Us 7563930

US007563930B2
(12) Ulllted States Patent
(10) Patent N0.:
Wizel et al.
(54)
(45) Date of Patent:
CRYSTAL FORMS OF CINACALCET HCI

AND PROCESSES FOR THEIR
6,211,244 B1
6,313,146 B1
PREPARATION
2005/0147669 A1*
2005/0234261 A1
(75)
US 7,563,930 B2
Inventors: Shlomit Wizel, Petah Tiqva (IL); Revital

Lifshitz-Liron, HertZlia (IL); Sharon
Jul. 21, 2009
4/2001 Van Wagenen et a1.

11/2001 Van Wagenen et a1.
7/2005
Lawrence et a1. ......... .. 424/464
10/2005 Wilken et al.
2006/0276534 A1 12/2006 Mamn et 31'

FOREIGN PATENT DOCUMENTS
Avhar-Maydan, Givataym (IL)

W0
WO 2006/125026
(73) Assignee: Teva Pharmaceutical Industries Ltd,

Petah Tlqva (IL)
Anonymous,
(*)
Notice:
Subject to any disclaimer, the term of this

patent is extended or adjusted under 35
U_S_C_ 154(1)) by 58 days_
(21)
Appl' NO" 11/605149
(22)
Med
.
-
N-[l-(R)-(-)(1-naphthyl)]-3-[3-[3
(tri?uoromethyl)phenyl}-1-aminopropane hydrochloride, IP.COM

J0uII1aLMay23, 2005,XPO002424259~
Devasher et al., Aqueous-Phase, Palladium-catalyzed cross-cou
pling of aryl bromides under mild conditions, using Water soluable,
sterically demanding alkylphosphines, Journal of Organic Chemis
try, American Chemical Society, vol. 69, 2004, pp. 7919-7927.
Database Belistein; Belistein Institute for Organic Chemistry, Frank
Nov 22 2006
furt-Main, DE; XP002451055 (& Pharmazie, vol. 59, N0. 10, 2004,
(65)
11/2006
OTHER PUBLICATIONS
pp. 744-752).
Pnor Pubhcatlon Data

Us 2007/0185211 A1
Aug' 9 2007
Sensipar (Cinacalcet HCI) Tablets Summary Basis of Approval of

New Drug Application #21-688 By FDA, (2004).
J. Iqbal, et al. Cinacalcet Hydrochloride IDrugs, vol. 6, No. 6, p.
(60)
Related U's' Apphcatlon Data

Provisional application No. 60/739,215, ?led on Nov.
22 2005 provisional application NO_ 60/742,626
?led on Dec_ 5 2005
(51)
Int Cl
Snyder, L.R. et al., Introduction To Modern Liquid Chromatography,
2nd Ed., (1979), pp. 549-572, John Wiley & Sons, Inc.
I
Strobel, H.A. et al., Chemical Instrumentation. A Systematic
C07C 211/00
(52)
587-592, (2003).
L.A. Sorbera, et al. Cinacalcet Hydrochloride Drugs ofthe Future,

V0l~ 27, N0~ 9, P 831-836, (2002)
X. Wang, et a1. Synthesis of Cinacalcet Congeners Tetrahedron
Letters, vol. 45, p. 8355-8358, (2004).
(200601)
Approach, 3rd Ed., (1989), pp. 391-393, 879-894, 922-925, 953.
US. Cl. ....................... .. 564/337; 564/336; 560/41;
560/28; 514/487; 514/649
(58) Field of Classi?cgtgi4o/r3l3S6eagc6l/ll...:..5i.4/ig4/36347

S
1,
?l f
ee app lcanon
(56)
L h,
e or Comp ete Seam
References Cited
lstory'
* Cited by examiner
Primary ExamineriKarl J Punhtz

Assistant ExamineriSudhakar Katakam
(74) Attorney, Agent, or FirmiKenyon & Kenyon LLP
(57)
ABSTRACT
U.S. PATENT DOCUMENTS

4,966,988
5,648,541
6,011,068
6,031,003
A
A
A
A
10/1990
7/1997
1/2000
2/2000
Schinski et a1.
Van Wagenen et a1.
Nemeth et a1.
Nemeth et a1.
Provided are crystalline forms of Cinacalet HCl and pro

cesses for their preparation.
37 Claims, 6 Drawing Sheets
US. Patent
Ex53s_E25189235%
Jul. 21, 2009
Sheet 1 of6
US 7,563,930 B2
US. Patent
5ExB5:3__E2285855
Jul. 21, 2009
Sheet 2 of6
US 7,563,930 B2
US. Patent
EE25:$3EXE2U8SQ6E Q
Jul. 21, 2009
Sheet 3 of6
US 7,563,930 B2
US. Patent
Jul. 21, 2009
Sheet 4 of6
US 7,563,930 B2
080 thermagram at Cinacatcet H01 farm 1

Cinacalcet HCt MS-1303-d
Cinacaicet H01 MS-1303-d, 3.1200 mg
k
'
Ir
Method: 30-2200 100/min 40mI/min N2

30.0220.00 10.000/min N2 40.0 ml/min
5
Integral
29.68 mi
Integral
normalized 9.51 Jg1
478.33 nlJ
narmaiized -57.16 Jg 1
Peak
Left Limit
172.89 C
157.41C
Peak
Left Limit
183.73 T
170.49 0C
Right Limit
176.07C
Right Limit
189.35 "C
D50 thermagram at Cinaaatcet H01 farm 11
Cinacalcet H01 ms-1421w

Cinacalcet H101 ms-1421w, 3,1600 mg
Method: 25-2500. 100/min 40rn1/min N2

25.0250.00 10.000/min N2 40.0 ml/min
% integral
normalized
mw
Peak
Integral
-14B.20 mJ
normalized ~46.27 Jg1
Left Limit
109.44 "0
Right Limit
139-.180
integral
40.74 m]
narmatized 12.89JgA1
Integral
114.18 mJ
narmatized 46.13.1974
Peak
Left Limit
71.63 0
37.611?
Peak
Lett Limit
165.47 "0
140660
Peak
Left Limit
176.82 "0
168.57%)
Right Limit
82.760
Right Limit
168.670
Right Limit
182.800
4a.6.0_s0I100120.100.10010010020240?
0"2'i
6'8
ia'i'21'41s'1072b'iinn
US. Patent
Jul. 21, 2009
Sheet 5 of6
US 7,563,930 B2
DSC thermogrom of Cinocolcet HCI form l||
Cinocolcet HCt ins-14200!

