`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`3 January 2013 (03.01.2013)
`
`P O P CT
`
`(10) International Publication Number
`WO 2013/001457 Al
`
`(74) Common Representative: RANBAXY LABORATOR¬
`IES LIMITED; c/o Dr. B . Vijayaraghavan,
`Intellectual
`Property Dept., 600 College Road East, Suite 2100, Prin
`ceton, New Jersey 08540 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report (Art. 21(3))
`
`(51) International Patent Classification:
`A61P 3/10 (2006.01)
`C07D 487/04 (2006.01)
`A61K 31/4985 (2006.01)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`30 June 201 1 (30.06.201 1)
`1867/DEL/201 1
`2323/DEL/201 1 16 August 201 1 (16.08.201 1)
`
`PCT/IB2012/053234
`
`26 June 2012 (26.06.2012)
`
`English
`
`English
`
`IN
`IN
`
`(71) Applicant (for all designated States except US): RAN-
`BAXY LABORATORIES LIMITED [IN/IN]; Head O f
`fice: 12th Floor, Devika Tower, 06 Nehru Place, New Del
`hi, Delhi 110019 (IN).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): JAYACHANDRA,
`Suresh, Babu [IN/IN]; C-237, Phase - I, Sushant Lok,
`Gurgaon, Haryana 122001 (IN). SHAH, Jigar, Bhas-
`karbhai
`[IN/IN]; B-753, Tumdi Street, Sonari Mahal,
`Bharuch, Gujarat 392001 (IN). CHIGURU, Sailu [IN/IN];
`s/o Laxman CHIGURU, Post & Village Kondapoor,
`Musthabad, Karimnager, Andhra Pradesh 505303 (IN).
`
`(54) Title: NOVEL SALTS OF SITAGLIPTIN
`
`o©
`
`Formula 1
`
`(57) Abstract: The present invention provides sitagliptin 4-methylsalicylate, sitagliptin myristate, sitagliptin isophthalate, sitagliptin
`© isonicotinide, sitagliptin adipate, their polymorphic form, processes for their preparation and pharmaceutical compositions thereof.
`
`
`
`NOVEL SALTS OF SITAGLIPTIN
`
`Field of the Invention
`
`The present invention provides novel salts of sitagliptin, its polymorphic form,
`
`processes for their preparation and pharmaceutical compositions thereof.
`
`Background of the Invention
`
`Sitagliptin dihydrogen phosphate monohydrate of Formula A, an orally-active
`
`inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, chemically designated as 7-[(3R)-
`
`3-amino- l -oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-
`
`l,2,4-triazolo[4,3-a]pyrazine phosphate ( 1:1) monohydrate is indicated as an adjunct to
`
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`Formula A
`
`U.S. Patent No. 6,699,87 1 (hereinafter "the ' 87 1 patent"), in particular Example 7,
`
`provides a process for the preparation of sitagliptin base and its hydrochloride salt. A list
`
`of pharmaceutically acceptable salts is generally included in the '87 1 patent.
`
`U.S. Patent No. 7,326,708 provides a process for the preparation of sitagliptin
`
`dihydrogen phosphate monohydrate.
`
`PCT Publication WO 2005/072530 provides a process for the preparation of
`
`crystalline salts of sitagliptin with hydrochloric acid, benzene sulfonic acid, /^-toluene
`
`sulfonic acid, D- and L-tartaric acid and (l S)-(+)- and (lR)-(-)- 10-camphorsulfonic acid.
`
`PCT Publication WO 2005/030 127 (hereinafter "PCT Ί 27") provides a process
`
`for the preparation of sitagliptin dihydrogen phosphate anhydrate Form IV which involves
`
`heating sitagliptin dihydrogen phosphate monohydrate at 120°C for about 2 hours or by
`
`heating the sitagliptin dihydrogen phosphate monohydrate above 58°C for about 8 hours.
`
`
`
`PCT 27 also provides a process for the preparation of sitagliptin dihydrogen
`
`phosphate anhydrate Form I by heating sitagliptin dihydrogen phosphate anhydrate Form
`
`IV at a temperature above 140°C for about 1 hour. According to this publication, Form IV
`
`is metastable and converts to the crystalline monohydrate slowly under ambient conditions
`
`and rapidly under high relative humidity (98%) at room temperature.
