(i9) United States
`(12) Patent Application Publication
`(io) Pub. No.: US 2006/0074046 Al
`(43) Pub. Date:
`Apr. 6, 2006
`Redkar et al.
`
`US 20060074046A1
`
`(54) ORAL ADMINISTRATION OF DECITABINE
`SALT
`
`(76)
`
`Inventors: Sanjeev Redkar, Hayward, CA (US);
`Pasit Phiasivongsa, Brentwood, CA
`(US)
`
`Correspondence Address:
`WILSON SONSINI GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304-1050 (US)
`
`(21) Appl. No.:
`
`11/238,168
`
`(22) Filed:
`
`Sep. 27, 2005
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 10/952,252,
`filed on Sep. 27, 2004.
`
`Publication Classification
`
`514/49; 536/28.3
`
`(2006.01)
`(2006.01)
`
`(51) Int. CI.
`A61K 31/7072
`C07H 19/12
`(52) U.S. CI
`ABSTRACT
`(57)
`The present invention relates to salts of decitabine as well as
`methods for synthesizing the salts described herein. Phar(cid:173)
`maceutical compositions and methods of using the decitab(cid:173)
`ine salts are also provided, including methods of orally
`administering the salts or pharmaceutical compositions
`thereof to treat conditions, such as cancer and hematological
`disorders.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0001
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 1 of 68
`
`US 2006/0074046 Al
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0002
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 2 of 68
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0003
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 3 of 68
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0004
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 4 of 68
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0005
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 5 of 68
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0006
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 6 of 68
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0007
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 7 of 68
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0008
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 8 of 68
`
`US 2006/0074046 Al
`
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`
`Temperature fC)
`
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`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0009
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 9 of 68
`
`US 2006/0074046 Al
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`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0010
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 10 of 68
`
`US 2006/0074046 Al
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0011
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 11 of 68
`
`US 2006/0074046 Al
`
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`
`too :
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`Temperature (*C)
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`Figure 11
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0012
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 12 of 68
`
`US 2006/0074046 Al
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`
`Figure 12
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0013
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 13 of 68
`
`US 2006/0074046 Al
`
`63,76*C
`14.301%
`
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`
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`
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`Universs! VZ.GO TA (.-amjmwts
`
`Figure 13
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0014
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 14 of 68
`
`US 2006/0074046 Al
`
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`
`155.0%
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`
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`
`Figure 14
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0015
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 15 of 68
`
`US 2006/0074046 Al
`
`&»Up
`
`Temperature f C)
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`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0016
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 16 of 68
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0017
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 17 of 68
`
`US 2006/0074046 Al
`
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`
`Temperature {"C)
`
`Unhrersd V2.6D TA harumefis
`
`Figure 17
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0018
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 18 of 68
`
`US 2006/0074046 Al
`
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`
`Figure 18
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0019
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 19 of 68
`
`US 2006/0074046 Al
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`
`Figure 19
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0020
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 20 of 68
`
`US 2006/0074046 Al
`
`1.146%
`(0.0246»mg)
`
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`Figure 20
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0021
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 21 of 68
`
`US 2006/0074046 Al
`
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0022
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 22 of 68
`
`US 2006/0074046 Al
`
`Temperature fC)
`
`Urtweaal \t2m m bwruraewa
`
`Figure 22
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0023
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 23 of 68
`
`US 2006/0074046 Al
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`100
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`Figure 23
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0024
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 24 of 68
`
`US 2006/0074046 Al
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`Figure 24
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0025
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 25 of 68
`
`US 2006/0074046 Al
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`120
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`Ternperatiire (°C)
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`
`Figure 25
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0026
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 26 of 68
`
`US 2006/0074046 Al
`
`300
`
`TemperatufsfC)
`
`Figure 26
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0027
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 27 of 68
`
`US 2006/0074046 Al
`
`100
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`250
`
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`
`Figure 27
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0028
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 28 of 68
`
`US 2006/0074046 Al
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`100
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`
`Figure 28
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0029
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 29 of 68
`
`US 2006/0074046 Al
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`100
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`Figure 29
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0030
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 30 of 68
