to--on (12) United States Patent US 8,329,696 B2 Dec. 11, 2012 (45) Date of Patent: (10) Patent No.: Pillarski et al.

U8329696B2 (12) United tate Patent Pillarki et al. (10) Patent No.: (45) Date of Patent: U 8,329,696 B2 Dec. 11, 2012 (54) LID TATE FRM F ITAGLIPTIN ALT (75) Inventor: Gideon Pilarki, Holon (IL); Nurit Perlman, Kfar aba (IL); Ariel Mittelman, Elad (IL); Nada Koutic Hulita, Zagreb (HR); Marina Kalujny, Ariel (IL); Revital Ramaty, Ramat-Haharon (IL) (73) Aignee: Teva Pharmaceutical Indutrie Ltd., Petach-Tikva (IL) (*) Notice: ubject to any diclaimer, the term of thi patent i extended or adjuted under 35 U..C. 154(b) by 144 day. (21) Appl. No.: 12/749,486 (22) Filed: Mar. 29, 2010 (65) Prior Publication Data U 2010/024914.0 A1 ep. 30, 2010 Related U.. Application Data (60) Proviional application No. 61/164,563, filed on Mar. 30, 2009, proviional application No. 61/170,697, filed on Apr. 20, 2009, proviional application No. 61/174,073, filed on Apr. 30, 2009, proviional application No. 61/182,772, filed on Jun. 1, 2009, proviional application No. 61/186,031, filed on Jun. 11, 2009, proviional application No. 61/302.626, filed on Feb. 9, 2010, proviional application No. 61/304,615, filed on Feb. 15, 2010, proviional application No. 61/309,024, filed on Mar. 1, 2010, proviional application No. 61/312,376, filed on Mar. 10, 2010, proviional application No. 61/315,149. filed on Mar. 18, 2010. (51) Int. Cl. A6 IK3I/495 (2006.01) (52) U.. Cl.... 514/249; 544/350 (58) Field of Claification earch... 514/249; 544/350 ee application file for complete earch hitory. (56) Reference Cited FREIGN PATENT DCUMENT W W 2004/085378 10, 2004 W W 2004/085661 10, 2004 W W 2004/0876.50 10, 2004 W W 2005/3135 1, 2005 W W 2005/020920 3, 2005 W W 2005/030127 4/2005 W W 2005, 725.30 8, 2005 W W 2006/033848 3, 2006 W W 2007/0351.98 3, 2007 W W 2009/070314 6, 2009 W W2009/085990 T 2009 W W2010/469 1, 2010 W W2010/12781 2, 2010 Primary Examiner Dougla MWilli (74) Attorney, Agent, or Firm Arent Fox LLP (57) ABTRACT olid tate form of itagliptin alt (e.g. itagliptin ulfate, Formula I), procee for preparing the olid tate form, and pharmaceutical compoition thereof, are provided. Thee compound are of a cla of dipeptidyl peptidae IV enzyme inhibitor which are ueful, for example, for the manufacture of a medicament for the treatment of type 2 diabete mellitu. r-, -( N N / 10 Claim, 70 Drawing heet N CF3 Formula I to--on

U.. Patent Dec. 11, 2012 heet 1 of 70 U 8,329,696 B2 x& x 'Yex axxxx& & & & & E. Yxxxxx VVVV.vvy...Vy' ---------- wi. x vway xxx & Ma '' awaaaaa. irren un

U.. Patent U 8,329,696 B2

U.. Patent Dec. 11, 2012 heet 3 f 70 U 8,329,696 B2 YYYYYYxxxxx A aa waaaa Waxxxxx. xx - x arr a. ww.x aw y yr NYYYYYYYY------ a\a ar 0007 000 0

U.. Patent Dec. 11, 2012 heet 4 of 70 U 8,329,696 B2 ***********......».? «0009 0007 un

U.. Patent Dec. 11, 2012 heet 5 f 70 U 8,329,696 B2 ---a. wwwae& Yaaaavaaaaaaaaa. ^y.. aaaaaaaaaaaaaaaaaaaaaaaa-r -3. M------ oxenx 'aa YYYaax raxx. ex w C V i CN un

U.. Patent Dec. 11, 2012 heet 6 of 70 U 8,329,696 B2 N N & www www. 000Z 700Z). un C wwwpy N

U.. Patent Dec. 11, 2012 heet 7 f 70 U 8,329,696 B2 ix... Y Y--------wor & YYYY-rararara-aaaaaaaaaaaaaaa. tax x8 ea xva ^a. ******** Aarara 0007 un 0

U.. Patent Dec. 11, 2012 heet 8 of 70 U 8,329,696 B2 & roe.. f K a - & wer yaw, & wa. w aaaaaaaay N& *Yaxxx aa N NNNN va wx ^Na N CN C V V V un

U.. Patent Dec. 11, 2012 heet 9 f 70 U 8,329,696 B2 & a xy& a y xxxxxxxxxx WNY. & ŠNy.xxaaax V y& x-aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa-n$š www. & le 8 9 7 Z

U.. Patent Dec. 11, 2012 heet 10 f 70 U 8,329,696 B2. w xxxxx xxxxxxxxxx & -3 &Naf 8x ee ea^* tawa& e CD reperperpeeperpere &aaawa le.) 8 9 7 Z i

U.. Patent Dec. 11, 2012 heet 11 of 70 U 8,329,696 B2 N4 V 9

U.. Patent Dec. 11, 2012 heet 12 of 70 U 8,329,696 B2 xxxxxxxxxx x axxxxxx taxxyyxxyyx - (NWu) NI leeh dn E

U.. Patent Dec. 11, 2012 heet 13 f 70 U 8,329,696 B2 ey axa a a aw. Šva nf ea e aa x

U.. Patent Dec. 11, 2012 heet 14 of 70 U 8,329,696 B2 8 le 9 7 9. Z

U.. Patent Dec. 11, 2012 heet 15 f 70 U 8,329,696 B2 eul 8 9 7 Z

U.. Patent Dec. 11, 2012 heet 16 of 70 U 8,329,696 B2 3 le 8 9 7 Z

U.. Patent Dec. 11, 2012 heet 17 f 70 U 8,329,696 B2 wa a un

U.. Patent Dec. 11, 2012 heet 18 f 70 U 8,329,696 B2 &&&&&&&&&&&&& zzzzzzzzzzzzzzzzzzzzz... zwaetz Z

U.. Patent Dec. 11, 2012 heet 20 f 70 U 8,329,696 B2 xxxxxxxxxxxxxxx...' 8-8-888-8-8-888-8-8-888-8-8-88 a &x. &-av-wr:8 un

U.. Patent Dec. 11, 2012 heet 21 of 70 U 8,329,696 B2 ae xxx xxxxxxxx x- ------xx' xxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx-xxxxxxxxyyyyyyyyyyyyyy m M un N

U.. Patent Dec. 11, 2012 heet 23 f 70 U 8,329,696 B2 Yxy.yyayyyyyyy 3 ay yxxxxxxxxx":::::: : : 000 000Z un 000

U.. Patent Dec. 11, 2012 heet 24 of 70 U 8,329,696 B2 axy xxyyxxx CN r un

U.. Patent Dec. 11, 2012 heet 26 of 70 U 8,329,696 B2 : & k, a xe **** a t. axxxxxx xxx : ki& un

U.. Patent Dec. 11, 2012 heet 27 f 70 U 8,329,696 B2 Y... F000c 000Z un

U.. Patent Dec. 11, 2012 heet 28 f 70 U 8,329,696 B2 \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\aywyy weex un

U.. Patent Dec. 11, 2012 heet 29 f 70 U 8,329,696 B2 a am e etter:y &aa. &&^ - - - - - - - - - - - - - - - - - Š. 3a. - - - - - - - & 3 Ak & & &\ & $89 $ ) ax & a. &ete Near & Ya N V y we& wemwy a. a exyy \r ye aa x: & y ea t w e & xway & xxx-xx-xxxx x www. r &xxx-xxxx W & le 9. 9 7 Z

U.. Patent Dec. 11, 2012 heet 30 f 70 U 8,329,696 B2 &----------------- &K. w xxxx aa\ y & Na t Y. ex& ax. ^. aax 3 www.www.www8888 i er

U.. Patent Dec. 11, 2012 heet 31 f 70 U 8,329,696 B2 K& ea - 3. un

U.. Patent Dec. 11, 2012 heet 32 f 70 U 8,329,696 B2

U.. Patent Dec. 11, 2012 heet 33 f 70 U 8,329,696 B2-3 -3

U.. Patent Dec. 11, 2012 heet 34 of 70 U 8,329,696 B2 -xx-x-x. Wox. \xxxxxx w w w && WA *''''''''''''''''''''''''''''''' aa un

U.. Patent Dec. 11, 2012 heet 35 of 70 U 8,329,696 B2 --------------------------------------------------------------------------------, v & ^ 000 N aree un \\\\\\\\\\\ 1000

U.. Patent Dec. 11, 2012 heet 37 f 70 U 8,329,696 B2 * ee i 3 aay & ^n, aa a a nat Wy t. & yxxxxaa a\y N & 8. N. -. 8 ra 8... 8 8. 8. xxxxxx N. y ae. ^y w 8 9 v Z

U.. Patent Dec. 11, 2012 heet 38 of 70 U 8,329,696 B2 ------------.. ex' & YYYY: 'eat& Waaaa YYYYYxxxx : t& aau' x& &: Yxxxxxxx x. x {xt& xxxxx **** &cce:& aa wa xxx' aaaaaar & waxe a CN un

U.. Patent Dec. 11, 2012 heet 39 f 70 U 8,329,696 B2 xxxxxxxx...xxxxxxxxxxxxxxxxxxxxxxxxxxx...xxxxxxxxxxxxxxxxxxxxxx... axxxxxxxxx man.. &x xxxx N wy& e 8 9 7 Z reper xx&&x& x W

U.. Patent Dec. 11, 2012 heet 40 of 70 U 8,329,696 B2 xxx w' x& y W & xxx *Šema. : 8 i eu 8

U.. Patent Dec. 11, 2012 heet 41 of 70 U 8,329,696 B2 &xxxxxxxxx-xx-xx-xxxxxxxx-xx-xx-xxxxxxxxx-xx-xx-xxxxxxxxx-xx-xxxxxxxxxxx-xx-ex : &xxxxxxxxxxxxx xxxxx' t w. v N N

i U.. Patent Dec. 11, 2012 heet 42 of 70 U 8,329,696 B2 WWWWWWWaway'..... e. a w &YYYYYY ^x xxxxxxxxxxxxxxxx v. yee www.& Y & v. - t xxxxxxxxxxxxxxxx xxxx xxxxxxxxxxxxxxx reaeee e xxxexxyw&xxx un x-r

U.. Patent Dec. 11, 2012 heet 43 of 70 U 8,329,696 B2 xxxxxx-xxxxxx-xxxxx-xxxxxxx-xxxxx-xxxxxxx-xxxxx-xxxxxx-xxxxx-x-xxxx-xxxxx-xxxxxx-xxxxx-xxxxxx-xxxxx-xxxxx-xxxxxxx-xxxxx-xx: : && w a 3 un

U.. Patent Dec. 11, 2012 heet 44 of 70 U 8,329,696 B2 o 9 N 9 N CN C CD CD 2 3 C C V V V...Eixxxxxxxxxxxxxxxx C N un

U.. Patent Dec. 11, 2012 heet 45 of 70 U 8,329,696 B2 \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\y\ra. ra Y a a xxxyyy waxxtaxa a. Coor weway NYa\\\\\\\\\\\\\\\a. r Ya & ---------------------- y un

