U.S. patent application number 13/550665 was filed with the patent office on 2013-01-10 for crystalline forms of tigecycline hydrochloride.
This patent application is currently assigned to SANDOZ AG. Invention is credited to Andreas Hotter, Arthur Pichler, Josef Wieser.
Application Number | 20130012481 13/550665 |
Document ID | / |
Family ID | 39186791 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130012481 |
Kind Code |
A1 |
Wieser; Josef ; et
al. |
January 10, 2013 |
CRYSTALLINE FORMS OF TIGECYCLINE HYDROCHLORIDE
Abstract
The present invention relates to crystalline forms A and B of
Tigecycline hydrochloride and to methods for the preparation of the
same. Furthermore the present invention relates to the use of
crystalline forms A and B of Tigecycline hydrochloride as
intermediates for the formulation of an anti-infective medicament.
Moreover the present invention relates to pharmaceutical
compositions comprising crystalline form A of Tigecycline
hydrochloride in an effective amount and to the use of crystalline
form A of Tigecycline hydrochloride as anti-infective
medicament.
Inventors: |
Wieser; Josef; (Polling,
AT) ; Hotter; Andreas; (Woergl, AT) ; Pichler;
Arthur; (Buch bei Jenbach, AT) |
Assignee: |
SANDOZ AG
Basel
CH
|
Family ID: |
39186791 |
Appl. No.: |
13/550665 |
Filed: |
July 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12742706 |
May 13, 2010 |
8252946 |
|
|
PCT/EP2008/065398 |
Nov 12, 2008 |
|
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13550665 |
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Current U.S.
Class: |
514/152 ;
552/200 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07C 237/26 20130101; A61P 31/00 20180101; A61P 31/04 20180101;
C07C 2603/46 20170501 |
Class at
Publication: |
514/152 ;
552/200 |
International
Class: |
C07C 50/36 20060101
C07C050/36; A61P 31/00 20060101 A61P031/00; A61K 31/65 20060101
A61K031/65 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 14, 2007 |
EP |
07120732.8 |
Claims
1-36. (canceled)
37. Crystalline Tigecycline hydrochloride
38. A crystalline form A of Tigecycline hydrochloride.
39. The crystalline form A of Tigecycline hydrochloride according
to claim 38, having wherein the crystalline form A is a
monohydrochloride.
40. The crystalline form A of Tigecycline hydrochloride according
to claim 38, wherein the water content of the crystalline form A
ranges from about 0 to 6.0%.
41. The crystalline form A of Tigecycline hydrochloride according
to claim 38, containing less than 10% of form B or amorphous
Tigecycline.
42. The crystalline form A of Tigecycline hydrochloride according
to claim 38, containing less than 5% of form B or amorphous
Tigecycline.
43. The crystalline form A of Tigecycline hydrochloride according
to claim 38, containing less than 1% of form B or amorphous
Tigecycline.
44. The crystalline form A of Tigecycline hydrochloride according
to claim 38, the crystalline form A is an essentially pure
polymorphic form.
45. The crystalline form A of Tigecycline hydrochloride according
to claim 38, having enhanced water solubility compared to forms I
to V of Tigecycline.
46. The crystalline form A of Tigecycline hydrochloride according
to claim 38, having enhanced storage stability compared to forms
Ito III and amorphous Tigecycline.
47. A process for the preparation of crystalline form A of
Tigecycline hydrochloride, comprising the steps of: a) stirring a
suspension of Tigecycline in a suitable solvent at room temperature
to form a suspension; b) adding hydrochloric acid to the
suspension; and c) isolating crystalline form A of Tigecycline
hydrochloride.
48. A process for the preparation of crystalline form A of
Tigecycline hydrochloride, comprising the steps of: a) dissolving
Tigecycline in a suitable solvent at a temperature ranging from
room temperature to the boiling point of the used solvent to form a
solution; b) adding hydrochloric acid to the solution of step a),
wherein a precipitate forms to form a suspension; c) cooling down
the suspension to room temperature or below; and d) isolating
crystalline form A of Tigecycline hydrochloride.
49. A method of using crystalline form A of Tigecycline
hydrochloride as an anti-infective medicament comprising treating a
patient with an effective amount of crystalline form A of
Tigecycline hydrochloride.
50. A pharmaceutical composition formed from an effective amount of
crystalline form A of Tigecycline hydrochloride.
51. A crystalline form B of Tigecycline hydrochloride.
Description
THE FIELD OF THE INVENTION
[0001] The present invention relates to crystalline forms A and B
of Tigecycline hydrochloride and to methods for the preparation of
the same. Furthermore the present invention relates to the use of
crystalline forms A and B of Tigecycline hydrochloride as
intermediates for the formulation of an anti-infective medicament.