`
`US 2006/0074046 Al
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`Figure 30
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0031
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 31 of 68
`
`US 2006/0074046 Al
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`1®
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`200
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`
`Figure 31
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0032
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 32 of 68
`
`US 2006/0074046 Al
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`100
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`Figure 32
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0033
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 33 of 68
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`US 2006/0074046 Al
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`Figure 33
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0034
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 34 of 68
`
`US 2006/0074046 Al
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`100
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`Figure 34
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0035
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 35 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0036
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 36 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0037
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 37 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0038
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 38 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0039
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 39 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0040
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 40 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0041
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`Patent Application Publication Apr. 6, 2006 Sheet 41 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0042
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 42 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0043
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`Patent Application Publication Apr. 6, 2006 Sheet 43 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0044
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 44 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0045
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 45 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0046
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`Patent Application Publication Apr. 6, 2006 Sheet 46 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0047
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`Patent Application Publication Apr. 6, 2006 Sheet 47 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0048
`
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`Patent Application Publication Apr. 6, 2006 Sheet 48 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0049
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 49 of 68
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`Petitioner Apotex Exhibit 1019-0050
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`Patent Application Publication Apr. 6, 2006 Sheet 50 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0051
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0052
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`Patent Application Publication Apr. 6, 2006 Sheet 52 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0053
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 53 of 68
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`Figure 53
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0054
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0055
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 55 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0056
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 56 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0057
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 57 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0058
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`

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`Patent Application Publication Apr. 6, 2006 Sheet 58 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0059
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 59 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0060
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 60 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0061
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 61 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0062
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 62 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0063
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 63 of 68
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0064
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 64 of 68
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0065
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 65 of 68
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0066
`
`

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`Patent Application Publication Apr. 6, 2006 Sheet 66 of 68
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0067
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 67 of 68
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0068
`
`

`

`Patent Application Publication Apr. 6, 2006 Sheet 68 of 68
`
`US 2006/0074046 Al
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0069
`
`

`

`US 2006/0074046 Al
`
`Apr. 6, 2006
`
`ORAL ADMINISTRATION OF DECITABINE SALT
`
`CROSS-REFERENCE
`[0001] This application is a continuation-in-part applica(cid:173)
`tion of Sen No. 10/952,252, filed Sep. 27, 2004, which is
`incorporated herein by reference in its entirety and to which
`application we claim priority under 35 USC § 120.
`
`STATEMENT AS TO FEDERALLY SPONSORED
`RESEARCH
`[0002] This invention was made with the support of the
`United States government by the National Institutes of
`Health.
`
`BACKGROUND OF THE INVENTION
`
`[0003] A few azacytosine nucleosides, such as 5-aza-2'-
`deoxycytidine (also called decitabine) and 5-azacytidine
`(also called azacitidine), have been developed as antagonist
`of its related natural nucleoside, 2'-deoxycytidine and cyti-
`dine, respectively. The only structural difference between
`azacytosine and cytosine is the presence of a nitrogen at
`position 5 of the cytosine ring in azacytosine as compared to
`a carbon at this position for cytosine.
`
`[0004] Two isomeric forms of decitabine can be distin(cid:173)
`guished. The P-anomer is the active form. The modes of
`decomposition of decitabine in aqueous solution are (a)
`conversion of the active P-anomer to the inactive a-anomer
`(Pompon et al. (1987) J. Chromat. 388:113-122); (b) ring
`cleavage of the aza-pyrimidine ring to form N-(formylami-
`dino)-N'-P-D-2'-deoxy-(ribofuranosy)-urea
`(Mojaverian
`and Repta (1984) J. Pharm. Pharmacol. 36:728-733); and (c)
`subsequent formation of guanidine compounds (Kissinger
`and Stemm (1986) J. Chromat. 353:309-318).
