CRYSTALLINEFORMS OF PALBOCICLIB
Field of the Invention
The present invention provides crystalline Form I, Form II, Form III, Form IV,
Form V, Form V-A, Form VI, Form VII, and Form VIII of palbociclib, processes for their
preparation, pharmaceutical compositions comprising these crystalline forms, and their use
for the treatment of cyclin-dependent kinase (cdk) associated diseases.
Background of the Invention
Palbociclib of Formula I is chemically described as 6-acetyl-8-cyclopentyl-5-
methyl-2-[[5-( l-piperazinyl)-2-pyridinyl]amino]pyrido[2, 3-£/|pyrimidin-7(8H )-one.
Formula I
U.S. Patent No. 6,936,612 provides a process for the preparation of palbociclib
hydrochloride.
U.S. Patent No. 7,78 1,583 provides a process for the preparation of palbociclib
isoethionate.
U.S. Patent No. 7,863,278 provides polymorphs of various salts of palbociclib.
PCT Publication No. WO 2014/128588 provides crystalline Forms A and B of
palbociclib.
Summary of the Invention
The present invention provides crystalline Form I, Form II, Form III, Form IV,
Form V, Form V-A, Form VI, Form VII, and Form VIII of palbociclib, processes for their
preparation, pharmaceutical compositions comprising these crystalline forms, and their use
for the treatment of cyclin-dependent kinase (cdk) associated diseases.
Brief Description of the Drawings
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of crystalline Form
I of palbociclib.
Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of
crystalline Form I of palbociclib.
Fif 3 depicts an Infra-red (IR) spectrum of crystalline Form I of palbociclib.
Fiflure 4 depicts an XRPD pattern of crystalline Form II of palbociclib.
Fiflure 5 depicts a DSC thermogram of crystalline Form II of palbociclib.
Fiflure 6 depicts an IR spectrum of crystalline Form II of palbociclib.
Fi lure 7 depicts an XRPD pattern of crystalline Form III of palbociclib.
Fiflure 8 depicts an XRPD pattern of crystalline Form IV of palbociclib.
Fiflure 9 depicts an XRPD pattern of crystalline Form V of palbociclib.
Fiflure 10 depicts a DSC thermogram of crystalline Form V of palbociclib.
Fiflure 11 depicts an IR spectrum of crystalline Form V of palbociclib.
Fiflure 12 depicts an XRPD pattern of crystalline Form VI of palbociclib.
Fiflure 13 depicts an XRPD pattern of crystalline Form VII of palbociclib.
Fiflure 14 depicts a DSC thermogram of crystalline Form VII of palbociclib.
Fiflure 15 depicts an XRPD pattern of crystalline Form VIII of palbociclib.
Fiflure 16 depicts an XRPD pattern of crystalline Form V-A of palbociclib.
Fiflure 17 depicts DSC thermogram of crystalline Form V-A of palbociclib.
Fiflure 18 depicts IR spectrum of crystalline Form V-A of palbociclib.
Figure 19 depicts Thermogravimetric analysis (TGA) thermogram of crystalline
Form V-A of palbociclib.
Fiflure 20 depicts Scanning electron microscopy (SEM) image of crystalline Form
V-A of palbociclib.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within t e range
defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to a temperature in the
range of25°C to 35°C.
The term "contacting," as used herein, refers to dissolving, slurrying, stirring,
suspending, or combinations thereof.
The term "cyclin-dependent kinase (cdk) associated diseases," as used herein refers
to t e diseases mediated by cdk, which include but are not limited to, the cancers of the
breast, ovary, cervix, prostate, testis, esophagus, and stomach.
A first aspect of the present invention provides a crystalline form of palbociclib,
designated as Form I, characterized by an X-ray powder diffraction (XRPD) pattern
having peaks at d-spacings of about 2.8, 3.3, 3.6, 3.9, and 7.2 A, and additional peaks at dspacings
of about 4.4, 5.3, 11.2, 14.0, and 20.4 A.
Table 1 provides the d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of crystalline Form I of palbociclib.
Table 1
Crystalline Form I is characterized by a differential scanning calorimetry (DSC)
thermogram having endothermic peaks at about 81.3°C, 155.2°C, 238. 0°C, and 265.3°C
and an exothermic peak at about 185.7°C. Crystalline Form I is characterized by an infra
red (IR) absorption spectrum having characteristic peaks expressed in cm 1 at about
3420.2, 3233.7, 2953.9, 2481.6, 1696.9, 1649.5, 1580.9, 1552.2, 1454.5, 1400.0, 1371.7,
1289.4, 1250.4, 1151.1, 1122.0, 1084.4, 1017.6, 923.8, 821.5, 802.0, 745.8, 722.7, 689.0,
631.5, 562.0, and 465.8.
Crystalline Form I of palbociclib is also characterized by an XRPD pattern
substantially as depicted in Figure 1, a DSC thermogram substantially as depicted in
Figure 2, or an IR absorption spectrum substantially as depicted in Figure 3.
A second aspect of t e present invention provides a process for the preparation of
crystalline Form I of palbociclib, comprising:
i) contacting palbociclib hydrochloride with a mixture of methanol and water;
ii) adding an acid to the reaction mixture of step i); and
iii) adding a base to the reaction mixture of step ii) to obtain the crystalline
Form I of palbociclib.
Palbociclib hydrochloride used for the preparation of crystalline Form I of
palbociclib may be prepared by any method provided in the art, for example, the methods
as disclosed in U.S. Patent Nos. 7,863,278, 6,936,612, or 7,781,583, or by the method as
described herein.
Examples of acids include hydrochloric acid, hydrobromic acid, formic acid,
propionic acid, methane sulfonic acid, and toluene sulfonic acid.
Examples of bases include sodium hydroxide, potassium hydroxide, potassium
bicarbonate, sodium carbonate, and triethylamine.
The preparation of crystalline Form I of palbociclib is carried out at ambient
temperature for a period of about 30 minutes to about 2 hours, for example, for about 30
minutes to about one hour.
Crystalline Form I of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization, and dried under reduced pressure, by air
drying, or by vacuum tray drying.
A third aspect of the present invention provides a crystalline form of palbociclib,
designated as Form II, characterized by an XRPD pattern having peaks at d-spacings of
about 2.8, 4.0, 4.5, 5.2, and 8.6 A. Crystalline Form II of palbociclib is further
characterized by an XRPD pattern having additional peaks at d-spacings of about 3.3, 3.9,
4.8, 7.7, and 8.8 A.