Cinocolcet HCI ms-I420w, 3.6300 mg
Method: 25-2500 iOC/min 40mI/min N2

25.0*250.0C 10.00 C/min N2 40.0 ml/min
Z Integral
41.i2 mJ
/ Peok
Left Limit
156.54 0C
148.35C
mW
_; Right Limit
16959 0C
normalized 11.33 Jg"1
W Integrol
-179.16 mJ
normalized 49.36 Jg'1
Peak
Letl Limit
1 78,70 C
169.59 cC
& Right Limit
183.61 0
H 4p.60180I100_1Z0|tlt0_10010010012014011
0'2'i'ts'8'1o'1'2'1'4
i's'i'a'io'?n
FIG.6
TGA thermogrom of Cindcolcet HCI form |

Cinocolcet HCI MS-1196~blonk
Cinocolcet HCI M54196, 12.2701 mg
Method: 25-200C, 10C/min,N2 40ml/min

25.0-200.0C 10.00C/min NZ 40.0 mI/min
ki
01
m9
Step
-76.2O6e03 %
-9.351e~03 mg
Left Limit 25.00C
Right Limit 100.01 C

20
4
40
l
I
60
l
I
80
|
|
100
|
|
4
I
120
l
140
l
160
1
180
a'10'1'2'1'4"1's'Tnin
US. Patent
Jul. 21, 2009
Sheet 6 of6
US 7,563,930 B2
TGA thermogrom of Cinocolcet HC1 form ll

-
Cinocolcet HCI MS-1421w-blunk
Cinocolcet HCI MS-1421w, 9.1399 mg
Method: 25-200C, 10C/min,N2 40ml/min

ZSD'ZOQOOC 10.00C/min N2 40.0 ml/min
01
m'
Step
17.994 7;
.
Left Limit
1.645 mg
0
25.00 C
Right Limit 100.12C
40
60
80
I 100
I 120 I 140
100 I 180
TCA thermogrom of Cinocolcet HC1 form |||

Cinocolcet HCI MS-1420w-blonk
Cinocolcet HCI MS-1420w, 13.8289 mg
Method: 25-2000, 1OC/min,N2 40ml/min

________
\_
0.1
25.0200.0C 10.00C/min N2 40.0 mI/min
Step
-0.322 2,
Left Limit
44.514e03 mg
25.00 "0
Right Limit 160.09C

T
40
60
80
I 100 I 120 I 140 I 100
FIG.9
180
cI
US 7,563,930 B2
1
CRYSTAL FORMS OF CINACALCET HCI

AND PROCESSES FOR THEIR
PREPARATION
in US. Pat. No. 6,211,244, DRUGS or THE FUTURE, 27 (9), 831
(2002) and US. Pat. No. 5,648,541.

The present invention relates to the solid state physical
properties of Cinacalcet hydrochloride. These properties can
be in?uenced by controlling the conditions under Which
Cinacalcet hydrochloride is obtained in solid form. Solid state
CROSS-REFERENCE TO RELATED
APPLICATIONS
physical properties include, for example, the ?oWability of

This application claims the bene?ts of US. Provisional
Patent Application Ser. Nos. 60/739,215, ?led Nov. 22, 2005
the milled solid. FloWability affects the ease With Which the
material is handled during processing into a pharmaceutical

product. When particles of the poWdered compound do not
?oW past each other easily, a formulation specialist must take
and 60/742,626, ?led Dec. 5, 2005, hereby incorporated by

reference.
that fact into account in developing a tablet or capsule formu

lation, Which may necessitate the use of glidants such as
FIELD OF INVENTION
colloidal silicon dioxide, talc, starch, or tribasic calcium
phosphate.
The present invention relates to novel crystalline forms of

Cinacalcet HCl.
Another important solid state property of a pharmaceutical

compound is its rate of dissolution in aqueous ?uid. The rate
of dissolution of an active ingredient in a patients stomach
?uid can have therapeutic consequences, as it imposes an
BACKGROUND OF THE INVENTION

(R)-0t-methyl -N- [3 - [3 - (tri?uoromethyl)phenyl]propyl] -
20
Cinacalcet hydrochloride has the molecular formula

C22H22F3NHCl, a molecular Weight of 393.9 and the chemi
cal structure:
upper limit on the rate at Which an orally-administered active
ingredient can reach the patients bloodstream. The rate of

dissolution is also a consideration in formulating syrups,
elixirs and other liquid medicaments. The solid state form of
a compound may also affect its behavior on compaction and
1-naphthalenemethane amine is knoWn as Cinacalcet. The
25
its storage stability.

The discovery of neW polymorphic forms of a pharmaceu
tically useful compound and of processes of preparing such
polymorphic forms provides opportunities to improve the
2m
-HC1
30
CH3
The CAS number for the hydrochloride is 364782-34-3, and
35
performance characteristics of a pharmaceutical product.

Such discoveries enlarge the repertoire of materials that a
formulation scientist has available for designing, for
example, a pharmaceutical dosage form of a drug With a
targeted release pro?le or other desired characteristic. Thus,
the present invention presents neW crystalline forms of Cina
calcet HCl to the pharmaceutical sciences.
that of the free base is 226256-56-0.

