U.S. patent application number 14/312006 was filed with the patent office on 2014-10-09 for crystalline pharmaceutical.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Sanjay Chemburkar, Daniel A. Dickman, James J. Fort, Rodger F. Henry, David Lechuga-Ballesteros, Yuping Niu, William R. Porter.
Application Number | 20140303369 14/312006 |
Document ID | / |
Family ID | 26889137 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140303369 |
Kind Code |
A1 |
Dickman; Daniel A. ; et
al. |
October 9, 2014 |
Crystalline Pharmaceutical
Abstract
New crystalline forms of lopinavir are disclosed.
Inventors: |
Dickman; Daniel A.; (Gurnee,
IL) ; Chemburkar; Sanjay; (Gurnee, IL) ; Fort;
James J.; (Midlothian, VA) ; Henry; Rodger F.;
(Wildwood, IL) ; Lechuga-Ballesteros; David;
(Santa Clara, CA) ; Niu; Yuping; (River Vale,
NJ) ; Porter; William R.; (Vernon Hills, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
26889137 |
Appl. No.: |
14/312006 |
Filed: |
June 23, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13107780 |
May 13, 2011 |
8796451 |
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14312006 |
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11542075 |
Oct 2, 2006 |
8058433 |
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13107780 |
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10984393 |
Nov 9, 2004 |
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11542075 |
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10387175 |
Mar 12, 2003 |
6864369 |
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10984393 |
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09793536 |
Feb 27, 2001 |
6608198 |
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10387175 |
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60193573 |
Mar 30, 2000 |
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Current U.S.
Class: |
544/316 |
Current CPC
Class: |
A61K 31/513 20130101;
A61K 31/00 20130101; C07D 239/10 20130101; A61K 2300/00 20130101;
A61K 47/44 20130101; A61K 9/4866 20130101; A61K 31/00 20130101;
A61P 31/18 20180101; A61K 47/10 20130101 |
Class at
Publication: |
544/316 |
International
Class: |
C07D 239/10 20060101
C07D239/10 |
Claims
1. A hydrated crystalline form of lopinavir with characteristic
peaks in the powder X-ray diffraction pattern at values of two
theta of 7.25.degree..+-.0.1.degree., 8.53.degree..+-.0.1.degree.,
10.46.degree..+-.0.1.degree., 11.05.degree..+-.0.1.degree.,
11.71.degree..+-.0.1.degree., 14.76.degree..+-.0.1.degree.,
15.30.degree..+-.0.1.degree., 16.67.degree..+-.0.1.degree.,
17.32.degree..+-.0.1.degree., 19.10.degree..+-.0.1.degree.,
19.57.degree..+-.0.1.degree., 21.24.degree..+-.0.1.degree.,
21.84.degree..+-.0.1.degree. and 22.46.degree..+-.0.1.degree..
2. A higher hydrated crystalline form of lopinavir with
characteristic peaks in the powder X-ray diffraction pattern at
values of two theta of 3.89.degree..+-.0.1.degree.,
6.55.degree..+-.0.1.degree., 7.76.degree..+-.0.1.degree.,
8.55.degree..+-.0.1.degree., 9.70.degree..+-.0.1.degree.,
10.56.degree..+-.0.1.degree., 14.76.degree..+-.0.1.degree.,
15.57.degree..+-.0.1.degree., 18.30.degree..+-.0.1.degree.,
18.95.degree..+-.0.1.degree. and 22.74.degree..+-.0.1.degree..
3. A higher hydrated crystalline form of lopinavir with
characteristic peaks in the powder X-ray diffraction pattern at
values of two theta of 3.89.degree..+-.0.1.degree.,
6.55.degree..+-.0.1.degree., 7.76.degree..+-.0.1.degree.,
8.55.degree..+-.0.1.degree., 9.70.degree..+-.0.1.degree.,
10.56.degree..+-.0.1.degree., 14.76.degree..+-.0.1.degree.,
15.06.degree..+-.0.1.degree., 15.57.degree..+-.0.1.degree.,
16.49.degree..+-.0.1.degree., 17.51.degree..+-.0.1.degree.,
18.30.degree..+-.0.1.degree., 18.95.degree..+-.0.1.degree.,
21.73.degree..+-.0.1.degree. and 22.74.degree..+-.0.1.degree..
4. A solvated crystalline form of lopinavir with characteristic
peaks in the solid state infrared spectrum at a position within the
ranges of 1661-1673 cm.sup.-1, 1645-1653 cm.sup.-1 and 1619-1629
cm.sup.-1.
5. A desolvated crystalline form of lopinavir with at least one
characteristic peak in the solid state infrared spectrum at a
position within the range 1655-1662 cm.sup.-1.
6. A desolvated crystalline form of lopinavir with characteristic
peaks in the solid state infrared spectrum at a position within the
ranges of 1655-1662 cm.sup.-1 and 1636-1647 cm.sup.-1.
7. A desolvated crystal form of lopinavir with characteristic peaks
in the powder X-ray diffraction pattern at values of two theta of
4.85.degree..+-.0.1.degree., 6.39.degree..+-.0.1.degree.,
7.32.degree..+-.0.1.degree., 8.81.degree..+-.0.1.degree.,
12.20.degree..+-.0.1.degree., 12.81.degree..+-.0.1.degree.,
14.77.degree..+-.0.1.degree., 16.45.degree..+-.0.1.degree. and
17.70.degree..+-.0.1.degree..
8. A desolvated crystal form of lopinavir with characteristic peaks
in the powder X-ray diffraction pattern at values of two theta of
4.85.degree..+-.0.1.degree., 6.39.degree..+-.0.1.degree.,
7.32.degree..+-.0.1.degree., 8.81.degree..+-.0.1.degree.,
12.20.degree..+-.0.1.degree., 12.81.degree..+-.0.1.degree.,
14.77.degree..+-.0.1.degree., 16.45.degree..+-.0.1.degree.,
17.70.degree..+-.0.1.degree., 18.70.degree..+-.0.1.degree.,
20.68.degree..+-.0.1.degree., 20.92.degree..+-.0.1.degree.,
22.06.degree..+-.0.1.degree. and 22.76.degree..+-.0.1.degree..
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/107,780 filed May 13, 2011, now pending,
which is a continuation of U.S. patent application Ser. No.
11/542,075, filed Oct. 2, 2006, now U.S. Pat. No. 8,058,433 which
is a continuation of U.S. patent application Ser. No. 10/984,393,
filed Nov. 9, 2004, abandoned, which is a divisional of U.S. patent
application Ser. No. 10/387,175, filed Mar. 12, 2003, now U.S. Pat.
No. 6,864,369, which is a divisional of U.S. patent application
Ser. No. 09/793,536, filed Feb. 27, 2001, now U.S. Pat. No.
6,608,198, which claims the benefit of U.S. Provisional Application
No. 60/193,573, filed Mar. 30, 2000, the entire contents of which
are incorporated herein by reference.
TECHNICAL FIELD
[0002] This invention relates to novel crystalline forms of
(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(1-tetrahydr-
opyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane (also
known as lopinavir) and methods for their preparation. The novel
crystalline forms of the invention can be used to purify or isolate
lopinavir or for the preparation of pharmaceutical compositions for
the administration of lopinavir.
BACKGROUND OF THE INVENTION
[0003] Inhibitors of human immunodeficiency virus (HIV) protease
have been approved for use in the treatment of HIV infection for
several years. A particularly effective and recently approved HIV
protease inhibitor is
(2S,3S,5S)-2-(-2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(1-tetrahy-
dropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane (also
known as lopinavir).
##STR00001##
[0004] Lopinavir is known to have utility for the inhibition of HIV
protease and the inhibition of HIV infection. Lopinavir is
particularly effective for the inhibition of HIV protease and for
the inhibition of HIV infection when coadministered with ritonavir.
Lopinavir, when combined with ritonavir, is also particularly
effective for the inhibition of HIV infection when used in
combination with one or more reverse transcriptase inhibitors
and/or one or more other HIV protease inhibitors.
[0005] Lopinavir and processes for its preparation are disclosed in
U.S. Pat. No. 5,914,332, issued Jun. 22, 1999, which is hereby
incorporated herein by reference. This patent also discloses
processes for preparing amorphous lopinavir.
[0006] Pharmaceutical compositions comprising lopinavir or a
pharmaceutically acceptable salt thereof are disclosed in U.S. Pat.
No. 5,914,332, issued Jun. 22, 1999; U.S. patent application Ser.
No. 08/966,495, filed Nov. 7, 1997; U.S. Provisional Application
for Patent No. 60/177,020, filed Jan. 19, 2000 and U.S. patent
application Ser. No. 09/487,739, filed Jan. 19, 2000, all of which
are hereby incorporated herein by reference.
[0007] It has now been unexpectedly discovered that lopinavir can
be prepared and isolated as each of a number of crystal forms.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is the powder X-ray diffraction pattern of the Type I
hydrated crystal form of lopinavir comprising about 0.5 molecules
of water per molecule of lopinavir.
[0009] FIG. 2 is the 100 MHz solid state .sup.13C nuclear magnetic
resonance spectrum of the Type I hydrated crystal form of lopinavir
comprising about 0.5 molecules of water per molecule of
lopinavir.
[0010] FIG. 3 is the solid state FT near infrared spectrum of the
Type I hydrated crystal form of lopinavir comprising about 0.5
molecules of water per molecule of lopinavir.
[0011] FIG. 4 is the solid state FT mid infrared spectrum of the
Type I hydrated crystal form of lopinavir comprising about 0.5
molecules of water per molecule of lopinavir.
[0012] FIG. 5 is the powder X-ray diffraction pattern of a Type I
higher hydrated crystal form of lopinavir.
[0013] FIG. 6 is the 100 MHz solid state .sup.13C nuclear magnetic
resonance spectrum of a Type I higher hydrated crystal form of
lopinavir.
[0014] FIG. 7 is the solid state FT near infrared spectrum of a
Type I higher hydrated crystal form of lopinavir.
[0015] FIG. 8 is the solid state FT mid infrared spectrum of a Type
I higher hydrated crystal form of lopinavir.
[0016] FIG. 9 is the solid state FT mid-infrared spectrum of the
Type II isopropanol hemisolvate crystal form of lopinavir.