`
`[0005] Decitabine possesses multiple pharmacological
`characteristics. At a molecular level, it is S-phase dependent
`for incorporation into DNA. At a cellular level, decitabine
`can induce cell differentiation and exert hematological tox(cid:173)
`icity. Despite having a short half-life in vivo, decitabine has
`an excellent tissue distribution.
`
`[0006] One of the functions of decitabine is its ability to
`specifically and potently inhibit DNA methylation. Methy-
`lation of cytosine to 5-methylcytosine occurs at the level of
`DNA. Inside the cell, decitabine is first converted into its
`active form, the phosphorylated 5-aza-deoxycytidine, by
`deoxycytidine kinase which is primarily synthesized during
`the S phase of the cell cycle. The affinity of decitabine for
`the catalytical site of deoxycytidine kinase is similar to the
`natural substrate, deoxycytidine. Momparler et al. (1985)
`30:287-299. After conversion to its triphosphate form by
`deoxycytidine kinase, decitabine is incorporated into repli(cid:173)
`cating DNA at a rate similar to that of the natural substrate,
`dCTP Bouchard and Momparler (1983) Mol. Pharmacol.
`24:109-114.
`
`[0007]
`Incorporation of decitabine into the DNA strand
`has a, hypomethylation effect. Each class of differentiated
`cells has its own distinct methylation pattern. After chro(cid:173)
`mosomal duplication, in order to conserve this pattern of
`methylation, the 5-methylcytosine on the parental strand
`serves to direct methylation on the complementary daughter
`DNA strand. Substituting the carbon at the 5 position of the
`cytosine for a nitrogen interferes with this normal process of
`
`DNA methylation. The replacement of 5-methylcytosine
`with decitabine at a specific site of methylation produces an
`irreversible inactivation of DNA methyltransferase, presum(cid:173)
`ably due to formation of a covalent bond between the
`enzyme and decitabine. Juttermann et al. (1994) Proc. Natl.
`Acad. Sci. USA 91:11797-11801. By specifically inhibiting
`DNA methyltransferase, the enzyme required for methyla(cid:173)
`tion, the aberrant methylation of the tumor suppressor genes
`could be prevented.
`
`[0008] Decitabine is commonly supplied as a sterile lyo-
`philized powder for injection, together with buffering salt,
`such as potassium dihydrogen phosphate, and pH modifier,
`such as sodium hydroxide. For example, decitabine is sup(cid:173)
`plied by SuperGen, Inc., as lyophilized powder packed in 20
`mL glass vials, containing 50 mg of decitabine, monobasic
`potassium dihydrogen phosphate, and sodium hydroxide.
`When reconstituted with 10 mL of sterile water for injection,
`each mL contain 5 mg of decitabine, 6.8mgof KH2P04, and
`approximately 1.1 mg NaOH. The pH of the resulting
`solution is 6.5-7.5. The reconstituted solution can be further
`diluted to a concentration of 1.0 or 0.1 mg/mL in cold
`infusion i.e., 0.9% Sodium Chloride; or 5% Dextrose; or 5%
`Glucose; or Lactated Ringer's. The unopened vials are
`typically stored under refrigeration (2-8° C; 36-46° F.), in
`the original package.
`
`[0009] Decitabine is most typically administrated to
`patients by injection, such as by a bolus I.V. injection,
`continuous I.V. infusion, or I.V. infusion. Similar to decit(cid:173)
`abine, azacitidine is also formulated as aqueous solution and
`delivered to patients intravenously. According to clinical
`studies of azacitidine, longer or continuous infusions were
`more effective than shorter ones. Santini et al. (2001) Ann.
`Int. Med. 134: 573-588. However, the length of I.V. iniusion
`is limited by the decomposition of decitabine or azacitidine
`and low solubility of the drugs in aqueous solutions. The
`present invention provides innovative solutions to such
`problems.
`
`SUMMARY OF THE INVENTION
`
`[0010] According to the present invention, a salt of a
`cytidine analog is provided.
`[0011]
`In one embodiment, the cytidine analog is 5-aza-
`2'-deoxycytidine or 5-azacytidine.