U.. Patent Dec. 11, 2012 heet 46 of 70 U 8,329,696 B2 x. w & RN &y w war& N way ŠNx Y ex a exir Ye, & ixx ------------- xx xxxxxxx-xxxxx8 &

U.. Patent Dec. 11, 2012 heet 47 of 70 U 8,329,696 B2 a e e x GN V e& w & a W ex.. 3. axx ixwir i f forf

U.. Patent Dec. 11, 2012 heet 48 of 70 U 8,329,696 B2 YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY 3 rw rxxxxx a rare arra arr YYYYYxx ovr r ra ^xaca. e w owaax"r axy. & r. -- tranx8x. xxxxxxx...--------------------yyyyyyyyyyyyar *w-mix8:::::... Yeo a cy N errrrrrrrrrrr" un N

U.. Patent Dec. 11, 2012 heet 49 of 70 U 8,329,696 B2 un

U.. Patent Dec. 11, 2012 heet 52 of 70 U 8,329,696 B2 WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW.. xxxy ar ^, e w ix a &. ^ Co Y 3. R -. * e-. o www.xxxx. ^- N...Y w ix. Yw. Y y i. a Ya. ey & aaaaaaa... ax\\ un

U.. Patent Dec. 11, 2012 heet 53 of 70 U 8,329,696 B2 un

U.. Patent Dec. 11, 2012 heet 54 f 70 U 8,329,696 B2 ax& 3xa& * YYYYYYYYYYYYYYYYYYYYYYYY xxxxxxxxxxxx &&xxxxxxxxx xx& exe un

U.. Patent Dec. 11, 2012 heet 55 of 70 U 8,329,696 B2 --------------. ----------------------

U.. Patent Dec. 11, 2012 heet 56 of 70 U 8,329,696 B2 &R eitya a & Y yyyyyyy waxe ix yt &ae & W axxxxxxx aw eeeeeewa N y aa ^y vaw ayn Në& & N.& referrero referrrrrrrrrrr w le. 9. 9 7 Z aaaaaaaa

U.. Patent Dec. 11, 2012 heet 57 f 70 U 8,329,696 B2 & i &y raw& &. e. 8 r 9 reprope Terry

U.. Patent Dec. 11, 2012 heet 58 f 70 U 8,329,696 B2 &ee. &e & text: &ww &a- & 8& a re aa N V *r r. e womex &.

U.. Patent Dec. 11, 2012 heet 59 of 70 U 8,329,696 B2 8 8 8 8 war aaaaay N & wamw. re&y &. a y Ny aa Y. N m ^. aay & 'N Yaa N&y ''''xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx a wy &\* ^w www.xx y. &N & w y ^. x aaa e ^xa ax w w r -i. am x^ ^& & rxge

U.. Patent Dec. 11, 2012 heet 60 of 70 U 8,329,696 B2. Lieu) 8 9 7 Z

U.. Patent Dec. 11, 2012 heet 61 of 70 U 8,329,696 B2 awy ex^ Raae. Ya Y ^xy ay axxxxxxxxx xxxxxxxxxx^* wr. awy ^wy ye N N xxxxx Yar &xa ^x y. xxxyr &w. *Y. & x -. axxxxxxx^ ee & R we wif & (e.) 8

U.. Patent 70007 aara 3-ax33-3-3-3-3-3-a Dec. 11, 2012 c un heet 62 of 70 N a aaaaaaaaaaaaaaaaaaaa '000 1 1, U 8,329,696 B2

U.. Patent U 8,329,696 B2 CIZI, " -

U.. Patent Dec. 11, 2012 heet 64 of 70 U 8,329,696 B2 axx aavaar un

U.. Patent Dec. 11, 2012 heet 65 f 70 U 8,329,696 B2 YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY "0007 000 un f000z

U.. Patent Dec. 11, 2012 heet 66 of 70 U 8,329,696 B2 Ywa aa Ya\a. axaaw w r waxxxxx y Yaa?Z?, "IH 000 "000Z un

U.. Patent Dec. 11, 2012 heet 67 of 70 U 8,329,696 B2 r 9 v- w v- w - w w v (un) ul

U.. Patent Dec. 11, 2012 heet 69 f 70 U 8,329,696 B2 006Z 0092 (un) ul

U.. Patent Dec. 11, 2012 heet 70 of 70 U 8,329,696 B2 n Y CD (5 C/D. on. 5 C H CN V V CD 1 co 2 V cy N V (un) ul -- N

1. LID TATE FRM F TAGLIPTN ALT CR-REFERENCE T RELATED APPLICATIN Thi application claim the benefit of U.. Proviional Patent Application er. No. 61/164,563, filed Mar. 30, 2009: 61/170,697, filed Apr. 20, 2009: 61/174,073, filed Apr. 30, 2009: 61/182,772, filed Jun. 1, 2009: 61/186,031, filed Jun. 11, 2009: 61/302.626, filed Feb. 9, 2010: 61/304,615, filed Feb. 15, 2010: 61/309,024, filed Mar. 1, 2010: 61/312,376, filed Mar. 10, 2010; and 61/315,149, filed Mar. 18, 2010, which are incorporated herein by reference. FIELD F THE INVENTIN The invention relate to crytalline and amorphou form of itagliptin alt, procee for preparing the crytalline form, and pharmaceutical compoition thereof. BACKGRUND F THE INVENTIN itagliptin, (3R)-3-amino-1-9-(trifluoromethyl)-1,4,7,8- tetrazabicyclo-4.3.0nona-6,8-dien-4-yl)-4-(2,4,5-trifluo rophenyl)butan-1-one, ha the following chemical tructure: F F F NH itagliptin N N -- N N N--K CF itagliptin phophate i a glucagon-like peptide 1 metabo lim modulator, hypoglycemic agent, and dipeptidyl pepti dae IV inhibitor. itagliptin i currently marketed in the United tate a it phophate alt in it monohydrate form under the trade name JANUVIATM. JANUVIATM i indicated to improve glycemic control in patient with type 2 diabete mellitu. The following PCT Publication decribe the ynthei of itagliptin via tereoelective reduction: W 2004/087650, W 2004/085661, and W 2004/085378. everal crytalline form of itagliptin phophate are decribed in the literature. W 2005/020920 decribe cry talline form I, II, III and an ethanol olvate; W 2005/ 030127 decribe crytalline form IV: W 2005/003135 decribe a monohydrate form, and W 2006/033848 decribed the amorphou form. Crytalline form of itagliptin alt are decribed in PCT publication no. W2009/085990, W2010/000469, and W21 /12781. Polymorphim, the occurrence of different crytal form, i a property of ome molecule and molecular complexe. A ingle molecule may give rie to a variety of polymorph having ditinct crytal tructure and phyical propertie like melting point, thermal behaviour (e.g. meaured by thermo gravimetric analyi "TGA, or differential canning calo rimetry DC), -ray diffraction pattern, infrared aborp tion fingerprint, and olid tate NMR pectrum. ne or more U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 2 of thee technique may be ued to ditinguih different poly morphic form of a compound. Dicovering new polymorphic form and olvate of a pharmaceutical product can provide material having deir able proceing propertie. uch a eae of handling, eae of proceing, torage tability, and eae of purification or a deirable intermediate crytal form that facilitate converion to other polymorphic form. New polymorphic form and olvate of a pharmaceutically ueful compound or alt thereof can alo provide an opportunity to improve the per formance characteritic of a pharmaceutical product. It enlarge the repertoire of material that a formulation cien tit ha available for formulation optimization, for example by providing a product with different propertie, e.g., better proceing or handling characteritic, improved diolution profile, or improved helf-life. For at leat thee reaon, there i a need for additional polymorph of itagliptin (or a alt thereof). The preent invention dicloe olid tate form of ita gliptin alt. UMMARY F THE INVENTIN The preent invention provide crytalline form of ita gliptin alt, and procee for preparing them. The invention further provide a pharmaceutical formula tion compriing the below decribed crytalline form of itagliptin alt. Thi pharmaceutical compoition may addi tionally comprie at leat one pharmaceutically acceptable excipient. The invention further provide the ue of the olid tate form decribed below for the manufacture of a medicament for the treatment of type 2 diabete mellitu. BRIEF DECRIPTIN F THE FIGURE FIG. 1a how a powder RD pattern of crytalline Form 1 of itagliptin ulfate. FIG. 1b how a powder RD pattern of crytalline Form 2 of itagliptin ulfate. FIG. 1c how a powder RD pattern of crytalline Form 3 of itagliptin ulfate. FIG. 1d how a powder RD pattern of crytalline Form 4 of itagliptin ulfate. FIG. 1e how a powder RD pattern of crytalline Form 5 of itagliptin ulfate. FIG. 1fhow a powder RD pattern of crytalline Form 6 of itagliptin ulfate. FIG. 1g how a powder RD pattern of crytalline Form 7 of itagliptin ulfate. FIG. 1h how a powder RD pattern of crytalline Form 7 of itagliptin ulfate. FIG. 1i how a olid tate CNMR pectrum of itaglip tin ulfate Form 7 in the 0-200 ppm range. FIG. 1jhow a olid tate CNMR pectrum of itaglip tin ulfate Form 7 in the 100-180 ppm range. FIG. 1 k how a powder RD pattern of crytalline Form 8 of itagliptin ulfate. The peak at 28.5 i attributed to ilicon powder, added to the ample a internal tandard. FIG. 11 how a DC thermogram of the heating proce of itagliptin ulfate form 2 to obtain form 8. FIG. 1m how a olid-tate 'C NMR pectrum of ita gliptin ulfate Form 2 in the 0-200 ppm range. FIG. 1n how a olid-tate 'C NMR pectrum of ita gliptin ulfate Form 2 in the 100-180 ppm range. FIG. 1o how a olid-tate 'C NMR pectrum of ita gliptin ulfate Form 3 in the 0-200 ppm range.