Table 2 provides t e d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of the crystalline Form II of palbociclib.
Table 2
Crystalline Form II is characterized by a DSC thermogram having an endothermic
peak at about 78.0°C and an exothermic peak at about 275. 1°C. Crystalline Form II is
further characterized by an IR absorption spectrum having characteristic peaks expressed
in cm 1 at about 3417, 3298, 3232, 3173, 3084, 2947, 2869, 2843, 2469, 1770, 1664, 1602,
1581, 1548, 1528, 1488, 1449, 1396, 1366, 1332, 1310, 1284, 1248, 1235, 1188, 1148,
1122, 1078, 1039, 1022, 978, 937, 924, 899, 873, 860, 827, 805, 795, 776, 758, 747, 737,
720, 689, 646, 627, 617, 572, 533, 457, 431, and 407.
Crystalline Form II of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 4, a DSC thermogram substantially as depicted in
Figure 5, or an IR absorption spectrum substantially as depicted in Figure 6 .
A fourth aspect of t e present invention provides a process for t e preparation of
crystalline Form II of palbociclib, comprising:
i) contacting crystalline Form I of palbociclib with a mixture of solvents
selected from the group consisting of water and acetone, and water and 2-
propanol;
ii) adding hydrochloric acid to the reaction mixture of step i); and
iii) adding sodium hydroxide to the reaction mixture of step ii) to obtain the
crystalline Form II of palbociclib.
The preparation of the crystalline Form II of palbociclib is carried out at ambient
temperature for a period of about 15 minutes to about 2 hours, for example, for about 20
minutes to about one hour.
Crystalline Form II of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. Crystalline Form II of palbociclib may
be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
A fifth aspect of the present invention provides a crystalline form of palbociclib,
designated as Form III, characterized by an XRPD pattern having peaks at d-spacings of
about 4.0, 5.2, 8.6, and 8.8 A, and additional peaks at d-spacings of about 3.2, 3.9, 4.5, 4.8,
and 7.7 A.
Table 3 provides the d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of the crystalline Form III of palbociclib.
Table 3
Crystalline Form III of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 7.
A sixth aspect of t e present invention provides a process for the preparation of
crystalline Form III of palbociclib, comprising:
i) contacting crystalline Form I of palbociclib with a mixture of solvents
selected from the group consisting of water and 2-propanol, water and
acetonitrile, and water and acetone;
ii) adding hydrochloric acid to the reaction mixture of step i); and
iii) adding ammonia to the reaction mixture of step ii) to obtain the crystalline
Form III of palbociclib.
The preparation of crystalline Form III of palbociclib is carried out at ambient
temperature for a period of about 15 minutes to about 2 hours, for example, for about 25
minutes to about one hour.
Crystalline Form III of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. Crystalline Form III of palbociclib may
be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
A seventh aspect of the present invention provides a crystalline form of
palbociclib, designated as Form IV, characterized by an XRPD pattern having peaks at dspacings
of about 4.4, 5.8, 8.7, 11.1, and 17.3 A, and further characterized by an XRPD
pattern having additional peaks at d-spacings of about 2.5, 3.2, 4.8, 5.6, and 6.3 A.
Table 4 provides t e d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of crystalline Form IV of palbociclib.
Table 4
Crystalline Form IV of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 8.
An eighth aspect of t e present invention provides a process for t e preparation of
crystalline Form IV of palbociclib, comprising:
i) contacting crystalline Form I of palbociclib with a mixture of water and 1-
propanol;
ii) adding hydrochloric acid to the reaction mixture of step i); and
iii) adding ammonia to the reaction mixture of step ii) to obtain the crystalline
Form IV of palbociclib.
The preparation of crystalline Form IV of palbociclib is carried out at ambient
temperature for a period of about 5 minutes to about one hour, for example, for about 5
minutes to about 30 minutes.
Crystalline Form IV of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. Crystalline Form IV of palbociclib may
be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
A ninth aspect of the present invention provides a crystalline form of palbociclib,
designated as Form V, characterized by an XRPD pattern having peaks at d-spacings of
about 4.2, 5.4, 10.0, 11.3, and 15.6 A, and further characterized by additional peaks at dspacings
of about 3.3, 3.7, 4.4, 4.9, and 6.8 A.
Table 5 provides t e d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of crystalline Form V of palbociclib.
Table 5
Crystalline Form V of palbociclib is characterized by a DSC thermogram having
endothermic peaks at about 62.6°C, 126.0°C, and 262. 8°C. Crystalline Form V is further
characterized by an IR absorption spectrum having characteristic peaks expressed in cm 1
at about 3418.3, 3231.6, 3166.9, 2947.6, 2865.3, 1691.1, 1655.1, 1585.3, 1552.9, 1489.6,
1453.6, 1398.7, 1376.3, 1349.8, 1315.8, 1283.3, 1233.7, 1159.8, 1122.3, 1082.4, 1039.7,
1015.6, 990.3, 929.9, 906.5, 825.9, 800.9, 748.4, 723.8, 691.0, 623.7, 564.9, 542.6, 447.8,
and 430.2.
Crystalline Form V of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 9, a DSC thermogram substantially as depicted in
Figure 10, or an IR absorption spectrum substantially as depicted in Figure 11.
A tenth aspect of the present invention provides a process for the preparation of
crystalline Form V of palbociclib, comprising:
i) contacting crystalline Form III of palbociclib with a mixture of water and
methanol;
ii) adding an inorganic acid selected from the group consisting of sulphuric
acid and phosphoric acid to the reaction mixture of step i); and
iii) adding an inorganic base selected from the group consisting of sodium
bicarbonate and potassium carbonate to t e reaction mixture of step ii) to
obtain the crystalline Form V of palbociclib.
The preparation of crystalline Form V of palbociclib is carried out at ambient
temperature for a period of about 30 minutes to about 10 hours, for example, for about 30
minutes to about 5 hours.
Crystalline Form V of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. Crystalline Form V of palbociclib may
be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
An eleventh aspect of t e present invention provides a crystalline form of
palbiociclib designated as Form V-A, characterized by an XRPD pattern having peaks at
d-spacing of 11.3, 6.8, 5.3, 4.2, and 3.7 A, and further characterized by additional peaks at
d-spacings of about 15.5, 10.0, 4.4, 4.1, and 3.3 A.