Moreover the present invention relates to pharmaceutical
compositions comprising crystalline form A of Tigecycline
hydrochloride in an effective amount and to the use of crystalline
form A of Tigecycline hydrochloride as anti-infective
medicament.
BACKGROUND OF THE INVENTION
[0002] Tigecycline,
(4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-[[[(1,1-dimethylethyl)amino]ac-
etyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-d-
ioxo-2-naphthacenecarboxamide, is a 9-t-butylglycylamido derivative
of minocycline (Merck Index 14.sup.th Edition, monograph number
9432, CAS Registry Number 220620-09-7). Compared to other
tetracycline antibiotics Tigecycline is more active against
tetracycline-resistant strains and also more tolerable. Tigecycline
possesses activity against bacterial isolates containing the two
major determinants responsible for tetracycline-resistance:
ribosomal protection and active efflux of the drug out of the
bacterial cell. Furthermore Tigecycline possesses broad spectrum
activity, e.g. it is active against gram-positive pathogens (e.g.
methicillin-resistant Staphylococcus aureus, vancomycin-resistant
Enterococci), gram-negative pathogens (e.g. Acinetobacter
baumannii, Stenotrophomonas maltophilia) and anaerobic pathogens.
At the moment Tigecycline is indicated for the treatment of
complicated skin and soft-tissue infections and intra-abdominal
infections. (P. J. Petersen et al., Antimicrob. Agents Chemoth.
1999; 43: 738-744. R. Patel et al., Diagnostic Microbiology and
Infectious Disease 2000; 38: 177-179. H. W. Boucher et al.,
Antimicrob. Agents Chemoth. 44: 2225-2229. D. J. Biedenbach et al.,
Diagnostic Microbiology and Infectious Disease 2001; 40: 173-177.
P. J. Petersen et al., Antimicrob. Agents Chemoth. 2002; 46:
2595-2601. D. Milatovic et al., Antimicrob. Agents Chemoth. 47:
400-404. T. Hirata et al., Antimicrob. Agents Chemoth. 2004; 48:
2179-2184. G. A. Pankey, Journal of Antimicrobial Chemotherapy
2005; 56: 470-480. R. Harris et al., P&T 2006; 31: 18-59.).
[0003] U.S. Pat. No. 5,675,030 mentions a process for the
preparation of Tigecycline hydrochloride by "treating" the free
base with hydrochloric acid, but neither an explicit method for the
preparation of crystalline Tigecycline hydrochloride, nor the
existence of a crystalline form of Tigecycline hydrochloride are
described. In Example 9 of said patent an aqueous solution of
Tigecycline hydrochloride is lyophilized, whereas, according to
U.S. Pat. No. 5,675,030, Tigecycline hydrochloride dihydrate of
unknown solid state is obtained. However, repeating the experiment
resulted in amorphous Tigecycline hydrochloride.
[0004] WO 2005/056538, WO 2006/130418, WO 2006/130431, WO
2006/130500 and WO 2006/130501 disclose Tigecycline, acid addition
salts of Tigecycline and processes for the preparation of the same
as well. However, in literature no crystalline Tigecycline
hydrochloride is described.
[0005] Tigecycline is available on the market as lyophilized powder
for injection, the originator is Wyeth. During the formulation
process Tigecycline is first dissolved in water and then
lyophilized. Therefore a crystalline form of Tigecycline or an
alternative crystalline acid addition salt of Tigecycline should
show high water solubility.
[0006] In 2007 the originator launched a novel formulation of
Tigecycline in the US. The commercial Tygacil.RTM. 2.sup.nd
generation product contains, according to the originator, following
ingredients:
TABLE-US-00001 TABLE 1 Tygacil .RTM. 2.sup.nd generation INGREDIENT
QUANTITY PER VIAL Tigecycline 53 mg Lactose monohydrate 106 mg
Hydrochloric acid Q.S. to adjust pH Sodium hydroxide Q.S. to adjust
pH Water for injection Removed during lyophilization Nitrogen
Q.S.
[0007] The inventors of the present invention surprisingly found
that these originator vials contain amorphous Tigecycline
hydrochloride instead of the free base, which is due to the
addition of hydrochloric acid for pH-adjustment. Therefore it seems
to be reasonable to apply crystalline Tigecycline hydrochloride to
the lyophilization process instead of the free base, as the salt
shows higher water solubility than any crystalline form of the free
base.
[0008] Moreover the ratio of Tigecycline to hydrochloric acid can
be chosen such, that there is no need for pH-adjustment
anymore.
[0009] Generally, crystalline solids have improved chemical and
physical stability over the amorphous form and forms with low
crystallinity, therefore crystalline Tigecycline hydrochloride is
more preferred than amorphous Tigecycline hydrochloride. Thus there
remains a need for crystalline Tigecycline hydrochloride with
suitable solubility and stability properties for the formulation of
an anti-infective medicament.