U 8,329,696 B2 3 FIG. 1p how a olid-tate 'C NMR pectrum of ita gliptin ulfate Form 3 in the 100-200 ppm range. FIG. 19 how a tranformation of Form 7 to 1 at 100% relative humidity. The peak at 28.5 i attribute to ilicon powder. 5 FIG. 1r how a TGA termogram of itagliptin ulfate iopropanol olvate Form 7. FIG. 1 how a TGA termogram of itagliptin ulfate iopropanol olvate Form 7. FIG.2a how a powder RD pattern of crytalline Form 10 D1 of itagliptin (+)-dibenzoyl-tartrate. FIG.2b how a powder RD pattern of crytalline Form D2 of itagliptin (+)-dibenzoyl-tartrate. FIG.3a how a powder RD pattern of crytalline Form F1 of itagliptin fumarate. 15 FIG. 3b how a powder RD pattern of crytalline Form F2 of itagliptin fumarate. FIG. 3c how a powder RD pattern of crytalline Form F1 of itagliptin fumarate. FIG.3d how a powder RD pattern of crytalline Form F2 and F1 of itagliptin fumarate. FIG. 4a how a powder RD pattern of crytalline Form M1 of itagliptin (D)-(+)-malate. FIG. 4b how a powder RD pattern of crytalline Form M2 of itagliptin (D)-(+)-malate. 25 FIG. 4c how a powder RD pattern of crytalline Form I1 of itagliptin L-malate. FIG. 4d how a olid-tate 'C NMR pectrum of ita gliptin L-malate Form I1 in the -10-200 ppm range. FIG. 4e how a olid-tate CNMR pectrum of itaglip 30 tin L-malate Form I1 in the 100-190 ppm range. FIG. 4f how a powder RD pattern of crytalline Form I1. The peak at 28.5 i attributed to ilicon powder. FIG. 4g how a olid-tate 'C NMR pectrum of ita gliptin D-malate Form M1 in the 0-200 ppm range. 35 FIG. 4h how a olid-tate 'C NMR pectrum of ita gliptin D-malate Form M1 in the 110-200 ppm range. FIG. 5a how a powder RD pattern of crytalline Form 1 of itagliptin oxalate. FIG.5b how a powder RD pattern of crytalline Form 40 2 of itagliptin oxalate. FIG.5c how a olid tate CNMR pectrum of itaglip tin oxalate Form 2 in the 0-200 ppm range. FIG.5d how a olid tate CNMR pectrum of itaglip tin oxalate Form 2 in the 140-180 ppm range. 45 FIG. 6a how a powder RD pattern of crytalline Form Q1 of itagliptin quinate. FIG. 6b how a olid tate CNMR pectrum of itaglip tin quinate Form Q1 in the 0-200 ppm range. FIG. 6c how a olid tate CNMR pectrum of itaglip 50 tin quinate Form Q1 in the 100-190 ppm range. FIG. 7a how a powder RD pattern of crytalline Form U1 of itagliptin uccinate. FIG.7b how a powder RD pattern of crytalline Form U1 of itagliptin uccinate. 55 FIG. 7c how a powder RD pattern of crytalline Form U1 of itagliptin uccinate. FIG. 9a how a powder RD pattern of crytalline Form E1 of itagliptin acetate. FIG.9b how a RD diffractogram of Acetate form E1 60 pure from peak at 5.7, 19.2 and 22.8 2theta. The peak at 28.5 i attributed to ilicon powder, added to the ample a internal tandard. FIG.9c how a olid-tate CNMR pectrum of itaglip tin acetate Form E1 in the 0-200 ppm range. FIG. 9d how a olid-tate ''C NMR pectrum of ita gliptin acetate Form E1 in the 100-190 ppm range. 65 4 FIG.10a how a powder RD pattern of crytalline Form A1 of itagliptin maleate. FIG.11a how a powder RD pattern of crytalline Form N1 of itagliptin ()-mandelate. FIG.11b how a powder RD pattern of crytalline Form N2 of itagliptin ()-mandelate. FIG.11c how a powder RD pattern of crytalline Form N3 of itagliptin ()-mandelate. FIG. 11d how a powder RD pattern of crytalline Form N4 of itagliptin ()-mandelate. FIG.11e how a powder RD pattern of amorphou ita gliptin mandelate. FIG. 11fhow a powder RD pattern of crytalline Form N5 of itagliptin (R)-mandelate. FIG.11g how a powder RD pattern of crytalline Form N6 of itagliptin (R)-mandelate. FIG. 11h how a olid tate ''C NMR pectrum of ita gliptin ()-(+)-mandelate Form N4 in the 0-200 ppm range. FIG. 11i how a olid tate ''C NMR pectrum of ita gliptin ()-(+)-mandelate FormN4 in the 110-190 ppm range. FIG. 11j how a olid tate ''C NMR pectrum of ita gliptin ()-(+)-mandelate Form N1 in the 0-200 ppm range. FIG. 11k how a olid tate 'C NMR pectrum of ita gliptin ()-(+)-mandelate FormN1 in the 110-190 ppm range. FIG. 111 how a olid tate 'C NMR pectrum of ita gliptin ()-(+)-mandelate Form N2 in the 0-200 ppm range. FIG. 11m how a olid tate 'C NMR pectrum of ita gliptin ()-(+)-mandelate FormN2 in the 110-190 ppm range. FIG.12a how a powder RD pattern of crytalline Form L1 of itagliptin lactate. FIG.12b how a powder RD pattern of crytalline Form L2 of itagliptin lactate. FIG.12c how a powder RD pattern of crytalline Form L2 of itagliptin lactate. FIG.12d how a powder RD pattern of crytalline Form L3 of itagliptin lactate. FIG. 12e how a powder RD pattern of crytalline Form L4 of itagliptin lactate. FIG. 13a how a powder RD pattern of amorphou itagliptin orotate, before drying. FIG. 13b how a powder RD pattern of amorphou itagliptin orotate, after drying. FIG. 13c how a powder RD pattern of amorphou ita gliptin orotate, before drying. FIG. 13d how a powder RD pattern of amorphou itagliptin orotate, after drying. DETAILED DECRIPTIN F THE INVENTIN The preent application relate to new polymorphic form of itagliptin alt. In ome embodiment, the polymorph of itagliptin alt of the invention are ubtantially free of any other polymorphic form. By ubtantially free i meant that the form of the preent invention contain 20% (w/w) or le, 10% (w/w) or le, 5% (w/w) or le, 2% (w/w) or le, particularly 1% (w/w) or le, more particularly 0.5% (w/w) or le, and mot particularly 0.2% (w/w) or le of any other polymorph. In other embodiment, the polymorph of ita gliptin alt of the invention contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of any other polymorph. A crytal form may be referred to herein a being charac terized by graphical data a hown in a Figure. uch data include, for example, powder -ray diffractogram and olid tate NMR pectra. The killed peron will undertand that uch graphical repreentation of data may be ubject to mall variation, e.g., in peak relative intenitie and peak poition

5 due to factor uch a variation in intrument repone and variation in ample concentration and purity, which are well known to the killed peron. Nonethele, the killed peron would readily be capable of comparing the graphical data in the Figure herein with graphical data generated for an unknown crytal form and confirm whether the two et of graphical data are characterizing the ame crytal form or two different crytal form. A ued herein, the term room temperature refer to a temperature of about 20 C. to about 35 C., or about 25 C. to about 35 C., or about 25 C. to about 30 C., for example, about 25 C. A ued herein, the term overnight refer to a time inter val from about 14 hour to about 24 hour, or about 14 hour to about 20 hour, for example, about 16 hour. Unle indicated otherwie, the olid tate form of the preent invention can be dried. Drying may be carried out, for example, at elevated temperature under reduced preure. The crytalline form can be dried at a temperature from about 40 C. to about 60 C., or about 40 C. and about 50 C., for example, about 40 C. The drying can be carried out under reduced preure (i.e., le than 1 atmophere, for example, about 10 mbar to about 100 mbar, or about 10 mbar to about 25 mbar). The drying can take place over a period of about 8 hour to about 36 hour, or about 10 hour to about 24 hour, for example, about 16 hour. Drying can be carried out over night. itagliptin bae, ued in the preent application, can be prepared, for example, by hydrogenating of (Z)-3-amino-1- (3-(trifluoromethyl)-5,6-dihydro-1,2,4-triazolo 4,3-alpyra Zyn-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one uing a Rhodium-baed catalyt, in the preence of a C-C, alcohol, for example, methanol, e.g. a indicated in Example 1 herein. The preent invention relate to crytalline form of ita gliptin ulfate, referred herein a Form 2. Form 6, and From 7. In one embodiment, the preent invention provide a cry talline itagliptin ulfate, deignated Form 2, characterized by data elected from: a powder RD pattern with peak at 9.3, 9.7, 15.2, 15.6 and 25.4 +0.2 20; a powder RD pattern a hown in FIG.1b; a olid-tate CNMR pectrum with ignal at 119.2, 150.3 and 170.6+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 180 ppm of 13.7. 44.8 and 65.1+0.1 ppm; a 'C NMR pectrum a depicted in FIG. 1 m and 1n; and combination thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 100 to 180 ppm i typically at 105.5+1 ppm. itagliptin ulfate Form 2 can be alo characterized by a powder RD pattern with peak at 9.3, 9.7, 11.9, 15.2, 15.6, 17.6, 18.5, 18.9, 20.9 and 25.490.2 20. itagliptin ulfate Form 2 preferably ha advantageou propertie elected from at leat one of high crytallinity, olubility, diolution rate, morphology, thermal and mechanical tability to polymorphic converion and/or to dehydration, torage tability, low content of reidual olvent, a lower degree of hygrocopicity, flowability, and advanta geou proceing and handling characteritic uch a com preibility, and bulk denity. In particular, Form 2 may have at leat one of high crytallinity, good mechanical tability, thermal tability, flowability, and olubility over a wide range of ph. itagliptin ulfate crytalline Form 2 can be prepared by a proce compriing forming a olution of itagliptin bae in acetonitrile; combining the olution with ulfuric acid to form U 8,329,696 B2 5 10 15 25 30 35 40 45 50 55 60 65 6 a precipitate; and iolating the obtained precipitate. Prefer ably, the ulfuric acid i ued at a mol ratio of about 1:0.5 of itagliptin bae to ulfuric acid. In another embodiment, the preent invention provide a crytalline itagliptin ulfate, deignated Form 6, character ized by data elected from: a powder RD pattern with peak at 5.5, 13.4, 15.1, 19.0 and 21.1+0.3 20; a powder RD diffractogram hown in FIG. 1f and combination thereof. itagliptin ulfate Form 6 preferably ha advantageou propertie elected from at leat one of olubility, diolution rate, morphology, thermal and mechanical tability to poly morphic converion and/or to dehydration, torage tability, low content of reidual olvent, a lower degree of hygrocop icity, flowability, and advantageou proceing and handling characteritic uch a compreibility, and bulk denity. In particular, Form 6 may have at leat one of good mechanical tability, thermal tability, flowability, and olubility over a wide range of ph. itagliptin ulfate crytalline Form 6 can be prepared by a proce compriing forming a olution of itagliptin bae in ethyl acetate; combining the olution with ulfuric acid to form a precipitate; and iolating the obtained precipitate. The obtained precipitate can be further dried. Preferably, the ul furic acid i ued at a mol ratio of about 1:0.5 of itagliptin bae to ulfuric acid. In another embodiment, the preent invention provide a crytalline itagliptin ulfate iopropanol olvate, deignated Form 7, characterized by data elected from: a powder RD pattern with peak at 5.2, 15.6, 16.6, 18.7 and 21.1+0.2 20; a powder RD diffractogram hown in FIG. 1g, a olid tate 'C NMR pectrum with ignal at 120.4, 149.1 and 171.2+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 180 ppm of 15.1, 43.8 and 65.9-0.1 ppm; and a 'C NMR pectrum a depicted in FIG. 1i and 1j; and combina tion thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 100 to 180 ppm i typically at 105.3+1 ppm. Alternatively. Form 7 can be characterized a powder RD pattern with peak at 5.2, 15.6, 16.6, 17.1, 18.7, 19.4, 17.0, 20.2, 21.19, 21.7 and 22.9 0.2 20. itagliptin ulfate Form 7 can be characterized by the TGA thermogram a hown in FIG. 1r. itagliptin ulfate Form 7 preferably ha advantageou propertie elected from at leat one of olubility, diolution rate, morphology, thermal and mechanical tability to poly morphic converion and/or to dehydration, torage tability, a lower degree of hygrocopicity, flowability, and advanta geou proceing and handling characteritic uch a com preibility, and bulk denity. In particular, Form 7 may have at leat one of good mechanical tability, thermal tability, flowability, and olubility over a wide range of ph. itagliptin ulfate crytalline Form 7 can be prepared by a proce compriing forming a olution of itagliptin bae in iopropanol; combining the olution with ulfuric acid to form a precipitate; and iolating the obtained precipitate. The obtained precipitate can be further dried. Preferably, the ul furic acid i ued at a mol ratio of about 1:0.5 of itagliptin bae to ulfuric acid. In another embodiment, the preent invention provide a crytalline itagliptin ulfate deignated Form 1, character ized by data elected from: a powder RD pattern with peak at 11.8, 13.7, 14.4, 17.0 and 17.5 +0.2 28; a powder RD diffractogram a hown in FIG. 1a; and combination thereof.