[0017] FIG. 10 is the solid state FT mid-infrared spectrum of the
Type II isopropanol solvate crystal form of lopinavir having about
2% solvent by thermal gravimetry.
[0018] FIG. 11 is the solid state FT mid-infrared spectrum of the
Type II ethyl acetate hemisolvate crystal form of lopinavir.
[0019] FIG. 12 is the solid state FT mid-infrared spectrum of the
Type II ethyl acetate solvate crystal form of lopinavir having less
than 0.5 moles of ethyl acetate per 2 moles of lopinavir by thermal
gravimetry.
[0020] FIG. 13 is the solid state FT mid-infrared spectrum of the
Type II chloroform hemisolvate crystal form of lopinavir.
[0021] FIG. 14 is the solid state FT near infrared spectrum of the
Type II isopropanol hemisolvate crystal form of lopinavir.
[0022] FIG. 15 is the solid state FT near infrared spectrum of the
Type II isopropanol solvate crystal form of lopinavir having about
2% solvent by thermal gravimetry.
[0023] FIG. 16 is the solid state FT near infrared spectrum of the
Type II ethyl acetate hemisolvate crystal form of lopinavir.
[0024] FIG. 17 is the solid state FT near infrared spectrum of the
Type II ethyl acetate solvate crystal form of lopinavir having less
than 0.5 moles of ethyl acetate per 2 moles of lopinavir by thermal
gravimetry.
[0025] FIG. 18 is the solid state FT near infrared spectrum of the
Type II chloroform hemisolvate crystal form of lopinavir.
[0026] FIG. 19 is the solid state FT mid-infrared spectrum of the
Type III ethyl acetate solvated crystal form of lopinavir.
[0027] FIG. 20 is the solid state FT near infrared spectrum of the
Type III ethyl acetate solvated crystal form of lopinavir.
[0028] FIG. 21 is the solid state FT mid-infrared spectrum of the
Type III desolvated crystal form of lopinavir.
[0029] FIG. 22 is the solid state FT near infrared spectrum of the
Type III desolvated crystal form of lopinavir.
[0030] FIG. 23 is the powder X-ray diffraction pattern of the Type
III desolvated crystal form of lopinavir.
[0031] FIG. 24 is the 100 MHz solid state .sup.13C nuclear magnetic
resonance spectrum of the Type III desolvated crystal form of
lopinavir.
[0032] FIG. 25 is the differential scanning calorimetric (DSC)
thermogram for the Type III desolvated crystal form of
lopinavir.
[0033] FIG. 26 is the solid state FT mid-infrared spectrum of the
Type IV non-solvated crystal form of lopinavir.
[0034] FIG. 27 is the solid state FT near infrared spectrum of the
Type IV non-solvated crystal form of lopinavir.
[0035] FIG. 28 is the powder X-ray diffraction pattern of the Type
IV non-solvated crystal form of lopinavir.
[0036] FIG. 29 is the 100 MHz solid state .sup.13C nuclear magnetic
resonance spectrum of the Type IV non-solvated crystal form of
lopinavir.
[0037] FIG. 30 is the differential scanning calorimetric (DSC)
thermogram for the Type IV non-solvated crystal form of
lopinavir.
[0038] FIG. 31 is the powder X-ray diffraction pattern of the Type
III solvated (ethyl acetate) crystal form of lopinavir.
DISCLOSURE OF THE INVENTION
[0039] In accordance with the present invention, there are novel
crystal forms of
(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(1--
tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane
(lopinavir).
[0040] In one embodiment of the present invention there are
hydrated crystal forms of lopinavir. For the sake of
identification, the hydrated crystal forms are designated as Type
I. The Type I hydrated crystal forms of lopinavir comprise from
about 0.5 molecules of water per molecule of lopinavir to about 2
molecules of water per molecule of lopinavir.
[0041] The Type I hydrated crystal forms of lopinavir are useful in
the purification or isolation of lopinavir during the final steps
of the process for preparing lopinavir and in the preparation of
pharmaceutical compositions for administering lopinavir.
[0042] The Type I hydrated crystal form of lopinavir comprising
about 0.5 molecules of water per molecule of lopinavir is
hygroscopic. Therefore, unless maintained under conditions of about
0% relative humidity, the Type I hydrated crystal form of lopinavir
comprises greater than 0.5 molecules of water per molecule of
lopinavir. If a Type I hydrated crystal form of lopinavir is
dehydrated to below about 0.5 molecules of water per molecule of
lopinavir, amorphous lopinavir is obtained.
[0043] While the Type I crystal forms of lopinavir comprising 0.5
molecules of water per molecule of lopinavir and about 2 molecules
of water per molecule of lopinavir represent the lower and upper
ranges, respectively, of water of solvation observed for
crystalline Type I hydrated forms of lopinavir, water content of
the crystal form may vary within this range depending on the
temperature and water content of the environment of the crystal
form. The term "Type I higher hydrated crystal form" will be used
herein to refer to the Type I hydrated crystal forms of lopinavir
comprising from greater than 0.5 molecules of water per molecule of
lopinavir up to about 2 molecules of water per molecule of
lopinavir. Preferably, the Type I higher hydrated crystal form of
lopinavir comprises from about 0.75 to about 1.9 molecules of water
per molecule of lopinavir. More preferably, the Type I higher
hydrated crystal form of lopinavir comprises from about 1.0 to
about 1.8 molecules of water per molecule of lopinavir.
[0044] In a preferred embodiment, the Type I hydrated crystal forms
of lopinavir are substantially pure, relative to other forms of
lopinavir, including amorphous, solvated forms, non-solvated and
desolvated forms.
[0045] It has been found that the solid state FT mid-infrared
spectrum is a means of characterizing the Type I hydrated crystal
forms of lopinavir and differentiating the hydrated crystal forms
from other crystal forms of lopinavir.
[0046] The Type I hydrated crystal forms of lopinavir (including
the substantially pure Type I hydrated crystal forms of lopinavir)
have the characteristic solid state FT mid-infrared bands shown in
Table 1. Table 1 shows the range of peak positions for each of 17
characteristic mid-infrared bands in the solid state FT mid-IR
spectrum of Type I hydrated crystal forms of lopinavir. This means
that any Type I hydrated crystal form of lopinavir will have a peak
at a position within the range (minimum to maximum) for each of
peaks shown in Table 1.
[0047] Most characteristic of the Type I hydrated crystal forms of
lopinavir (including the substantially pure Type I hydrated crystal
forms of lopinavir) are the positions of the solid state FT
mid-infrared bands for the amide bond carbonyl stretching. These
bands are located within the ranges 1652-1666 cm.sup.-1 and
1606-1615 cm.sup.-1 for the Type I hydrated crystal forms of
lopinavir. Any Type I hydrated crystal form of lopinavir (including
the substantially pure Type I hydrated crystal forms of lopinavir)
will have a peak at a position within the range 1652-1666 cm.sup.-1
and a peak at a position within the range 1606-1615 cm.sup.-1.
[0048] The Type I hydrated crystal forms of lopinavir (including
the substantially pure Type I hydrated crystal forms of lopinavir)
are further characterized by a solid state infrared peak at a
position within each of the ranges 778-783 cm.sup.-1, 765-769
cm.sup.-1, 755-759 cm.sup.-1 and 738-742 cm.sup.-1.
TABLE-US-00001 TABLE 1 Ranges of Peak Positions for Solid State FT
Mid-IR Bands for Type I Hydrated Crystal Forms of Lopinavir Minimum
Maximum cm.sup.-1 cm.sup.-1 Intensity* 3495 3505 W/absent 3371 3386
S/MS 3281 3299 MS 3058 3064 W 3024 3031 W 2958 2967 M 2926 2938 W
2868 2875 W 1652 1666 VS 1606 1615 S/MS 1524 1532 S 1450 1456 MS
1404 1410 W/VW 1304 1311 MS 1187 1197 MS 1089 1094 M 1048 1056 W *W
= weak; M = moderate; MS = moderately strong; S = strong; VS = very
strong
[0049] The Type I crystal form of lopinavir comprising about 0.5
molecules of water per molecule of lopinavir has the powder X-ray
diffraction pattern which appears in FIG. 1. The Type I crystal
form of lopinavir comprising about 0.5 molecules of water per
molecule of lopinavir has the solid state .sup.13C nuclear magnetic
resonance spectrum, FT near infrared spectrum and FT mid infrared
spectrum which appear in FIGS. 2, 3 and 4, respectively. The sample
from which the infrared and nuclear magnetic resonance spectra were
obtained may contain somewhat more than 0.5 molecules of water per
molecule of lopinavir due to the hygroscopicity of the crystal form
when the level of hydration is about 0.5 molecules of water per
molecule of lopinavir.
[0050] The two-theta angle positions of characteristic peaks in the
powder X-ray diffraction pattern of the Type I hydrated crystal
form of lopinavir comprising about 0.5 molecules of water per
molecule of lopinavir (including the substantially pure Type I
hydrated crystal forms of lopinavir comprising about 0.5 molecules
of water per molecule of lopinavir) as shown in FIG. 1 are:
7.25.degree..+-.0.1.degree., 8.53.degree..+-.0.1.degree.,
10.46.degree..+-.0.1.degree., 11.05.degree..+-.0.1.degree.,
11.71.degree..+-.0.1.degree., 14.76.degree..+-.0.1.degree.,
15.30.degree..+-.0.1.degree., 16.67.degree..+-.0.1.degree.,
17.32.degree..+-.0.1.degree., 19.10.degree..+-.0.1.degree.,
19.57.degree..+-.0.1.degree., 21.24.degree..+-.0.1.degree.,
21.84.degree..+-.0.1.degree. and 22.46.degree..+-.0.1.degree..
[0051] The Type I hydrated crystal form of lopinavir comprising
about 0.5 molecules of water per molecule of lopinavir can be
prepared from the Type I hydrated crystal form of lopinavir
comprising greater than 0.5 molecules of water per molecule of
lopinavir by dehydrating at 0% relative humidity. If dehydration
continues beyond the stage of the hemihydrate, amorphous lopinavir
is obtained.