Cinacalcet is marketed as SENSIPARTM (Amgen, USA),
and is the ?rst drug in a class of compounds knoWn as calci
mimetics to be approved by the FDA. Cinacalcet is approved

for treatment of secondary hyperparathyroidism in patients
With chronic kidney disease on dialysis. Elevated levels of
parathyroidhorrnone (PTH), an indicator of secondary hyper
SUMMARY OF THE INVENTION

40
ized by a poWder XRD pattern, having four x-ray poWder

diffraction peaks selected from the folloWing: about 106,
139, 164, 17.1, and 21.6:0.2o 20. The crystalline form
parathyroidism, are associated With altered metabolism of
calcium and phosphorus, bone pain, fractures, and an
In one embodiment, the invention is directed to crystalline

form of Cinacalcet HCl, herein de?ned as form II, character
45
of Cinacalcet HCl may have x-ray poWder diffraction peaks at
about 106, 139, 17.1, and 21.6:0.2o 20. Alternatively,
increased risk for cardiovascular death.

Calcimimetics are a class of orally active, small molecules
the crystalline form of Cinacalcet HCl may have x-ray poW
that decrease the secretion of PTH by activating calcium

receptors. The secretion of PTH is normally regulated by the
calcium-sensing receptor. Calcimimetic agents increase the
sensitivity of this receptor to calcium, Which inhibits the
release of parathyroid hormone, and loWers parathyroid hor
21.6:0.2o 20. Form II may be considered a chloroform sol

vate of Cinacalet HCl. This chloroform solvate of Cinacalet
HCl may have about 10 to about 30% chloroform or prefer
der diffraction peaks at about 106, 164, 17.1, and

50
ably, about 15 to 25% chloroform.

form of Cinacalcet HCl, herein de?ned as form III, charac
mone levels Within a feW hours. Calcimimetics are used to
treat hyperparathyroidism, a condition characterized by the

over-secretion of PTH that results When calcium receptors on
55
parathyroid glands fail to respond properly to calcium in the

bloodstream. Treatment With Cinacalcet loWers serum levels
of PTH as Well as the calcium/phosphorus ion product, a
measure of the amount of calcium and phosphorus in the
blood, Which, When elevated, causes harmful deposition of

calcium in various parts of the body.
US. Pat. No. 6,011,068 discloses calcium receptor-active
molecules, such as those having the general structure of Cina
calcet. US. Pat. No. 6,211,244 discloses calcium receptor
60
active compounds related to Cinacalcet and methods ofmak

ing such compounds. Cinacalcet and its enantiomer may be
65
produced by various methods, using the processes disclosed
terized by poWder XRD pattern, having four x-ray poWder

diffraction peaks selected from the folloWing: about 13.8,
17.7, 196, 204, and 23.5:0.2o 20. The crystalline form
of Cinacalcet HCl may be characterized by a poWder XRD
pattern, With x-ray poWder diffraction peaks at about 13.80
and 17.7, 20.40 and 23.5:0.2o 20. Alternatively, the crys
talline form of Cinacalcet HCl may be characterized by a
poWder XRD pattern, With x-ray poWder diffraction peaks at

about 17.7, 196, 20.40 and 23.5:0.2o 26
In another embodiment the present invention encompasses
a process for preparing crystalline Cinacalcet HCl Form I by
heating Cinacalcet HCl form III, preferably at about 30 to 600
C.
US 7,563,930 B2
4
3
In another embodiment of the invention the present inven
Pat. No. 6,211,244, Which are incorporated herein by refer
tion encompasses pharmaceutical compositions comprising
ence, as Well as Examples 1 and 2.
Cinacalcet HCl Form II or III, Wherein the formulation is

form of Cinacalcet HCl, herein de?ned as form II, character
substantially stable against physical and chemical transfor
ized by a poWder XRD pattern, having four x-ray poWder

diffraction peaks selected from the folloWing: about 106,
139, 164, 17.1, and 21.6:0.2 26. The crystalline form
mation or the formulation is manufactured in accordance With
acceptable GMP requirements.

In yet another embodiment of the invention the present
invention encompasses any pharmaceutical compositions

comprising Form III. The composition is preferably substan
tially stable against physical and chemical transformation, for
example transformation into other polymorphic forms. The
of Cinacalcet HCl may have x-ray poWder diffraction peaks at

about 106, 139, 17.1, and 21.6:0.2 26. The crystalline
may be further characterized by x-ray poWder diffraction
peaks at about 16.4, 179, 204, 23.8, and 24.8:0.2 26.
Alternatively, the crystalline form of Cinacalcet HCl may
have x-ray poWder diffraction peaks at about 106, 164,
formulation is manufactured in accordance With acceptable
GMP requirements.
17.1 and 21 .6:0.2 26, in Which case, the crystalline form

of Cinacalcet HCl may be further characterized by x-ray
BRIEF DESCRIPTION OF THE DRAWINGS
poWder diffraction peaks at about 13.9, 179, 204, 23.8,

FIG. 1 illustrates an X-Ray PoWder Diffraction pattern of
Cinacalcet HCl form I.
Cinacalcet HCl form II.
Cinacalcet HCl form III.
FIG. 4 illustrates a DSC thermogram of Cinacalcet HCl
form I.
form II.
form III.
FIG. 7 illustrates a TGA thermogram of Cinacalcet HCl
form I.
form II.
form III.
and 24.8:0.2 26. XRD pattern of crystalline Form II is

substantially depicted in FIG. 2. Cinacalcet HCl form II may
have one DSC endothermic peak at about 72 C., Which
20
25
30
The TGA thermogram for this form is substantially depicted

in FIG. 8. Water content, as Was measured by KF titration
method Was less than about 1%. Form II may be considered a
chloroform solvate of Cinacalet HCl. This chloroform solvate
of Cinacalet HCl may have about 10 to about 30% chloroform
or preferably, about 15 to 25% chloroform.
In another embodiment, the present invention encom
passes a process for preparing crystalline Cinacalcet HCl