7 itagliptin ulfate Form 1 can be alo characterized by a powder RD pattern with peak at 5.0, 9.9, 11.8, 12.6, 13.7, 14.49, 17.0, 17.5 19.0 and 20.8 0.2 20. itagliptin ulfate Form 1 preferably ha advantageou propertie elected from at leat one of olubility, diolution rate, morphology, thermal and mechanical tability to poly morphic converion and/or to dehydration, torage tability, low content of reidual olvent, a lower degree of hygrocop icity, flowability, and advantageou proceing and handling characteritic uch a compreibility, and bulk denity. In particular, Form 6 may have at leat one of good mechanical tability, thermal tability, and flowability. itagliptin ulfate crytalline Form 1 can be prepared by a proce compriing forming a olution of itagliptin bae in iopropanol; combining that olution with ulfuric acid to form a precipitate; and iolating the obtained precipitate. Preferably, the ulfuric acid i ued at a mol ratio of about 1:1 of itagliptin bae to ulfuric acid. In thi proce, and in the procee for the preparation of any of the crytalline itagliptin ulfate, after combining with ulfuric acid, the olution can be maintained at a temperature from about room temperature to about 50 C., or at about room temperature, for example overnight. The precipitate i recovered by any conventional method known in the art, for example, by filtration. The precipitate may be dried at about 30 C. to about 60 C., or about 40 C. and about 50 C., for example, about 40 C. The drying can be carried out under reduced preure (i.e., le than 1 atmophere, for example, about 10 mbar to about 100 mbar, or about 10 mbar to about 25 mbar). The drying can take place over a period of about 8 hour to about 36 hour, about 10 hour to about 24 hour, for example, about 16 hour, or can be carried out overnight. The preent invention relate to crytalline form of ita gliptin acetate, referred herein a Form E1. In one embodiment, the preent invention provide a cry talline itagliptin acetate, deignated Form E1, characterized by data elected from: a powder RD pattern with peak at 6.2, 11.1, 12.5, 17.7, and 18.4 +0.2 28; a powder RD pattern a hown in FIG.9a; a olid-tate CNMR pectrum with ignal at 122.3, 150.5 and 167.4+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 190 ppm of 18.5, 46.7 and 63.6+0.1 ppm; and a CNMR pectrum a depicted in FIG. 9c and 9d, and combination thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 100 to 180 ppm i typically at 103.8+1 ppm. itagliptin acetate Form E1 can be alo characterized by a powder RD pattern with peak at 6.2, 8.3, 11.1, 12.5, 15.3, 16.4, 17.7, 18.4, 20.4, and 22.2 0.2 20. itagliptin acetate Form El preferably ha advantageou propertie elected from at leat one of good crytallinity, olubility, diolution rate, morphology, thermal and mechanical tability to polymorphic converion and/or to dehydration, torage tability, low content of reidual olvent, a lower degree of hygrocopicity, flowability, and advanta geou proceing and handling characteritic uch a com preibility, and bulk denity. In particular, Form E1 may have at leat one of good mechanical tability, thermal tability, flowability, and olubility over a wide range of ph. itagliptin acetate crytalline Form E1 can be prepared by a proce compriing forming a olution or a lurry of ita gliptin bae in ethyl acetate; combining the olution or the lurry with acetic acid to form a precipitate; and iolating the obtained precipitate. The obtained precipitate can be further dried. Preferably, the acetic acid i ued at a mol ratio of about 1:1 of itagliptin bae to acetic acid. U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 8 After the addition of the acid, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room tempera ture, preferably overnight, before collecting the obtained pre cipitate. The obtained precipitate can further be dried. The preent invention relate to crytalline form of ita gliptin L-malate, referred herein a Form I1. In one embodiment, the preent invention provide a cry talline itagliptin L-malate, deignated Form I1, character ized by data elected from: a powder RD pattern with peak at 6.0, 8.0, 12.8, 18.0 and 20.4 +0.2 20; a powder RD diffractogram hown in FIG. 4f a olid-tate CNMR pec trum with ignal at 121.7, 150.8 and 173.0+0.2 ppm; a olid tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 190 ppm of 17.2, 46.3 and 68.5+0.1 ppm; and a CNMR pectrum a depicted in FIG. 4d and 4e; and combination thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 100 to 180 ppm i typically at 104.5+1 ppm. Form I1 can be alo characterized by a powder RD pat tern with peak at 6.1, 8.2, 13.0, 18.1 and 20.5-0.2 20. Form I1 can be alo characterized by a powder RD pat tern with peak at 6.0, 8.0, 12.0, 12.8, 14.5, 16.3, 18.0, 19.4, 20.4 and 21.1+0.2 20. Form I1 can be alo characterized by a powder RD pat tern with peak at 6.19, 8.2, 12.1, 13.0, 14.6, 16.4, 18.1, 19.5, 20.5 and 21.2-0.2 20. itagliptin L-malate Form I1 preferably ha advantageou propertie elected from at leat one of high crytallinity, olubility, diolution rate, morphology, thermal and mechanical tability to polymorphic converion and/or to dehydration, torage tability, low content of reidual olvent, a lower degree of hygrocopicity, flowability, and advanta geou proceing and handling characteritic uch a com preibility, and bulk denity. Form I1 can be prepared by a proce compriing forming a olution of itagliptin bae in acetonitrile; combining the olution with L-malic acid to form a precipitate; and iolating the obtained precipitate. The obtained precipitate can be fur ther dried. Preferably, the ulfuric acid i ued at a mol ratio of about 1:1 of itagliptin bae to L-malic acid. The preent invention relate to crytalline form of ita gliptin quinate, referred herein a Form Q1. In one embodiment, the preent invention provide a cry talline itagliptin quinate, deignated Form Q1, characterized by data elected from: a powder RD pattern with peak at 7.3, 8.6, 10.5, 12.6 and 13.9 +0.2 20; a powder RD pattern a hown in FIG. 6a; a olid-tate CNMR pectrum with ignal at 121.5, 169.0 and 180.3-0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 190 ppm of 16.8. 64.3 and 75.6+0.1 ppm; and a 'CNMR pectrum i depicted in FIG. 6b and 6c; and combination thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 100 to 190 ppm i typically at 104.7+1 ppm. itagliptin quinate Form Q1 can be alo characterized by a powder RD pattern with peak at 7.3, 8.6, 10.5, 12.6, 13.9, 16.19, 16.4, 16.8, 17.8 and 19.2 0.2 20. itagliptin quinate Form Q1 can be prepared by a proce compriing forming a olution of itagliptin bae in an

9 organic olvent elected from acetonitrile, and iopropanol: and adding (1R,3R,4R,5R)-(-)-quinic acid to the olution to obtain Form Q1. Preferably, the (1R,3R.4R,5R)-(-)-quinic acid i ued at a mol ratio of about 1:1 of itagliptin bae to (1R,3R,4R,5R)-(-)-quinic acid. After the addition of the acid, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room tempera ture, preferably overnight, before collecting the obtained pre cipitate. The obtained precipitate can further be dried. itagliptin acetate Form Q1 preferably ha advantageou propertie elected from at leat one of good crytallinity, olubility, diolution rate, morphology, thermal and mechanical tability to polymorphic converion and/or to dehydration, torage tability, low content of reidual olvent, a lower degree of hygrocopicity, flowability, and advanta geou proceing and handling characteritic uch a com preibility, and bulk denity. The preent invention provide additional itagliptin alt olid tate form. Hereinafter, i decribed a crytalline itagliptin ulfate, deignated Form 3, characterized by data elected from: a powder RD pattern with peak at 7.4, 16.1, 18.3 and 24.9 +0.2 20; a powder RD pattern a hown in FIG. 1c; a olid-tate 'C NMR pectrum with ignal at 119.9, 152.0 and 169.5+0.2 ppm; a olid-tate CNMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 200 ppm of 16.7, 48.8 and 66.3+0.1 ppm: 'CNMR pectrum i depicted in FIG. 1o and 1p; and combination thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 100 to 200 ppm i typically at 103.2+1 ppm. itagliptin ulfate Form 3 can be alo characterized by a powder RD pattern with peak at 4.8, 5.7, 7.4, 13.5, 14.3, 15.0, 16.1, 18.3, 22.8 and 24.9 0.2 20. itagliptin ulfate crytalline Form 3 can be prepared by a proce compriing forming a olution of itagliptin bae in ethyl acetate; combining the olution with ulfuric acid to form a precipitate; and iolating the obtained precipitate. Preferably, the ulfuric acid i ued at a mol ratio of about 1:0.5 of itagliptin bae to ulfuric acid. Hereinafter, i decribed a crytalline itagliptin ulfate, deignated Form 4, characterized by data elected from: a powder RD pattern with peak at 5.3, 7.8, 16.7, 19.4 and 21.6 +0.2 20; a powder RD pattern a hown in FIG. 1d. and combination thereof. itagliptin ulfate Form 4 can be alo characterized by a powder RD pattern with peak at 5.3, 5.9, 11.7, 12.4, 15.7, 16.7, 17.3, 18.8, 19.3, 21.2 and 21.6-0.2 20. itagliptin ulfate Form 4 can be alo characterized by a powder RD pattern with peak at 5.3, 5.9, 7.8, 11.7, 12.4, 15.7, 16.7, 17.3, 18.8, 19.3, 21.2 and 21.6-0.29 20. itagliptin ulfate crytalline Form 4 can be prepared by a proce compriing forming a mixture of itagliptin bae in ethanol; combining the mixture with ulfuric acid to form a precipitate; and iolating the obtained precipitate. Preferably, the ulfuric acid i ued at a mol ratio of about 1:0.5 of itagliptin bae to ulfuric acid, repectively. Hereinafter, i decribed a crytalline itagliptin ulfate, deignated Form 5, characterized by data elected from: a U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 10 powder RD pattern with peak at 4.8, 13.6, 14.3, 15.5 and 18.2 +0.2 20; a powder RD diffractogram hown in FIG. 1e; and combination thereof. Alternatively. Form 5 can be characterized by a powder RD pattern with peak at 4.8, 13.6, 14.3, 15.5, 18.2, 19.0, 19.4, 22.1, 23.4 and 24.5-0.2 20. Hereinafter, i decribed a crytalline itagliptin ulfate, deignated Form 8, characterized by data elected from: a powder RD pattern with peak at 5.8, 9.7, 15.4, 19.1 and 20.8 +0.2 20; a powder RD diffractogram hown in FIG. 1k, and combination thereof. Alternatively. Form 8 can be characterized a powder RD pattern with peak at 4.8, 5.8, 9.7, 11.9, 13.7, 15.4, 17.6, 19.1, 20.8 and 22.0-0.2 20. Hereinafter, i decribed a crytalline itagliptin (+)- dibenzoyl-tartrate, deignated Form D1, characterized by data elected from: a powder RD pattern with peak at 7.1, 9.9, 13.4, 16.3 and 18.0 +0.2 20; a powder RD pattern a hown in FIG. 2a; and combination thereof. itagliptin dibenzoyl-tartrate Form D1 can be alo charac terized by a powder RD pattern with peak at 7.1, 9.9, 13.4, 15.2, 16.3, 18.0, 18.4, 20.3, 21.6 and 24.9 0.2 20. itagliptin (+)-dibenzoyl-tartrate Form D1 can be prepared by a proce compriing forming a olution of itagliptin bae in an organic olvent elected from acetonitrile, and ethyl acetate; and adding (+)-dibenzoyl-d-tartaric acid to the olu tion to obtain Form D1. Preferably, the (+)-dibenzoyl-dtartaric acid i ued at a mol ratio of about 1:1 of itagliptin bae to (+)-dibenzoyl-d-tartaric acid. After the addition of the acid, in thi proce or any proce for the preparation of any of the itagliptin (+)-dibenzoyl tartrate polymorph dicloed herein, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating can be maintained for about 1 to about 10 hour, or from about 1 to about 4 hour, for example for about 2 hour. Afterward, the mixture can be cooled to a tempera ture from about 0 C. to about room temperature, or from about 10 C. to about room temperature, or about room tem perature, for example, overnight, before collecting the obtained precipitate. The obtained precipitate can further be dried. Hereinafter, i decribed a crytalline itagliptin (+)- dibenzoyl-tartrate, deignated Form D2, characterized by data elected from: a powder RD pattern with peak at 6.9, 11.9, 15.9 and 17.9 0.2 20; a powder RD pattern a hown in FIG. 2b; and combination thereof. itagliptin (+)-dibenzoyl-tartrate Form D2 can be alo characterized by a powder RD pattern with peak at 5.0. 6.9, 10.7, 11.9, 14.5, 15.9, 17.9, 19.0, 22.6 and 23.802 20. itagliptin (+)-dibenzoyl-tartrate Form D2 can be prepared by a proce compriing forming a mixture (e.g. a olution or a lurry) of itagliptin bae in ethanol; and adding (+)-diben Zoyl-D-tartaric acid to obtain Form D2. Preferably, the (+)- dibenzoyldibenzoyl-d-tartaric acid i ued at a mol ratio of about 1:1 of itagliptin bae to (+)-dibenzoyl-d-tartaric acid. Hereinafter, i decribed a crytalline itagliptin fumarate, deignated Form F1, characterized by data elected from: a powder RD pattern with peak at 6.3, 7.2, 12.6, 14.5 and 15.0-0.3 20; a powder RD pattern a hown in FIG.3a; and combination thereof. itagliptin fumarate Form F1 can be alo characterized by a powder RD pattern with peak at 6.3, 7.2, 12.6, 14.5, 15.0, 16.0, 17.3, 19.3 and 22.0-0.3 20.