Table 5A provides the d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of crystalline Form V-A of palbociclib.
Table 5A
Crystalline Form V-A of palbociclib is characterized by a DSC thermogram having
endothermic peaks at about 148.2°C, 269.2°C, 272. 1°C, and 284.2°C and an exothermic
peak at about 222. 9°C. Crystalline Form V-A of palbociclib is further characterized by an
IR absorption spectrum having characteristic peaks expressed in cm 1 at about 3422, 3235,
3168, 2948, 2865, 2804, 2468, 1692, 1654, 1585, 1555, 1488, 1454, 1399, 1377, 1349,
1315, 1293, 1279, 1263, 1233, 1160, 1143, 1125, 1083, 1040, 1016, 990, 931, 906, 826,
801, 749, 724, 691, 635, 624, 567, 543, 445, and 431.
Crystalline Form V-A of palbociclib has a specific surface area (SSA) of greater
than 2 m /g.
In an embodiment, the crystalline Form V-A of palbociclib has a specific surface
area (SSA) for example, of about 3 m /g to about 10 m /g.
Crystalline Form V-A of palbociclib has a particle size distribution (PSD) having
at least one of:
a) a Dio value of about 1 m i to about 5 m i;
b) a D 0 value of about 5 um to about 20 um;
c) a D90 value of about 15 m i to about 50 m i.
Crystalline Form V-A of palbociclib has a volume mean diameter (D[4,3]) of about
5 m i to about 50 m i.
Crystalline Form V-A of palbociclib has improved filterability, electrostatic nature,
and flowability.
Crystalline Form V-A of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 16, a DSC thermogram substantially as depicted in
Figure 17, an IR absorption spectrum substantially as depicted in Figure 18, a
thermogravimetric analysis (TGA) thermogram substantially as depicted in Figure 19, or a
scanning electron microscopy (SEM) image substantially as depicted in Figure 20.
A twelfth aspect of the present invention provides a process for the preparation of
crystalline Form V-A of palbociclib, comprising:
i) contacting palbociclib hydrochloride with a mixture of water and methanol
or a mixture of water or acetone; and
ii) adding an inorganic base to the reaction mixture of step (i) to obtain the
crystalline Form V of palbociclib.
Palbociclib hydrochloride used for the preparation of crystalline Form V-A of
palbociclib may be prepared by any method provided in the art, for example, the method
as disclosed in U.S. Patent Nos. 7,863,278, 6,936,6 12, or 7,78 1,583 or by the method as
described herein.
Examples of inorganic bases include sodium bicarbonate, potassium bicarbonate,
and calcium bicarbonate.
The preparation of crystalline Form V-A of palbociclib is carried out at about 20°C
to about 55°C for a period of about 30 minutes to about 5 hours, for example, for about
one hour to about 4 hours.
Crystalline Form V-A of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. Cryatalline Form V-A of palbociclib
may be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
An thirteenth aspect of the present invention provides a crystalline form of
palbociclib, designated as Form VI, characterized by an XRPD pattern having peaks at dspacings
of about 3.5, 3.6, 3.7, 4.0, and 4.3 Aand further characterized by additional
peaks at d-spacings of about 3.2, 3.4, 4.9, 5.2, and 5.4 A.
Table 6 provides t e d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of t e crystalline Form VI of palbociclib.
Table 6
d-spacing (A) Position (±0.2° 2Q) Relative Intensity (%)
15.5 5.7 1.9
11.2 7.9 4.3
9.8 9.0 3.0
8.7 10.1 9.1
8.4 10.5 7.2
7.6 11.6 2.2
6.6 13.4 19.6
5.4 16.3 38.7
5.2 17.0 32.1
4.9 18.2 31.8
4.3 20.6 41.6
4.0 22.1 100.0
3.7 23.9 53.2
3.6 24.7 50.1
3.5 25.3 39.8
3.4 25.9 37.6
3.2 27.7 37.0
3.0 29.9 23.0
2.8 32.2 14.9
2.6 34.3 8.6
2.5 35.5 9.1
2.3 39.0 5.5
Crystalline Form VI of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 12.
A fourteenth aspect of the present invention provides a process for t e preparation
of crystalline Form VI of palbociclib, comprising contacting crystalline Form III of
palbociclib with a solvent selected from the group consisting of 2-propanol, acetone,
tetrahydrofuran, and 2-propyl acetate to obtain the crystalline Form VI of palbociclib.
The preparation of t e crystalline Form VI of palbociclib is carried out at about
40°C to about 60°C, for example, at about 40°C to about 45°C, for about 2 hours to about
6 hours, for example, for about 2 hours to about 4 hours.
The crystalline Form VI of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. The crystalline Form VI of palbociclib
may be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
A fifteenth aspect of the present invention provides a crystalline form of
palbociclib, designated as Form VII, characterized by an XRPD pattern having peaks at dspacings
of about 3.6, 4.0, 4.2, 5.7, and 8.7 A, and further characterized by additional
peaks at d-spacings of about 3.7, 3.8, 4.3, 4.7, and 5.0 A.
Table 7 provides the d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of the crystalline Form VII of palbociclib.
Table 7
Crystalline Form VII of palbociclib is characterized by a DSC thermogram having
endothermic peaks at about 98.5°C, 251.2°C, 269.3°C, and 285.0°C.
Crystalline Form VII of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 13 or a DSC thermogram substantially as depicted in
Figure 14.
A sixteenth aspect of the present invention provides a process for t e preparation
of crystalline Form VII of palbociclib, comprising:
i) contacting crystalline Form III of palbociclib with a mixture of water and
methanol;
ii) adding sulphuric acid to the reaction mixture of step i); and
iii) adding ammonia to the reaction mixture of step ii) to obtain crystalline
Form VII of palbociclib.
The preparation of crystalline Form VII of palbociclib is carried out at ambient
temperature for a period of about 30 minutes to about 5 hours, for example, for about one
hour to about 4 hours.
The crystalline Form VII of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. The crystalline Form VII of palbociclib
may be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
A seventeenth aspect of t e present invention provides a crystalline form of
palbociclib, designated as Form VIII, characterized by an XRPD pattern having peaks at
d-spacings of about 2.7, 3.9, 4 . 0, 4.7, and 4.8 Aand further characterized by additional
peaks at d-spacings of about 4.2, 4.5, 5.3, 7.7, and 8.7 A.