SUMMARY OF THE INVENTION
[0010] In one embodiment, the present invention refers to
crystalline form A of Tigecycline hydrochloride.
[0011] Crystalline form A of Tigecycline hydrochloride can be
described by an X-ray powder diffraction pattern comprising peaks
at 2-theta angles of 7.6.degree..+-.0.2.degree.,
9.1.+-.0.2.degree., 12.2.+-.0.2.degree., 13.7.+-.0.2.degree.,
15.2.+-.0.2.degree., 18.0.+-.0.2.degree., 20.6.+-.0.2.degree.,
22.8.+-.0.2.degree. and 23.7.+-.0.2.degree..
[0012] Alternatively crystalline form A of Tigecycline
hydrochloride can be described by an infrared spectrum comprising
peaks at wavenumbers of 3443.+-.2 cm.sup.-1, 3278.+-.2 cm.sup.-1,
2393.+-.2 cm.sup.-1, 1689.+-.2 cm.sup.-1, 1651.+-.2 cm.sup.-1,
1544.+-.2 cm.sup.-1, 1362.+-.2 cm.sup.-1, 1271.+-.2 cm.sup.-1,
1130.+-.2 cm.sup.-1, 1050.+-.2 cm.sup.-1, 871.+-.2 cm.sup.-1 and
808.+-.2 cm.sup.-1.
[0013] A first process for the preparation of crystalline form A of
Tigecycline hydrochloride comprising the steps of: [0014] a)
stirring a suspension of Tigecycline in a suitable solvent at room
temperature; [0015] b) adding hydrochloric acid to the suspension;
[0016] c) isolating crystalline form A of Tigecycline
hydrochloride; is also subject matter of the present invention.
[0017] In addition a second process for the preparation of
crystalline form A of Tigecycline hydrochloride, comprising the
steps of: [0018] a) dissolving Tigecycline in a suitable solvent at
a temperature ranging from room temperature to the boiling point of
the used solvent; [0019] b) adding hydrochloric acid to the
solution; [0020] c) cooling down the obtained suspension to room
temperature or below; [0021] d) isolating crystalline form A of
Tigecycline hydrochloride; is subject matter of the present
invention as well.
[0022] In another embodiment, the present invention refers to
crystalline form B of Tigecycline hydrochloride.
[0023] Crystalline form B of Tigecycline hydrochloride can be
described by an X-ray powder diffraction pattern comprising peaks
at 2-theta angles of 5.8.degree..+-.0.2.degree.,
7.0.+-.0.2.degree., 9.1.+-.0.2.degree., 9.7.+-.0.2.degree.,
14.1.+-.0.2.degree., 15.5.+-.0.2.degree., 17.3.+-.0.2.degree.,
18.3.+-.0.2.degree., 19.6.+-.0.2.degree., 22.4.+-.0.2.degree.,
25.5.+-.0.2.degree., 27.1.+-.0.2.degree. and
28.5.+-.0.2.degree..
[0024] Alternatively crystalline form B of Tigecycline
hydrochloride can be described by an infrared spectrum comprising
peaks at wavenumbers of 3365.+-.2 cm.sup.-1, 3228.+-.2 cm.sup.-1,
1685.+-.2 cm.sup.-1, 1648.+-.2 cm.sup.-1, 1545.+-.2 cm.sup.-1,
1360.+-.2 cm.sup.-1, 1263.+-.2 cm.sup.-1, 1204.+-.2 cm.sup.-1 and
872.+-.2 cm.sup.-1.
[0025] A process for the preparation of crystalline form B of
Tigecycline hydrochloride comprising the steps of: [0026] a)
stirring a mixture of Tigecycline and methylenehloride; [0027] b)
adding hydrochloric acid; [0028] c) stirring the solution at room
temperature or below to effect crystallization of crystalline form
B of Tigecycline hydrochloride; [0029] d) isolating crystalline
form B of Tigecycline hydrochloride; is also subject matter of the
present invention.
[0030] Furthermore the present invention relates to the use of
crystalline forms A and B of Tigecycline hydrochloride as
intermediates for the formulation of an anti-infective
medicament.
[0031] Moreover the present invention relates to pharmaceutical
compositions comprising crystalline form A of Tigecycline
hydrochloride in an effective amount.
[0032] In addition the present invention refers to the use of
crystalline form A of Tigecycline hydrochloride as an
anti-infective medicament.