`
`PCT Publication WO 2005/020920 provides a process for the preparation of
`
`crystalline anhydrate Form I, crystalline desolvated anhydrate Form II, crystalline
`
`anhydrate Form III, crystalline ethanol solvate of sitagliptin dihydrogen phosphate.
`
`It also
`
`provides a process for the preparation of mixture of sitagliptin dihydrogen phosphate
`
`anhydrate Form I and anhydrate Form III.
`
`PCT Publication WO 2006/033848 provides a process for the preparation of
`
`crystalline sitagliptin dihydrogen phosphate monohydrate and amorphous sitagliptin
`
`dihydrogen phosphate.
`
`PCT Publication WO 2007/035198 provides a process for the preparation of
`
`dodecylsulfate salt of sitagliptin.
`
`PCT Publication WO 2008/000418 provides a process for the preparation of
`
`anhydrous sitagliptin hydrochloride in amorphous form.
`
`PCT Publication WO 2009/120746 provides processes for the preparation of
`
`crystalline form of sitagliptin phosphate, characterized by a powder XRD pattern with
`peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7 ±0.2° 2Q and sitagliptin phosphate Form II.
`
`U.S. Publication 2009/247532 provides processes for the preparation of polymorph
`
`Form V of crystalline sitagliptin phosphate and polymorph Form I of sitagliptin phosphate.
`
`PCT Publication WO 2009/084024 provides a process for the preparation of R-
`
`sitagliptin dibenzyl-L-tartrate.
`
`PCT Publication WO 2009/085990 provides a process for the preparation of
`
`crystalline anhydrate Form A of the dihydrogen phosphate salt of sitagliptin, crystalline
`
`sitagliptin sulfate, crystalline sitagliptin hydrobromide, crystalline sitagliptin methane
`
`sulfonate, crystalline sitagliptin acetate, crystalline sitagliptin benzoate, crystalline
`
`sitagliptin oxalate, crystalline sitagliptin succinate, crystalline sitagliptin mandelate,
`
`crystalline sitagliptin fumarate and crystalline sitagliptin lactate.
`
`
`
`PCT Publication WO 2010/032264 provides a process for the preparation of
`
`crystalline Form 3 of sitagliptin, crystalline form of dibenzoyl-L-tartaric acid salt of
`
`sitagliptin, amorphous form of sitagliptin and anhydrous and hydrated crystalline form of
`
`phosphate salt of sitagliptin.
`
`PCT Publication 2010/000469 provides a process for the preparation of sitagliptin
`
`hydrochloride Form I, sitagliptin hydrochloride Form II, sitagliptin fumarate Form I,
`
`sitagliptin fumarate Form II, sitagliptin malate, sitagliptin sulfate Form I, sitagliptin sulfate
`
`Form II, sitagliptin phosphate, sitagliptin succinate Form I and Form II, sitagliptin
`
`succinate Form III, sitagliptin lactate, sitagliptin glycolate, sitagliptin maleate Form I,
`
`sitagliptin maleate Form II, sitagliptin citrate, amorphous sitagliptin citrate, sitagliptin
`
`mesylate Form I and sitagliptin mesylate Form II.
`
`PCT Publication WO 2010/012781 provides a process for the preparation of
`
`sitagliptin galactarate, sitagliptin hemi-L-malate, sitagliptin D-gluconate, sitagliptin
`
`succinate, sitagliptin hydrobromide, sitagliptin thiocyanate, sitagliptin oxalate, sitagliptin
`
`aspartate, sitagliptin ethanedisulfonate, sitagliptin pyroglutamate, sitagliptin glutarate,
`
`sitagliptin acetate, sitagliptin hydrochloride amorphous form, sitagliptin citrate amorphous
`
`form, sitagliptin hemicitrate amorphous form, sitagliptin glycolate amorphous form and
`
`sitagliptin malate amorphous form.