Form II comprising providing a solution of Cinacalet HCl and
Chloroform, preferably at ambient temperature; admixing

35
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides crystalline forms II and III

of Cinacalcet hydrochloride, and processes for preparing
them, mixtures thereof, and stable pharmaceutical composi
indicates a solvent removal, an exothermic peak at about 125

C., and tWo additional endothermic peaks at about 165 C.
and about 175-185 C. The DSC thermogram for this form is
substantially as depicted in FIG. 5. Cinacalcet HCl form II
may shoW Weight loss at around 18%, as detected by TGA.
40
n-Pentane to obtain precipitated Form II. The precipitate may

be maintained as a slurry, for example, by stirring for about 5
minutes to 6 hours, preferably about 5 minutes to about tWo
hours, more preferably about 5 minutes to about 15 minutes.
Preferably, maintaining the slurry is at about room tempera
ture. Form II is then recovered by any method knoWn in the
tions based thereon. Each of the neW forms is differentiated
art, preferably by ?ltration.
by a unique poWder X-ray diffraction pattern, a DSC thermo

gram and TGA thermogram.
passes another process for preparing crystalline Cinacalcet
In the published Summary Basis forApproval of NeW Drug

Application #21688, it is mentioned that Cinacalcet hydro
In another embodiment, the present invention encom
45
chloride has only one stable crystalline form at ambient tem

perature. This form is designated herein as Form I and is
characterized by a poWder XRD peaks at about: 13.9, 19.0,

21.3, 25510.2 deg. 26. The crystalline Form I may be further
characterized by a PXRD pattern With peaks at about: 15.0,
15.5, 16.0, 17.9, 23.7, and 24.3 2610.2 deg. 26. The XRD
pattern of Crystalline Form I is substantially depicted in FIG.
then stirred Within the reaction mixture for at least 8 hours,

preferably for about 8 to 24 hours, more preferably about 12
to 18 hours, more preferably about 16 hours. The form II is
50
55
form is substantially depicted in FIG. 4. TGA thermograms

shoW Weight loss of less than 1% for Form I, thus, this form
may be considered as anhydrous. The TGA thermogram for
this form is substantially as depicted in FIG. 7.
As used throughout herein, the term ambient tempera
ture refers to room temperature. Preferably, the term ambi
ent temperature refers to a temperature of from about 18 C.
to about 28 C., preferably about 20 C. to about 25 C.
The Cinacalcet hydrochloride [HCl] used to prepare the
crystalline forms described may be prepared according to any

method knoWn in the art such as the one described in a
co-pending US. application Ser. No. 11/435,430, and US.
then recovered by any method knoWn in the art, preferably by

?ltration.
form of Cinacalcet HCl, herein de?ned as form III, charac
1. Differential Scanning Calorimetry (DSC) thermogram of

Cinacalcet HCl form I shoWs tWo endotherms at about 160
170 C. and at about 175-185 C. The DSC pattern for this
HCl Form II comprising providing a solution of Cinacalcet

HCl and Chloroform, preferably at ambient temperature, and
admixing n-Heptane to obtain a precipitate. The precipitate is
60
65
terized by poWder XRD pattern, having four x-ray poWder

diffraction peaks selected from the folloWing: about 13.8,
17.7, 196, 204, and 23.5:0.2 26. The crystalline form
of Cinacalcet HCl may be characterized by a poWder XRD
pattern, With x-ray poWder diffraction peaks at about 138
and 17.7, 20.4 and 23.5:0.2 26 and may be optionally
further characterized by x-ray poWder diffraction peaks at
about 70, 13.8, 157, 162 and 19.6:0.2 26. Altema
tively, the crystalline form of Cinacalcet HCl may be charac
terized by a poWder XRD pattern, With x-ray poWder diffrac
tion peaks at about 17.7, 196, 204 and 23.5:0.2 26 and
optionally further characterized by x-ray poWder diffraction

peaks at about 70, 138, 157, and 16.2:0.2 26. The
poWder XRD pattern of Form III is substantially depicted in
US 7,563,930 B2
6
Solid pharmaceutical compositions that are compacted
FIG. 3. The DSC thermogram of Form III is substantially

depicted in FIG. 6. Cinacalcet HCl Form IEI shows two
endothermic peaks at about l60-l70 C., and about 175
1850 C. Weight loss of less than 1% was detected by TGA.
The TGA of Form III is substantially depicted in FIG. 9. This
form may be considered anhydrous.
In yet another embodiment, the present invention encom
Form III comprising providing a solution of Cinacalet HCl
into a dosage form, such as a tablet, may include excipients

whose functions include helping to bind the active ingredient
and other excipients together after compression. Binders for
ing water to obtain a precipitate. The precipitate may be

stirred with the reaction mixture at ambient temperature, pref
solid pharmaceutical compositions include acacia, alginic

acid, carbomer (e.g. carbopol), carboxymethylcellulose
sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydroge
nated vegetable oil, hydroxyethyl cellulose, hydroxypropyl
cellulose (e.g. Klucel), hydroxypropyl methyl cellulose
(e.g. Methocel), liquid glucose, magnesium aluminum sili
cate, maltodextrin, methylcellulose, polymethacrylates,
povidone (e.g. Kollidon, Plasdone), pregelatiniZed
erably for about 2 to about 4 days, preferably about 3 days.
starch, sodium alginate and starch.
and Chloroform; inducing precipitation by cooling or admix
The form III is then recovered by any method known in the
The dissolution rate of a compacted solid pharmaceutical
art, preferably by ?ltration.
composition in the patients stomach may be increased by the

addition of a disintegrant to the composition. Disintegrants
include alginic acid, carboxymethylcellulose calcium, car
In yet another embodiment, the present invention encom