[0033] Other objects, features, advantages and aspects of the
present invention will become apparent to those of skill from the
following description. It should be understood, however, that the
description and the following specific examples, while indicating
preferred embodiments of the invention, are given by way of
illustration only. Various changes and modifications within the
spirit and scope of the disclosed invention will become readily
apparent to those skilled in the art from reading the description
and from reading the other parts of the present disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1: X-ray powder diffraction pattern of crystalline form
A of Tigecycline hydrochloride
[0035] FIG. 2: Infrared spectrum of crystalline form A of
Tigecycline hydrochloride
[0036] FIG. 3: Differential Scanning calorimetric curve of
crystalline form A of Tigecycline hydrochloride
[0037] FIG. 4: X-ray powder diffraction pattern of crystalline form
B of Tigecycline hydrochloride
[0038] FIG. 5: Infrared spectrum of crystalline form B of
Tigecycline hydrochloride
[0039] FIG. 6: Differential Scanning calorimetric curve of
crystalline form B of Tigecycline hydrochloride
DETAILED DESCRIPTION OF THE INVENTION
[0040] As used herein the term "amorphous" relates to solid
material which lacks a regular crystalline structure.
[0041] The term "room temperature" as used herein indicates that
the applied temperature is not critical and that no exact
temperature value has to be kept. Usually, "room temperature" is
understood to mean temperatures of about 15.degree. C. to about
25.degree. C. [see e.g. EU Pharmacopoeia 6.0, 1.2 (2008)].
[0042] The term "concentrated hydrochloric acid" relates to
hydrochloric acid having a hydrochloride concentration of 37%.
[0043] The present invention relates to crystalline forms A and B
of Tigecycline hydrochloride and to processes for the preparation
thereof.
[0044] The chemical structure of Tigecycline hydrochloride is shown
in Figure A.
##STR00001##
[0045] The crystalline forms A and B of Tigecycline hydrochloride
may be characterized e.g. by a typical X-ray powder diffraction
pattern, an infrared spectrum or a differential scanning
calorimetric curve. Each of these characteristics on its own is
sufficient to unambiguously define and identify the crystalline
form of Tigecycline hydrochloride but they also may be combined
with each other.
[0046] The present invention relates to crystalline form A of
Tigecycline hydrochloride characterized by an X-ray powder
diffraction pattern with peaks at 2-theta angles of
7.6.degree..+-.0.2.degree., 9.1.+-.0.2.degree.,
12.2.+-.0.2.degree., 13.7.+-.0.2.degree., 15.2.+-.0.2.degree.,
18.0.+-.0.2.degree., 20.6.+-.0.2.degree., 22.8.+-.0.2.degree. and
23.7.+-.0.2.degree.. A characteristic X-ray powder diffraction
pattern of crystalline form A of Tigecycline hydrochloride is shown
in FIG. 1 and some characteristic peaks are listed in Table 2.
[0047] Accordingly, in a preferred embodiment, the present
invention relates to crystalline form A of Tigecycline
hydrochloride characterized by an X-ray powder diffraction pattern
substantially in accordance with Table 2 and FIG. 1.
TABLE-US-00002 TABLE 2 Characteristic X-Ray Powder Diffraction
(XRPD) peaks of crystalline form A of Tigecycline hydrochloride
ANGLE RELATIVE INTENSITY [.degree.2-THETA] [%] 7.6 41.5 9.1 58.1
12.2 27.2 13.7 37.3 15.2 92.3 18.0 81.6 20.6 100.0 22.8 42.3 23.7
41.1
[0048] Crystalline form A of Tigecycline hydrochloride also may be
characterized by a typical infrared spectrum as shown in FIG. 2.
Accordingly in a further preferred embodiment, the present
invention relates to crystalline form A of Tigecycline
hydrochloride characterized by an infrared spectrum substantially
in accordance with FIG. 2. Characteristic bands are present at
wavenumbers of 3443.+-.2 cm.sup.-1, 3278.+-.2 cm.sup.-1, 2393.+-.2
cm.sup.-1, 1689.+-.2 cm.sup.-1, 1651.+-.2 cm.sup.-1, 1544.+-.2
cm.sup.-1, 1362.+-.2 cm.sup.-1, 1271.+-.2 cm.sup.-1, 1130.+-.2
cm.sup.-1, 1050.+-.2 cm.sup.-1, 871.+-.2 cm.sup.-1 and 808.+-.2
cm.sup.-1.
[0049] In addition crystalline form A of Tigecycline hydrochloride
may be characterized by a typical differential scanning
calorimetric curve as shown in FIG. 3. The curve displays a first
endothermic peak with a maximum at about 59.degree. C., which may
be due to desolvation. The second endothermic peak with a maximum
at about 232.degree. C. may be due to the melting process. Compared
to the melting points of the crystalline forms I to V disclosed in
WO 2006/128150, which range from 167.degree. C. to 174.degree. C. a
melting point of 232.degree. C. proves high thermal stability.
[0050] Accordingly in another preferred embodiment the present
invention relates to crystalline form A of Tigecycline
hydrochloride characterized by a differential scanning calorimetric
curve substantially in accordance with FIG. 3.