11 itagliptin fumarate Form F1 can be prepared by a proce compriing forming a olution of itagliptin bae in an organic olvent elected from acetonitrile, and ethanol; and adding fumaric acid to the olution to obtain Form F1. Pref erably, n-heptane i added a a co-olvent to induce precipi tation. Preferably, the fumaric acid i ued at a mol ratio of about 1:1 of itagliptin bae to fumaric acid. In thi proce, a well in the proceeding procee for the preparation of any of the crytalline form of itagliptin fuma rate dicloed herein, after the addition of the acid, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. The mixture can be heated for a time interval from about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. Afterward, the mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example to about room temperature, for example overnight, before collecting the obtained precipitate. The obtained precipitate can further be dried. Hereinafter, i decribed a crytalline itagliptin fumarate, deignated Form F2, characterized by data elected from: a powder RD pattern with peak at 10.5, 11.4, 13.2 and 13.8 +0.3 20; a powder RD pattern a hown in FIG.3b; and combination thereof. itagliptin fumarate F2 i alo characterized by a powder RD pattern with peak at 10.5, 11.4, 13.2, 13.8, 16.0, 17.3, 21.0, and 25.0-0.3 20. itagliptin fumarate Form F2 can be prepared by a proce compriing forming a olution of itagliptin bae in ethyl acetate; and adding fumaric acid to obtain Form F2. Prefer ably, the fumaric acid i ued at a mol ratio of about 1:1 of itagliptin bae to fumaric acid. Hereinafter, i decribed a crytalline itagliptin (D)-(+)- malate, deignated Form M1, characterized by data elected from: a powder RD pattern with peak at 13.1, 14.1, 15.7 and 19.6-0.2 20; a powder RD pattern a hown in FIG. 4a: a olid-tate 'C NMR pectrum with ignal at 119.7, 151.9 and 183.3+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhib iting the lowet chemical hift and another in the chemical hift range of 110 to 200 ppm of 3.6, 35.8 and 67.2+0.1 ppm. 'C NMR pectrum a hown in FIG. 4g and 4h; and com bination thereof. The ignal exhibiting the lowet chemical hift in the chemical hift area of 110 to 200 ppm i typically at 116.1+1 ppm. itagliptin (D)-(+)-malate Form M1 can be alo character ized by a powder RD pattern with peak at 10.7, 13.1, 14.1, 15.7, 17.3, 17.9, 19.6, 20.8 and 21.6-0.2 20. itagliptin (D)-(+)-malate Form M1 can be prepared by a proce compriing forming a olution of itagliptin bae in acetonitrile; and adding D-(+)-malic acid to the olution to obtain Form M1. Preferably, the D-(+)-malic acid i ued at a mol ratio of about 1:1 of itagliptin bae to D-(+)-malic acid. After the addition of the acid, in any of the procee for preparing any of the crytalline itagliptin malate form di cloed herein, the obtained mixture can be heated to a tem perature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room temperature, preferably overnight, before collecting the obtained precipitate. The obtained precipitate can further be dried. U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 12 Hereinafter, i decribed a crytalline itagliptin (D)-(+)- malate, deignated Form M2. itagliptin malate Form M2 i characterized by the RD diffractogram hown in FIG. 4b. itagliptin (D)-(+)-malate Form M2 can be prepared by a proce compriing forming a olution of itagliptin bae in ethanol; and adding D-(+)-malic acid to the olution to obtain Form M2. Preferably, the D-(+)-malic acid i ued at a mol ratio of about 1:1 of itagliptin bae to D-(+)-malic acid. Hereinafter, i decribed a crytalline itagliptin oxalate, deignated Form 1, characterized by data elected from: a powder RD pattern with peak at 8.4, 11.2, 14.5, 17.0 and 17.6-0.2 20; a powder RD pattern a hown in FIG. 5a; and combination thereof. itagliptin oxalate Form 1 can be alo characterized by a powder RD pattern with peak at 8.4, 11.2, 14.5, 15.4, 17.0, 17.6, 19.8, 21.0, 25.4 and 27.1-0.2 20. itagliptin oxalate Form 1 can be prepared by a proce compriing forming a olution of itagliptin bae in acetoni trile, or alternatively, forming a lurry in iopropanol; and adding oxalic acid to the olution or lurry, repectively, to obtain Form 1. Preferably, the oxalic acid i ued at a mol ratio of about 1:1 of itagliptin bae to oxalic acid. After the addition of the acid, in any of the procee for preparing any of the crytalline itagliptin oxalate form dicloed herein, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room temperature, preferably overnight, before collecting the obtained precipitate. The obtained precipitate can further be dried. Hereinafter, i decribed a crytalline itagliptin oxalate, deignated Form 2, characterized by data elected from: a powder RD pattern with broad peak at 5.7, 10.7, 14.7, 17.1 and 18.2 +0.3 20; a powder RD pattern a hown in FIG. 5b, and combination thereof. itagliptin oxalate Form 2 can be alo characterized by data elected from: a olid-tate 'C NMR pectrum with ignal at 152.2, 165.1 and 167.5+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 140 to 180 ppm of 8.8, 21.7 and 24.1+0.1 ppm; and a 'CNMR pectrum a depicted in FIG. 5c and 5d. The ignal exhibiting the lowet chemical hift in the chemical hift area of 140 to 180 ppm i typically at 143.4+1 ppm. itagliptin oxalate Form 2 can be prepared by a proce compriing forming a olution of itagliptin bae in ethyl acetate; and adding oxalic acid to the olution to obtain Form 2. Preferably, the oxalic acid i ued at a mol ratio of about 1:1 of itagliptin bae to oxalic acid. Hereinafter, i decribed a crytalline itagliptin uccinate, deignated Form U1, characterized by data elected from: a powder RD pattern with peak at 11.6, 13.1, 13.6, 14.2 and 15.8 +0.2 20; a powder RD pattern a hown in FIG. 7b; and combination thereof. itagliptin uccinate Form U1 can be alo characterized by a powder RD pattern with peak at 10.6, 11.6, 13.1, 13.6, 14.2, 15.8, 17.4, 24.5, 25.3 and 25.8 +0.2 20. itagliptin uccinate Form U1 can be prepared by a proce compriing forming a olution of itagliptin bae in an organic olvent elected from ethanol, acetonitrile, and ethyl acetate; and adding uccinic acid to obtain Form U1. Prefer

13 ably, the uccinic acid i ued at a mol ratio of about 1:1 of itagliptin bae to uccinic acid. After the addition of the acid, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room tempera ture, preferably overnight, before collecting the obtained pre cipitate. The obtained precipitate can further be dried. Hereinafter, i decribed a crytalline itagliptin maleate, deignated Form A1, characterized by data elected from: a powder RD pattern with peak at 5.8, 11.5, 14.7, 16.7 and 18.0-0.2 20; a powder RD pattern a hown in FIG. 10a; and combination thereof. itagliptin maleate Form A1 can be alo characterized by a powder RD pattern with peak at 5.8, 11.5, 14.7, 16.7, 17.3, 18.0, 18.6, 19.5, 21.0 and 22.9 0.2 20. itagliptin maleate crytalline Form A1 can be prepared by a proce compriing forming a olution of itagliptin bae in ethanol; combining the olution with maleic acid; adding n-heptane to form a precipitate; and iolating the obtained precipitate. Preferably, the maleic acid i ued at a mol ratio of about 1:1 of itagliptin bae to maleic acid. After the addition of the acid, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room temperature, preferably overnight, before collecting the obtained precipitate. The obtained pre cipitate can be further dried. Hereinafter, i decribed a crytalline itagliptin ()-man delate, deignated Form N1, characterized by data elected from: a powder RD pattern with peak at 12.1, 17.5. 20.2, 21.0 and 26.0 +0.2 20; a powder RD pattern a hown in FIG.11a; and combination thereof. itagliptin ()-mandelate Form N1 can be alo character ized by a powder RD pattern with peak at 3.3, 5.8, 6.9, 12.1, 14.6, 17.5, 19.6, 20.2, 21.0 and 26.0-0.2 20. itagliptin ()-mandelate From N1 can be alo character ized by data elected from: a olid-tate CNMR pectrum with ignal at 144.2, 168.3 and 179.1+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 110 to 190 ppm of 24.6, 48.7 and 59.5+0.1 ppm; and a 'CNMR pectrum i depicted in FIG. 11j and 11 k. The ignal exhibiting the lowet chemi cal hift in the chemical hift area of 110 to 190 ppm i typically at 119.6:1 ppm itagliptin ()-mandelate crytalline Form N1 can be pre pared by a proce compriing forming a olution of itaglip tin bae in acetonitrile; combining the olution with mandelic acid to form a precipitate; and iolating the obtained precipi tate. Preferably, the mandelic acid i ued at a mol ratio of about 1:1 of itagliptin bae to mandelic acid. Preferably, the acid i ()-(+)-mandelic acid. After the addition of the acid, in any of the procee herein for preparing any of the crytalline itagliptin mandelate form, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 14 about 4 hour, for example, for about 2 hour to about 3 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room temperature, preferably overnight, before collecting the obtained precipi tate. The obtained precipitate can further be dried. Hereinafter, i decribed a crytalline itagliptin ()-man delate, deignated Form N2, characterized by data elected from: a powder RD pattern with peak at 11.8, 17.0, 18.1, 22.4 and 24.2 +0.220; a powder RD pattern a hown in FIG.11b; and combination thereof. itagliptin ()-Form N2 can be alo characterized by a powder RD pattern with peak at 3.3, 5.9, 6.8, 11.8, 14.6, 17.0, 18.1, 18.6, 22.4 and 24.2-0.2 20. itagliptin ()-mandelate Form N2 can be alo character ized by data elected from: a olid-tate 'C NMR pectrum with ignal at 144.4, 167.8 and 179.0+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 110 to 190 ppm of 24.7, 48.1 and 59.3+0.1 ppm; and a 'CNMR pectrum i depicted in FIG. 111 and 11m. The ignal exhibiting the lowet chemi cal hift in the chemical hift area of 110 to 190 ppm i typically at 119.7+1 ppm. itagliptin ()-mandelate crytalline Form N2 can be pre pared by a proce compriing forming a olution of itaglip tin bae in ethyl acetate; combining the olution with man delic acid to form a precipitate; and iolating the obtained precipitate. Preferably, the mandelic acid i ued at a mol ratio of about 1:1 of itagliptin bae to mandelic acid. Preferably, the acid i ()-(+)-mandelic acid. Hereinafter, i decribed a crytalline itagliptin ()-man delate, deignated Form N3, characterized by data elected from: a powder RD pattern with peak at 6.0, 6.7, 7.2. 14.4 and 18.1+0.220; a powder RD pattern a hown in FIG.11c; and combination thereof. itagliptin ()-mandelate Form N3 can be alo character ized by a powder RD pattern with peak at 6.0, 6.7, 7.2, 13.2, 14.49, 16.9, 18.1, 18.8, 20.7 and 22.9 0.2 20. itagliptin ()-mandelate crytalline Form N3 can be pre pared by a proce compriing forming a olution of itaglip tin bae in ethanol; combining the olution with mandelic acid to form a precipitate; and iolating the obtained precipi tate. Preferably, the mandelic acid i ued at a mol ratio of about 1:1 of itagliptin bae to mandelic acid. Preferably, the acid i ()-(+)-mandelic acid. Hereinafter, i decribed a crytalline itagliptin ()-man delate, deignated Form N4, characterized by data elected from: a powder RD pattern with peak at 2.8, 4.0, 7.9, 16.3 and 17.5-0.2 20; a powder RD pattern a hown in FIG. 11d; and combination thereof. itagliptin ()-mandelate Form N4 can be alo character ized by a powder RD pattern with peak at 2.8, 4.0, 7.9, 14.8, 15.5, 16.3, 17.0, 17.5, 17.9 and 23.6-0.2 20. itagliptin ()-mandelate Form N4 can be alo character ized by data elected from: a olid-tate 'C NMR pectrum with ignal at 126.0, 149.7 and 179.7+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 110 to 190 ppm of 6.3, 30.0 and 60.0+0.1 ppm; and a CNMR pectrum i depicted in FIG. 11h and 11 i. The ignal exhibiting the lowet chemi cal hift in the chemical hift area of 110 to 190 ppm i typically at 119.7+1 ppm. itagliptin ()-mandelate crytalline Form N4 can be pre pared by a proce compriing forming a olution of itaglip tin bae in acetone; combining the olution with mandelic