Table 8 provides the d-spacing values (A), the corresponding 2Qvalues, and the
relative intensity of the crystalline Form VIII of palbociclib.
Table 8
The crystalline Form VIII of palbociclib is characterized by an XRPD pattern
substantially as depicted in Figure 15.
An eighteenth aspect of t e present invention provides a process for the
preparation of crystalline Form VIII of palbociclib, comprising the steps of:
i) contacting crystalline Form I of palbociclib with a mixture of water and
dimethyl formamide;
ii) adding an acid to the reaction mixture of step i); and
iii) adding a base to the reaction mixture of step ii) to obtain crystalline Form
VIII of palbociclib.
Examples of acids include hydrochloric acid and sulphuric acid.
Examples of bases include ammonia and sodium bicarbonate.
The preparation of crystalline Form VIII of palbociclib is carried out at ambient
temperature for a period of about 30 minutes to about 5 hours, for example, for about one
hour to about 3 hours.
Crystalline Form VIII of palbociclib may be isolated by filtration, decantation,
extraction, distillation, evaporation, chromatography, precipitation, concentration,
crystallization, centrifugation, or recrystallization. Crystalline Form VIII of palbociclib
may be dried by drying under reduced pressure, by air drying, or by vacuum tray drying.
A nineteenth aspect of the present invention provides a pharmaceutical
composition comprising crystalline forms selected from the group consisting of Form I,
Form II, Form III, Form IV, Form V, Form V-A, Form VI, Form VII, and Form VIII of
palbociclib, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
A twentieth aspect of the present invention provides a method for treating cyclindependent
kinase associated diseases comprising administering to a patient in need thereof
a therapeutically effective amount of a composition comprising crystalline forms selected
from the group consisting of Form I, Form II, Form III, Form IV, Form V, Form V-A,
Form VI, Form VII, and Form VIII of palbociclib.
While t e present invention has been described in terms of its specific aspects and
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art, and are intended to be included within the scope of the present invention.
Methods
XRPD of the samples was determined by using a PANalytical®instrument; Model
X'pert PRO; Detector: X'celerator ®.
IR of the samples was recorded using a PerkinElmer® instrument, potassium
bromide pellet method.
DSC of the samples was recorded using a Mettler-Toledo® 82 le instrument.
TGA was recorded using a TA Instruments® Q500.
SEM analysis was carried out using a JEOL® JSM-6010LV instrument. The
samples were coated by a JEOL® Platinum Sputter Coater.
Particle size distribution was measured using a Malvern Mastersizer 2000
instrument.
Specific surface area was determined using a Micromeritic ® Gemini® VII 2390
Surface Analyzer (Software: Gemini VII, version 1.03).
The following examples are for illustrative purposes only and should not be
construed as limiting the scope of t e invention in any way.
EXAMPLES
Example 1: Preparation of palbociclib hydrochloride
Concentrated hydrochloric acid (13 mL) was added to a solution of -butyl 4-(6-
{[6-(l-butoxyemenyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-£/]pyrimidin-
2-yl]amino}pyridin-3-yl)piperazine-l-carboxylate (15 g) (obtained per the procedure
disclosed in U.S. Patent No. 7,781,583) in methanol (150 mL) at 25°Cto 30°C to obtain a
reaction mixture. The reaction mixture was heated to 50°C to 55°C for 2 hours, then
cooled to ambient temperature. Sodium hydroxide solution (20%, 20 mL) was added to
t e reaction mixture to adjust the pH to 7.5 to 8.0 to obtain a solid. The solid was stirred
at 25°C to 30°C for one hour. The solid was filtered, then washed with water (30 mL),
and then washed with methanol (30 mL) to obtain the title compound as a light grey solid.
Yield: 14 g
Example 2 : Preparation of a crystalline Form I of palbociclib
Palbociclib hydrochloride (14 g, as obtained in Example 1) was suspended in a
mixture of water and methanol (1:1, 160 mL) at 25°C to 30°C to obtain a reaction mixture.
Concentrated hydrochloric acid (25 mL) was added to the reaction mixture to obtain a
clear solution. Activated carbon ( 1.4 g) was added to the reaction mixture and the mixture
was stirred for 10 minutes to 15 minutes. The reaction mixture was filtered through a
Hyflo® bed and then washed with a mixture of water and methanol ( 1:1, 28 mL) to obtain
a filtrate. Sodium hydroxide (20%, 35 mL) was added to the filtrate to adjust the pH to 7.5
to 8.0 to obtain a solid. The solid was stirred for 45 minutes to 60 minutes at 25°C to
30°C. The solid was filtered, then washed with a mixture of water and methanol (1: 1, 40
mL), and then dried under vacuum at 35°C to 40°C for 8 hours to 10 hours to obtain the
title compound.
Yield: 10 g
Example : Preparation of a crystalline Form II of palbociclib
Method A: Palbociclib ( 1 g, Form I as obtained in Example 2) was suspended in a
mixture of water and acetone (1:1, 10 mL) at 25°C to 30°C to obtain a reaction mixture.
Concentrated hydrochloric acid (6 mL) was added to the reaction mixture and the mixture
was stirred for 5 minutes to 10 minutes. Activated carbon (100 mg) was added to the
reaction mixture and the mixture was stirred for 10 minutes. The reaction mixture was
filtered, and then washed with a mixture of water and acetone (1:1, 4 mL) to obtain a
filtrate. Sodium hydroxide (20%, 12 mL) was added to the filtrate to adjust t e pH to 7.5
to 8.0 to obtain a solid. The solid was stirred for 20 minutes to 30 minutes at 25°C to
30°C. The solid was filtered, then washed with a mixture of water and acetone (1:1, 10
mL), and then dried under vacuum at 35°C to 40°C for 10 hours to 12 hours to obtain the
title compound.
Yield: 0.65 g
Method B: Palbociclib ( 1 g, Form I as obtained in Example 2) was suspended in a
mixture of water and 2-propanol (1:1, 10 mL) at 25°C to 30°C to obtain a reaction
mixture. Concentrated hydrochloric acid (7 mL) was added to the reaction mixture and
the mixture was stirred for 5 minutes to 10 minutes at 25°C to 30°C. Activated carbon
(100 mg) was added to the reaction mixture and the mixture was stirred for 10 minutes.