`[0012]
`In another embodiment, the salt of the cytidine
`analog is synthesized with an acid, optionally with an acid
`having a pKa of about 5 or less, optionally with an acid
`having pKa of about 4 or less, optionally with an acid having
`pKa ranging from about 3 to about 0, or optionally with an
`acid having pKa ranging from about 3 to about -10.
`[0013] Preferably, the acid is selected from the group
`consisting of hydrochloric, L-lactic, acetic, phosphoric, (+)-
`L-tartaric, citric, propionic, butyric, hexanoic, L-aspartic,
`L-glutamic, succinic, EDTA, maleic, methanesulfonic acid,
`HBr, HF, HI, nitric, nitrous, sulfuric, sulfurous, phospho(cid:173)
`rous, perchloric, chloric, chlorous acid, carboxylic acid,
`sulfonic acid, ascorbic, carbonic, and fumaric acid. In par(cid:173)
`ticular, the sulfonic acid is selected from the group consist(cid:173)
`ing of ethanesulfonic, 2-hydroxyethanesulfonic, and tolu-
`enesulfonic acid.
`
`[0014]
`In yet another embodiment, a salt of decitabine is
`provided. The salt of decitabine preferably is selected from
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1019-0070
`
`

`

`US 2006/0074046 Al
`
`Apr. 6, 2006
`
`the group consisting of hydrochloride, mesylate, EDTA,
`sulfite, L-Aspartate, maleate, phosphate, L-Glutamate, (+)-
`L-Tartrate, citrate, L-Lactate, succinate, acetate, hexanoate,
`butyrate, or propionate salt.
`
`[0015]
`In one variation of the embodiment, the salt of
`decitabine is hydrochloride salt in crystalline form charac(cid:173)
`terized by an X-ray diffraction pattern having diffraction
`peaks (26) at 14.79°, 23.63°, and 29.81°. The salt is further
`characterized by a melting endotherm of 125-155° C,
`optionally 130-144° C, as measured by differential scanning
`calorimetry at a scan rate of 10° C. per minute.
`
`In another variation of the embodiment, the salt of
`[0016]
`decitabine is a mesylate salt in crystalline form characterized
`by an X-ray diffraction pattern having diffraction peaks (29)
`at 8.52°, 22.09°, and 25.93°. The salt is iurther characterized
`by a melting endotherm of 125-140° C, or optionally
`125-134° C, as measured by differential scanning calorim(cid:173)
`etry at a scan rate of 10° C. per minute.
`
`[0017]
`In yet another variation of the embodiment, the salt
`of decitabine is an EDTA salt in crystalline form character(cid:173)
`ized by an X-ray diffraction pattern having diffraction peaks
`(26) at 7.14°, 22.18°, and 24.63°. The salt is iurther char(cid:173)
`acterized by multiple reversible melting endotherms at
`50-90° C, 165-170° C, and 170-200° C, or optionally at
`73° C, 169° C, and 197° C, as measured by differential
`scanning calorimetry at a scan rate of 10° C. per minute
`
`[0018]
`In yet another variation of the embodiment, the salt
`of decitabine is a sulfite salt in crystalline form characterized
`by an X-ray diffraction pattern having diffraction peaks (26)
`at 15.73°, 19.23°, and 22.67°. The salt is iurther character(cid:173)
`ized by a melting endotherm at 100-140° C. as measured by
`differential scanning calorimetry at a scan rate of 10° C. per
`minute.
`
`[0019]
`In yet another variation of the embodiment, the salt
`of decitabine is a L-aspartate salt in crystalline form char(cid:173)
`acterized by an X-ray diffraction pattern having diffraction
`peaks (26) at 21.61°, 22.71°, and 23.24°. The salt is further
`characterized by multiple reversible melting endotherms at
`30-100° C, 170-195° C, and 195-250° C, optionally at 86°
`C, 187° C, and 239° C, as measured by differential
`scanning calorimetry at a scan rate of 10° C. per minute.