`
`PCT Publication WO 2010/1 17738 provides a process for the preparation of
`
`crystalline Form S1 of sitagliptin sulfate, crystalline Form S2 of sitagliptin sulfate,
`
`crystalline Form S3 of sitagliptin sulfate, crystalline Form S4 of sitagliptin sulfate,
`
`crystalline Form S5 of sitagliptin sulfate, crystalline Form S6 of sitagliptin sulfate,
`
`crystalline Form S7 of sitagliptin sulfate, crystalline Form S8 of sitagliptin sulfate,
`
`crystalline Form D 1 of sitagliptin (+)-dibenzoyl- tartrate, crystalline Form D2 of sitagliptin
`
`(+)-dibenzoyl-tartrate, crystalline Form F 1 of sitagliptin fumarate, crystalline Form F2 of
`
`sitagliptin fumarate, crystalline Form M l of sitagliptin (D)-(+)-malate, crystalline Form
`
`M2 of sitagliptin (D)-(+)-malate, crystalline Form I I of sitagliptin L-malate, crystalline
`
`Form 0 1 of sitagliptin oxalate, crystalline Form 0 2 of sitagliptin oxalate, crystalline Form
`
`Q l of sitagliptin quinate, crystalline Form U l of sitagliptin succinate, crystalline Form E l
`
`of sitagliptin acetate, crystalline Form A l of sitagliptin maleate, crystalline Form N l of
`
`sitagliptin (S)-mandelate, crystalline Form N2 of sitagliptin (S)-mandelate, crystalline
`
`Form N3 of sitagliptin (S)-mandelate, crystalline Form N4 of sitagliptin (S)-mandelate,
`
`
`
`amorphous sitagliptin mandelate, crystalline Form N5 of sitagliptin (R)-mandelate,
`
`crystalline FormN6 of sitagliptin (R)-mandelate, crystalline Form L I of sitagliptin lactate,
`
`crystalline Form L2 of sitagliptin lactate, crystalline Form L3 of sitagliptin lactate,
`
`crystalline Form L4 of sitagliptin lactate and amorphous sitagliptin orotate.
`
`PCT Publication WO 2010/092090 provides a process for the preparation of
`
`crystalline sitagliptin D-glucuronate, crystalline sitagliptin glutarate, crystalline sitagliptin
`
`hydrogen sulfate, crystalline sitagliptin L-lactate, crystalline sitagliptin oxalate, sitagliptin
`
`caprate, sitagliptin L-mandelate, crystals of sitagliptin ethanesulfonate.
`
`PCT Publication WO 2010/122578 provides a process for the preparation of
`
`sitagliptin hydrogen phosphate monohydrate and sitagliptin mandalate.
`
`PCT Publication WO 201 1/025932 provides a process for the preparation of
`
`sitagliptin phosphate and sitagliptin hydrochloride.
`
`PCT Publication WO 201 1/060213 provides a process for the preparation of
`
`sitagliptin phosphate, sitagliptin formate and sitagliptin acetate.
`
`PCT Publication WO 201 1/018494 provides a process for the preparation of
`
`sitagliptin fumarate.
`
`Journal of Medicinal Chemistry, 48(1), p . 141-151 (2005) provides a process for
`
`the preparation of sitagliptin hydrochloride and sitagliptin fumarate.
`
`Several processes are known in the literature for making sitagliptin or a salt
`
`thereof, for example, PCT Publications WO 201 1/049344, WO 2010/131025, WO
`
`2010/078440, WO 2004/083212, WO 2006/065826, WO 2010/097420, WO 2004/080958,
`
`WO 2004/087650 and WO 2004/085661.
`
`In the pharmaceutical industry, there is a constant need to identify the critical
`
`physicochemical parameters such as novel salts, novel polymorphic forms that affect the
`
`drug's performance, stability, etc., which may play a key role in determining a drug's
`
`market acceptance and success.
`
`Since sitagliptin is an important therapeutic agent, developing other, hitherto
`
`unknown salts is of value to pharmaceutical science, especially in terms of having
`
`improved solubility, stability, excellent storage and handling stabilities, bioavailability,
`
`etc.
`
`
`
`Polymorphism is commonly defined as the ability of any substance to have two or
`
`more different crystal structures. Drug substances may also encapsulate solvent molecules
`
`when crystallized. These solvates or hydrates are referred to as pseudo polymorphs.
`
`Different polymorphs, pseudo polymorphs or the amorphous form differ in their
`
`physical properties such as melting point, solubility, etc. These can appreciably influence
`
`pharmaceutical properties such as dissolution rate and bioavailability.
`
`It is also
`
`economically desirable that the product is stable for extended periods of time without the
`
`need for specialized storage conditions.