The reaction mixture was filtered through a Hyflo® bed, and then washed with a mixture
of water and 2-propanol (1:1, 4 mL) to obtain a filtrate. Sodium hydroxide (20%, 15 mL)
was added to the filtrate to adjust the pH to 9.0 to 9.5 to obtain a solid. The solid was
stirred for 20 minutes to 30 minutes at 25°C to 30°C. The solid was filtered, then washed
with a mixture of water and 2-propanol (1:1, 10 mL), and then dried under vacuum at
35°C to 40°C for 10 hours to 12 hours to obtain the title compound.
Yield: 0.5 g
Example 4 : Preparation of a crystalline Form III of palbociclib
Method A: Palbociclib (0.3 g, Form I as obtained in Example 2) was suspended in a
mixture of water and 2-propanol ( 1:1, 20 mL) at 25°C to 30°C to obtain a reaction
mixture. Concentrated hydrochloric acid (100 m ) was added to the reaction mixture and
the mixture was stirred for 5 minutes. Aqueous ammonia (25%, 500 m ) was added to the
reaction mixture and the mixture was stirred for 25 minutes to obtain a solid. The solid
was filtered, then washed with water (5 mL), and then dried under vacuum at 25°C to
30°C for 18 hours to obtain the title compound.
Yield: 0.19 g
Method B: Palbociclib (0.3 g, Form I as obtained in Example 2) was suspended in a
mixture of water and acetonitrile (1:1, 10 mL) at 25°C to 30°C to obtain a reaction
mixture. Concentrated hydrochloric acid (300 m ) was added to the reaction mixture and
t e mixture was stirred for 2 minutes to 3 minutes. Aqueous ammonia (25%, 500 m ) was
added to the reaction mixture and the mixture was stirred for one hour to obtain a solid.
The solid was filtered, then washed with water (5 mL), and then dried under vacuum at
25°C to 30°C for 16 hours to obtain the title compound.
Yield: 0.187 g
Method C: Palbociclib (0.3 g, Form I as obtained in Example 2) was suspended in a
mixture of water and acetone (1:1, 14 mL) at 25°C to 30°C to obtain a reaction mixture.
Concentrated hydrochloric acid (100 m ) was added to the reaction mixture and the
mixture was stirred for 2 minutes to 3 minutes. Liquid ammonia (25%, 500 m ) was
added to the reaction mixture and the mixture was stirred for one hour to obtain a solid.
The solid was filtered, then washed with water (5 mL), and then dried under vacuum at
25°C to 30°C for 16 hours to obtain the title compound.
Yield: 0.197 g
Example 5: Preparation of a crystalline Form IV of palbociclib
Palbociclib (0.3 g, Form I as obtained in Example 2) was suspended in a mixture of
water and 1-propanol (1: 1, 20 mL) at 25°C to 30°C to obtain a reaction mixture.
Concentrated hydrochloric acid (100 m ) was added to the reaction mixture and the
mixture was stirred for 5 minutes. Aqueous ammonia (25%, 500 m ) was added to the
reaction mixture and the mixture was stirred for 10 minutes to obtain a solid. The solid
obtained was filtered, then washed with water (5 mL), and then dried under vacuum at
25°C to 30°C for 17 hours to obtain the title compound.
Yield: 0.185 g
Example 6 : Preparation of a crystalline Form V of palbociclib
Method A: Palbociclib ( 1 g, Form III as obtained in Example 4) was suspended in a
mixture of water and methanol (1:1, 36 mL) at 25°C to 30°C to obtain a reaction mixture.
Dilute sulphuric acid (2:1 ratio of H20:H 2S0 4) was added drop-wise to the reaction
mixture until the pH was about 2 to 3 . The reaction mixture was stirred for 20 minutes at
25°C to 30°C. Saturated sodium bicarbonate solution in water was added to the reaction
mixture until the pH was 7 to 8. The reaction mixture was stirred for 3 hours to 4 hours at
25°C to 30°C to obtain a solid. The solid was filtered, then washed with deionized (DI)
water (22 mL), and then dried under vacuum at 50°C for 12 hours to obtain the title
compound.
Yield: 0.9 g
Method B: Palbociclib ( 1 g, Form III as obtained in Example 4) was suspended in a
mixture of water and methanol (1:1, 36 mL) at 25°C to 30°C to obtain a reaction mixture.
Dilute sulphuric acid (2: 1 ratio of H20:H 2S0 4) was added drop-wise to the reaction
mixture until the pH was about 2 to 3 . The reaction mixture was stirred for 10 minutes at
25°C to 30°C. Saturated sodium bicarbonate solution in water was added to the reaction
mixture until the pH was 7 to 8. The reaction mixture was stirred for 30 minutes at 25°C
to 30°C to obtain a solid. The solid obtained was filtered, then washed with DI water (22
mL), and then dried under vacuum at 50°C for 9 hours to obtain the title compound.
Yield: 0.85 g
Method C: Palbociclib ( 1 g, Form III as obtained in Example 4) was suspended in a
mixture of water and methanol (1:1, 36 mL) at 25°C to 30°C to obtain a reaction mixture.
Dilute sulphuric acid (2: 1 ratio of H20:H 2S04) was added drop-wise to the reaction
mixture until the pH was about 2 to 3 . The reaction mixture was stirred for 10 minutes at
25°C to 30°C. Saturated sodium bicarbonate solution in water was added to the reaction
mixture until the pH was 7 to 8. The reaction mixture was stirred for 4 hours at 25°C to
30°C to obtain a solid. The solid obtained was filtered, then washed with DI water (22
mL), and then dried under vacuum at 50°C for 9 hours to obtain the title compound.
Yield: 0.95 g
Method D: Palbociclib (0.1 g, Form III as obtained in Example 4) was suspended in a
mixture of water and methanol (1:1, 4 mL) at 25°C to 30°C to obtain a reaction mixture.
Dilute phosphoric acid (1:1 ratio of H20:H 3P0 4) was added drop-wise to the reaction
mixture until the pH was about 2 to 3. The reaction mixture was stirred for one hour at
25°C to 30°C. Saturated sodium bicarbonate solution in water was added to the reaction
mixture until the pH was 7 to 8. The reaction mixture was stirred for 3.5 hours at 25°C to
30°C to obtain a solid. The solid obtained was filtered, then dried under vacuum at 50°C
for 6 hours to obtain the title compound.