`
`[0020]
`In yet another variation of the embodiment, the salt
`of decitabine is a maleate salt in crystalline form character(cid:173)
`ized by an X-ray diffraction pattern having diffraction peaks
`(26) at 20.81°, 27.38°, and 28.23°. The salt is further
`characterized by multiple reversible melting endotherms at
`95-130° C. and 160-180° C, or optionally at 119° C. and
`169° C, as measured by differential scanning calorimetry at
`a scan rate of 10° C. per minute.
`
`[0021]
`In yet another variation of the embodiment, the salt
`of decitabine is a phosphate salt in crystalline form charac(cid:173)
`terized by an X-ray diffraction pattern having diffraction
`peaks (26) at 17.09°, 21.99°, and 23.21°. The salt is further
`characterized by a melting endotherm at 130-145° C. as
`measured by differential scanning calorimetry at a scan rate
`of 10° C. per minute.
`
`[0022]
`In yet another variation of the embodiment, the salt
`of decitabine is a L-glutamate salt in crystalline form
`characterized by an X-ray diffraction pattern having diffrac(cid:173)
`tion peaks (26) at 13.33°, 21.39°, and 30.99°. The salt is
`
`iurther characterized by multiple reversible melting endot(cid:173)
`herms at 50-100° C, 175-195° C, and 195-220° C, or
`optionally at 84° C, 183° C, and 207° C. as measured by
`differential scanning calorimetry at a scan rate of 10° C. per
`minute.
`
`In yet another variation of the embodiment, the salt
`[0023]
`of decitabine is a (+)-L-tartarate salt in crystalline form
`characterized by an X-ray diffraction pattern having diffrac(cid:173)
`tion peaks (26) at 7.12°, 13.30°, and 14.22°. The salt is
`iurther characterized by multiple reversible melting endot(cid:173)
`herms at 60-110° C, and 185-220° C, optionally at 91° C,
`and 203° C, as measured by differential scanning calorim(cid:173)
`etry at a scan rate of 10° C. per minute.
`
`[0024]
`In yet another variation of the embodiment, the salt
`of decitabine is a citrate salt in crystalline form characterized
`by an X-ray diffraction pattern having diffraction peaks (26)
`at 13.31°, 14.23°, and 23.26°. The salt is iurther character(cid:173)
`ized by multiple reversible melting endotherms at 30-100°
`C. and 160-220° C, or optionally at 84° C. and 201° C, as
`measured by differential scanning calorimetry at a scan rate
`of 10° C. per minute.
`
`[0025]
`In yet another variation of the embodiment, the salt
`of decitabine is a L-lactate salt in crystalline form charac(cid:173)
`terized by an X-ray diffraction pattern having diffraction
`peaks (26) at 13.27°, 21.13°, and 23.72°. The salt is further
`characterized by multiple reversible melting endotherms at
`30-100° C. and 160-210° C, or optionally at 84° C. and 198°
`C, as measured by differential scanning calorimetry at a
`scan rate of 10° C. per minute.
`
`In yet another variation of the embodiment, the salt
`[0026]
`of decitabine is a succinate salt in crystalline form charac(cid:173)
`terized by an X-ray diffraction pattern having diffraction
`peaks (26) at 13.30°, 22.59°, and 23.28°. The salt is further
`characterized by multiple reversible melting endotherms at
`50-100° C. and 190-210° C, or optionally at 79° C. and 203°
`C, as measured by differential scanning calorimetry at a
`scan rate of 10° C. per minute.
`
`[0027]
`In yet another variation of the embodiment, the salt
`of decitabine is an acetate salt in crystalline form charac(cid:173)
`terized by an X-ray diffraction pattern having diffraction
`peaks (26) at 7.14°, 14.26°, and 31.25°. The salt is further
`characterized by multiple reversible melting endotherms at
`60-90° C. and 185-210° C, or optionally at 93° C. and 204°
`C, as measured by differential scanning calorimetry at a
`scan rate of 10° C. per minute.
`
`[0028]
`In yet another variation of the embodiment, the salt
`o