15 acid to form a precipitate; and iolating the obtained precipi tate. Preferably, the mandelic acid i ued at a mol ratio of about 1:1 of itagliptin bae to mandelic acid. Preferably, the acid i ()-(+)-mandelic acid. Hereinafter, i decribed a crytalline itagliptin (R)-(-)- mandelate, deignated Form N5, characterized by data elected from: a powder RD pattern with peak at 5.5, 7.6, 14.4, 16.0 and 17.7 0.2 20; a powder RD pattern a hown in FIG. 11f and combination thereof. Preferably, Form N5 i ubtantially free of a peak at 6.-.2 20. itagliptin (R)-(-)-mandelate Form N5 can be alo char acterized by a powder RD pattern with peak at 5.5, 7.6, 14.4, 16.0, 17.7, 22.1, 22.8, 24.0, 25.1 and 26.5-0.29 20. Hereinafter, i decribed a crytalline itagliptin (R)-(-)- mandelate, deignated Form N6, characterized by data elected from: a powder RD pattern with peak at 5.8, 14.7, 16.1, 16.6 and 17.1 +0.2 20; a powder RD pattern a hown in FIG.11g, and combination thereof. itagliptin (R)-(-)-mandelate Form N6 can be alo char acterized by a powder RD pattern with peak at 5.8, 14.7. 16.1, 16.6, 17.1, 18.6, 19.5, 21.7, 23.9 and 25.7 0.29 20. Hereinafter, i decribed amorphou itagliptin mandelate. The amorphou itagliptin mandelate i characterized by the RD diffractogram hown in FIG. 11e. The amorphou itagliptin mandelate can be prepared by a proce compriing forming a lurry of itagliptin bae in methyl tert-butyl ether; combining the lurry with mandelic acid; and iolating the obtained precipitate. Preferably, the mandelic acid i ued at a mol ratio of about 1:1 of itagliptin bae to mandelic acid. Preferably, the acid i ()-(+)-man delic acid. After the addition of the acid, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10 hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example about room tempera ture, preferably overnight, before collecting the obtained pre cipitate. The obtained precipitate can be further dried. Hereinafter, i decribed a crytalline itagliptin lactate, deignated Form Ll, characterized by data elected from: a powder RD pattern with peak at 10.7, 17.9, 20.3 and 21.4+0.220; a powder RD pattern a hown in FIG. 12a: and combination thereof. itagliptin lactate Form L1 can be alo characterized by a powder RD pattern with peak at 6.1, 8.3, 10.7, 17.9, 20.3, 21.4, 23.5, 25.1 and 27.2 0.2 20. itagliptin lactate crytalline Form L1 can be prepared by a proce compriing forming a olution of itagliptin bae in acetonitrile; combining the olution with lactic acid to form a precipitate; and iolating the obtained precipitate. Preferably, the lactic acid i ued at a mol ratio of about 1:1 of itagliptin bae to lactic acid. After the addition of the acid, in any of the procee for preparing any of the crytalline itagliptin lactate form, the obtained mixture can be heated to a temperature from about 40 C. to about 60 C., or from about 45 C. to about 55 C., for example about 50 C. Heating i applied for example, for about 1 to about 10hour, or from about 1 to about 4 hour, for example, for about 2 hour. The mixture can be cooled to a temperature from about 0 C. to about room temperature, or from about 10 C. to about room temperature, for example U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 16 about room temperature, preferably overnight, before collect ing the obtained precipitate. The obtained precipitate can further be dried. Hereinafter, i decribed a crytalline itagliptin lactate, deignated Form L2, characterized by data elected from: a powder RD pattern with peak at 6.6, 7.8, 10.6, 17.9 and 20.3 +0.2 20; a powder RD pattern a hown in FIG. 12c: and combination thereof. itagliptin lactate Form L2 can be alo characterized by a powder RD pattern with peak at 3.3, 5.9, 6.6, 7.8, 10.6, 16.19, 17.9, 19.5, 20.3, 21.7, 25.8 and 27.4 0.2 20. itagliptin lactate crytalline Form L2 can be prepared by a proce compriing forming a olution of itagliptin bae in an organic olvent elected from acetone, and ethyl acetate; combining the olution with lactic acid to form a precipitate; and iolating the obtained precipitate. Preferably, the lactic acid i ued at a mol ratio of about 1:1 of itagliptin bae to lactic acid. Hereinafter, i decribed a crytalline itagliptin lactate, deignated Form L3, characterized by data elected from: a powder RD pattern with peak at 5.3, 6.2, 8.5, 10.6 and 17.8 +0.2 20; a powder RD pattern a hown in FIG. 12d: and combination thereof. itagliptin lactate Form L3 can alo be characterized by a powder RD pattern with peak at 5.3, 6.2, 8.5, 10.6, 15.3, 17.8, 19.5, 19.99, 22.4 and 28.0-0.2 20. itagliptin lactate crytalline Form L3 can be prepared by a proce compriing forming a lurry of itagliptin bae in methyl tert-butyl ether; combining the lurry with lactic acid to form a precipitate; and iolating the obtained precipitate. Preferably, the lactic acid i ued atamol ratio of about 1:1 of itagliptin bae to lactic acid. Hereinafter, i decribed a crytalline itagliptin lactate, deignated Form L4, characterized by data elected from: a powder RD pattern with peak at 7.7, 10.7, 17.3, 18.1 and 25.2 +0.220; a powder RD pattern a hown in FIG. 12e; and combination thereof. itagliptin lactate Form L4 can be alo characterized by a powder RD pattern with peak at 7.7, 9.7, 10.7, 12.6, 16.6, 17.3, 18.1, 20.7, 23.1 and 25.2 0.2 28. itagliptin lactate crytalline Form L4 can be prepared by a proce compriing forming a olution of itagliptin bae in ethanol; combining the olution with lactic acid to form a precipitate; and iolating the obtained precipitate. Preferably, the lactic acid i ued at a mol ratio of about 1:1 of itagliptin bae to lactic acid. Hereinafter, i decribed amorphou itagliptin orotate. The amorphou itagliptin orotate i characterized by the RD diffractogram hown in FIG. 13a-d. The preent invention further encompae 1) a pharma ceutical compoition compriing any one, or combination, of olid tate Form, a decribed above and at leat one phar maceutically acceptable excipient and 2) the ue of any one, or combination, of the above-decribed olid tate Form, in the manufacture of a pharmaceutical compoition. The phar maceutical compoition can be ueful for the treatment of type 2 diabete mellitu. The preent invention alo provide crytalline form a decribed above for ue a a medicament, preferably for the treatment of type 2 diabete mellitu. Having decribed the invention with reference to certain preferred embodiment, other embodiment will become apparent to one killed in the art from conideration of the pecification. The invention i further defined by reference to the following example decribing in detail the preparation of the compoition and method of ue of the invention. It will be apparent to thoe killed in the art that many modification,