Yield: 0.09 g
Method E: Palbociclib (0. lg, Form III as obtained in Example 4) was suspended in a
mixture of water and methanol (1:1, 4 mL) at 25°C to 30°C to obtain a reaction mixture.
Dilute phosphoric acid (1:1 ratio of H O Ή R O , was added drop-wise to the reaction
mixture until the pH was about 2 to 3. The reaction mixture was stirred for one hour at
25°C to 30°C. Saturated potassium carbonate solution in water was added to the reaction
mixture until the pH was 7 to 8. The reaction mixture was stirred for 3.5 hours at 25°C to
30°C to obtain a solid. The solid obtained was filtered, then dried under vacuum at 50°C
for 6 hours to obtain the title compound.
Yield: 0.07 g
Example 7 : Preparation of a crystalline Form V-A of palbociclib
Palbociclib hydrochloride (100 g, as obtained in Example 1) was dissolved in a
mixture of water and methanol (1:1, 4000 mL) at 25°C to 30°C to obtain a reaction
mixture. Eno anti chromos carbon (20 g) and sodium metabisulphite (2 g) were added to
the reaction mixture and the mixture was stirred for 30 minutes. The reaction mixture was
filtered through a Hyflo® bed and then washed with water (500 mL) to obtain a filtrate.
The filtrate was passed through a 0.45 micron filter. The filtrate obtained was heated at
40°C to 50°C. The filtrate was treated with aqueous sodium bicarbonate (5 %) to adjust
the pH to 7.0 to 7.2 over 90 minutes at 40°C to 50°C. The reaction mixture was stirred at
40°C to 50°C for 2 hours to 3 hours. The reaction mixture was filtered, and then washed
with water (2 200 mL), methanol ( l 200 mL) and acetone ( l 200 mL) to obtain a
solid. The solid obtained was dried at 50°C to 60°C for 12 hours to obtain t e title
compound.
Yield: 75 g
Example 8 : Preparation of a crystalline Form VI of palbociclib
Method A: Palbociclib (0.15 g, Form III as obtained in Example 4) was suspended in 2-
propanol (0.5 mL) to obtain a slurry. The slurry was stirred at 45°C for 2 hours on a
Rotavapor®. The solvent was dried under vacuum at room temperature for 5 hours to
obtain a solid. The solid was further dried under vacuum at 50°C for 12 hours to obtain
t e title compound.
Yield: 0.1 g
Method B: Palbociclib (0.15 g, Form III as obtained in Example 4) was suspended in
acetone (0.5 mL) to obtain a slurry. The slurry was stirred at 45°C for 2 hours on a
Rotavapor®. The solvent was dried under vacuum at room temperature for 5 hours to
obtain a solid. The solid was further dried under vacuum at 50°C for 12 hours to obtain
the title compound.
Yield: 0.11 g
Method C: Palbociclib (0.15 g, Form III as obtained in Example 4) was suspended in
tetrahydrofuran (0.5 mL) to obtain a slurry. The slurry was stirred at 45°C for 2 hours on
a Rotavapor®. The solvent was dried under vacuum at room temperature for 5 hours to
obtain a solid. The solid was further dried under vacuum at 50°C for 12 hours to obtain
the title compound.
Yield: 0.1 g
Method D: Palbociclib (0.15 g, Form III as obtained in Example 4) was suspended in 2-
propylacetate (0.5 mL) to obtain a slurry. The slurry was stirred at 45°C for 2 hours on a
Rotavapor®. The solvent was dried under vacuum at room temperature for 5 hours to
obtain a solid. The solid was dried further under vacuum at 50°C for 12 hours to obtain
the title compound.
Yield: 0.1 g
Example 9 : Preparation of a crystalline Form VII of palbociclib
Palbociclib (1.5 g, Form III as obtained in Example 4) was suspended in a mixture
of water and methanol (1:1, 50 mL) at 25°C to 30°C to obtain a reaction mixture. Dilute
sulphuric acid (1200 m ) was added drop-wise to t e reaction mixture until the pH was 2
to 3. The reaction mixture was stirred for one hour at 25°C to 30°C. Aqueous ammonia
was added to t e reaction mixture until the pH was 10 to 11. The reaction mixture was
stirred for 3.5 hours at 25°C to 30°C to obtain a solid. The solid obtained was filtered,
then dried under vacuum at 50°C for 6 hours to obtain the title compound.
Yield: 1.5 g
Example 10: Preparation of a crystalline Form VIII of palbociclib
Palbociclib (0.3 g, Form I as obtained in Example 2) was suspended in a mixture of
water and dimethyl formamide (1:1, 10 mL) at 25°C to 30°C to obtain a reaction mixture.
Concentrated hydrochloric acid (500 m ) was added to the reaction mixture and the
mixture was stirred for 2 minutes to 3 minutes at 25°C to 30°C. Aqueous ammonia (25%,
800 m ) was added to the reaction mixture and then the reaction mixture was stirred at
25°C to 30°C for 30 minutes to obtain a solid. The solid obtained was filtered, then
washed with water (5 mL), and then dried under vacuum at 25°C to 30°C for 7 hours to
obtain the title compound.

We claim:
1. Crystalline Form V-A of palbociclib characterized by an X-ray powder diffraction
(XRPD) pattern having peaks at d-spacings of about 11.3, 6.8, 5.3, 4.2, and 3.7 A.
2 . The crystalline Form V-A of claim 1 characterized by an XRPD pattern having
additional peaks at d-spacings of about 15.5, 10.0, 4.4, 4.1, and 3.3 A.
3. The crystalline Form V-A of claim 1 characterized by a differential scanning
calorimetry (DSC) thermogram having endothermic peaks at about 148.2°C, 269.2°C,
272. 1°C, and 284.2°C and an exothermic peak at about 222.9°C.
4 . The crystalline Form V-A of claim 1 characterized by an Infra-red (IR) absorption
spectrum having characteristic peaks at about 3422, 3235, 3168, 2948, 2865, 2804, 2468,
1692, 1654, 1585, 1555, 1488, 1454, 1399, 1377, 1349, 1315, 1293, 1279, 1263, 1233,
1160, 1143, 1125, 1083, 1040, 1016, 990, 931, 906, 826, 801, 749, 724, 691, 635, 624,
567, 543, 445, and 431cm 1.