[0052] The Type I hydrated crystal form of lopinavir can be
prepared from solution or suspension in water or from solutions in
mixtures of water and water miscible organic solvents. Examples of
water miscible organic solvents include C1-C4 alcohols such as
methanol, ethanol and the like; acetonitrile; and the like. In the
mixtures of water and water miscible organic solvents, the amount
of water can vary from about 10% by volume to about 90% by volume
(preferably, from about 40% to about 60% by volume). In a preferred
method, the Type I higher hydrated crystal form of lopinavir can be
prepared by crystallization of hydrated lopinavir from a warm
solution in a mixture of water and ethanol, followed by extended
exposure to an elevated relative humidity environment.
[0053] In addition, the Type I higher hydrated crystal form of
lopinavir can be prepared by hydrating the Type I hemihydrate
crystal form of lopinavir at elevated relative humidity (for
example, at relative humidity of about 20% or more).
[0054] The Type I higher hydrated crystal form of lopinavir has the
powder X-ray diffraction pattern, solid state .sup.13C nuclear
magnetic resonance spectrum, solid state FT near infrared spectrum
and solid state FT mid infrared spectrum which appear in FIGS. 5,
6, 7 and 8, respectively.
[0055] The two-theta angle positions of characteristic peaks in the
powder X-ray diffraction pattern of the Type I higher hydrated
crystal form of lopinavir (including the substantially pure Type I
higher hydrated crystal form of lopinavir) as shown in FIG. 5 are:
3.89.degree..+-.0.1.degree., 6.55.degree..+-.0.1.degree.,
7.76.degree..+-.0.1.degree., 8.55.degree..+-.0.1.degree.,
9.70.degree..+-.0.1.degree., 10.56.degree..+-.0.1.degree.,
14.76.degree..+-.0.1.degree., 15.57.degree..+-.0.1.degree.,
18.30.degree..+-.0.1.degree., 18.95.degree..+-.0.1.degree. and
22.74.degree..+-.0.1.degree..
[0056] More preferably, the Type I higher hydrated crystal form of
lopinavir (including the substantially pure Type I higher hydrated
crystal form of lopinavir) is characterized by peaks in the powder
X-ray diffraction pattern having two-theta angle positions as shown
in FIG. 5 of 3.89.degree..+-.0.1.degree.,
6.55.degree..+-.0.1.degree., 7.76.degree..+-.0.1.degree.,
8.55.degree..+-.0.1.degree., 9.70.degree..+-.0.1.degree.,
10.56.degree..+-.0.1.degree., 14.76.degree..+-.0.1.degree.,
15.06.degree..+-.0.1.degree., 15.57.degree..+-.0.1.degree.,
16.49.degree..+-.0.1.degree., 17.51.degree..+-.0.1.degree.,
18.30.degree..+-.0.1.degree., 18.95.degree..+-.0.1.degree.,
21.73.degree..+-.0.1.degree. and 22.74.degree..+-.0.1.degree..
[0057] The single crystal X-ray parameters and experimental details
for the Type I higher hydrated crystal form of lopinavir are as
follows.
TABLE-US-00002 Single Crystal X-ray Parameters and Experimental
Details for the Type I Higher Hydrated Crystal Form of Lopinavir
Experimental Details Crystal Data Crystal System Monoclinic Lattice
Parameters a = 46.922 (2) .ANG. b = 13.9945 (4) .ANG. c = 11.7231
(4) .ANG. .beta. = 105.605 (1) .degree. V = 7414.2 (4) .ANG..sup.3
Space Group C2(#5) Z Value 8 D.sub.calc 1.19 g/cm.sup.3 Intensity
Measurements Diffractometer Bruker SMART Radiation Mo K.alpha.
(.lamda. = 0.7107 .ANG.) Temperature ambient 2.theta..sub.max
46.6.degree. Correction Lorentz-polarization Number of Reflections
Measured Total: 27795 Structure Solution and Refinement Number of
Observations (I > 3.0 .sigma.(I)) 5368 Number of Variables 932
Reflections/Parameter Ratio 5.76 Residuals: R; R.sub.w 0.107;
0.128
[0058] In two further embodiments of the present invention there
are solvated crystal forms of lopinavir. Based on single crystal
X-ray structure determination, the first embodiment of the solvated
crystal forms of lopinavir involves a crystal structure in which
stacks of lopinavir molecules are held together by hydrogen bond
interactions and aligned along the short crystallographic axis. The
solvent molecules play no role in the hydrogen bonding, but simply
fill pockets that exist between the stacks of lopinavir molecules.
For the sake of identification, the solvated crystal forms of
lopinavir of this embodiment are designated as Type II.
[0059] Based on single crystal X-ray structure determination, the
second embodiment of the solvated crystal forms of lopinavir
involves a crystal structure in which the molecules of lopinavir
are hydrogen bonded in sheets. The sheets of hydrogen bonded
lopinavir molecules are wrinkled, producing channels that are
occupied by varying amounts of solvent molecules. The solvent
molecules play no role in the hydrogen bonding of the second
embodiment of solvated crystal forms of lopinavir. For the sake of
identification, the solvated crystal forms of lopinavir of this
embodiment are designated as Type III.
[0060] Type II
[0061] The Type II solvated crystal forms of lopinavir are useful
for the purification or isolation of lopinavir during the final
steps of the process for preparing lopinavir.
[0062] The Type II solvated crystal forms of lopinavir are
particularly useful for obtaining crystalline lopinavir which is
free from, or has greatly reduced amounts of, a variety of the
impurities that result during the process for preparing
lopinavir.
[0063] The Type II solvated crystal forms of lopinavir are
typically hemisolvates. In other words, for every asymmetric unit
of the crystal there are two molecules of lopinavir and one
molecule of solvent. Lower levels of solvation are also possible.
The Type II solvated crystal forms of lopinavir can be partially
desolvated by drying under vacuum with heating. However, if more
than about 75% of the maximum allowable solvent (maximum allowable
is hemisolvated) is removed, amorphous lopinavir is obtained.
Therefore, the Type II solvated crystal forms of lopinavir comprise
from about 0.125 molecules of solvent per molecule of lopinavir to
about 0.5 molecules of solvent per molecule of lopinavir.
[0064] The Type II solvated crystal forms of lopinavir comprise
relatively small polar organic solvents. Examples of such
relatively small polar organic solvents include methanol, ethanol,
n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol, n-amyl
alcohol, iso-amyl alcohol, t-pentanol, ethyl acetate, acetone,
tetrahydrofuran, chloroform, methylene chloride, propylene glycol,
methylethyl ketone, dimethylsulfoxide and the like.
[0065] In a preferred embodiment, the Type II solvated crystal
forms of lopinavir are substantially pure, relative to other forms
of lopinavir, including amorphous, hydrated forms, other solvated
forms, non-solvated and desolvated forms.
[0066] It has been found that the solid state FT mid-infrared
spectrum is a means for characterizing the Type II solvated crystal
forms of lopinavir and differentiating the Type II solvated crystal
forms of lopinavir from other crystal forms of lopinavir.
[0067] The Type II solvated crystal forms of lopinavir (including
the substantially pure Type II solvated crystal forms of lopinavir)
have the characteristic solid state FT mid-infrared bands shown in
Table 2. Table 2 shows the range of peak positions for each of the
18 characteristic mid-infrared bands in the solid state FT mid-IR
spectrum of Type II solvated crystal forms of lopinavir. This means
that any Type II solvated crystal form of lopinavir will have a
peak at a position within the range (minimum to maximum) for each
of the peaks shown in Table 2.
[0068] Most characteristic of the Type II solvated crystal forms of
lopinavir (including the substantially pure Type II solvated
crystal forms of lopinavir) are the positions of the solid state FT
mid-infrared bands for the amide bond carbonyl stretching. These
bands are located within the ranges 1661-1673 cm.sup.-1, 1645-1653
cm.sup.-1 and 1619-1629 cm.sup.-1 for the Type II solvated crystal
forms of lopinavir. Any Type II solvated crystal form of lopinavir
(including the substantially pure Type II solvated crystal forms of
lopinavir) will have a peak at a position within the range
1661-1673 cm.sup.-1, a peak at a position within the range
1645-1653 cm.sup.-1 and a peak at a position within the range
1619-1629 cm.sup.-1.
[0069] The Type II solvated crystal forms of lopinavir (including
the substantially pure Type II solvated crystal forms of lopinavir)
are further characterized by a solid state infrared peak at a
position within each of the ranges 776-781 cm.sup.-1, 767-771
cm.sup.-1, 747-758 cm.sup.-1 and 742-746 cm.sup.-1.
TABLE-US-00003 TABLE 2 Ranges of Peak Positions for Solid State FT
Mid-IR Bands for Type II Solvated Crystal Forms of Lopinavir
Minimum Maximum cm.sup.-1 cm.sup.-1 Intensity* 3391 3415 M 3324
3340 MS 3057 3063 W 3023 3029 W 2961 2970 M 2913 2938 W 2866 2879 W
1661 1673 S 1645 1653 S 1619 1629 VS 1540 1548 MS 1514 1522 S 1450
1456 MS 1418 1426 M 1302 1309 M 1181 1193 MS 1089 1095 M 1045 1056
W *W = weak; M = moderate; MS = moderately strong; S = strong; VS =
very strong
[0070] The solid state FT mid-infrared spectra of Type II solvated
crystal forms of lopinavir (isopropanol, ethyl acetate and
chloroform) appear in FIGS. 9, 10, 11, 12 and 13. The solid state
FT near infrared spectra of Type II solvated crystal forms of
lopinavir (isopropanol, ethyl acetate and chloroform) appear in
FIGS. 14, 15, 16, 17 and 18.
[0071] The Type II solvated crystal forms of lopinavir can be
prepared by suspending excess solid lopinavir in the solvent and
allowing the suspension to equilibrate over time. The Type II
solvated crystal form of lopinavir is then isolated by
filtration.
[0072] The Type II solvated crystal forms of lopinavir can also be
prepared by cooling a supersaturated solution of lopinavir in the
solvent, with or without the addition of seed crystals. The Type II
solvated crystal form of lopinavir is then isolated by
filtration.
[0073] The Type II solvated crystal forms of lopinavir can also be
prepared by allowing slow evaporation of the solvent from a
solution of lopinavir. The Type II solvated crystal form of
lopinavir is then isolated by filtration.