`
`It is therefore important to evaluate polymorphism of drug substances. Therefore,
`
`there is also strong need for developing various polymorphic forms of salts of sitagliptin.
`
`Summary of the Invention
`
`In one general aspect, the present invention provides sitagliptin 4-methyl
`
`salicylate.
`
`In another general aspect, the present invention provides amorphous form of
`
`sitagliptin 4-methyl salicylate.
`
`In another general aspect, the present invention provides sitagliptin myristate.
`
`In yet another general aspect, the present invention provides crystalline form of
`
`sitagliptin myristate.
`
`In another general aspect, the present invention provides sitagliptin isophthalate.
`
`In yet another general aspect, the present invention provides crystalline form of
`
`sitagliptin isophthalate.
`
`In another general aspect, the present invention provides sitagliptin isonicotinate.
`
`In yet another general aspect, the present invention provides crystalline form of
`
`sitagliptin isonicotinate.
`
`In another general aspect, the present invention provides sitagliptin adipate.
`
`In yet another general aspect, the present invention provides crystalline form of
`
`sitagliptin adipate.
`
`
`
`In another general aspect, the present invention provides a process for the
`
`preparation of a compound of Formula 1.
`
`Formula 1
`
`The process comprises: treating sitagliptin or its salt and HA, wherein HA is selected from
`
`the group consisting of 4-methylsalicylic acid, myristic acid, isophthalic acid, isonicotinic
`
`acid and adipic acid.
`
`In another general aspect, the present invention provides the use of sitagliptin 4-
`
`methyl salicylate, sitagliptin myristate, sitagliptin isophthalate, sitagliptin isonicotinate or
`
`sitagliptin adipate for the preparation of sitagliptin, salts, solvates, or polymorphs thereof.
`
`In yet another general aspect, the present invention provides a pharmaceutical
`
`composition comprising salt of sitagliptin 4-methyl salicylate, sitagliptin myristate,
`
`sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate and a pharmaceutical
`
`acceptable carrier.
`
`In another general aspect, the present invention provides a method of treating or
`
`preventing type 2 diabetes mellitus which comprises administering to a patient in need
`
`thereof a therapeutically effective amount of sitagliptin 4-methyl salicylate, sitagliptin
`
`myristate, sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate and a
`
`pharmaceutical acceptable carrier.
`
`Detailed Description of the Invention
`
`The present invention provides various salts of sitagliptin. For example, the present
`
`invention provides sitagliptin 4-methyl salicylate. Sitagliptin 4-methyl salicylate of the
`
`present invention may be in amorphous form. Amorphous form of sitagliptin 4-methyl
`
`salicylate of the present invention may be characterized by an XRPD pattern substantially
`
`
`
`the same as depicted in Figure 1. Amorphous form of sitagliptin 4-methyl salicylate of the
`
`present invention may be characterized by FTIR as depicted in Figure 2.
`
`The present invention also provides sitagliptin myristate. Sitagliptin myristate of
`
`the present invention may be in crystalline form. Crystalline form of sitagliptin myristate
`
`of the present invention may be characterized by an XRPD pattern substantially the same
`
`as depicted in Figure 3. Crystalline form of sitagliptin myristate of the present invention
`
`may be characterized by FTIR as depicted in Figure 4. The crystalline form of sitagliptin
`
`myristate has an XRPD pattern which may include interplanar spacing (d) values
`
`substantially at about 18.31, 9.21, 4.20, 4.19, and 3.71 A . The crystalline form of
`
`sitagliptin myristate has an XRPD pattern which may further include interplanar spacing
`
`(d) values substantially at about 4.76, 4.68, 4.56, 4.43, 4.44, 4.30, 3.82, 3.49, 3.42, 3.36,
`and 3.18 A . The crystalline form of sitagliptin myristate has an XRPD pattern with the
`following characteristic peak values (2Q ) at about 4.82, 9.60, 21.1 1, 21.20, and 23.91 ±
`0.2°. The crystalline form of sitagliptin myristate has an XRPD pattern with the following
`additional characteristic peak values (2Q ) at about: 18.63, 18.97, 19.46, 19.96, 20.06,
`20.62, 23.26, 25.46, 25.99, 26.48, and 27.98 ± 0.2°.