[0051] In one embodiment, the present invention provides a first
process for the preparation of crystalline form A of Tigecycline
hydrochloride, comprising the steps of: [0052] a) stirring a
suspension of Tigecycline in a suitable solvent at room
temperature; [0053] b) adding hydrochloric acid to the suspension;
[0054] c) isolating crystalline form A of Tigecycline
hydrochloride;
[0055] In another embodiment, the present invention provides a
second process for the preparation of crystalline form A of
Tigecycline hydrochloride, comprising the steps of: [0056] a)
dissolving Tigecycline in a suitable solvent at a temperature
ranging from room temperature to the boiling point of the used
solvent; [0057] b) adding hydrochloric acid to the solution; [0058]
c) cooling down the obtained suspension to room temperature or
below; [0059] d) isolating crystalline form A of Tigecycline
hydrochloride;
[0060] Any form of Tigecycline may be used in step a) of the above
processes, e.g. amorphous forms, crystalline forms, mixtures of
amorphous and crystalline forms, mixtures of different crystalline
forms, hydrates or solvates. Suitable crystalline forms may be
forms I to V of WO 2006/128150, forms I and II of WO 2007/127292 or
mixtures thereof.
[0061] The concentration of Tigecycline in step a) of the above
processes depends on the form of Tigecycline and on the solvent
used. Generally the second process asks for lower concentrations
than the first, because prior to the acid addition Tigecycline is
completely dissolved. In the first process Tigecycline preferably
is used at a concentration ranging from 5 to 200 g/L, more
preferably from 10 to 50 g/L. Concentrations preferably ranging
from 5 to 50 g/L, most preferably from 5 to 15 g/L are applied in
the second process.
[0062] The temperature in step a) of the above second process may
vary. However, the temperature is chosen such that at a given
concentration of a particular form of Tigecycline in a particular
solvent a clear solution is obtained. Therefore it may become
necessary to heat the solvent to reflux.
[0063] Suitable solvents in step a) of the above processes are for
example ketones such as acetone or ethylmethylketone, nitriles such
as acetonitrile, esters such as methylacetate, ethylacetate and
isopropylacetate and ethers such as tetrahydrofuran and
1,4-dioxane. Also suitable are mixtures of polar and apolar
solvents such as dimethylformamid/diethylether. Preferably the
solvent is chosen from acetone or acetonitrile, most preferably the
solvent is acetonitrile.
[0064] Any suitable hydrochloric acid may be used in step b) of the
above described processes. Either diluted or concentrated
hydrochloric acid having a concentration ranging from 3 to 38% can
be employed. Preferably hydrochloric acid having a concentration of
about 10 to 37%, most preferably having a concentration of about
18% is used.
[0065] The ratio of Tigecycline to hydrochloric acid used may vary.
Typically about 0.9 to about 1.5 equivalents, most preferably 1.0
to 1.4 equivalents of hydrochloric acid to 1 equivalent Tigecycline
(mol:mol) will be employed. However, the ratio should be chosen
such that no free base is present anymore 1.0 mol equivalent HCl in
crystal structure) and that the amount of undesired byproducts is
as low as possible. In addition the ratio also depends on the
concentration of the hydrochloric acid used. For example when using
concentrated hydrochloric acid, 1.1 mol equivalent are preferably
used, when using 5 N hydrochloric acid, 1.0 equivalent hydrochloric
acid is preferably used in order to find at least 1.0 mol
equivalent HCl in the crystal lattice of Tigecycline hydrochloride
and keeping undesired by products under an acceptable limit. Table
3 shows the amount of hydrochloride in the crystal structure of
Tigecycline hydrochloride and the undesired byproducts found in
dependence on the amount and concentration of hydrochloric acid
used. The inventors found 0.9 to 1.4 mol equivalents HCl in the
crystal lattice, therefore form A is a monohydrochloride.
TABLE-US-00003 TABLE 3 Varying amounts of HCl and of undesired
byproducts depending on the amount and concentration of
hydrochloric acid applied HCL.sub.CONC.(37%) USED 5N HCL USED HCL
FOUND 4-EPI- TOTAL [MOL [MOL [MOL TIGECYCLINE IMPURITIES
EQUIVALENT] EQUIVALENT] EQUIVALENT] [AREA %] [AREA %] 1.0 0.9 0.08
0.52 1.1 1.0 0.09 0.45 1.2 1.1 0.20 0.53 1.3 1.2 0.54 1.09 1.4 1.2
0.37 0.69 1.5 1.4 1.02 1.35 1.0 1.1 0.15 0.50 1.1 1.2 0.18 0.51
[0066] The above mentioned processes represent straight forward
processes for preparing crystalline Tigecycline hydrochloride form
A in a simple and fast manner suitable for pharmaceutical scale-up.
Form A of Tigecycline hydrochloride is also a particularly suitable
form for the isolation of Tigecycline hydrochloride in the last
step of the synthesis.