Form III comprising dissolving Cinacalet HCl in Chloroform,

preferably at ambient temperature, and adding n-Heptane to
obtain a precipitate. Preferably, the precipitate is stirred with
the reaction mixture at ambient temperature, preferably for
20
magnesium aluminum silicate, methyl cellulose, microcrys

talline cellulose, polacrilin potassium, powdered cellulose,
less than 6 hours, preferably about 1 minute to 4 hours, more

preferably for about 4 to 15 minutes. The form III is then
pregelatiniZed starch, sodium alginate, sodium starch glyco

late (e.g. Explotab) and starch.
recovered by any method known in the art, preferably by

?ltration.
In another embodiment the present invention encompasses
a process for preparing crystalline Cinacalcet HCl Form I by
heating Cinacalcet HCl form III, preferably at about 30 to 60
C., more preferably 40 to 50 C. Heating may be performed
for at least about 4 hours, more preferably about 16 to 24
hours. The heating process is preferably conducted in an inert
25
dered cellulose, starch, talc, and tribasic calcium phosphate.

30
In another embodiment of the invention the present inven

35
ing Cinacalcet HCl Form II or III, wherein the formulation is
substantially stable against physical and chemical transfor
acceptable GMP requirements.

40
invention encompasses any pharmaceutical compositions

comprising Form III. The composition is preferably substan
tially stable against physical and chemical transformation, for
example transformation into other polymorphic forms. The
45
Flavoring agents and ?avor enhancers make the dosage

form more palatable to the patient. Common ?avoring agents
and ?avor enhancers for pharmaceutical products that may be
included in the composition of the present invention include
maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric

acid, ethyl maltol, and tartaric acid.
invention contain Cinacalcet HCl Form II or III. In addition to
the active ingredient(s), the pharmaceutical formulations of

50
Solid and liquid compositions may also be dyed using any

pharmaceutically acceptable colorant to improve their
appearance and/or facilitate patient identi?cation of the prod
uct and unit dosage level.
In liquid pharmaceutical compositions of the present
readily determined by the formulation scientist based upon

experience and consideration of standard procedures and ref
erence works in the ?eld.
Diluents increase the bulk of a solid pharmaceutical com
glyceryl palmitostearate, hydrogenated castor oil, hydroge

nated vegetable oil, mineral oil, polyethylene glycol, sodium
benZoate, sodium lauryl sulfate, sodium stearyl fumarate,
stearic acid, talc and Zinc stearate.
GMP requirements.
Pharmaceutical formulations/compositions of the present
the present invention may contain one or more excipients.
Excipients are added to the formulation for a variety of pur
poses. Selection of excipients and the amounts to use may be
active ingredients have a tendency to adhere to the surfaces of

the punch and dye, which can cause the product to have
pitting and other surface irregularities. A lubricant can be
added to the composition to reduce adhesion and ease the
release of the product from the dye. Lubricants include mag

nesium stearate, calcium stearate, glyceryl monostearate,
mation or the formulation is manufactured in accordance with
formulation is manufactured in accordance with acceptable
When a dosage form such as a tablet is made by the com
paction of a powdered composition, the composition is sub

jected to pressure from a punch and dye. Some excipients and
atmosphere. Preferably, the heating is conducted under
In yet another embodiment of the invention the present
Glidants can be added to improve the ?owability of a
non-compacted solid composition and to improve the accu

racy of dosing. Excipients that may function as glidants
include colloidal silicon dioxide, magnesium trisilicate, pow
vacuum.
tion encompasses any pharmaceutical compositions compris
boxymethylcellulose sodium (e.g. Ac-Di-Sol, Primel

lose), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g. Kollidon, Polyplasdone), guar gum,
55
invention, Cinacalcet HCl Form II or III, and any other solid

excipients are dissolved or suspended in a liquid carrier such
as water, vegetable oil, alcohol, polyethylene glycol, propy
position, and may make a pharmaceutical dosage form con

taining the composition easier for the patient and care giver to
lene glycol or glycerin.
handle. Diluents for solid compositions include, for example,

microcrystalline cellulose (e.g. Avicel), micro?ne cellu
ceutically acceptable colorant to improve their appearance

and/or facilitate patient identi?cation of the product and unit
dosage level.
Liquid pharmaceutical compositions may contain emulsi
Liquid compositions may also be dyed using any pharma

60
lose, lactose, starch, pregelatiniZed starch, calcium carbon

ate, calcium sulfate, sugar, dextrates, dextrin, dextrose, diba
sic calcium phosphate dihydrate, tribasic calcium phosphate,
kaolin, magnesium carbonate, magnesium oxide, maltodex
trin, mannitol, polymethacrylates (e.g. EUDRAGIT),

potassium chloride, powdered cellulose, sodium chloride,
sorbitol and talc.
fying agents to disperse uniformly throughout the composi

tion an active ingredient or other excipient that is not soluble
65
in the liquid carrier. Emulsifying agents that may be useful in
liquid compositions of the present invention include, for
example, gelatin, egg yolk, casein, cholesterol, acacia, traga
US 7,563,930 B2
7
canth, chondrus, pectin, methyl cellulose, carbomer, ceto

stearyl alcohol, and cetyl alcohol.
Liquid pharmaceutical compositions of the present inven
tableting is knoWn to those in the art With experience and skill
in particular formulation challenges of direct compression
tableting
A capsule ?lling of the present invention may comprise any
tion may also contain a viscosity enhancing agent to improve

the mouth-feel of the product and/or coat the lining of the
of the aforementioned blends and granulates that Were

