US 20100204204A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2010/0204204 A1
Zaworotko et al. (43) Pub. Date: Aug. 12, 2010

(54) NUTRACEUTICAL CO-CRYSTAL Related US. Application Data

COMPOSITIONS
(60) Provisional application No. 60/942,355, ?led on Jun.
(75) Inventors: Michael ZaWorotko, Tampa, FL 6, 2007, provisional application No. 60/982,619, ?led
(US); Heather Clarke, Tampa, FL on Oct. 25, 2007.
(US); Arora Kapildev, Tampa, FL
(US); Padmini Kavuru, Lakeland, Publication Classi?cation
FL (US); Roland Douglas Shytle,
Largo, FL (US); TWarita Puj ari, (51) Int. Cl.
Tampa, FL (US); Lissette A61K 31/55 (2006.01)
Marshall, Tampa, FL (US); Tien A61K 31/522 (2006.01)
Teng Ong, Tampa, FL (US) A61K 31/44 (2006.01)
A61K 31/35 (2006.01)
Correspondence Address: A61K 31/34 (2006.01)
BRYAN CAVE LLP A61K 31/19 (2006.01)
211 NORTH BROADWAY, SUITE 3600
ST. LOUIS, MO 63102-2750 (US) (52) U.S. Cl. ............. .. 514/212.03; 514/263.34; 514/354;
514/453; 514/456; 514/474; 514/568
(73) Assignee: UNIVERSITY OF SOUTH
FLORIDA, Tampa, FL (US)
(57) ABSTRACT
(21) Appl.No.: 12/663,212 Co-crystals comprising at least one nutraceutical compound
(22) PCT Filed: Jun. 6, 2008 and at least one co-crystal former With or Without impurities.
These co-crystals may be included in compositions (option
(86) PCT No.: PCT/US08/07129 ally also including other components such as pharmaceuti
cally acceptable excipients, other nutritional supplements,
§ 371 (0X1), etc.) having utility as pharmaceuticals, nutraceuticals, nutri
(2), (4) Date: Apr. 15, 2010 tional supplements, and foodstuffs.
Patent Application Publication Aug. 12, 2010 Sheet 1 0f 64 US 2010/0204204 A1

FIG. 1
Patent Application Publication Aug. 12, 2010 Sheet 2 0f 64 US 2010/0204204 Al

on

-u.s ~

143.58":

131
i
E -1 n -
LL
-o-I
(U
UJ
I

.1 ,5 — . 246.3413

‘2'0 l j I l I
0 50 m0 150 200 250 2:00
Temperatuna (°C)
Patent Application Publication Aug. 12, 2010 Sheet 3 0f 64 US 2010/0204204 A1

FIG. 3

2|] 000 U 26.5

18 D00 0

16 D00 0

14000 O

iRenltaisvety
1 2 D00 0

1 D 000 I]

8 00D 0

6 000 D

4000 D

2 D01] 0 t'“ 11.51:.2 15.2 24.2 25‘! $1.:

- UV 1 rnfrr
? I I I I
5 1 0 1 5 20 2 5 3 D 35 4D

2 6 degree
Patent Application Publication Aug. 12, 2010 Sheet 4 0f 64 US 2010/0204204 A1

FIG. 4

IBUDDD

ISIJUIJIJ

itUDDD

iRenltaivsety 1unuuu

GUIJEIEI

CDIJCID

2DDDU

I
2D 25 3D 35 1D

2 6 degree
Patent Application Publication Aug. 12, 2010 Sheet 5 0f 64 US 2010/0204204 A1

FIG. 5

220000 —

200000;
180000

180000;
140000;
iRenlta sviety 120000 —_
100000 —

B0000 —

S0000 —

40000 -
E xperimental (293K)

_ I Calculated (100K)
0
I ' I ' l ' l ' l
5 10 15 20 25 30 35 40

2 6 degree
Patent Application Publication Aug. 12, 2010 Sheet 6 0f 64 US 2010/0204204 A1

FIG. 6
Patent Application Publication Aug. 12, 2010 Sheet 7 0f 64 US 2010/0204204 A1

FIG. 7
Patent Application Publication Aug. 12, 2010 Sheet 8 0f 64 US 2010/0204204 A1

312.89
34-:
168.9

4060 ' ' ' 30'00 ' ' l 2060

Wavenumbers (cm-1)
Patent Application Publication Aug. 12, 2010 Sheet 9 0f 64 US 2010/0204204 A1

FIG. 9

25~

1.5 ~

—Q—Q.|eroe?n

1 _
Jrmrate

0.5

0 :Mr I
O ‘ 50 1(1) 150 2(1) 250 3CD

Tlme (Mnulns)
Patent Application Publication Aug. 12, 2010 Sheet 10 0f 64 US 2010/0204204 A1

FIG. 10

100um
Patent Application Publication Aug. 12, 2010 Sheet 11 0f 64 US 2010/0204204 A1

FIG. 11

(FHWleioagwt)

I ‘mac I

[l 50 100 150 200 250 300 350

Temperature (“6)
Patent Application Publication Aug. 12, 2010 Sheet 12 0f 64 US 2010/0204204 A1

FIG. 12

10000

iRenltasvy BIJUU

500D

4000

2000

. . I . . .

s 10 1s 20 25 an as 40

26 degree
Patent Application Publication Aug. 12, 2010 Sheet 13 0f 64 US 2010/0204204 A1

FIG. 13

- 254‘

10000 —

8000 —

3‘
g _
E 6000 — “J
m
‘(Q25 - 14.2 T
E, 4000 - H T
_ T 11.1 “'5 14.1
.3

2000 -— 7T" ‘5-’ T T T

_ T M CalculatedHC
0 _ I ' I ' 1 f - I I | |
I . . .

5 10 15 20 25 30 35 40
ZBdegree
Patent Application Publication Aug. 12, 2010 Sheet 14 0f 64 US 2010/0204204 A1

FIG. 14

12000 —

10000 -

g 8000 -
I!)
C
.93
.E
m 6000 —
.2
L?(D
[E 4000 -

2000 — Experimental“

* Calculated (1

0 _

I ' I ' I ' I ' l I I ' I ' I

5 10 15 2O 25 3O 35 44
2 9 degree
Patent Application Publication Aug. 12, 2010 Sheet 15 0f 64 US 2010/0204204 A1

FIG. 15
Patent Application Publication Aug. 12, 2010 Sheet 16 0f 64 US 2010/0204204 A1

FIG. 16
Patent Application Publication Aug. 12, 2010 Sheet 17 0f 64 US 2010/0204204 A1

FIG. 17

1649.8 5015 4 14953

5790464
7
4
632.8

108.71
40'00 ' ' ' 30'00 ' ' ' zobo ' ' ' 10'00 738198
Wavenumbers (cm-1)
Patent Application Publication Aug. 12, 2010 Sheet 18 0f 64 US 2010/0204204 A1

FIG. 18

1.4

C(oncemtragi 0.8 —

0.6 —

0.4 —

0.2 -

1(1) 150 200

Tune lninutes)
Patent Application Publication Aug. 12, 2010 Sheet 19 0f 64 US 2010/0204204 A1

FIG. 19

Rienlta sviety 80
l
60 I
|
|
|
l

‘2D | ' I ' l - I ' | - 1 ' l ' |

2 6 degree