`
`The present invention also provides sitagliptin isophthalate. Sitagliptin isophthalate
`
`of the present invention may be in crystalline form. Crystalline form of sitagliptin
`
`isophthalate of the present invention may be characterized by an XRPD pattern
`
`substantially the same as depicted in Figure 5. Crystalline form of sitagliptin isophthalate
`
`of the present invention may be characterized by FTIR as depicted in Figure 6. The
`
`crystalline form of sitagliptin isophthalate has an XRPD pattern which may include
`
`interplanar spacing (d) values substantially at about 3.49, 4.59, 3.91, 3.77, and 4.71 A . The
`
`crystalline form of sitagliptin isophthalate has an XRPD pattern which may further include
`
`interplanar spacing (d) values substantially at about 23.73, 14.89, 7.03, 6.12, 5.80, 5.66,
`
`5.51, 5.23, 5.16, 4.99, 4.78, 4.42, 4.32, 4.06, 3.99, 3.58, 3.34, 3.24, 3.13, 3.00, and 2.81 A .
`
`The crystalline form of sitagliptin isophthalate has an XRPD pattern with the following
`characteristic peak values (2Q ) at about 18.82, 19.35, 22.72, 23.59, and 25.54 ± 0.2°. The
`crystalline form of sitagliptin isophthalate has an XRPD pattern with the following
`additional characteristic peak values (2Q ) at about: 3.72, 5.94, 12.59, 14.48, 15.27, 15.67,
`16.09, 16.95, 17.19, 17.76, 18.55, 20.10, 20.56, 21.90, 22.24, 24.86, 26.72, 27.56, 28.54,
`
`29.73, and 3 1.84 ± 0.2°.
`
`
`
`The present invention also provides sitagliptin isonicotinate. Sitagliptin
`
`isonicotinate of the present invention may be in crystalline form. Crystalline form of
`
`sitagliptin isonicotinate of the present invention may be characterized by an XRPD pattern
`
`substantially the same as depicted in Figure 7. Crystalline form of sitagliptin isonicotinate
`
`of the present invention may be characterized by FTIR as depicted in Figure 8. The
`
`crystalline form of sitagliptin isonicotinate has an XRPD pattern which may include
`
`interplanar spacing (d) values substantially at about 7.95, 5.17, 3.99, 3.65, and 3.58 A . The
`
`crystalline form of sitagliptin isonicotinate has an XRPD pattern which may further
`
`include interplanar spacing (d) values substantially at about: 15.84, 5.39, 5.32, 4.52, 4.16,
`
`3.83, 3.81, 3.35, and 3.24 A . The crystalline form of sitagliptin isonicotinate has an XRPD
`pattern with the following characteristic peak values (2Q ) at about: 11.12, 17.14, 22.26,
`24.41, and 24.85 ± 0.2°. The crystalline form of sitagliptin isonicotinate has an XRPD
`pattern with the following additional characteristic peak values (2Q ) at about: 5.58, 16.45,
`16.66, 19.64, 21.34, 23.23, 23.36, 26.59 and 27.53 ± 0.2°.
`
`The present invention also provides sitagliptin adipate. Sitagliptin adipate of the
`
`present invention may be in crystalline form. Crystalline form of sitagliptin adipate of the
`
`present invention may be characterized by an XRPD pattern substantially the same as
`
`depicted in Figure 9. Crystalline form of sitagliptin adipate of the present invention may
`
`be characterized by FTIR as depicted in Figure 10. Crystalline form of sitagliptin adipate
`
`has an XRPD pattern which may include interplanar spacing (d) values substantially at
`
`about 4.70, 4.38, 4.00, 3.82, 3.77 and 3.71 A . Crystalline form of sitagliptin adipate has an
`
`XRPD pattern which may further include interplanar spacing (d) values substantially at
`
`about 17.57, 10.99, 6.31, 5.50, 4.79, 4.74, 4.22, 3.95, 3.70, 3.62 and 3.33 A . Crystalline
`
`form of sitagliptin adipate has an XRPD pattern with the following characteristic peak
`values (2Q ) at about 18.90, 20.27, 22.20, 23.29, 23.63 and 23.97 ± 0.2°. Crystalline form
`of sitagliptin adipate has an XRPD pattern with the following additional characteristic
`peak values (2Q ) at about: 5.03, 8.05, 14.04, 16.13, 18.53, 18.72, 21.03, 22.50, 24.04,
`24.60 and 26.74 ± 0.2°.