17 both to material and method, may be practiced without departing from the cope of the invention. -Ray Power Powder Diffraction Unle recited otherwie, -Ray powder diffraction data wa obtained by uing method known in the art uing a CINTAG powder -Ray diffractometer model TRA equipped with a olid-tate detector. Copper radiation of 1.5418 A wa ued. A round aluminum ample holder with Zero background wa ued. The canning parameter included: range: 2-40 degree two-theta; can mode: continu ou can; tep ize: 0.05 deg.; and a rate of 3 deg/min. 'C NMR pectra: 'C NMR at 125 MHz uing Bruker Avance II+500. B probe uing 4 mm rotor Magic angle wa et uing KBr. Homogeneity of magnetic field checked uing adamantane. Parameter for Cro polar ization optimized uing glycine. pectral reference et according to glycine a external tan dard (176.03 ppm for low field carboxyl ignal). Magic Angle pinning Rate: 11 khz Pule Program: cp with tppm 15 during decoupling Delay time: 5 (except for itagliptin acetate, wherein the delay time wa 10) Contact time: 2 m Number of can: 1024 TGA Thermogram TGA thermogram wa meaured uing METTLER TLED TGA/DC TAR. Heating rate: 10 /minute. N. flow rate: 40 ml/minute EAMPLE Example 1 Rhodium(I) chloride 1,5-cyclooctadiene complex (24.1 mg, 0.2%) and (R)-(-)-1-()-2-diphenylphophino) ferroce nylethyl di-tert-butylphophine (56.8 mg, 0.44%) were added to degaed methanol (20 ml). The reulting olution wa tirred at 25 C. degaed again, and then tirred for one hour at 25 C. Thi catalyt olution wa ued in the hydro genation decribed below. (Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-1,2,4 triazolo 4.3-a-pyrazyn-7(8H)-yl)-4-(2,4,5-trifluorophenyl) but-2-en-1-one (10 gr, 1 equivalent) and methanol (50 ml) were added to a 250 ml hydrogenation bottle at 25 C. and the bottle wa ubjected to vacuum and nitrogen backfluh three time. The catalyt olution wa added to the hydrogenation bottle and the bottle wa again ubjected to vacuum and nitrogen backfluh three time and then to vacuum and back fluh with hydrogen ga three time. The reulting reaction mixture wa maintained under hydrogenata preure of 5 bar and heated to 55 C. The heated mixture wa tirred at 5 bar preure, at 55 C. for 3 day to obtain itagliptin bae in methanol olution (optical purity by HPLC 97%, purity by HPLC 63.7%). Example 2 itagliptin (TG) ulfate Crytalline Form 1 Anhalfamount of the olution obtained in Example 1, wa evaporated and diolved in iopropanol (25 ml). A olution of ulfuric acid (0.6 gr in 25 ml of iopropanol) wa added over 40 minute and the reulting mixture wa tirred at 25 C. for 16 hour. The product wa eparated by vacuum filtration, and the filtered product wa wahed with iopropanol (10 ml) U 8,329,696 B2 5 10 15 25 30 35 40 45 50 55 60 65 18 and dried in vacuum oven at 40 C. for 16 hour to obtain 2.9 gr of itagliptin ulfate crytalline form 1. Example 3 TG Dibenzoyl-D-Tartarate Crytalline Form D1 TG (itagliptin) bae (350 mg) wa diolved in acetoni trile (2 ml) at 25 C. (+)-Dibenzoyl-D-tartaric acid (98%, 323 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C. The mixture became a very thick lurry, therefore additional acetonitrile (1.5 ml) wa added. The reulting mixture wa tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. overnight. The prod uct wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG dibenzoyl-d-tartarate crytalline form D1. Example 4 TG Dibenzoyl-D-Tartarate Crytalline Form D1 TG bae (350mg) wa diolved in ethyl acetate (4.5 ml) at 25 C. (+)-Dibenzoyl-D-tartaric acid (98%, 323 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C. The mixture became a very thick lurry, therefore additional ethyl acetate (1.5 ml) wa added. The reulting mixture wa tirred at 50 C. for 2 hour, cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG dibenzoyl-d-tartarate crytalline form D1. Example 5 TG Dibenzoyl-D-Tartarate Crytalline Form D2 TG bae (350mg) wa partially diolved in ethanol (3.5 ml) at 25 C. (+)-Dibenzoyl-D-tartaric acid (98%, 323 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG dibenzoyl-d-tartarate crytalline form D2. Example 6 Mixture of TG Dibenzoyl-D-Tartarate Crytalline Form D1 and D2 TG bae (350mg) wa diolved in iopropanol (3.5 ml) at 25 C. (+)-Di-benzoyl-D-tartaric acid (98%, 323 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain a mixture of itagliptin dibenzoyl-d-tartarate crytalline form D1 and D2. Example 7 TG Fumarate Crytalline Form F1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. Fumaric acid (100 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and

19 dried at 40 C. for 16 hour to obtain a mixture of itagliptin fumarate crytalline form F1 and fumaric acid. Example 8 TG Fumarate Crytalline Form F2 TG bae (350mg) wa diolved in ethyl acetate (4.5 ml) at 25 C. Fumaric acid (92 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG fumarate crytal line form F2. Example 9 TG Malate Crytalline Form M1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. D-(+)-malic acid (115 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG D-malate crytalline form M1. Example 10 TG xalate Crytalline Form 1 TG bae (350 mg) wa diolved in ethanol (3.5 ml) at 25 C. xalic acid (108 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG oxalate crytal line form 1. Example 11 TG xalate Crytalline Form 1 TG bae (350mg) wa diolved in iopropanol (3.5 ml) at 25 C. xalic acid (108 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG oxalate crytal line form 1. Example 12 TG Quinate Crytalline Form Q1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. (1R,3R.4R,5R)-(-)-quinic acid (98%, 165 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG quinate crytalline form Q1. Example 13 TG uccinate crytalline form U1 TG bae (350 mg) wa diolved in ethanol (3.5 ml) at 25 C. uccinic acid (101 mg, 1 eq) wa then added and the U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 20 reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG uccinate cry talline form U1, a hown in FIG. 7a. Example 14 TGuccinate Crytalline Form U1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. uccinic acid (99%, 101 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to produce TG uccinate crytalline form U1, a hown in FIG.7b. Example 15 TGuccinate Crytalline Form U1 TG bae (350mg) wa diolved in ethyl acetate (4.5 ml) at 25 C. uccinic acid (99%, 101 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG uccinate crytalline form U1, a hown in FIG. 7c. Example 16 TG xalate Crytalline Form 1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. xalic acid (108 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG oxalate crytalline form 1. Example 17 TG xalate Form 2 TG bae (350mg) wa diolved in ethyl acetate (4.5 ml) at 25 C. xalic acid (108 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG oxalate form 2. Example 18 TG ulfate Crytalline Form 2 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. ulfuric acid (95.6%, 24 ml, 0.5eq) wa then added and the mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. over weekend. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG ulfate cry talline form 2. Example 19 TG bae (350mg) wa diolved in ethyl acetate (4.5 ml) at 25 C. ulfuric acid (95.6%, 24 ul, 0.5 eq) wa then added

21 and the mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. over weekend. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG ulfate cry talline form 3. Example 20 TG bae (350 mg) wa partially diolved in ethanol (3.5 ml) at 25 C. ulfuric acid (95.6%. 24 ul, 0.5 eq) wa then added and the mixture wa heated to 50 C., diolved while heating, then tirred at 50 C. for 2 hour, cooled gradually to 25 C. and tirred at 25 C. over weekend. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG ulfate crytalline form 4. Example 21 TG Fumarate Crytalline Form F1 TG bae (350mg) wa lurry in ethanol (3.5 ml) at 25 C. Fumaric acid (99.5 mg 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The olution wa clear; therefore, it wa maintained at 4 C. for over a weekend. Then n-heptane (6 ml) wa added, and the reulting mixture wa tirred for 16 hour at 25 C. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG quinate crytalline form F1. Example 22 TG Fumarate Mixture of Form F2 and F1 TG bae (350 mg) wa partially diolved in iopropanol (3.5 ml) at 25 C. Fumaric acid (100 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The olution wa clear; therefore it wa maintained at 4 C. over a weekend. Then n-heptane (6 ml) wa added, and the reulting mixture wa tirred for 16 hour at 25 C. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain itagliptin fumarate polymorphic mix ture of form F2 and F1, a hown in FIG. 3d. Example 23 TG Quinate Crytalline Form Q1 TG bae (350mg) wa lurried in iopropanol (3.5 ml) at 25 C. (1R,3R.4R,5R)-(-)-Quinic acid (98%, 166 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG quinate crytalline form Q1. Example 28 TG Malate Crytalline Form M2 TG bae (350 mg) wa diolved in ethanol (3.5 ml) at 25 C. D-(+)-malic acid (115 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 22 for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG D-malate crytalline form M2. Example 29 TG Acetate Crytalline Form E1 TG bae (350mg) wa partially diolved in ethyl acetate (3.5 ml) at 25 C. Acetic acid (50 ul. 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG acetate crytalline form E1. Example 30 TG Mandelate Crytalline Form N1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. -(+)-mandelic acid (130 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2.75 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG mandelate crytalline form N1. Example 31 TG Mandelate Crytalline Form N2 TG bae (350mg) wa partially diolved in ethyl acetate (3.5 ml) at 25 C. -(+)-mandelic acid (134 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C. tirred at 50 C. for 2.75 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG-mandelate crytalline form N2. Example 32 TG-Mandelate Crytalline Form N3 TG bae (350 mg) wa diolved in ethanol (2.5 ml) at 25 C. -(+)-mandelic acid (130 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2.75 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG -mandelate crytalline form N3. Example 33 TG-Mandelate Crytalline Form N4 TG bae (350 mg) wa diolved in acetone (1.5 ml) at 25 C. -(+)-mandelic acid (134 mg, 1 eq) wa then added and the reulting mixture wa heated to 40 C., tirred at 40 C. for 2.75 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG -mandelate crytalline form N4. Example 34 Amorphou TG Mandelate TG bae (350 mg) wa lurried in methyl tert-butyl ether (3.5 ml) at 25 C. -(+)-mandelic acid (132 mg, 1 eq) wa

23 then added and the reulting mixture wa heated to 40 C., tirred at 40 C. for 2.75 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain amorphou TG mandelate. Example 35 TG Lactate Crytalline Form L1 TG bae (350mg) wa diolved in acetonitrile (2 ml) at 25 C. DL-lactic acid (110 ml, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2.5 hour, then cooled gradually to 25 C. and tirred 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG lactate crytalline form L1. Example 36 TG Lactate Crytalline Form L2 TG bae (350 mg) wa diolved in acetone (1.5 ml) at 25 C. DL-Lactic acid (110 ml, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2.5 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The mixture formed wa clear, therefore wa put in a refrigerator at 4 C. for 16 hour. The mixture wa till clear, therefore n-heptane (5 ml) wa added and the reulting mixture wa tirred at 25 C. for 5 day. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG lactate crytalline form L2, a hown in FIG. 12b. Example 37 TG Lactate Crytalline Form L2 TG bae (350mg) wa partially diolved in ethyl acetate (3.5 ml) at 25 C. DL-lactic acid (110 ml, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2.5 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG lactate crytalline form L2, a hown in FIG. 12c. Example 38 TG Lactate Crytalline Form L3 TG bae (350 mg) wa lurried in methyl tert-butyl ether (3.5 ml) at 25 C. DL-lactic acid (110 ml, 1 eq) wa then added and the reulting mixture wa heated to 40 C., tirred at 40 C. for 2.5 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG lactate crytalline form L3. The material wa reteted by PRD after 1 month torage and found to tranform to form L1. Example 39 TG Lactate Crytalline Form L4 TG bae (350 mg) wa diolved in ethanol abolute (2.5 ml) at 25 C. DL-Lactic acid (110 ml, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 24 C. for 2.5 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The mixture formed wa clear, therefore wa put in a refrigerator at 4 C. for 16 hour. The product wa then iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG lactate crytalline form L4. Example 40 TG Maleate Crytalline Form A1 TG bae (350 mg) wa partially diolved in ethanol abolute (3.5 ml) at 25 C. Maleic acid (102 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C. tirred at 50 C. for 2 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The mixture formed wa clear, and therefore wa put in a refrigerator at 4 C. for a week. The mixture formed wa till clear, therefore n-heptane (3 ml) wa added. The product wa iolated by vacuum filtra tion and dried at 40 C. for 16 hour to obtain TG maleate crytalline form A1. Example 41 TG-Mandelate Crytalline Form N3 TG bae (350mg) wa diolved intetrahydrofuran: water 1:1 (1 ml) at 25 C. -(+)-mandelic acid (134 mg, 1 eq) wa then added and the reulting mixture wa heated to 50 C. tirred at 50 C. for 2.5 hour, then cooled gradually to 25 C. and tirred at 25 C. for 16 hour. The mixture formed wa clear, therefore wa put in a refrigerator at 4 C. for 16 hour. The mixture wa till clear, therefore n-heptane (5 ml), wa added and the reulting mixture wa tirred at 25 C. for 5 day. The product wa then iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG -mandelate crytalline form N3. Example 42 TG ulfate Crytalline Form 5 TG bae (1.07 g) wa diolved in ethyl acetate (13 ml) at 25 C., and wa heated to 40 C. to diolve. The olution wa then cooled to 25 C. ulfuric acid (95.6%, 0.133 ml, 0.5eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 2.5 hour, then cooled gradually to 25 C. and tirred at 25 C. for 19 hour. The product wa iolated by vacuum filtration and dried at 40 C. for 16 hour to obtain TG ulfate crytalline form 5 (0.92g, 69% yield). Example 43 TG ulfate Crytalline Form 5 TG bae (4 g) wa diolved in acetonitrile (24 ml) at 25 C. ulfuric acid (95.6%, 0.54 ml, 1 eq) wa then added and the reulting mixture wa heated to 50 C., tirred at 50 C. for 1.5 hour, then cooled gradually to 25 C. and tirred at 25 C. over night. The product wa iolated by vacuum filtration and dried at 40 C. over night to obtain 3.61 gr TG ulfate crytalline form 5. Example 44 TG ulfate Form 6 TG bae (5 g) wa diolved in ethyl acetate (65 ml) at 25 C., heated to 40 C. to diolution, and then cooled to 25