described With reference to tableting, hoWever, they are not
subjected to a ?nal tableting step.
gastrointestinal tract. Such agents include acacia, alginic acid

bentonite, carbomer, carboxymethylcellulose calcium or
sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose,
Cinacalcet HCl Form 11 or III is administered to a mammal,
gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cel
preferably a human in need thereof, to inhibit platelet aggre

gation and reduce the chance of a primary or secondary
lulose, hydroxypropyl methyl cellulose, maltodextrin, poly

vinyl alcohol, povidone, propylene carbonate, propylene gly
ischemic event such as a heart attack or stroke.
col alginate, sodium alginate, sodium starch glycolate, starch

tragacanth and xanthan gum.
EXAMPLES
SWeetening agents such as sorbitol, saccharin, sodium sac
charin, sucrose, aspartame, fructose, mannitol, and invert
Instrumentation
sugar may be added to improve the taste.
PXRD
Preservatives and chelating agents such as alcohol, sodium
X-Ray poWder diffraction data Were obtained using a
benZoate, butylated hydroxy toluene, butylated hydroxyani
SCINTAG poWder X-Ray diffractometer model XTRA
sole, and ethylenediamine tetraacetic acid may be added at
levels safe for ingestion to improve storage stability.

According to the present invention, a liquid composition
20
may also contain a buffer such as gluconic acid, lactic acid,

citric acid or acetic acid, sodium gluconate, sodium lactate,
cavity of 25(diameter)*0.5(depth) mm. Scanning parameters

range of: 2-40 deg. 20 and continuous scan rate of 3 deg./min.
sodium citrate or sodium acetate.
The solid compositions of the present invention may

include poWders, granulates, aggregates and compacted com
positions. The dosages include dosages suitable for oral, buc
25
and
intravenous),
inhalant
and
crimped and punched prior to analysis. The Weight of the
ophthalmic
administration. The most suitable administration in any given

case Will depend on the nature and severity of the condition
30
being treated. The dosages may be conveniently presented in

unit dosage form and prepared by any of the methods Well
knoWn in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, poW
samples Was about 3-5 mg; the samples Were scanned at a rate
of 10 C./min from 30 C. to 250 C. The oven Was constantly
purged With nitrogen gas at a How rate of 40 mL/min. Stan
dard 40 pl aluminum crucibles covered by lids With 3 holes

Were used.
Thermal Weight change measurements Were made on a

35
ders, capsules, suppositories, sachets, troches and loZenges,

as Well as liquid syrups, suspensions and elixirs. The dosage
form may be a capsule containing the composition, such as a
poWdered or granulated solid composition, Within either a
hard or soft shell. The shell may be made from gelatin and
optionally contain a plasticiZer such as glycerin and sorbitol,
Thermal Analysis
Differential Scanning Calorimetry (DSC) analysis Was
done using a Mettler Toledo 821 Starz. The crucible Was
cal, rectal, parenteral (including subcutaneous, intramuscu

lar,
equipped With a solid state detector and a variable gonimeter.

Copper radiation of 1.5418 A Was used. A round standard
aluminum sample holder With round Zero background, and
Mettler TG50 Thermogravimetric AnalyZer (TGA). Samples

of 7-1 5 mg Were placed in an aluminum pan and placed in the
device. The data Was collected from about 50 C. to about
350 C. at a rate of 10 C./min.
40
Example 1
and an opacifying agent or colorant.
The active ingredient and excipients may be formulated

into compositions and dosage forms according to methods
knoWn in the art. A composition for tableting or capsule ?lling
may be prepared by Wet granulation. In Wet granulation, some
or all of the active ingredients and excipients in poWder form
Preparation of Cinacalcet Base

25 .5 gr of (2E)-3-[3-(tri?uoromethyl)phenyl]prop-2-en-1 45
ethyl amine (14.5 ml) and anhydrous KZCO3 (24.9 gr) Were
are blended and then further mixed in the presence of a liquid,
typically Water, Which causes the poWders to clump into gran

ules. The granulate is screened and/or milled to the desired
particle siZe. The granulate may then be tableted, or other
excipients may be added prior to tableting, such as a glidant
50
added and the reaction mixture Was heated to re?ux tempera

ture for 16 hours. Then salts Were ?ltered out and the solvent
Was removed under reduced pressure. The residue Was dis
solved in toluene (75 ml) and the solution Was heated to 70
C. The obtained solution Was Washed With 0.2N aqueous HCl
solution (pH:1), Water, a saturated solution of NaHCO3

(pH:8-9) and ?nally With Water. The organic phase Was dried
and/ or a lubricant.
A tableting composition may be prepared conventionally

by dry blending. For example, the blended composition of the
01 Were dissolved in Acetonitrile (204 ml). (R)-1-Naphtyl
55
over NaZSO4 (optionally), ?ltered and the solvent Was evapo

rated until dryness to obtain 33.4 gr of Cinacalcet base.
actives and excipients may be compacted into a slug or a sheet

and then comminuted into compacted granules. The com
Example 2
pacted granules may subsequently be compressed into a tab

let.
As an alternative to dry granulation, a blended composition
Preparation of Cinacalcet HCl

60
may be compressed directly into a compacted dosage form
Cinacalcet base (0.8 gr) Was dissolved in MTBE (50 ml) at
using direct compression techniques. Direct compression
room temperature. Then HCl gas Was bubbled into the solu
tion. The solution Was stirred at room temperature for 0.5
produces a more uniform tablet Without granules. Excipients

that are particularly Well suited for direct compression tablet
ing include microcrystalline cellulose, spray dried lactose,
65
hour to obtain precipitate. The product Was isolated by ?ltra

tion, Washed With MTBE (8 ml) and dried at 50 C. in a
dicalcium phosphate dihydrate, and colloidal silica. The
vacuum oven for 15 hours to obtain 0.5 gr of Cinacalcet
proper use of these and other excipients in direct compression
hydrochloride.
US 7,563,930 B2
9
10
Example 3
spirit and scope of the invention as disclosed in the speci?

cation. The examples are set forth to aid in understanding the
Preparation of Cinacalcet HCl Form II
invention but are not intended to, and should not be construed
to limit its scope in any Way. The examples do not include
0.52 gr of Cinacalcet HCl Was dissolved in Chloroform
detailed descriptions of conventional methods. Such methods
(3.5 ml) at room temperature. Then n-Pentane (30 ml) Was
are Well knoWn to those of ordinary skill in the art and are
described in numerous publications. All references men
added in one portion to obtain a precipitate. The slurry Was

stirred at room temperature for 5 minutes. The solid Was then
tioned herein are incorporated in their entirety.