`
`The present invention provides a process for the preparation of a compound of
`
`Formula 1.
`
`
`
`Formula 1
`
`The process comprises: treating sitagliptin or its salt and HA, wherein HA is
`
`selected from the group consisting of 4-methylsalicylic acid, myristic acid, isophthalic
`
`acid, isonicotinic acid or adipic acid.
`
`The sitagliptin or its salt prepared by any of the methods known in the art including
`
`those described in, for example, U.S. Patent Nos. 6,699,871, 7,326,708, US Publication
`
`No. 2009/247532, PCT Publication Nos. WO 2010/131025, WO 2004/083212, WO
`
`2006/065826, WO 2010/097420, WO 2004/080958, WO 2004/087650, WO 2004/085661,
`
`WO 2005/072530, WO 2005/030127, WO 2005/020920, WO 2007/035198, WO
`
`2008/000418, WO 2009/120746, WO 2006/033848, WO 2009/085990, WO 2010/032264,
`
`WO 2010/000469, WO 2010/012781, WO 2010/1 17738, WO 2010/092090, WO
`
`2010/122578 may be used as the starting material.
`
`The sitagliptin or its salt prepared by any of the methods known in the art may be
`
`isolated or directly treated with HA.
`
`The sitagliptin or its salt prepared by any of the methods known in the art before
`
`treatment with HA may be optionally clarified to remove foreign particulate matter or
`
`treated with activated charcoal to remove coloring and other related impurities in a
`
`suitable solvent. The solution of sitagliptin or its salt may be optionally concentrated to
`
`reduce the amount of solvent. The sitagliptin salt may optionally be converted to
`
`sitagliptin base before the treatment with HA.
`
`Treating sitagliptin or its salt with HA may include adding, dissolving, slurrying,
`
`stirring or a combination thereof. Sitagliptin or its salt may be treated with HA directly or
`
`in the presence of a suitable solvent at a suitable temperature.
`
`
`
`The term "solvent" includes any solvent or solvent mixture, including, for
`
`example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic
`
`solvents, or mixtures thereof.
`
`The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl
`
`acetate, and n-butyl acetate. Examples of alkanol include those primary, secondary and
`
`tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include
`
`methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated
`
`hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of
`
`ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include
`
`diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one
`or more of N,N-dimethylformamide, N
`,N
`acetonitrile and N-methylpyrrolidone.
`
`-dimethylacetamide, dimethylsulphoxide,
`
`Sitagliptin or its salt may be treated with HA at a temperature of about 30°C to
`
`reflux temperature for a time period sufficient to complete the reaction, preferably for
`
`about 10 minutes to 6 hours.
`
`After the completion of the reaction, the compound of Formula 1 can be isolated
`
`by the common isolation technique such as cooling, extraction, one or more of washing,
`
`crystallization, precipitation, filtration, filtration under vacuum, decantation and
`
`centrifugation, or a combination thereof.
`
`The present invention also provides for the use of sitagliptin 4-methyl salicylate,
`
`sitagliptin myristate, sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate
`
`for the preparation of sitagliptin, salts, solvates, or polymorphs thereof.
`
`The compound of Formula 1 may be used for preparation of sitagliptin by
`
`contacting with a base. The base may be selected from group comprising of hydroxides,
`
`carbonates and bicarbonates of alkali and alkaline earth metals, ammonia, alkyl amines,
`
`hydrazine, and the like. Examples of hydroxides, carbonates and bicarbonates of alkali
`
`and alkaline earth metals may include lithium hydroxide, sodium hydroxide, potassium
`
`hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium
`
`bicarbonate. Examples of alkyl amines may include diethyl amine, triethyl amine or
`
`methyl diethyl amine. Sitagliptin thus obtained may be converted to salts, solvates, or
`
`polymorphs thereof.
`
`
`
`The present invention also provides for a pharmaceutical composition comprising
`
`salt of sitagliptin 4-methyl salicylate, sitagliptin myristate, sitagliptin isophthalate,
`
`sitagliptin isonicotinate or sitagliptin adipate and a pharmaceutical acceptable carrier.
`
`The present invention provides for a method of treating or preventing type 2
`
`diabetes mellitus which comprises administering to a patient in need thereof a
`
`therapeutically effective amount of sitagliptin 4-methyl salicylate, sitagliptin myristate,
`
`sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate and a pharmaceutical
`
`acceptable carrier.