5. The crystalline Form V-A of claim 1 having specific surface area greater than 2
m /g.
6. The crystalline Form V-A of claim 5 having t e specific surface area of about 3
m /g to about 10 m /g.
7. The crystalline Form V-A of claim 1 having particle size distribution of at least
one of:
a) a Dio value of about Im i to about 5 m i;
b) a D 0 value of about 5 m i to about 20 m i; or
c) a D 0 value of about 15 m i to about 50 m i.
8. The crystalline Form V-A of claim 1 having a volume mean diameter (D[4,3]) of
about 5 m i to about 50 um.
9. The crystalline Form V-A of claim 1 characterized by an XRPD pattern
substantially as depicted in Figure 16.
10. The crystalline Form V-A of claim 1 characterized by a DSC thermogram
substantially as depicted in Figure 17.
11. The crystalline Form V-A of claim 1 characterized by an IR absorption
substantially as depicted in Figure 18.
12. The crystalline Form V-A of claim 1 characterized by a thermogravimetric analysis
(TGA) thermogram substantially as depicted in Figure 19.
13. The crystalline Form V-A of claim 1 characterized by a scanning electron
microscopy (SEM) image substantially as depicted in Figure 20.
14. A process for t e preparation of t e crystalline Form V-A of claim 1, comprising
i) contacting palbociclib hydrochloride with water and mixture of methanol or
acetone; and
ii) adding an inorganic base to the reaction mixture of step i) to obtain the
crystalline Form V of palbociclib.
15. The process of claim 14, wherein the inorganic base is selected from the group
consisting of sodium bicarbonate, potassium bicarbonate, and calcium bicarbonate.
16. Crystalline Form I of palbociclib, characterized by an X-ray powder diffraction
(XRPD) pattern having peaks at d-spacings of about 2.8, 3.3, 3.6, 3.9, and 7.2 A.
17. The crystalline Form I of claim 16 characterized by an XRPD pattern having
additional peaks at d-spacings of about 4.4, 5.3, 11.2, 14.0, and 20.4 A.
18. The crystalline Form I of claim 16 characterized by a differential scanning
calorimetry (DSC) thermogram having endothermic peaks at about 81.3°C, 155.2°C,
238.0°C, and 265.3°C and an exothermic peak at 185.7°C.
19. The crystalline Form I of claim 16 characterized by an infra-red (IR) absorption
spectrum having characteristic peaks at about 3420.2, 3233.7, 2953.9, 2481 .6, 1696.9,
1649.5, 1580.9, 1552.2, 1454.5, 1400.0, 1371.7, 1289.4, 1250.4, 1151.1, 1122.0, 1084.4,
1017.6, 923.8, 821.5, 802.0, 745.8, 722.7, 689.0, 631.5, 562.0, and 465.8 cm 1.
20. The crystalline Form I of claim 16 characterized by an XRPD pattern substantially
as depicted in Figure 1.
2 1. The crystalline Form I of claim 16 characterized by a DSC thermogram
substantially as depicted in Figure 2 .
22. The crystalline Form I of claim 16 characterized by an IR absorption spectrum
substantially as depicted in Figure 3.
23. A process for the preparation of t e crystalline Form I of claim 16, comprising:
i) contacting palbociclib hydrochloride with a mixture of methanol and water;
ii) adding an acid to the reaction mixture of step i); and
iii) adding a base to the reaction mixture of step ii) to obtain the crystalline
Form I of palbociclib.
24. The process of claim 23, wherein the acid is selected from the group consisting of
hydrochloric acid, hydrobromic acid, formic acid, propionic acid, methane sulfonic acid,
and />-toluene sulfonic acid.
25. The process of claim 23, wherein the base is selected from the group consisting of
sodium hydroxide, potassium hydroxide, potassium bicarbonate, sodium carbonate, and
triethylamine.
26. Crystalline Form II of palbociclib, characterized by an XRPD pattern having peaks
at d-spacings of about 2.8, 4.0, 4.5, 5.2, and 8.6 A.
27. The crystalline Form II of claim 26 characterized by an XRPD pattern having
additional peaks at d-spacings of about 3.3, 3.9, 4.8, 7.7, and 8.8 A.
28. The crystalline Form II of claim 26 characterized by a DSC thermogram having an
endothermic peak at about 78.0°C and an exothermic peak at about 275. 1°C.
29. The crystalline Form II of claim 26 characterized by an IR absorption spectrum
having characteristic peaks at about 3417, 3298, 3232, 3173, 3084, 2947, 2869, 2843,
2469, 1770, 1664, 1602, 1581, 1548, 1528, 1488, 1449, 1396, 1366, 1332, 1310, 1284,
1248, 1235, 1188, 1148, 1122, 1078, 1039, 1022, 978, 937, 924, 899, 873, 860, 827, 805,
795, 776, 758, 747, 737, 720, 689, 646, 627, 617, 572, 533, 457, 431, and 407 cm 1.
30. The crystalline Form II of claim 26 characterized by an XRPD pattern substantially
as depicted in Figure 4 .
31. The crystalline Form II of claim 26 characterized by a DSC thermogram
substantially as depicted in Figure 5.
32. The crystalline Form II of claim 26 characterized by an IR spectrum as depicted in
Figure 6 .
33 . A process for the preparation of the crystalline Form II of claim 26 comprising:
i) contacting crystalline Form I of palbociclib with a mixture of solvents
selected from the group consisting of water and acetone, and water and 2-
propanol;
ii) adding hydrochloric acid to the reaction mixture of step i); and
iii) adding sodium hydroxide to the reaction mixture of step ii) to obtain the
crystalline Form II of palbociclib.
34. Crystalline Form III of palbociclib, characterized by an XRPD pattern having
peaks at d-spacings of 4.0, 5.2, 8.6, and 8.8 A.
35 . The crystalline Form III of claim 34 characterized by an XRPD pattern having
additional peaks at d-spacings of 3.2, 3.9, 4.5, 4.8, and 7.7 A.
36. The crystalline Form III of claim 34 characterized by an XRPD pattern as depicted
in Figure 7 .
37. A process for t e preparation of crystalline Form III of claim 34, comprising:
i) contacting crystalline Form I palbociclib with a mixture of solvents
selected from the group consisting of water and 2-propanol, water and
acetonitrile, and water and acetone;
ii) adding hydrochloric acid to the reaction mixture of step i); and
iii) adding ammonia to the reaction mixture of step ii) to obtain the crystalline
Form III of palbociclib.