[0074] The Type II solvated crystal forms of lopinavir can also be
prepared by slowly adding an antisolvent to a heated solution of
lopinavir in the solvent, thereby inducing crystallization. The
Type II solvated crystal form of lopinavir is then isolated by
filtration.
[0075] The single crystal X-ray parameters and experimental details
for the Type II ethyl acetate hemisolvate crystal form of lopinavir
and the Type II chloroform hemisolvate crystal form of lopinavir
are as follows.
TABLE-US-00004 Single Crystal X-ray Parameters and Experimental
Details for the Type II Ethyl Acetate Hemisolvate Crystal Form of
Lopinavir Experimental Details Crystal Data Crystal System
Monoclinic Lattice Parameters a = 11.3456 (1) .ANG. b = 33.9490 (2)
.ANG. c = 9.8641 (2) .ANG. .beta. = 89.930 (1) .degree. V = 3799.37
(7) .ANG..sup.3 Space Group P2.sub.1(#4) Z Value 4 D.sub.calc 1.18
g/cm.sup.3 Intensity Measurements Diffractometer Bruker SMART
Radiation Mo K.alpha. (.lamda. = 0.7107 .ANG.) Temperature ambient
2.theta..sub.max 46.7.degree. Correction Lorentz-polarization
Number of Reflections Measured Total: 14824 Unique: 5211 Structure
Solution and Refinement Number of Observations (I > 3.0
.sigma.(I)) 4411 Number of Variables 882 Reflections/Parameter
Ratio 5.0 Residuals: R; R.sub.w 0.104; 0.099
TABLE-US-00005 Single Crystal X-ray Parameters and Experimental
Details for the Type II Chloroform Hemisolvate Crystal Form of
Lopinavir Experimental Details Crystal Data Crystal System
Orthorhombic Lattice Parameters a = 9.7703 (51) .ANG. b = 33.410
(2) .ANG. c = 11.4874 (6) .ANG. V = 3749.8 (3) .ANG..sup.3 Space
Group P2.sub.12.sub.12(#18) Z Value 4 D.sub.calc 1.22 g/cm.sup.3
Intensity Measurements Diffractometer Bruker SMART Radiation Mo
K.alpha. (.lamda. = 0.7107 .ANG.) Temperature ambient
2.theta..sub.max 46.6.degree. Correction Lorentz-polarization
Number of Reflections Measured Total: 14960 Unique: 4359 Structure
Solution and Refinement Number of Observations (I > 3.0
.sigma.(I)) 4234 Number of Variables 438 Reflections/Parameter
Ratio 9.67 Residuals: R; R.sub.w 0.094; 0.104
[0076] Type III
[0077] The Type III solvated crystal forms of lopinavir are useful
in the purification or isolation of lopinavir during the final
steps of the process for preparing lopinavir.
[0078] The Type III solvated crystal forms of lopinavir are
particularly useful for obtaining crystalline lopinavir which is
free from, or has greatly reduced amounts of, a variety of the
impurities that result during the process for preparing
lopinavir.
[0079] The Type III solvated crystal forms of lopinavir are the
thermodynamically stable crystal forms isolated from solvents that
generally comprise hydrophobic organic solvents or solvents too
large to fit within the crystal lattice of the Type II solvated
crystal forms of lopinavir. The Type III solvated crystal forms of
lopinavir comprise solvents including n-hexanol, n-octanol,
3-ethyl-3-pentanol, polyethylene glycol, ethyl acetate, isopropyl
acetate, n-butyl acetate, glycerol triacetate, acetone, methyl
isobutyl ketone, 2,4-dimethylpentanone, alpha-tetralone, methyl
t-butyl ether, 2,2,4,4-tetramethyltetrahydrofuran, isosorbide
dimethyl ether, toluene, tetralin, nitrobenzene, p-xylene,
sulfolane, hexane, heptane, decalin, oleic acid and the like.
[0080] In a preferred embodiment, the Type III solvated crystal
forms of lopinavir are substantially pure, relative to other forms
of lopinavir, including amorphous, hydrated forms, other solvated
forms, non-solvated and desolvated forms.
[0081] It has been found that the solid state FT mid-infrared
spectrum is a means for characterizing the Type III solvated forms
of lopinavir and differentiating the Type III solvated crystal
forms of lopinavir from other crystal forms of lopinavir.
[0082] The Type III solvated crystal forms of lopinavir (including
the substantially pure Type III solvated crystal forms of
lopinavir) have the characteristic solid state FT mid-infrared
bands shown in Table 3. Table 3 shows the range of peak positions
for each of the 16 characteristic mid-infrared bands in the solid
state FT mid-IR spectrum of Type III solvated crystal forms of
lopinavir. This means that any Type III solvated crystal form of
lopinavir will have a peak at a position within the range (minimum
to maximum) for each of the peaks shown in Table 3.
[0083] Most characteristic of the Type III solvated crystal forms
of lopinavir (including the substantially pure Type III solvated
crystal forms of lopinavir) are the positions of the solid state FT
mid-infrared bands for the amide bond carbonyl stretching. A band
is located within the range 1655-1662 cm.sup.-1 for the Type III
solvated crystal forms of lopinavir. Frequently, a second band is
located within the range 1636-1647 cm.sup.-1 for the Type III
solvated crystal forms of lopinavir. However, in some instances the
second band (in the range 1636-1647 cm.sup.-1) appears as a
shoulder on the first band or is not well enough resolved from the
first band to be distinguishable as a second band. Any Type III
solvated crystal form of lopinavir (including the substantially
pure Type III solvated crystal forms of lopinavir) will have a peak
at a position within the range 1655-1662 cm.sup.-1 and may also
have a peak at a position within the range 1636-1647 cm.sup.-1.
[0084] The Type III solvated crystal forms of lopinavir (including
the substantially pure Type III solvated crystal forms of
lopinavir) are further characterized by a solid state infrared peak
at a position within each of the ranges 772-776 cm.sup.-1, 766-770
cm.sup.-1 and 743-747 cm.sup.-1.
[0085] The two-theta angle positions of characteristic peaks in the
powder X-ray diffraction pattern of the Type III solvated (ethyl
acetate) crystal form of lopinavir (including the substantially
pure Type III solvated (ethyl acetate) crystal form of lopinavir)
as shown in FIG. 31 are: 4.85.degree..+-.0.1.degree.,
6.52.degree..+-.0.1.degree., 7.32.degree..+-.0.1.degree.,
12.82.degree..+-.0.1.degree., 12.96.degree..+-.0.1.degree.,
16.49.degree..+-.0.1.degree. and 19.31.degree..+-.0.1.degree..
TABLE-US-00006 TABLE 3 Ranges of Peak Positions for Solid State FT
Mid-IR Bands for Type III Solvated and Desolvated Crystal Forms of
Lopinavir Minimum Maximum cm.sup.-1 cm.sup.-1 Intensity* 3394 3405
S 3278 3302 MS 3061 3071 W 3024 3033 W 2954 2965 M 2924 2939 W 2853
2872 W 1655 1662 VS 1636 1647 S 1517 1525 S 1501 1513 MS 1450 1455
MS 1300 1309 MS 1193 1200 MS 1090 1098 W 1051 1057 M *W = weak; M =
moderate; MS = moderately strong; S = strong; VS = very strong
[0086] The solid state FT mid-infrared spectrum of the Type III
ethyl acetate solvated crystal form of lopinavir appears in FIG.
19. The solid state FT near infrared spectrum of the Type III ethyl
acetate solvated crystal form of lopinavir appears in FIG. 20.
[0087] The Type III solvated crystal forms of lopinavir can be
prepared by suspending excess solid lopinavir in the solvent and
allowing the suspension to equilibrate over time. The Type III
solvated crystal form of lopinavir is then isolated by
filtration.
[0088] The Type III solvated crystal forms of lopinavir can also be
prepared by cooling a supersaturated solution of lopinavir in the
solvent, with or without the addition of seed crystals. The Type
III solvated crystal form of lopinavir is then isolated by
filtration.
[0089] The Type III solvated crystal forms of lopinavir can also be
prepared by allowing slow evaporation of the solvent from a
solution of lopinavir. The Type III solvated crystal form of
lopinavir is then isolated by filtration.
[0090] The Type III solvated crystal forms of lopinavir can also be
prepared by slowly adding an antisolvent to a heated solution of
lopinavir in the solvent, thereby inducing crystallization. The
Type III solvated crystal form of lopinavir is then isolated by
filtration.
TABLE-US-00007 Single Crystal X-ray Parameters and Experimental
Details for the Type III Ethyl Acetate Solvated Crystal Form of
Lopinavir Experimental Details Crystal Data Crystal System
Orthorhombic Lattice Parameters a = 23.961 (9) .ANG. b = 27.58 (1)
.ANG. c = 11.967 (4) .ANG. V = 7907 (5) .ANG..sup.3 Space Group
C222.sub.1(#20) Z Value 8 Intensity Measurements Diffractometer
Rigaku AFCSR Radiation Cu K.alpha. (.lamda. =1.54178 .ANG.)
Temperature ambient 2.theta..sub.max 120.2.degree. Correction
Lorentz-polarization Absorption (trans. Factors: 0.87-1.00) Number
of Reflections Measured Total: 6520 Unique: 6520 Structure Solution
and Refinement Number of Observations (I > 3.0 .sigma.(I)) 2154
Number of Variables 443 Reflections/Parameter Ratio 4.86 Residuals:
R; R.sub.w 0.096; 0.093
[0091] One example of a Type III desolvated crystal form of
lopinavir has been prepared from acetonitrile. From all other
solvents it has not been possible to prepare a fully desolvated
Type III crystal form of lopinavir.
[0092] The Type III desolvated crystal form of lopinavir is useful
in the purification or isolation of lopinavir and in the
preparation of pharmaceutical compositions for administering
lopinavir.
[0093] It has been found that the solid state FT mid-infrared
spectrum is a means for characterizing the Type III desolvated form
of lopinavir and differentiating the Type III desolvated crystal
forms of lopinavir from other crystal forms of lopinavir, except
the Type III solvated crystal form.