[0067] The water content of crystalline form A of Tigecycline
hydrochloride may vary from about 0-6.0% e.g. the water content is
0% when stored at 1.7% relative humidity at 25.degree. C., 2.7%
when stored at 42.7% relative humidity at 25.degree. C. and 5.8%
when stored at 80% relative humidity at 25.degree. C.
[0068] Tigecycline hydrochloride form A crystallizes in small
ellipsoidal needles and columns having a length ranging from about
5-20 .mu.m.
[0069] Furthermore the present invention relates to crystalline
form B of Tigecycline hydrochloride characterized by an X-ray
powder diffraction pattern with peaks at 2-theta angles of
5.8.degree..+-.0.2.degree., 7.0.+-.0.2.degree., 9.1.+-.0.2.degree.,
9.7.+-.0.2.degree., 14.1.+-.0.2.degree., 15.5.+-.0.2.degree.,
17.3.+-.0.2.degree., 18.3.+-.0.2.degree., 19.6.+-.0.2.degree.,
22.4.+-.0.2.degree., 25.5.+-.0.2.degree., 27.1.+-.0.2.degree. and
28.5.+-.0.2.degree.. A characteristic X-ray powder diffraction
pattern of crystalline form B of Tigecycline hydrochloride is shown
in FIG. 4 and some characteristic peaks are listed in Table 4.
[0070] Accordingly, in a preferred embodiment, the present
invention relates to crystalline form B of Tigecycline
hydrochloride characterized by an X-ray powder diffraction pattern
substantially in accordance with Table 4 and FIG. 4.
TABLE-US-00004 TABLE 4 Characteristic X-Ray Powder Diffraction
(XRPD) peaks of crystalline form B of Tigecycline hydrochloride
ANGLE RELATIVE INTENSITY [.degree.2-THETA] [%] 5.8 100.0 7.0 33.0
9.1 59.2 9.7 64.9 14.1 30.6 15.5 65.1 17.3 42.2 18.3 31.5 19.6 39.4
22.4 42.1 25.5 26.2 27.1 28.8 28.5 23.4
[0071] Crystalline form B of Tigecycline hydrochloride also may be
characterized by a typical infrared spectrum as shown in FIG. 5.
Accordingly in a further preferred embodiment, the present
invention relates to crystalline form B of Tigecycline
hydrochloride characterized by an infrared spectrum substantially
in accordance with FIG. 5. Characteristic bands are present at
wavenumbers of 3365.+-.2 cm.sup.-1, 3228.+-.2 cm.sup.-1, 1685.+-.2
cm.sup.-1, 1648.+-.2 cm.sup.-1, 1545.+-.2 cm.sup.-1, 1360.+-.2
cm.sup.-1, 1263.+-.2 cm.sup.-1, 1204.+-.2 cm.sup.-1 and 872.+-.2
cm.sup.-1.
[0072] The DSC curve in FIG. 6 shows a broad endotherm from the
beginning of the measurement until about 170.degree. C. with a
maximum at about 92.degree. C. This peak may be due to
desolvation.
[0073] In one embodiment, the present invention provides a process
for the preparation of crystalline form B of Tigecycline
hydrochloride, comprising the steps of: [0074] a) stirring a
mixture of Tigecycline and methylenehloride; [0075] b) adding
hydrochloric acid; [0076] c) stirring the solution at room
temperature or below to effect crystallization of crystalline form
B of Tigecycline hydrochloride; [0077] d) isolating crystalline
form B of Tigecycline hydrochloride;
[0078] Any form of Tigecycline may be used in step a) of the above
process, e.g. amorphous forms, crystalline forms, mixtures of
amorphous and crystalline forms, mixtures of different crystalline
forms, hydrates or solvates. Suitable crystalline forms may be
forms I to V of WO 2006/128150, forms I and II of WO 2007/127292 or
mixtures thereof.
[0079] The concentration of Tigecycline in step a) of the above
process depends on the form of Tigecycline used. Tigecycline
preferably is used at a concentration ranging from 5 to 100 g/L,
more preferably from 5 to 50 g/L and most preferably the
concentration ranges from 5 g/L to 15 g/L.
[0080] Surprisingly crystalline form B of Tigecycline hydrochloride
does only crystallize from methylenehloride. When using other
solvents, like for example alcohols such as ethanol, isopropanol or
2-butanol, ketones such as acetone or ethylmethylketone, nitriles
such as acetonitrile, esters such as methylacetate, ethylacetate
and isopropylacetate or ethers such as tetrahydrofuran and
1,4-dioxane crystalline form B of Tigecycline hydrochloride does
not crystallize. The inventors of the present invention found out
that the methylenechloride content of crystalline form B of
Tigecycline hydrochloride ranges from 0.4 to 0.5 mol (analyzed by
GC, Table 5).