38. Crystalline Form IV of palbociclib, characterized by an XRPD pattern having
peaks at d-spacings of about 4.4, 5.8, 8.7, 11.1, and 17.3 A.
39. The crystalline Form IV of claim 38 characterized by an XRPD pattern having
additional peaks at d-spacings of about 2.5, 3.2, 4.8, 5.6, and 6.3 A.
40. The crystalline Form IV of claim 38 characterized by an XRPD pattern
substantially as depicted in Figure 8.
4 1. A process for the preparation of crystalline Form IV of claim 38 comprising:
i) contacting crystalline Form I of palbociclib with a mixture of water and 1-
propanol;
ii) adding hydrochloric acid to the reaction mixture of step i); and
iii) adding ammonia to the reaction mixture of step ii) to obtain the crystalline
Form IV of palbociclib.
42. Crystalline Form V of palbociclib, characterized by an XRPD pattern having peaks
at d-spacings of about 4.2, 5.4, 10.0, 11.3, and 15.6 A.
43. The crystalline Form V of claim 42 characterized by an XRPD pattern having
additional peaks at d-spacings of about 3.3, 3.7, 4.4, 4.9, and 6 . 8 A.
44. The crystalline Form V of claim 42 characterized by a DSC thermogram having
endothermic peaks at about 62.6°C, 126.0°C, and 262. 8°C.
45. The crystalline Form V of claim 42 characterized by an IR absorption spectrum
having characteristic peaks at about 3418.3, 3231.6, 3166.9, 2947.6, 2865.3, 1691.1,
1655.1, 1585.3, 1552.9, 1489.6, 1453.6, 1398.7, 1376.3, 1349.8, 1315.8, 1283.3, 1233.7,
1159.8, 1122.3, 1082.4, 1039.7, 1015.6, 990.3, 929.9, 906.5, 825.9, 800.9, 748.4, 723.8,
691.0, 623.7, 564.9, 542.6, 447.8, and 430.2 cm 1.
46. The crystalline Form V of claim 42 characterized by an XRPD pattern
substantially as depicted in Figure 9.
47. The crystalline Form V of claim 42 characterized by a DSC thermogram
substantially as depicted in Figure 10.
48. The crystalline Form V of claim 42 characterized by an IR absorption spectrum
substantially as depicted in Figure 11.
49. A process for the preparation of crystalline Form V of claim 42 comprising:
i) contacting crystalline Form III of palbociclib with a mixture of water and
methanol;
ii) adding an inorganic acid selected from the group consisting of sulphuric
acid and phosphoric acid to the reaction mixture of step i); and
iii) adding an inorganic base selected from the group consisting of sodium
bicarbonate and potassium carbonate to the reaction mixture of step ii) to
obtain the crystalline Form V of palbociclib.
50. Crystalline Form VI of palbociclib, characterized by an XRPD pattern having
peaks at d-spacings of about 3.5, 3.6, 3.7, 4.0, and 4.3 A.
51. The crystalline Form VI of claim 50 characterized by an XRPD pattern having
additional peaks at d-spacings of about 3.2, 3.4, 4.9, 5.2, and 5.4 A.
52. The crystalline Form VI claim 50 characterized by an XRPD pattern substantially
as depicted in Figure 12.
53. A process for t e preparation of crystalline Form VI of claim 50 comprising
contacting crystalline Form III palbociclib with a solvent selected from the group
consisting of 2-propanol, acetone, tetrahydrofuran, and 2-propyl acetate to obtain t e
crystalline Form VI palbociclib.
54. Crystalline Form VII of palbociclib, characterized by an XRPD pattern having
peaks at d-spacings of about 3.6, 4.0, 4.2, 5.7, and 8.7 A.
55. The crystalline Form VII of claim 54 characterized by an XRPD pattern having
additional peaks at d-spacings of 3.7, 3.8, 4.3, 4.7, and 5.0 A.
56. The crystalline Form VII of claim 54 characterized by a DSC thermogram having
endothermic peaks at about 98.5°C, 251.2°C, 269.3°C, and 285.0°C.
57. The crystalline Form VII of claim 54 characterized by an XRPD pattern
substantially as depicted in Figure 13.
58. The crystalline Form VII of claim 54 characterized by a DSC thermogram
substantially as depicted in Figure 14.
59. A process for the preparation of crystalline Form VII of claim 54 comprising:
i) contacting crystalline Form III of palbociclib with a mixture of water and
methanol;
ii) adding sulphuric acid to the reaction mixture of step i); and
iii) adding ammonia to the reaction mixture of step ii) to obtain the crystalline
Form VII of palbociclib.
60. Crystalline Form VIII of palbociclib, characterized by an XRPD pattern having
peaks at d-spacings of about 2.7, 3.9, 4.0, 4.7, and 4.8 A.
6 1. The crystalline Form VIII of claim 60 characterized by an XRPD pattern having
additional peaks at d-spacings of about 4.2, 4.5, 5.3, 7.7, and 8.7 A.
62. The crystalline Form VIII of claim 60 characterized by an XRPD pattern
substantially as depicted in Figure 15 .
63 . A process for t e preparation of crystalline Form VIII of claim 60, comprising:
i) contacting crystalline Form I of palbociclib with a mixture of water and
dimethyl formamide;
ii) adding an acid to the reaction mixture of step i); and
iii) adding a base to the reaction mixture of step ii) to obtain the crystalline
Form VIII of palbociclib.
64. The process according to claim 63, wherein the acid is selected from the group
consisting of hydrochloric acid and sulphuric acid.
65 . The process according to claim 63, wherein the base is selected from the group
consisting of ammonia and sodium bicarbonate.
66. A pharmaceutical composition comprising crystalline forms selected from the
group consisting of Form I, Form II, Form III, Form IV, Form V, Form V-A, Form VI,
Form VII, and Form VIII of palbociclib, and one or more pharmaceutically acceptable
carriers, diluents, or excipients.
67. A method for treating cyclin-dependent kinase associated diseases comprising
administering to a patient a therapeutically effective amount of a composition comprising
crystalline forms selected from the group consisting of Form I, Form II, Form III, Form
IV, Form V, Form V-A, Form VI, Form VII, and Form VIII of palbociclib.