25 C. ulfuric acid (95.6%, 0.34 ml, 0.5eq) wa then added and the reulting mixture heated to 50 C., tirred at 50 C. for 3 hour, and then cooled gradually to 25 C. and tirred at 25 C. for 1.5 hour. The product wa iolated by vacuum filtra tion and dried at 40 C. over night to obtain TG ulfate form 6 (5.23g, 85% yield). Example 45 TG (L)-Malate Crytalline Form I1 TG bae (5 g) wa diolved in acetonitrile (28.5 ml) at 25 C. (L)-Malic acid (1.65 g, 1 eq) wa then added and the reulting mixture wa heated to 50 C. After tirring at 50 C. for 3 hour it wa cooled gradually to 25 C. and tirred overnight. The mixture formed wa very vicou. It wa cooled in an ice bath for 1 hour and then heated back to 25 C. n-heptane (7 ml) wa added and the reulting mixture wa tirred at 25 C. for 2 hour. The product wa iolated by vacuum filtration and dried at 40 C. over night to obtain TG (L)-malate crytalline form I1 (3.01 gr). Example 46 TG R-(-)-Mandelate Crytalline Form N5 TG bae (5 g) wa diolved in acetonitrile (28.5 ml) at 25 C. (R)-Mandelic acid (1.87 g, 1 eq) wa then added and the reulting mixture wa heated to 50 C. and tirred for 3 hour, then cooled gradually to 25 C. and tirred overnight. The product wa iolated by vacuum filtration and dried at 40 C. overnight to obtain itagliptin R-(-)-mandelate crytalline form N5 (6.50 gr, 95% yield) Example 47 TG R-(-)-Mandelate Crytalline Form N6 TG bae (5 g) wa diolved in ethyl acetate (50 ml) at 25 C. and heated to 40 C. to diolve, then cooled back to room temperature. (R)-Mandelic acid (1.87 g, 1 eq) wa then added and the reulting mixture wa heated to 50 C. and tirred for 3 hour, then cooled gradually to 25 C. and tirred overnight. The product wa iolated by vacuum filtration and dried at 40 C. overnight to obtain itagliptin R-(-)-mande late crytalline form N6 (6.62 gr, 97% yield) Example 48 TG R-(-)-Mandelate Crytalline Form N5 TG bae (5g) wa diolved in abolute ethanol (35 ml) at 25 C. and heated to 40 C. to diolve, then cooled to RT. (R)-Mandelic acid (1.87 g, 1 eq) wa then added and the abolute mixture wa heated to 50 C. and tirred for 2.5 hour, then cooled gradually to 25 C. and tirred overnight. The product wa iolated by vacuum filtration and dried at 40 C. for 70 hour to obtain itagliptin R-(-)-mandelate crytal line form N5 (6 gr, 88% yield). Example 49 TG R-(-)-Mandelate Crytalline Form N5 TG bae (5 g) wa diolved in acetone (21.5 ml) at 25 C. (R)-Mandelic acid (1.87 g, 1 eq) wa then added and the reulting mixture wa heated to 40 C. and tirred for 2.5 U 8,329,696 B2 10 15 25 30 35 40 45 50 55 60 65 26 hour, then cooled gradually to 25 C. and tirred overnight. The product wa iolated by vacuum filtration and dried at 40 C. for 70 hour to obtain itagliptin R-(-)-mandelate crytal line form N5 (4.69 g, 69% yield). Example 50 Amorphou TG rotate TG bae (0.5 g) wa diolved inacetonitrile (6.25 ml) at 25 C. rotic acid (0.19 g, 1 eq) wa then added and the reulting mixture wa heated to 75 C., and tirred for 45 minute, then cooled gradually to 25 C. and tirred over night. The product wa iolated by vacuum filtration to obtain amorphou itagliptin orotate a depicted in FIG.13a. It wa then dried at 40 C. over night to obtain amorphou TG orotate, the powder -ray diffractogram of which i depicted in FIG. 13b (0.44 g. 64% yield). Example 51 Amorphou TG rotate TG bae (5 g) wa diolved in acetonitrile (60 ml) at 25 C. rotic acid (1.9 g, 1 eq) wa then added and the reulting mixture wa heated to 75 C., and tirred for 45 minute, then cooled gradually to 25 C. and tirred over night. The product wa iolated by vacuum filtration to obtain amorphou ita gliptin orotate (powder RD i depicted in FIG. 13c. It wa then dried at 40 C. over night to obtain amorphou TG orotate (6.85g. 99% yield). (powder RD i depicted in FIG. 13d) Example 52 iltagliptin ulfate Form 7 TG bae (5 gr) wa added into iopropanol (85 ml). The obtained mixture wa heated to diolution. The olution wa cooled to room temperature and ulfuric acid 96.5% (0.6 gr. 0.5 eq) wa added, then the lurry wa tirred for 4 hour. The product wa iolated by vacuum filtration; the cake wa wahed with hexane (10 ml), and dried at 40 C. in vacuum oven overnight to obtain Form 7 a hown in FIG. 1g, 5.76 gr (93% yield). The TGA termogram i hown in FIG. 1r. Example 53 iltagliptin ulfate Form 7 To TG bae (5 gr), iopropanol (70 ml) wa added, heated to diolution, and cooled to room temperature. ulfuric acid 96.5% (0.6 gr, 0.5 eq) wa added and the olution became lurry and wa tirred over night. The product wa iolated by vacuum filtration; the cake wa wahed with iopropanol (20 ml), and dried at 40 C. in vacuum oven over night to obtain Form 7 a hown in FIG. 1 h; 5.51 gr. The TGA termogram i hown in FIG. 1. Example 54 iltagliptin ulfate Form 8 A ample of form 2 wa heated by DC to 180 C. to obtain form 8 of itagliptin ulfate. -ray diffractogram of itagliptin ulfate form 8 i preented in FIG. 1 k. DC thermogram of the heating proce i preented in FIG. 11.

27 DC analyi wa performed on Q 1000 MDCTA intru ment with heating rate of 10 C./min, under nitrogen flow of 50 ml/min. Hermetic aluminum, cloed pan wa ued, ample ma wa about 8-10 mg. Intrument Type: DC-TA Q1000 ample after being heated in hermetic crucible under experimental condition decribed in DC experiment are applied directly on ilicon plate holder and mixed with mall amount of ipowder. The -ray powder diffraction pattern wa meaured with Philip Pert PR-ray powder diffrac tometer, equipped with Cu irradiation ource=1.54060 A (Angtröm), 'Celerator (2.022 2theta) detector. canning parameter: angle range: 3-40 deg., tep ize 0.0167, time per tep 39, continuou can. The accuracy of peak poition wa defined a +0.2 degree due to experimental difference like intrumentation and ample preparation. Example 55 iltagliptin Acetate Form E1 To TG bae (5 gr), ethyl acetate (35 ml) wa added, heated to diolution and cooled to room temperature. Then Acetic acid (0.703 ml, 1 eq) wa added and the reaction mixture wa heated to 50 C. After 0.5 hour at 50 C., precipitation were oberved and the mixture wa tirred for 2 hour. Then the reaction mixture wa cooled to room temperature and tirred for 1 hour. The product wa iolated by vacuum filtration, the cake wa wahed with ethyl acetate, and dried at 40 C. in vacuum oven over night to obtain Form E1; 4.19 gr (73% yield). Example 56 Tranformation of Form 7 to Form 1 About 150 mg of itagliptin ulfate form 7 were put in an open Petrii dih and kept at 100+5% RH (relative humidity) and room temperature for 12 day. It wa then analyzed by powder RD. The reulted form 1 i preented in FIG. 19. For RD meaurement ample are mixed with mall amount of i powder and applied directly on ilicon plate holder. The -ray powder diffraction pattern wa meaured with Philip Pert PR -ray powder diffractometer, equipped with Cuirradiation ource=1.54060a (Angtröm), Celerator (2.022 2) detector. canning parameter: angle range: 3-40 deg., tep ize 0.0167, time per tep 39, continuou can. What i claimed i: 1. A crytalline form of itagliptin ulfate, deignated Form 2, characterized by data elected from: a powder -ray diffraction pattern with peak at 9.3, 9.7, 15.2, 15.6 and 25.4 +0.220; a powder -ray diffraction patterna hown in FIG. 1b; a olid-tate 'C NMR pectrum with ignal at U 8,329,696 B2 5 10 15 25 30 35 40 45 50 28 119.2, 150.3 and 170.6+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ig nal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 180 ppm of 13.7, 44.8 and 65.1+0.1 ppm; a 'C NMR pectrum a depicted in FIG.1m and FIG. 1n; and combination thereof. 2. A pharmaceutical compoition compriing a crytalline form of claim 1, and at leat one pharmaceutically acceptable excipient. 3. A crytalline form of itagliptin ulfate iopropanol olvate, deignated Form 7, characterized by data elected from: a powder -ray diffraction pattern with peak at 5.2, 15.6, 16.6, 18.7 and 21.1+0.2 20; a powder -ray dif fraction pattern a hown in FIG. 1g; a olid-tate 'C NMR pectrum with ignal at 120.4, 149.1 and 171.2-0.2 ppm, a olid-tate 'C NMR pectrum having chemical hift differ ence between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 180 ppm of 15.1, 43.8 and 65.9+0.1 ppm; and a 'C NMR pectrum a depicted in FIG. 1i and FIG. 1j; and combination thereof. 4. A pharmaceutical compoition compriing a crytalline form of claim3, and at leat one pharmaceutically acceptable excipient. 5. A crytalline form of itagliptin ulfate, deignated Form 6, characterized by a powder -ray diffraction pattern a hown in FIG. 1f. 6. A pharmaceutical compoition compriing a crytalline form of claim 5, and at leat one pharmaceutically acceptable excipient. 7. A crytalline form of itagliptin ulfate iopropanol olvate characterized by data elected from: a powder -ray diffraction pattern with peak at 5.2, 15.6, 16.6, 17.0, 17.1, 18.7 and 21.1+0.2 20; a powder -ray diffraction pattern a hown in FIG. 1g; a olid-tate CNMR pectrum with ignal at 120.4, 149.1 and 171.2+0.2 ppm; a olid-tate 'C NMR pectrum having chemical hift difference between the ignal exhibiting the lowet chemical hift and another in the chemical hift range of 100 to 180 ppm of 15.1, 43.8 and 65.9+0.1 ppm; and a CNMR pectrum a depicted in FIG. 1i and FIG. 1j; and combination thereof. 8. A pharmaceutical compoition compriing the crytal line form of claim 7, and at leat one pharmaceutically accept able excipient. 9. A crytalline form of itagliptin ulfate deignated Form 1, characterized by data elected from: a powder -ray diffraction pattern with peak at 11.8, 13.7, 14.4, 17.0 and 17.5 +0.220; a powder -ray diffraction patterna hown in FIG. 1a; and combination thereof. 10. A pharmaceutical compoition compriing a crytalline form of claim 9, and at leat one pharmaceutically acceptable excipient.