[0094] The Type III desolvated crystal form of lopinavir (including
the substantially pure Type III desolvated crystal form of
lopinavir) also has the characteristic solid state FT mid-infrared
bands shown in Table 3. Table 3 shows the range of peak positions
for each of the 16 characteristic mid-infrared bands in the solid
state FT mid-IR spectrum of Type III desolvated crystal form of
lopinavir. This means that the Type III desolvated crystal form of
lopinavir will have a peak at a position within the range (minimum
to maximum) for each of the peaks shown in Table 3.
[0095] Most characteristic of the Type III desolvated crystal form
of lopinavir (including the substantially pure Type III desolvated
crystal form of lopinavir) are the positions of the solid state FT
mid-infrared bands for the amide bond carbonyl stretching. A band
is located within the range 1655-1662 cm.sup.-1 for the Type III
desolvated crystal form of lopinavir. Frequently, a second band (in
the range 1636-1647 cm.sup.-1) appears as a shoulder on the first
band or is not well enough resolved from the first band to be
distinguishable as a second band. Any Type III desolvated crystal
form of lopinavir (including the substantially pure Type III
desolvated crystal form of lopinavir) will have a peak at a
position within the range 1655-1662 cm.sup.-1 and may also have a
peak at a position within the range 1636-1647 cm.sup.-1 as a
shoulder on the peak at a position within the range 1655-1662
cm.sup.-1.
[0096] The solid state FT mid-infrared spectrum of the Type III
desolvated crystal form of lopinavir appears in FIG. 21. The solid
state FT near infrared spectrum of the Type III desolvated crystal
form of lopinavir appears in FIG. 22. The powder X-ray diffraction
pattern of the Type III desolvated crystal form of lopinavir
appears in FIG. 23. The 100 MHz solid state .sup.13C nuclear
magnetic resonance spectrum of the Type III desolvated crystal form
of lopinavir appears in FIG. 24. The DSC thermogram of the Type III
desolvated crystal form of lopinavir appears in FIG. 25.
[0097] The DSC thermogram of the Type III desolvated crystal form
of lopinavir exhibits a melting endotherm with onset at 95.degree.
C. and peak at 98.degree. C. (.DELTA.H=18 J/g) when differential
scanning calorimetry is performed with a scanning rate of 1.degree.
C./minute to 150.degree. C. for a sample which lost 0.0% of its
initial weight upon heating at 1.degree. C./minute to 150.degree.
C.
[0098] The two-theta angle positions of characteristic peaks in the
powder X-ray diffraction pattern of the Type III desolvated crystal
form of lopinavir (including the substantially pure Type III
desolvated crystal form of lopinavir) as shown in FIG. 23 are:
4.85.degree..+-.0.1.degree., 6.39.degree..+-.0.1.degree.,
7.32.degree..+-.0.1.degree., 8.81.degree..+-.0.1.degree.,
12.20.degree..+-.0.1.degree., 12.81.degree..+-.0.1.degree.,
14.77.degree..+-.0.1.degree., 16.45.degree..+-.0.1.degree. and
17.70.degree..+-.0.1.degree..
[0099] More preferably, the Type III desolvated crystal form of
lopinavir (including the substantially pure Type III desolvated
crystal form of lopinavir) is characterized by peaks in the powder
X-ray diffraction pattern having two-theta angle positions as shown
in FIG. 23 of: 4.85.degree..+-.0.1.degree.,
6.39.degree..+-.0.1.degree., 7.32.degree..+-.0.1.degree.,
8.81.degree..+-.0.1.degree., 12.20.degree..+-.0.1.degree.,
12.81.degree..+-.0.1.degree., 14.77.degree..+-.0.1.degree.,
16.45.degree..+-.0.1.degree., 17.70.degree..+-.0.1.degree.,
18.70.degree..+-.0.1.degree., 20.68.degree..+-.0.1.degree.,
20.92.degree..+-.0.1.degree., 22.06.degree..+-.0.1.degree. and
22.76.degree..+-.0.1.degree..
TABLE-US-00008 Single Crystal X-ray Parameters and Experimental
Details for the Type III Desolvated Crystal Form of Lopinavir
Experimental Details Crystal Data Crystal System Orthorhombic
Lattice Parameters a = 24.0465 (10) .ANG. b = 27.5018 (11) .ANG. c
= 11.9744 (3) .ANG. V = 7918.9 (8) .ANG..sup.3 Space Group
C222.sub.1(#20) Z Value 8 D.sub.calc 1.055 g/cm.sup.3 Intensity
Measurements Diffractometer Nonius KappaCCD Radiation Mo K.alpha.
(.lamda. = 0.71073 .ANG.) Temperature ambient 2.theta..sub.max
61.degree. Number of Reflections Measured Total: 28494 Unique: 5148
Structure Solution and Refinement Number of Observations (I >
2.0 .sigma.(I)) 4069 Number of Variables 442 Reflections/Parameter
Ratio 9.21 Residuals: R; R.sub.w 0.056; 0.116
[0100] In yet another embodiment of the present invention there is
a non-solvated crystal form of lopinavir. For the sake of
identification, the non-solvated crystal form of lopinavir of this
embodiment is designated as Type IV.
[0101] The Type IV non-solvated crystal form of lopinavir is useful
in the purification or isolation of lopinavir and in the
preparation of pharmaceutical compositions for administering
lopinavir.
[0102] In a preferred embodiment, the Type IV non-solvated crystal
forms of lopinavir are substantially pure, relative to other forms
of lopinavir, including amorphous, hydrated forms, solvated forms,
other non-solvated and desolvated forms.
[0103] It has been found that the solid state FT mid-infrared
spectrum is a means of characterizing the Type IV non-solvated
crystal form of lopinavir and differentiating the Type IV
non-solvated crystal form from other crystal forms of
lopinavir.
[0104] The Type IV non-solvated crystal form of lopinavir
(including the substantially pure Type IV non-solvated crystal
forms of lopinavir) has the characteristic solid state FT
mid-infrared bands shown in Table 4. Table 4 shows the range of
peak positions for each of 19 characteristic mid-infrared bands in
the solid state FT mid-IR spectrum of Type IV non-solvated crystal
form of lopinavir. This means that any Type IV non-solvated crystal
form of lopinavir will have a peak at a position within the range
(minimum to maximum) for each of peaks shown in Table 4. When the
solid state mid-IR spectrum is obtained at a resolution of 4
cm.sup.-1, a peak at a position in one or more of the following
additional characteristic bands may also be observed: 1668-1674
cm.sup.-1 (strong), 1656-1662 cm.sup.-1 (strong), 1642-1648
cm.sup.-1 (strong). At higher resolution, or after Fourier
deconvolution, these additional peaks are distinguishable.
[0105] Most characteristic of the Type IV non-solvated crystal form
of lopinavir (including the substantially pure Type IV non-solvated
crystal forms of lopinavir) is the positions of the solid state FT
mid-infrared bands for the amide bond carbonyl stretching. These
bands are located within the ranges 1680-1685 cm.sup.-1 and
1625-1630 cm.sup.-1 for the Type IV non-solvated crystal form of
lopinavir. In addition, especially at higher resolution, bands are
located within the ranges 1668-1674 cm.sup.-1, 1656-1662 cm.sup.-1
and 1642-1648 cm.sup.-1. Any Type IV non-solvated crystal form of
lopinavir (including the substantially pure Type IV non-solvated
crystal forms of lopinavir) will have a peak at a position within
the range 1680-1685 cm.sup.-1 and a peak at a position within the
range 1625-1630 cm.sup.-1 and may also have a peak at a position
within the range 1668-1674 cm.sup.-1, a peak within the range
1656-1662 cm.sup.-1 and a peak within the range 1642-1648
cm.sup.-1.
[0106] The Type IV non-solvated crystal form of lopinavir
(including the substantially pure Type IV non-solvated crystal form
of lopinavir) is further characterized by a solid state infrared
peak at a position within each of the ranges 780-784 cm.sup.-1,
764-768 cm.sup.-1 and 745-749 cm.sup.-1.
TABLE-US-00009 TABLE 4 Ranges of Peak Positions for Solid State FT
Mid-IR Bands for Type IV Non-Solvated Crystal Form of Lopinavir
Minimum Maximum cm.sup.-1 cm.sup.-1 Intensity* 3433 3439 M 3415
3421 M 3406 3412 M 3338 3345 MS 3309 3315 M 3272 3278 M 3082 3089 W
3025 3030 W 2959 2965 M 2926 2932 W 2870 2875 W 1680 1685 S 1625
1630 VS 1514 1526 S 1451 1456 MS 1306 1312 M 1189 1194 M 1089 1094
W 1044 1050 W *W = weak; M = moderate; MS = moderately strong; S =
strong; VS = very strong
[0107] The Type IV non-solvated crystal form of lopinavir has the
solid state FT mid infrared spectrum, the solid state FT near
infrared spectrum, the powder X-ray diffraction pattern, solid
state .sup.13C nuclear magnetic resonance spectrum and differential
scanning calorimetric (DSC) thermogram which appear in FIGS. 26,
27, 28, 29 and 30, respectively.
[0108] The two-theta angle positions of characteristic peaks in the
powder X-ray diffraction pattern of the Type IV non-solvated
crystal form of lopinavir (including the substantially pure Type IV
non-solvated crystal forms of lopinavir) as shown in FIG. 28 are:
6.85.degree..+-.0.1.degree., 9.14.degree..+-.0.1.degree.,
12.88.degree..+-.0.1.degree., 15.09.degree..+-.0.1.degree.,
17.74.degree..+-.0.1.degree., 18.01.degree..+-.0.1.degree. and
18.53.degree..+-.0.1.degree..
[0109] More preferably, the Type IV non-solvated crystal form of
lopinavir (including the substantially pure Type IV non-solvated
crystal forms of lopinavir) is characterized by peaks in the powder
X-ray diffraction pattern having two-theta angle positions as shown
in FIG. 28 of 6.85.degree..+-.0.1.degree.,
9.14.degree..+-.0.1.degree., 10.80.degree..+-.0.1.degree.,
12.04.degree..+-.0.1.degree., 12.88.degree..+-.0.1.degree.,
15.09.degree..+-.0.1.degree., 17.74.degree..+-.0.1.degree.,
18.01.degree..+-.0.1.degree., 18.26.degree..+-.0.1.degree.,
18.53.degree..+-.0.1.degree., 20.47.degree..+-.0.1.degree. and
25.35.degree..+-.0.1.degree..
