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SOLID STATE FORMS OF SITAGLIPTIN SALTS

IP.com Disclosure Number: IPCOM000236642D
Publication Date: 2014-May-07

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SOLID STATE FORMS OF SITAGLIPTIN SALTS

The present document relates to hydrochloric acid, hydrobromic acid, hemifumaric acid, L-

tartaric acid, benzoic acid and L-mandelic acid salts of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-

dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine, known as

Sitagliptin: N

    F F

F

NH2 O

N

F F F

N N

Sitagliptin base

These salts of Sitagliptin are useful for the preparation of pharmaceutical compositions and for

the treatment and prevention of diseases and conditions for which an inhibitor of dipeptidyl

peptidase-IV is indicated, in particular Type 2 diabetes, obesity, and high blood pressure.

In the document is also disclosed the preparation of crystalline Sitagliptin base.

Example 1 Preparation of Sitagliptin base

A suspension of Sitagliptin base in isopropanol (402.75 g of a 14.9% solution, equivalent to


60.01 g of Sitagliptin base, 147.3 mmols) was filtered on a Buchner funnel under vacuum. The

product was dried at 45 ºC under vacuum for 16 hours and then at 70 ºC under vacuum for 16

hours. Yield 43.38 g (72%). The product was analysed by Karl Fischer (0.07%) and by powder

X-ray diffraction, see Figure 1 and Table 1 below.

3500

3000

2500

2000

ts

n

u

o

c

1500

1000

500

0

0

5

10

15

20

25

30

35

40

45

50

2-theta (º)

Figure 1: X-ray powder diffractogram for Sitagliptin base


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 Height
[counts] Rel. Int. [%]

1 7.27 12.15 1452 41.1 2 11.44 7.73 294 8.3 3 14.52 6.10 42 1.2 4 14.98 5.91 59 1.7 5 16.67 5.31 1025 29.0 6 17.59 5.04 3530 100.0 7 18.81 4.71 472 13.4 8 21.20 4.19 652 18.5 9 21.41 4.15 1141 32.3 10 22.62 3.93 99 2.8 11 23.20 3.83 113 3.2 12 24.00 3.71 363 10.3 13 24.36 3.65 374 10.6 14 24.60 3.62 427 12.1 15 26.60 3.35 225 6.4 16 26.94 3.31 344 9.7 17 28.36 3.14 327 9.3 18 28.66 3.11 407 11.5 19 30.01 2.98 267 7.6 20 30.97 2.89 353 10.0 21 33.06 2.71 162 4.6 22 33.70 2.66 176 5.0 23 39.29 2.29 257 7.3

Table 1: X-Ray powder diffraction peak listing for Sitagliptin base

Example 2 Preparation of Sitagliptin Hydrochloride

A solution of hydrochloric acid (22 mL, 6M in isopropanol, 132 mmols) in isopropanol (150 mL)

was added to a suspension of Sitagliptin base in isopropanol (346.29 g of a 14.9% solution,

equivalent to 51.59 g of Sitagliptin base, 126.7 mmols) in a 1 L reactor equipped with overhead

stirrer. The mixture was heated to 50 ºC and then cooled to ambient temperature over 2 hours

and stirred for an additional 4 hours at ambient temperature. The product was filtered on a

Buchner funnel under vacuum and washed with isopropanol (50 mL). The product was dried at

45 ºC under vacuum for 16 hours and was passed through a sieve of 0.5 mm pore size. The

product was further dried under vacuum at 70 ºC for 16 hours, then at 80 ºC for 16 hours, then

at 90 ºC for 16 hours, then at 100 ºC under vacuum for 16 hours and finally at 120 ºC under

vacuum for 16 hours. Yield 54.02 g (96%). The product was analysed by Karl Fischer (4.1%)

and powder X-ray diffracti...