What is claimed:
1. A crystalline form of Cinacalcet HCl, characterized by a
isolated by ?ltration to obtain Cinacalcet HCl crystal form II.
Example 4
poWder XRD pattern, having x-ray poWder diffraction peaks
Preparation of Cinacalcet HCl Form II
at about 106, l3.9, 16.4, 17.1 and 21 .6:0.2 26.

2. The crystalline form of Cinacalcet HCl of claim 1, fur
0.58 gr of Cinacalcet HCl Was dissolved in Chloroform (6
ml) at room temperature. Then n-Heptane (30 ml) Was added

in one portion to obtain a precipitate. The slurry Was stirred at
room temperature for 16 hours. The solid Was then isolated by
?ltration to obtain Cinacalcet HCl crystal form II.
20
Example 5
FIG. 2.
Preparation of Cinacalcet HCl Form III

0.5 gr of Cinacalcet HCl Was dissolved in Chloroform (3.5
ml) at room temperature. Then Water (30 ml) Was added in
25
72 hours. The solid Was then isolated by ?ltration and Washed
With Water (5 ml) to obtain Cinacalcet HCl crystal form III.

30
Example 6
35
ml) at room temperature. Then n-Heptane (30 ml) Was added

in one portion to obtain a precipitate. The slurry Was stirred at
room temperature for 4 minutes. The solid Was then isolated
by ?ltration, Washed With n-Heptane (1.5 ml) to obtain Cina

calcet HCl crystal form III. The obtained Cinacalcet HCl
40
crystal form III Was then dried at 50 C. for 24 hours and the
crystalline structure Was maintained as form III.
Example 7
45

Cinacalcet HCl Form I (5 gr) Was stirred in Chloroform
(20-23 ml) at room temperature. The mixture Was heated to
re?ux temperature to obtain a clear solution: Then the solu
tion Was cooled to room temperature (optionalifurther cool
ing can be done using an ice-bath) to obtain a precipitate. The
product Was isolated by ?ltration and dried in a vacuum oven
at 50 C. for 14-24 hours to obtain 2 gr of Cinacalcet HCl
crystal form III.
claim 1 comprising: providing a solution by dissolving Cina
ering the precipitated Cinacalcet HCl.

50
Example 8
Preparation of Cinacalcet HCl Form I
60
Cinacalcet HCl form III, prepared according to example 3

Was heated at 50 C. under vacuum for 22 hours. Cinacalcet
HCl form I Was obtained.
Having thus described the invention With reference to par

those in the art Would appreciate modi?cations to the inven
tion as described and illustrated that do not depart from the
6. The crystalline form of Cinacalcet HCl of claim 1, char

acterized by a DSC thermogram as depicted in FIG. 5.
7. The crystalline form of Cinacalcet HCl of claim 1, hav
ing a Weight loss of about 18%.
ing a TGA thermogram as depicted in FIG. 8.
ing less than 1% Water content, as measured by KF.
10. A process for the preparation of the Cinacalcet HCl of
claim 1 comprising: providing a solution of Cinacalcet HCl
and chloroform; admixing n-Pentane to obtain a precipitate;
maintaining the slurry for about 5 minutes to about 6 hours;
and recovering the Cinacalcet HCl.
11. The process of claim 10 Wherein maintaining is for a
period of about 5 minutes to about tWo hours.
12. The process of claim 11 Wherein maintaining is for a
period of about 5 minutes to about 15 minutes.
13. A process for the preparation of the Cinacalcet HCl of
calcet HCl in Chloroform; admixing n-Heptane to obtain a
slurry; maintaining the slurry for at least 8 hours; and recov
55
ticular preferred embodiments and illustrative examples,

acterized by a DSC thermogram having one endothermic
peak at about 72 C., an exothermic peak at about 125 C., and
tWo additional endothermic peaks at about 165 C. and about
175 -1 85 C.
one portion. The mixture Was stirred at room temperature for
0.62 gr of Cinacalcet HCl Was dissolved in Chloroform (6
ther characterized by x-ray poWder diffraction peaks at about

164, 17.9, 204, 238, and 24.8:0.2 26.
3. The crystalline form of Cinacalcet HCl of claim 1, fur
ther characterized by x-ray poWder diffraction peaks at about
l3.9, 17.9, 204, 238, and 24.8:0.2 26.
acterized by x-ray poWder diffraction pattern as depicted in
65
14. The process of claim 13 Wherein the precipitate

obtained is stirred Within the reaction mixture for about 8 to
24 hours.
15. The process of claim 14 Wherein the precipitate
obtained is stirred Within the reaction mixture for about 16 to
24 hours.
16. A crystalline form of Cinacalcet HCl, characterized by

a poWder XRD pattern, having x-ray poWder diffraction
peaks at about 138, 17.7, 196, 204 and 23.5:0.2 26.
17. The crystalline form of Cinacalcet HCl of claim 16,
about 70, 138, 157, 162 and 19.6:0.2 26.
about 70, 138, 157, and 16.2:0.2 26.
further characterized by x-ray poWder diffraction pattern as
depicted in FIG. 3.
US 7,563,930 B2
11
12
30. The process of claim 28, Wherein maintaining is by

further characterized by a DSC thermogram having tWo
endothermic peaks at about l60-l70 C., and about 175
stirring for about 1 minute to about 4 hours.
31. The process of claim 28, Wherein maintaining is by
185 C.
stirring for about 4 to about 15 minutes.