[0110] The DSC thermogram of the Type IV non-solvated crystal form
of lopinavir exhibits a melting endotherm with onset at 117.degree.
C. and peak at 122.degree. C. (.DELTA.H=47 J/g) when differential
scanning calorimetry is performed with a scanning rate of 1.degree.
C./minute to 150.degree. C.
[0111] The single crystal X-ray parameters and experimental details
for the Type IV non-solvated crystal form of lopinavir are as
follows.
TABLE-US-00010 Single Crystal X-ray Parameters and Experimental
Details for the Type IV Non-Solvated Crystal Form of Lopinavir
Experimental Details Crystal Data Crystal System Orthorhombic
Lattice Parameters a = 15.065 (8) .ANG. b = 25.27 (1) .ANG. c =
9.732 (3) .ANG. V = 3704 (3) .ANG..sup.3 Space Group
P2.sub.12.sub.12.sub.1 (#20) Z Value 4 D.sub.calc 1.13 g/cm.sup.3
Intensity Measurements Diffractometer Rigaku AFC5R Radiation Cu
K.alpha. (.lamda. =1.54178 .ANG.) Temperature ambient
2.theta..sub.max 120.2.degree. Correction Lorentz-polarization
Absorption (trans. Factors: 0.8362-0.9496 Number of Reflections
Measured Total: 3145 Structure Solution and Refinement Number of
Observations (I > 3.0 .sigma.(I)) 1434 Number of Variables 415
Reflections/Parameter Ratio 3.46 Residuals: R; R.sub.w 0.081;
0.085
[0112] The Type IV non-solvated crystal form of lopinavir can be
prepared from acetonitrile by slow cooling and slow evaporation of
a saturated solution or by exposure of amorphous lopinavir to an
acetonitrile atmosphere. In addition, a solution of lopinavir in
acetonitrile can be seeded with Type IV non-solvated lopinavir
crystals to produce more Type IV non-solvated crystal form of
lopinavir.
[0113] The following examples will serve to further illustrate the
preparation of the novel crystalline forms of lopinavir of the
invention.
Example 1
Preparation of a Type I Higher Hydrated Crystal Form of
Lopinavir
[0114] A saturated solution of lopinavir was prepared at room
temperature in a mixture of 20 mL of ethanol and 40 mL of water.
The saturated solution was stirred at room temperature and water
(54 mL) was slowly added at a rate of 0.15 mL/minute using a
syringe pump. After stirring overnight, the resulting precipitate
(crystals) was suction filtered.
Example 2
Preparation of a Type I Higher Hydrated Crystal Form of
Lopinavir
[0115] An NMR tube was filled with 1.75 mL of water. Then 0.5 mL of
a solution of lopinavir in ethanol (99.482 mg of lopinavir/mL
ethanol) was very carefully layered on top of the water. The tube
capped to prevent evaporation and was allowed to stand undisturbed.
Crystals of the Type I hydrated crystal form of lopinavir
comprising greater than 0.5 molecules of water per molecule of
lopinavir were obtained after about 30 days.
Example 3
Preparation of a Type I Higher Hydrated Crystal Form of
Lopinavir
[0116] Lopinavir (30 g) was dissolved in a mixture of 360 mL of
deionized distilled water and 418 mL of 190 proof ethanol by
warming with moderate stirring at about 60.degree. C. The hot
solution was filtered by gravity to remove undissolved material.
The filtrate was slowly cooled with gentle stirring to room
temperature, at which point it was seeded with about 50 mg of the
product of Example 1. The mixture was stirred at moderate speed at
room temperature for three days. The resulting mixture was filtered
under vacuum. The filtered solid was transferred onto a filter
paper and any lumps were broken up with gentle manipulation with a
spatula. The solid was then transferred to a glass crystallizing
dish and placed in a desiccator over a saturated solution of sodium
chloride, to maintain a constant 75% relative humidity. After
drying for 12 days at room temperature (24.+-.1.degree. C.) and 75%
relative humidity, about 20.5 g of the desired hydrated crystal
form of lopinavir was obtained. Powder X-ray diffraction pattern
(FIG. 5). 100 MHz solid state .sup.13C nuclear magnetic resonance
spectrum (FIG. 6). Solid state FT near IR (FIG. 7). Solid state FT
mid-IR (FIG. 8). The product contained 4.3% volatile material by
thermal gravimetry.
Example 4
Preparation of Type I Hydrated Crystal Form of Lopinavir Comprising
about 0.5 Molecules of Water Per Molecule of Lopinavir
[0117] The product of Example 3 (about 100 mg) was loaded into the
sample holder of a powder X-ray diffractometer fitted with a
controlled atmosphere sample chamber and hot stage. The sample was
warmed at 1.degree. C./minute to 30.degree. C. in an atmosphere of
dry nitrogen and held at that temperature. Conversion to
hemihydrate was complete within 60-90 minutes. Powder X-ray
diffraction pattern (FIG. 1).
Example 5
Preparation of Type I Hydrated Crystal Form of Lopinavir Comprising
about 0.5 Molecules of Water Per Molecule of Lopinavir
[0118] The product of Example 3 (1 g) was spread as a thin layer in
a polypropylene weigh boat and dried overnight in a vacuum oven at
about -65 kPa at ambient temperature. The resultant hygroscopic
product (hemihydrate of lopinavir) was transferred to glass vials
and redried for 6 hours at about -65 kPa at ambient temperature.
The vials were then quickly capped with polypropylene caps and
stored in a desiccator over anhydrous calcium sulfate. 100 MHz
solid state .sup.13C nuclear magnetic resonance spectrum (FIG. 2).
Solid state FT near IR (FIG. 3). Solid state FT mid-IR (FIG. 4).
The product contained 2% volatile material by thermal
gravimetry.
Example 6
Preparation of Type II Isopropanol Hemisolvate Crystal Form of
Lopinavir
[0119] Lopinavir (16 g) was dissolved in 50 mL of isopropanol by
heating the mixture on a hot plate to the boiling point with
magnetic stirring. The solution was then cooled to room temperature
and a precipitate formed. The resulting mixture was stirred at room
temperature for 24 hours with just enough stirring to keep the
precipitate suspended. The precipitate was collected by suction
filtration and air dried to provide 9.9 g of the Type II
isopropanol hemisolvate crystal form of lopinavir. Thermal
gravimetry of the product indicated the presence of volatile
material corresponding to 1 mole of isopropanol for every two moles
of lopinavir. Powder X-ray diffraction analysis confirmed that the
product was crystalline and infrared spectrometry confirmed that
the product is the Type II solvated crystal form of lopinavir.
Solid state FT mid-IR (FIG. 9). Solid state FT near IR (FIG.
14).
Example 7
Preparation of Type II Isopropanol Solvate Crystal Form of
Lopinavir (1.6% Ispropanol by Weight by Thermal Gravimetry)
[0120] Lopinavir (1 g) was suspended in 2.5 mL of isopropanol in a
glass vial containing four 4 mm diameter glass beads to promote
mixing. The vial was capped and the suspension was tumbled
end-over-end at room temperature for 4 months. The suspension was
then transferred to a Petri dish and the solvent was allowed to
evaporate slowly. The Petri dish was then placed in a vacuum oven,
which was then warmed to 50.degree. C. and the sample was dried at
-65 kPa at 50.degree. C. for 25 days to give the title compound.
The product contained 1.6% volatile material by thermal
gravimetry.
Example 8
Preparation of Type II Isopropanol Solvate Crystal Form of
Lopinavir (2% Isopropanol by Weight by Thermal Gravimetry)
[0121] A sample of the product of Example 6 was rinsed with
heptane, then dried for two day in a rotary evaporator. The residue
was transferred to a Petri dish and dried in a vacuum oven, which
was then warmed to 50.degree. C. and the sample was dried at -65
kPa at 50.degree. C. for 3 days to give the title compound. The
product contained 2% volatile material by thermal gravimetry. Solid
state FT mid-IR (FIG. 10). Solid state FT near IR (FIG. 15).
Example 9
Preparation of Type II Ethyl Acetate Hemisolvate Crystal Form
Lopinavir
Example 9A
Preparation of Crude Lopinavir
[0122] Crude lopinavir, prepared according to U.S. Pat. No.
5,914,332 (Example 38) from (2S,3 S,5
S)-2-amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl]-
amino-1,6-diphenylhexane (S)-pyroglutamic acid salt (about 85 g,
corrected for solvent content), was dissolved in 318.5 grams of
ethyl acetate and the solution was concentrated to an oil in vacuo.
The residue was dissolved in 225 grams of ethyl acetate, then
concentrated to an oil in vacuo twice. The residue was dissolved in
ethyl acetate (approximately 300 mL) at 65.degree. C., filtered to
remove any trace undissolved solids, and concentrated to a foam in
vacuo. The foam was dissolved in 338 grams of ethyl acetate and
this solution was divided into four equal portions.
Example 9B
Preparation of Type II Ethyl Acetate Hemisolvate Crystal Form
Lopinavir
[0123] One portion of the lopinavir solution prepared in Example 9A
was concentrated to an oil in vacuo, then dissolved in 50 mL
absolute ethanol. Solvent was removed in vacuo. The residue was
maintained under vacuum with heating (approximately 55-60.degree.
C.) for an additional 30 minutes. The resulting foam was dissolved
in ethyl acetate (87 mL) at ambient temperature. In less than five
minutes of mixing, solids were evident. The resulting slurry was
mixed for 16 hours, then diluted with 87 mL of heptanes. After
three hours the solids were collected by filtration, washed with 36
mL EtOAc/heptanes (1:1 v/v), and dried under vacuum at 60.degree.
C. for 72 hours, affording 19.4 grams of the Type II ethyl acetate
hemisolvate of lopinavir. Solid state FT mid-IR (FIG. 11). Solid
state FT near IR (FIG. 16). The product contained 4.4% volatile
material by thermal gravimetry.
Example 9C
Alternative Preparation of Type II Ethyl Acetate Hemisolvate
Crystal Form Lopinavir
[0124] Crude lopinavir, prepared according to U.S. Pat. No.