`
`Brief Description of the Figures
`
`Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of sitagliptin 4-methyl
`
`salicylate prepared as per Example 1.
`
`Figure 2 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin 4-
`
`methyl salicylate prepared as per Example 1.
`
`Figure 3 and Figure 3a depict the X-Ray Powder Diffractogram (XRPD) of
`
`sitagliptin myristate and the associated values, respectively, prepared as per Example 2.
`
`Figure 4 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
`
`myristate prepared as per Example 2.
`
`Figure 5 and Figure 5a depict the X-Ray Powder Diffractogram (XRPD) of
`
`sitagliptin isophthalate and the associated values, respectively, prepared as per Example 3.
`
`Figure 6 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
`
`isophthalate prepared as per Example 3.
`
`Figure 7 and Figure 7a depict the X-Ray Powder Diffractogram (XRPD) of
`
`sitagliptin isonicotinate and the associated values, respectively, prepared as per Example
`
`4.
`
`Figure 8 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
`
`isonicotinate prepared as per Example 4.
`
`Figure 9 and Figure 9a depict the X-Ray Powder Diffractogram (XRPD) of
`
`sitagliptin adipate and the associated values, respectively, prepared as per Example 5.
`
`
`
`Figure 10 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
`
`adipate prepared as per Example 5.
`
`The X-ray powder diffractograms (XRPD) of the samples were determined by
`
`using Instrument: PANalytical, Mode: Expert PRO, Detector: Xcelerator, ScanRange: 3-
`
`40, Step size: 0.02, Range: 3-40 degree 2 theta, CuKa radiation at 45kV.
`
`FTIR of the samples was determined by using Instrument: Perkin Elmer, SCAN:
`
`16 scans, Resolution: 4.0 cm 1, potassium bromide pellet method.
`
`While the present invention has been described in terms of its specific
`
`embodiments, certain modifications and equivalents will be apparent to those skilled in the
`
`art and are intended to be included within the scope of the present invention.
`
`Example 1: Preparation of Sitagliptin 4-Methyl salicylate Salt
`
`EXAMPLES
`
`Sitagliptin base ( 1 g, 0.00245 mole) was charged in isopropyl alcohol (10 ml) at
`
`25°C to 32°C. 4-Methyl salicylic acid (0.37 g, 0.00245 mole) was charged at 25°C to
`
`32°C. The reaction mixture was heated to 50°C and stirred for 2 hours at 50°C. The
`
`reaction mixture was then cooled to 25°C to 32°C and distilled under vacuum completely
`
`at 50°C to obtain a solid. The solid was dried under vacuum at 40°C for 16 hours to
`
`obtain the titled compound.
`
`Yield: 1 g
`
`Example 2 : Preparation of Sitagliptin Myristate Salt
`
`Sitagliptin base (2 g, 0.0049 mole) was charged in isopropyl alcohol (20 ml) at
`
`25°C to 32°C. Myristic acid ( 1.12 g, 0.0049 mole) was charged at 25°C to 32°C to obtain
`
`a reaction mixture. The reaction mixture was heated to 50°C and stirred for 2.5 hours at
`
`50°C. The reaction mixture was cooled to 25°C to 32°C and stirred for 16 hours at 25°C
`
`to 32°C. The reaction mixture was concentrated completely under vacuum at 50°C.
`
`Hexanes (10 ml) was charged to reaction mixture and stirred for 1 hour at 20°C. The solid
`
`was filtered and washed with isopropyl alcohol (2x10 ml). Material was dried under
`
`vacuum at 40°C for 16 hours to obtain the titled compound.
`
`Yield: 2.9 g
`
`
`
`Example 3 : Preparation of Sitagliptin Isophthalate Salt
`
`Sitagliptin base (2 g, 0.0049 mole) was charged in isopropyl alcohol (20 ml) at
`
`25°C to 32°C. Isophthalic acid (0.81 g, 0.0049 mole) was charged at 25°C to 32°C to
`
`obtain a reaction mixture. The reaction mixture was heated to 50°C and stirred for 2 hours
`
`at 50°C. The reaction mixture was cooled to 25°C to 32°C and stirred for 16 hours at
`
`25°C to 32°C to obtain a solid. The solid was filtered and washed with isopropyl alcohol
`
`(2x10 ml). The solid was dried under vacuum at 40°C for 16 hours to obtain the titled
`
`compound.