[0081] Any suitable hydrochloric acid can be used in step b) of the
above described process. Either diluted or concentrated
hydrochloric acid having a concentration in the range from 3 to 38%
can be employed. Preferably hydrochloric acid having a
concentration of about 10 to 37%, most preferably having a
concentration of about 18% is used.
[0082] The ratio of Tigecycline to hydrochloric acid used may vary.
Typically about 0.9 to about 1.5 equivalents, most preferably 1.0
to 1.4 equivalents of hydrochloric acid to 1 equivalent Tigecycline
(mol:mol) will be employed. Table 5 displays that the amount of
hydrochloride in the crystal lattice is 1.0 mol equivalent no
matter if 1.0 or 1.4 mol equivalent hydrochloric acid are used.
Therefore crystalline form B of Tigecycline hydrochloride is a
monohydrochloride.
TABLE-US-00005 TABLE 5 Varying amounts of HCl, methylenchloride and
undesired byproducts depending on the amount of hydrochloric acid
applied 5N HCL USED HCL FOUND 4-EPI- TOTAL METHYLENCHLORIDE [MOL
[MOL TIGECYCLINE IMPURITIES FOUND [MOL EQUIVALENT] EQUIVALENT]
[AREA %] [AREA %] EQUIVALENT] 1.0 1.0 1.20 2.41 0.5 1.1 1.0 1.81
2.99 0.5 1.3 1.0 1.73 2.97 0.4 1.4 1.0 1.06 2.20 0.5
[0083] The crystalline form B of Tigecycline hydrochloride
crystallizes in small needles having a length ranging from about
10-15 .mu.m.
[0084] The finished dosage form contains lyophilized amorphous
Tigecycline respectively Tigecycline hydrochloride. Before
lyophilizing, Tigecycline respectively Tigecycline hydrochloride is
dissolved in water, thus water solubility is an important factor to
consider. Table 6 displays the solubility data of the different
crystalline forms of Tigecycline free base compared with these of
crystalline forms A and B of Tigecycline hydrochloride.
[0085] Crystalline form A of Tigecycline hydrochloride clearly
shows the highest water solubility. For example crystalline form A
shows higher water solubility than forms I, II, III, IV and V of WO
2006/128150 and also higher water solubility than crystalline forms
I and II of WO 2007/127292. On the other hand form B of Tigecycline
hydrochloride shows lower solubility than form A. Nevertheless form
B nearly shows the same water solubility as the most soluble free
base, namely form IV of WO 2006/128150. Consequently the
crystalline forms of Tigecycline hydrochloride of the present
invention, especially form A, are particularly suitable forms for
the lyophilization process in order to formulate an anti-infective
medicament.
TABLE-US-00006 TABLE 6 Water solubility of different crystalline
forms of Tigecycline and Tigecycline hydrochloride CONCENTRATION
BASE USED FORM [MG/ML] [MG BASE EQUIVALENT] WO 2006/128150 (Free
base) I 201 206 II 170 280 III 174 198 IV 322 387 V 134 180 WO
2007/127292 (Free base) I 54 156 II 76 198 Present invention
(Hydrochloride) A 503 621 B 323 332
[0086] The crystalline forms of Tigecycline hydrochloride of the
present invention represent thermodynamically stable forms, which
means they do not convert into other crystalline or amorphous forms
when storing them even at elevated temperatures. For example the
crystalline forms A and B of Tigecycline hydrochloride of the
present invention did not convert into other crystalline or
amorphous forms after storing for 7 days at 80.degree. C.
[0087] Tigecycline must be available in a physical stable form as
well, in order to avoid degradation and as a consequence the
building of undesired byproducts. Table 7 displays the stability
data of the different crystalline forms of Tigecycline free base
compared with the stability data of the crystalline forms of
Tigecycline hydrochloride from the present invention. After storing
for 7 days at 80.degree. C. one can see that forms I and II of WO
2006/128150 show a tremendous increase in total impurities. All the
other crystalline forms of Tigecycline respectively Tigecycline
hydrochloride which have been tested showed satisfying stability
data when considering that 7 days at 80.degree. C. are extreme
conditions, which an active pharmaceutical ingredient will never
experience in his life-cycle under ordinary circumstances. For
example the 4-Epi-Tigecycline content of crystalline form A of
Tigecycline hydrochloride practically did not change and also the
increase of total impurities was low.
TABLE-US-00007 TABLE 7 Thermal stability of crystalline forms of
Tigecycline respectively Tigecycline hydrochloride 4-EPI- TOTAL
TIGECYCLINE 4-EPI- IMPURITIES TOTAL AT AMBIENT TIGECYCLINE AT
AMBIENT IMPURITIES FORM CONDITIONS 7 DAYS AT 80.degree. C.