5,914,332 (Example 38) from (2S,3
S,5S)-2-amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutano-
yl]amino-1,6-diphenylhexane (s)-pyroglutamic acid salt (about 20 g,
corrected for solvent content), was dissolved in 118 grams of ethyl
acetate and was then concentrated to an oil in vacuo. The residue
was dissolved in 95.7 grams of ethyl acetate at 46.degree. C., then
concentrated to an oil in vacuo. The residue was dissolved in 95.8
grams ethyl acetate at 64.degree. C. Measurement for moisture by KF
showed less than 0.05% water. The product solution was cooled to
41.degree. C. and seeded with 0.20 grams of the product of Example
9B. The solution was cooled to 35.degree. C. and mixed at that
temperature for 1.25 hours. The resulting slurry was then cooled to
15.degree. C. over 10 minutes, and mixed at 15-18.degree. C. for
1.5 hours. The solids were collected by filtration, washed with
13.3 grams of ethyl acetate, and dried under vacuum at
56-58.degree. C. for 16 hours, affording 12.3 grams of the Type II
ethyl acetate hemisolvate of lopinavir
Example 10A
Preparation of Type II Ethyl Acetate Solvate Crystal Form Lopinavir
(Having Less than 0.5 Moles of Ethyl Acetate Per 2 Moles of
Lopinavir by Thermal Gravimetry)
[0125] One portion of the lopinavir solution prepared in Example 9A
was concentrated to an oil in vacuo, then dissolved in 50 mL of
absolute ethanol. Solvent was removed in vacuo. The residue was
maintained under vacuum with heating (approximately 55-60.degree.
C.) for an additional 30 minutes. Seed crystals of the product of
Example 9B were added to the resulting foam. The foamy residue was
then dissolved in ethyl acetate (87 mL) at ambient temperature. In
less than five minutes of mixing, solids were evident. The
resulting slurry was mixed for 16 hours, then diluted with 87 mL of
heptanes. After three hours, the solids were collected by
filtration, washed with 36 mL of EtOAc/heptanes (1:1 v/v), and
dried under vacuum at 60.degree. C. for 72 hours, affording 19.37
grams of the Type II ethyl acetate solvate of lopinavir. Solid
state FT mid-IR (FIG. 12). Solid state FT near IR (FIG. 17). The
product contained 1.7% volatile material by thermal gravimetry.
Example 10B
Alternative Preparation of Type II Ethyl Acetate Solvate Crystal
Form Lopinavir (Having Less than 0.5 Moles of Ethyl Acetate Per 2
Moles of Lopinavir by Thermal Gravimetry)
[0126] A solution of crude lopinavir prepared according to U.S.
Pat. No. 5,914,332 (Example 2; coupling of 17.0 g of
(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphe-
nylhexane with 8.0 g of
25-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoic acid via EDAC/HOBT
coupling) in isopropyl acetate (about 250 mL) was concentrated to
an oil in vacuo. The residue was dissolved in 250 mL of ethyl
acetate and concentrated to a foam in vacuo. The foam was dissolved
in 120 mL of warm ethyl acetate. The solution was divided into
three portions of 44.9 grams each. The solutions were cooled to
ambient temperature after which crystallization occurred rapidly.
One of those portions was mixed at ambient temperature overnight.
The solids were collected by filtration, washed with 8 ml of ethyl
acetate, then dried under vacuum at 22.degree. C. for 40 hours,
then dried an additional 44 hours under vacuum at 70.degree. C.
affording 6.23 grams of the Type II ethyl acetate solvate of
lopinavir.
Example 11
Preparation of Type II Chloroform Hemisolvate Crystal Form
Lopinavir
[0127] Lopinavir (10 g) was dissolved in 30 mL of chloroform. The
solution was then heated to boiling on a hot plate with magnetic
stirring. After reducing the volume of the solution to about 1/2 of
the initial volume, about 10 mL of n-heptane was added dropwise
until the solution started to become turbid. Then about 30 mL more
of chloroform was added and boiling was continued until the volume
was again about 1/2 of the original volume. Then about 20 mL of
chloroform was added and boiling was continued until the volume was
again about 1/2 of the original volume. The mixture was then cooled
slowly to room temperature and allowed to partially evaporate.
After the slow evaporation, a glassy residue with the consistency
of molasses remained. This was mixed with about 20 mL of chloroform
and warmed on a hot plate. Then n-heptane was added dropwise until
a precipitate began to form. The precipitate was dissolved by
rewarming of the mixture. The warm solution was transferred to a
beaker, which was placed inside ajar containing about 20 mL of
heptane, and allowed to cool. After about 1 hour a thick solid
precipitate formed. Most of the precipitate was redissolved by
adding about 20 mL of chloroform to the contents of the beaker.
After letting this mixture stand for about 1 hour, a few needle
shaped crystals formed. More heptane (about 40 mL) was added to the
jar containing the beaker and the jar was capped and allowed to
stand. After one day, the beaker contained large numbers of
crystals. The crystals were collected by vacuum filtration. The
crystal mass was broken up gently using a spatula and the crystals
were washed with the chloroform/heptane mixture from the jar
external to the beaker in which the crystals had been grown.
Thermal gravimetry of the product indicated the presence of
volatile material corresponding to 1 mole of chloroform for every
two moles of lopinavir. Powder X-ray diffraction analysis confirmed
that the product was crystalline and infrared spectrometry
confirmed that the product is the Type II solvated crystal form of
lopinavir. Solid state FT mid-IR (FIG. 13). Solid state FT near IR
(FIG. 18).
Example 12
Preparation of Type III Ethyl Acetate Solvated Crystal Form
Lopinavir
[0128] Lopinavir (7.03 g) was dissolved in ethyl acetate (33.11 g)
at 71.degree. C. The solution was cooled to 42.degree. C. over 45
minutes, at which point solids were evident. The slurry was cooled
to 35.degree. C. over 30 minutes, then mixed for one hour. Then the
slurry was cooled to 15.degree. C. over 13 minutes and then mixed
for one hour. Mixed heptanes (25.1 g) were added dropwise over 13
minutes. The resulting slurry was mixed for 30 minutes. The
resulting solids were collected by filtration, washed with ethyl
acetate/mixed heptanes (1:1 v/v, 20 mL) and dried under vacuum at
62.degree. C. for 20 hours to give 6.4 g of the title compound.
Powder X-ray diffraction analysis confirmed that the product was
crystalline and infrared spectrometry confirmed that the product is
the Type III solvated crystal form of lopinavir. Solid state FT
mid-IR (FIG. 19). Solid state FT near IR (FIG. 20). The product
contained 2.3% volatile material by thermal gravimetry.
Example 13
Preparation of Type III Ethyl Acetate Solvated Crystal Form of
Lopinavir
[0129] Approximately 100 mg of lopinavir was dissolved in about 3
mL of ethyl acetate. To this solution was slowly and carefully
added about 3 mL of heptane. After standing, crystals of the Type
III solvated crystal form of lopinavir grew by liquid diffusion
crystallization.
Example 14
Preparation of Type III Ethyl Acetate Solvated Crystal Form of
Lopinavir
[0130] One portion of the lopinavir solution prepared in Example 9A
was diluted with 14.8 grams of ethyl acetate and heated to
70-75.degree. C., then diluted with 75 grams of heptanes while
maintaining an internal temperature greater than 70.degree. C. The
resulting solution was heated to 75.degree. C. for 15 minutes, then
allowed to cool to ambient temperature gradually. After mixing
overnight at ambient temperature the solids were collected by
filtration, washed with 36 mL of ethyl acetate/heptanes (1:1 v/v),
and dried under vacuum at 60.degree. C. for 72 hours, affording
21.5 grams of the title compound.
Example 15
Preparation of Type III Desolvated Crystal Form of Lopinavir
[0131] Lopinavir (5 g) was placed in a 100 mL beaker. Just enough
acetonitrile was added to dissolve approximately 95% of the
lopinavir. Some needle-shaped crystals remained undissolved. The
beaker was placed inside a jar containing about a 1 cm deep layer
of anhydrous calcium sulfate (DRIERITE). The jar was capped and the
material was left undisturbed at ambient temperature. After
standing overnight, a large amount of white crystalline material
had precipitated. The supernatant (about 6 mL) was decanted from
the beaker. Fresh acetonitrile (3-4 mL) was added to the
precipitate, which was then gently broken up with a spatula. The
solid was collected by suction filtration and rinsed with about 1
mL of acetonitrile. The solid was transferred to a Petri dish and
dried under vacuum at ambient temperature to give the Type III
desolvated crystal form of lopinavir. Powder X-ray diffraction
analysis confirmed that the product was crystalline and infrared
spectrometry confirmed that the product is the Type III crystal
form of lopinavir. The product contained less than 0.05% volatile
material by thermal gravimetry. Solid state FT mid-IR (FIG. 21).
Solid state FT near IR (FIG. 22). Powder X-ray diffraction pattern
(FIG. 23). 100 MHz solid state .sup.13C nuclear magnetic resonance
spectrum (FIG. 24). DSC thermogram (FIG. 25).
Example 16
Preparation of Type IV Non-Solvated Crystal Form of Lopinavir
[0132] Lopinavir (amorphous, 1 g) was placed in a crystallizing
dish (A). This dish was placed in a bigger crystallizing dish (B)
containing about 10 mL of acetonitrile and sitting on a hot plate.
An intermediate size crystallizing dish (C) was inverted and placed
over dish A, but still inside of dish B. A large crystallizing dish
(D) was inverted and placed over dishes A, B and C. The hot plate
was warmed to about 35.degree. C. and then the hot plate was turned
off. The whole assembly was then allowed to sit for 10 days at
ambient temperature. After 10 days, all of the acetonitrile had
evaporated.
[0133] A portion of the resulting crystalline product (0.1 g) was
mixed with acetonitrile (0.6 mL) and stirred for 1 hour. The
mixture was filtered and the solid allowed to air dry to give the
Type IV non-solvated crystal form of lopinavir.