`
`Yield: 2.6 g
`
`Example 4 : Preparation of Sitagliptin Isonicotinate Salt
`
`Sitagliptin base ( 1 g, 0.00245 mole) was charged in ethanol (10 ml) at 25°C to
`
`32°C. Isonicotinic acid (0.3 g, 0.00245 mole) was charged at 25°C to 32°C. The reaction
`
`mixture was heated to 60°C and stirred for 30 minutes at 60°C. The reaction mixture was
`
`cooled to 25°C to 32°C and stirred for 30 minutes at 25°C to 32°C to obtain a solid. The
`
`solid was filtered and washed with ethanol (10 ml). The solid was dried under air oven at
`
`40°C for 16 hours to obtain the titled compound.
`
`Yield: 0.5 g
`
`Example 5 : Preparation of Sitagliptin Adipate
`
`Sitagliptin base (2 g, 0.0049 moles) was charged in isopropyl alcohol (20 ml) at
`
`25°C to 32°C. Adipic acid (0.71 g, 0.0049 moles) was charged at 25°C to 32°C. The
`
`reaction mixture was heated to 50°C and stirred for 2 hours at 50°C. The reaction mixture
`
`was then cooled to 25°C to 32°C and distilled under vacuum completely at 50°C to obtain
`
`a solid. The solid was dried under vacuum at 40°C for 16 hours to obtain the titled
`
`compound.
`
`Melting point: 99°C to 104°C
`
`Yield: 2.6 g (1.3 w/w, 95.9%)
`
`
`
`CLAIMS
`
`1.
`
`A salt of sitagliptin with an organic acid selected from the group consisting of 4-
`
`methylsalicyclic acid, myristic acid, isophthalic acid, isonicotnic acid, and adipic acid.
`
`2.
`
`3.
`
`4.
`
`Sitagliptin 4-methyl salicylate.
`
`Sitagliptin 4-methyl salicylate of claim 2, in amorphous form.
`
`Sitagliptin 4-methyl salicylate of claim 3, wherein the amorphous form is
`
`characterized by an XRPD pattern substantially the same as depicted in Figure 1.
`
`5.
`
`Sitagliptin 4-methyl salicylate of claim 3, wherein the amorphous form is
`
`characterized by FTIR as depicted in Figure 2.
`
`6.
`
`7.
`
`8.
`
`Sitagliptin myristate.
`
`Sitagliptin myristate of claim 6, in crystalline form.
`
`Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by an
`
`XRPD pattern substantially the same as depicted in Figure 3.
`
`9.
`
`Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by
`
`FTIR as depicted in Figure 4.
`
`10.
`
`Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by an
`
`X-ray powder diffractogram which includes interplanar spacing (d) values substantially at
`
`about 18.31, 9.21, 4.20, 4.19, and 3.71 A .
`
`11.
`
`Sitagliptin myristate of claim 10, wherein the crystalline form is further
`
`characterized by an X-ray powder diffractogram which includes interplanar spacing (d)
`
`values substantially at about 4.76, 4.68, 4.56, 4.43, 4.44, 4.30, 3.82, 3.49, 3.42, 3.36, and
`
`3.18 A .
`
`Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by an
`12.
`X-ray powder diffractogram which includes characteristic peak values (2Q ) at about 4.82,
`9.60, 21.1 1, 21.20, and 23.91 ± 0.2°.
`
`13.
`
`Sitagliptin myristate of claim 12, wherein the crystalline form is further
`
`characterized by an X-ray powder diffractogram with the following additional
`characteristic peak values (2Q ) at about: 18.63, 18.97, 19.46, 19.96, 20.06, 20.62, 23.26,
`25.46, 25.99, 26.48, and 27.98 ± 0.2°.
`
`14.
`
`15.
`
`Sitagliptin isophthalate.
`
`Sitagliptin isophthalate of claim 14, in crystalline form.
`
`
`
`16.
`
`Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
`
`by an XRPD pattern substantially the same as depicted in Figure 5.
`
`17.
`
`Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
`
`by FTIR as depicted in Figure 6.
`
`18.
`
`Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
`
`by an X-ray powder diffractogram which includes interplanar spacing (d) values
`
`substantially at about