stable amorphous form of Sitagliptin malate which comprises the steps of:
i) providing Sitagliptin free base in a mixture of solvents,
ii) adding the solution obtained in step (i) to malic acid, and
iii) isolating amorphous Sitagliptin malate.

8. Process for the preparation of stable amorphous form of Sitagliptin malate which comprises the steps of:
i) providing a solution of Sitagliptin free base and malic acid in a suitable solvent,
ii) adding a suitable anti-solvent, and
iii) isolating amorphous Sitagliptin malate.

9. Solid dispersion/premix comprising amorphous Sitagliptin malate of Formula I and a pharmaceutically acceptable excipient.

10. Process for the preparation of stable amorphous form of Sitagliptin Malate by solid dispersion method along with pharmaceutically acceptable excipients.

Dated this Third (3rd) day of February, 2018.

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Dr. S. Padmaja
Agent for the Applicant
IN/PA/883