32.A process for the preparation of Cinacalcet HCl Form 1,

characterized by a DSC thermogram substantially as depicted
characterized by x-ray poWder diffraction peaks at about

l3.9, 190, 21 .3, 25.5:0.2 20, comprising heating a crys
in FIG. 6.

having a Weight loss ofless than 1%.
having a TGA thermogram as depicted in FIG. 9.
24. A process for preparing the crystalline form of Cina
calcet HCl of claim 16, comprising providing a solution of
talline form of Cinacalcet HCl characterized by a poWder
XRD pattern, having four x-ray poWder diffraction peaks

selected from the folloWing: about l3.8, l7.7, 196, 204
20
and 23.5:0.2 26.

33. The process of claim 32, Wherein the Cinacalcet HCl is
heated at about 30 to about 60 C.
heated at about 40 to about 50 C.
35. The process of claim 32, Wherein the Cinacalcet is
heated for at least 4 hours.
36. The process of claim 32, Wherein the Cinacalcet is
heated for about 16 to about 24 hours.
25
37. A pharmaceutical solid composition, comprising the

Cinacalcet HCl Form ll, characterized by x-ray poWder dif
fraction peaks at about 106, l3.9, l6.4, l7.l, 2l.6:0.2
20, or III, characterized by x-ray poWder diffraction peaks at
about l3.8, l7.7, 196, 204, 23.5:0.2 20, and at least
Cinacalcet HCl and chloroform, and inducing precipitation

by cooling or admixing Water to obtain a precipitate.
25. The process of claim 24, Wherein Cinacalcet HCl in
chloroform is heated folloWed by cooling.

26. The process of claim 24, further comprising stirring at
ambient temperature.
27. The process of claim 26 Wherein stirring is for about
three days.
28. A process for preparing the crystalline form of Cina
calcet HCl of claim 16, comprising: dissolving Cinacalcet
HCl in chloroform; admixing n-heptane to obtain mixture;

and maintaining the mixture for less than 6 hours to obtain
Form Ill.
added to the chloroform at ambient temperature.
one pharmaceutically acceptable excipient.

*

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US007563930B2

(12) Ulllted States Patent

(10) Patent N0.:

(45) Date of Patent:

CRYSTAL FORMS OF CINACALCET HCI

Inventors: Shlomit Wizel, Petah Tiqva (IL); Revital

Jul. 21, 2009

4/2001 Van Wagenen et a1.

Lawrence et a1. ......... .. 424/464

10/2005 Wilken et al.

2006/0276534 A1 12/2006 Mamn et 31'

Avhar-Maydan, Givataym (IL)

(73) Assignee: Teva Pharmaceutical Industries Ltd,

Subject to any disclaimer, the term of this

Appl' NO" 11/605149

(tri?uoromethyl)phenyl}-1-aminopropane hydrochloride, IP.COM

try, American Chemical Society, vol. 69, 2004, pp. 7919-7927.

Database Belistein; Belistein Institute for Organic Chemistry, Frank

Pnor Pubhcatlon Data

Sensipar (Cinacalcet HCI) Tablets Summary Basis of Approval of

Related U's' Apphcatlon Data

Snyder, L.R. et al., Introduction To Modern Liquid Chromatography,

Strobel, H.A. et al., Chemical Instrumentation. A Systematic

L.A. Sorbera, et al. Cinacalcet Hydrochloride Drugs ofthe Future,

Approach, 3rd Ed., (1989), pp. 391-393, 879-894, 922-925, 953.

US. Cl. ....................... .. 564/337; 564/336; 560/41;

560/28; 514/487; 514/649

(58) Field of Classi?cgtgi4o/r3l3S6eagc6l/ll...:..5i.4/ig4/36347

e or Comp ete Seam

Primary ExamineriKarl J Punhtz

(74) Attorney, Agent, or FirmiKenyon & Kenyon LLP

U.S. PATENT DOCUMENTS

Provided are crystalline forms of Cinacalet HCl and pro

37 Claims, 6 Drawing Sheets

Jul. 21, 2009

Jul. 21, 2009

Jul. 21, 2009

Jul. 21, 2009

080 thermagram at Cinacatcet H01 farm 1

Method: 30-2200 100/min 40mI/min N2

normalized 9.51 Jg1

D50 thermagram at Cinaaatcet H01 farm 11

Cinacalcet H01 ms-1421w

Method: 25-2500. 100/min 40rn1/min N2

normalized ~46.27 Jg1

Jul. 21, 2009

DSC thermogrom of Cinocolcet HCI form l||

Cinocolcet HCt ins-14200!

Method: 25-2500 iOC/min 40mI/min N2

normalized 11.33 Jg"1

& Right Limit

TGA thermogrom of Cindcolcet HCI form |

Method: 25-200C, 10C/min,N2 40ml/min

Right Limit 100.01 C

Jul. 21, 2009

TGA thermogrom of Cinocolcet HC1 form ll

Cinocolcet HCI MS-1421w-blunk

Cinocolcet HCI MS-1421w, 9.1399 mg

Method: 25-200C, 10C/min,N2 40ml/min

Right Limit 100.12C

TCA thermogrom of Cinocolcet HC1 form |||

Method: 25-2000, 1OC/min,N2 40ml/min

25.0200.0C 10.00C/min N2 40.0 mI/min

Right Limit 160.09C