Example 17
Preparation of Type IV Non-Solvated Crystal Form of Lopinavir
[0134] Lopinavir (259 g) was dissolved in 500 g of acetonitrile at
40-42.degree. C. The hazy solution was filtered through a 0.45
{circle around (3)} Nylon membrane into a 2 L round bottom flask
and the solution was seeded with a few crystals of the product of
Example 16. The flask was rotated at 10-20 rpm overnight without
heat or vacuum using a rotary evaporator apparatus. A thick slurry
of needle-like crystals resulted. The slurry was cooled in an ice
bath for 1 hour and then filtered in a table-top Neutsche filter
blanketed with nitrogen and covered with plastic film. The filter
cake was washed with acetonitrile and sucked dry under nitrogen for
about 30 minutes. The filter cake was transferred to a
crystallizing dish and dried over a weekend at 60-65.degree. C. at
20-21'' Hg with a nitrogen bleed to provide 194.3 g of the Type IV
non-solvated crystal form of lopinavir. The product was crystalline
by powder X-ray diffractometry and was classified as the Type IV
non-solvated crystal form of lopinavir by solid state FT mid-IR.
Solid state FT mid-IR (FIG. 26). Solid state FT near IR (FIG. 27).
Powder X-ray diffraction pattern (FIG. 28). 100 MHz solid state
.sup.13C nuclear magnetic resonance spectrum (FIG. 29). DSC
thermogram (FIG. 30). The product contained less than 0.1% volatile
material by thermal gravimetric analysis.
[0135] When administered for treatment of an HIV infection,
lopinavir is preferably administered in combination with ritonavir
in a ratio of 4:1 (lopinavir:ritonavir). A preferred pharmaceutical
composition for administering lopinavir, comprising a 4:1 ratio of
lopinavir:ritonavir has the following composition, encapsulated in
a soft elastic gelatin capsule.
TABLE-US-00011 Lopinavir 133.3 mg Ritonavir 33.3 mg Oleic acid, NF
598.6 mg Propylene Glycol, USP 64.1 mg Polyoxyl 35 Castor Oil, NF
21.4 mg (Cremephor EL .RTM.) Water, purified, USP (distilled) 4.3
mg
[0136] If a hydrated or solvated crystal form of lopinavir is used
in the composition, the amount of the hydrated or solvated crystal
form of lopinavir is adjusted to take into account the amount of
water or other solvent present in the crystal form.
[0137] The preferred composition can be prepared according to the
following method.
[0138] The following protocol is employed in the preparation of
1000 soft gelatin capsules:
TABLE-US-00012 Scale Amount (mg/capsule) Name (g) Q.S. Nitrogen,
N.F. Q.S. 578.6 Oleic Acid, NF 578.6 33.3 Ritonavir 33.3 64.1
Propylene Glycol, USP 64.1 4.3 Water, purified, USP (distilled) 4.3
133.3 Lopinavir 133.3 10.0 Oleic Acid, NF 10.0 21.4 Polyoxyl 35
Castor Oil, NF 21.4 10.0 Oleic Acid, NF 10.0
[0139] A mixing tank and suitable container are purged with
nitrogen. 578.6 g of oleic acid is then charged into the mixing
tank. The mixing tank is heated to 28.degree. C. (not to exceed
31.degree. C.) and mixing is started. 33.3 g of ritonavir is then
added to the oleic acid with mixing. The propylene glycol and water
are added to the mixing tank and mixing is continued until the
solution is clear. 133.3 g of lopinavir is then added into the
mixing tank and mixing is continued. 10 g of oleic acid is then
charged into the tank and mixed until the solution is clear. 21.4 g
of polyoxyl 35 castor oil, NF is added to the mixing tank and
mixing is continued, followed by the addition of 10 g of oleic
acid. The solution is stored at 2-8.degree. C. until encapsulation.
0.855 g of the solution is filled into each soft gelatin capsule
and the soft gelatin capsules are then dried, and stored at
2-8.degree. C.
[0140] As used herein, the term "substantially pure", when used in
reference to a crystalline form of lopinavir, refers to that
crystalline form of lopinavir which is greater than about 90% pure.
This means that the crystalline form of lopinavir does not contain
more than about 10% of any other compound and, in particular, does
not contain more than about 10% of any other form of lopinavir,
such as amorphous, solvated forms, non-solvated forms and
desolvated forms. More preferably, the term "substantially pure"
refers to a crystalline form of lopinavir which is greater than
about 95% pure. This means that the crystalline form of lopinavir
does not contain more than about 5% of any other compound and, in
particular, does not contain more than about 5% of any other form
of lopinavir, such as amorphous, solvated forms, non-solvated forms
and desolvated forms. Even more preferably, the term "substantially
pure" refers to a crystalline form of lopinavir which is greater
than about 97% pure. This means that the crystalline form of
lopinavir does not contain more than about 3% of any other compound
and, in particular, does not contain more than about 3% of any
other form of lopinavir, such as amorphous, solvated forms,
non-solvated forms and desolvated forms.
[0141] Yet even more preferably, the term "substantially pure"
refers to a crystalline form of lopinavir which is greater than
about 98% pure. This means that the crystalline form of lopinavir
does not contain more than about 2% of any other compound and, in
particular, does not contain more than about 2% of any other form
of lopinavir, such as amorphous, solvated forms, non-solvated forms
and desolvated forms.
[0142] Most preferably, the term "substantially pure" refers to a
crystalline form of lopinavir which is greater than about 99% pure.
This means that the crystalline form of lopinavir does not contain
more than about 1% of any other compound and, in particular, does
not contain more than about 1% of any other form of lopinavir, such
as amorphous, solvated forms, non-solvated forms and desolvated
forms.
[0143] Powder X-ray diffraction analysis of samples was conducted
in the following manner. Samples for X-ray diffraction analysis
were prepared by spreading the sample powder (ground to a fine
powder with a mortar and pestle, or with glass microscope slides
for limited quantity samples) in a thin layer on the sample holder
and gently flattening the sample with a microscope slide. Samples
were run in one of three configurations: circular bulk holder, a
quartz zero background plate or hot stage mount (similar mounting
to a zero background plate). X-ray powder diffraction was performed
using an XDS 2000 .theta./.theta. diffractometer (Scintag; 2 kW
normal focus X-ray tube with either a liquid nitrogen or Peltier
cooled germanium solid state detector; 45 kV and 30-40 ma; X-ray
source: Cu-K.alpha.1; Range: 2.00-40.00.degree. Two Theta; Scan
Rate: 0.5 or 2 degrees/minute), a XRD-6000 diffractometer
(Shimadzu; fine focus X-ray tube with a NaI scintillation detector;
40-45 kV and 30-40 ma; X-ray source: Cu-K.alpha.1; Range:
2.00-40.00.degree. Two Theta; Scan Rate: 2 degrees/minute) or a I-2
X-ray diffractometer (Nicolet; scintillation detector; 50 kV and 30
ma; X-ray source: Cu-K.alpha.1; Range: 2.00-40.00.degree. Two
Theta; Scan Rate: 2 degrees/minute. The relative humidity of the
sample in the hot stage mount could be controlled using a relative
humidity generator (model RH200, VTI Corp.).
[0144] Characteristic powder X-ray diffraction pattern peak
positions are reported for polymorphs in terms of the angular
positions (two theta) with an allowable variability of
.+-.0.1.degree.. This allowable variability is specified by the
U.S. Pharmacopeia, pages 1843-1844 (1995). The variability of
.+-.0.1.degree. is intended to be used when comparing two powder
X-ray diffraction patterns. In practice, if a diffraction pattern
peak from one pattern is assigned a range of angular positions (two
theta) which is the measured peak position.+-.0.1.degree. and a
diffraction pattern peak from the other pattern is assigned a range
of angular positions (two theta) which is the measured peak
position.+-.0.1.degree. and if those ranges of peak positions
overlap, then the two peaks are considered to have the same angular
position (two theta). For example, if a diffraction pattern peak
from one pattern is determined to have a peak position of
5.20.degree., for comparison purposes the allowable variability
allows the peak to be assigned a position in the range of
5.10.degree.-5.30.degree.. If a comparison peak from the other
diffraction pattern is determined to have a peak position of
5.35.degree., for comparison purposes the allowable variability
allows the peak to be assigned a position in the range of
5.25.degree.-5.45.degree.. Because there is overlap between the two
ranges of peak positions (i.e., 5.10.degree.-5.30.degree. and
5.25.degree.-5.45.degree.) the two peaks being compared are
considered to have the same angular position (two theta).
[0145] Solid state nuclear magnetic resonance analysis of samples
was conducted in the following manner. A Bruker AMX-400 instrument
was used with the following parameters: CP-MAS (cross-polarized
magic angle spinning); spectrometer frequency for .sup.13C was
100.6 MHz; pulse sequence was VA-CP2LEV; contact time was 2.5
milliseconds; spin rate was 7000 Hz; recycle delay time was 5.0
sec; 3000 scans).
[0146] FT near infrared analysis of samples was conducted in the
following manner. Samples were analyzed as neat, undiluted powders
contained in a clear glass 1 dram vial. A Nicolet Magna System 750
FT-IR spectrometer with a Nicolet SabIR near infrared diffuse
reflectance fiber optic probe accessory was used with the following
parameters: the detector was PbS; the beamsplitter was CaF2; the
number of sample scans was 16; the resolution was 8 cm-1.
[0147] FT mid infrared analysis of samples was conducted in the
following manner Samples were analyzed as neat, undiluted powders.
A Nicolet Magna System 750 FT-IR spectrometer with a Nicolet
NIC-PLAN Microscope with a MCT-A liquid nitrogen cooled detector
was used. The sample was placed on a 13 mm.times.1 mm BaF2 disc
sample holder. 64 scans were collected at 4 cm-1 resolution.
[0148] Differential scanning calorimetric analysis of samples was
conducted in the following manner. A T.A. Instruments Model 2920
differential scanning calorimeter with TA Instruments DSC cell with
Thermal Solutions version 2.3 software for data analysis. The
analysis parameters were: Sample size: 4-10 mg, placed in an
aluminum pan and sealed after a pin hole was poked in the lid;
Heating rate: 1.degree. C./minute under a dry nitrogen purge (40-50
mL/minute).
[0149] Thermal gravimetric analysis was conducted by heating the
sample at 1.degree. C. or 5.degree. C./minute from ambient to
200.degree. C.
[0150] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed embodiments.
Variations and changes which are obvious to one skilled in the art
are intended to be within the scope and nature of the invention
which are defined in the appended claims.
* * * * *