CONDITIONS 7 DAYS AT 80.degree. C. WO2006/128150 (free base) I 0.36
2.15 0.75 11.20 II 1.04 10.83 1.60 18.44 III 0.16 2.18 0.16 4.46 IV
0.23 0.38 0.40 0.87 V <0.05 0.18 0.22 0.37 WO2007/127792 (free
base) I 0.34 1.26 0.59 2.22 II 0.17 0.38 0.24 0.91 Present
invention (Hydrochloride) A 0.84 0.89 1.07 1.81 B 0.93 1.60 1.91
4.19
[0088] Moreover crystalline forms A and B of Tigecycline
hydrochloride of the present invention show better physical
stability than amorphous Tigecycline hydrochloride. For example
amorphous Tigecycline hydrochloride was prepared by lyophilization
and stored for about 9 months at room temperature. The batch showed
a 4-Epi-Tigecycline content of 19.56% and 21.55% total impurities.
Therefore amorphous Tigecycline hydrochloride is not suitable as an
intermediate for the formulation of an anti-infective medicament,
due to the low stability.
[0089] To sum it up, crystalline forms A and B of Tigecycline
hydrochloride, especially form A, possess excellent water
solubility and good physical and thermodynamical stability and are
therefore suitable intermediates for the formulation of an
anti-infective medicament.
[0090] Water solubility is an important factor to consider as
Tigecycline respectively Tigecycline hydrochloride is dissolved in
water before lyophilization during the formulation process. That's
why the crystalline forms of the present invention, especially form
A which shows the highest water solubility, are particularly
suitable intermediates for the formulation of an anti-infective
medicament.
[0091] In addition the thermodynamical and physical stabilities of
the crystalline forms of the present invention were satisfying as
well. The two crystalline forms of the present invention neither
showed a noticeable increase in impurities nor a conversion of the
crystal structure after storing at extreme conditions.
[0092] The novel crystalline form A of Tigecycline hydrochloride of
the present invention may be used alone as antibacterial drug or in
the form of a suitable pharmaceutical composition containing the
novel form. In addition the present invention relates to the use of
crystalline form A of Tigecycline hydrochloride as an
anti-infective medicament.
[0093] The novel forms A and B of Tigecycline hydrochloride are
particularly useful for the treatment of infections. Therefore, the
present invention relates to the use of crystalline forms A and B
of Tigecycline hydrochloride as intermediates for the formulation
of an anti-infective medicament.
[0094] Moreover the present invention relates to pharmaceutical
compositions comprising an effective amount of crystalline form A
of Tigecycline hydrochloride.
[0095] The invention is further described by reference to the
following examples. These examples are provided for illustration
purposes only and are not intended to be limiting the present
invention in any way.
EXAMPLES
[0096] X-ray powder diffraction pattern (XRPD) were collected on a
Unisantis XMD 300 X-ray powder diffractometer with a position
sensitive detector in parallel beam optics using the following
acquisition conditions: tube anode: Cu, 40 kV, 0.8 mA; 3-43.degree.
theta/2theta; simultaneous detection of regions of 10.degree. per
step with detector resolution 1024, counting time 300 seconds per
step. Samples were measured at room temperature in a standard
sample holder on a rotating sample spinner. A typical precision of
the 2-theta values is in the range of .+-.about 0.2.degree.
2-Theta. Thus a diffraction peak that appears at 5.0.degree.
2-theta can appear between 4.8.degree. and 5.2.degree. 2-theta on
most X-ray diffractometers under standard conditions.
[0097] Infrared spectra (IR) were collected on a MKII Golden
Gate.TM. Single Reflection Diamond ATR (attenuated total
reflection) cell with a Bruker Tensor 27 FTIR spectrometer with 4
cm.sup.-1 resolution at ambient conditions. To collect a spectrum a
spatula tip of a sample was applied to the surface of the diamond
in powder form. Then the sample was pressed onto the diamond with a
sapphire anvil and the spectrum was recorded. A spectrum of the
clean diamond was used as background spectrum. A typical precision
of the wavenumber values is in the range of about .+-.2 cm.sup.-1.
Thus, an infrared peak that appears at 1716 cm.sup.-1 can appear
between 1714 and 1718 cm.sup.-1 on most infrared spectrometers
under standard conditions.
[0098] Differential scanning calorimetry (DSC) was performed on a
Netzsch DSC 204. About 4 mg sample was heated in 25 .mu.l Al-Pans
with loose lids from room temperature to 250.degree. C. at a rate
of 10.degree. C./min. Nitrogen (purge rate 20 ml/min) was used as
purge gas.
Example 1
Preparation of Crystalline Form A of Tigecycline Hydrochloride
[0099] A suspension of Tigecycline was prepared by mixing a solid
Tigecycline sample and acetonitrile in amounts as shown in Table A.
The mixture was than stirred for 1 hour at room temperature before
5 N hydrochloric acid was added in amounts corresponding to Table
A. After stirring for about 20 hours the solid was filtered off and
dried at room temperature under vacuum to obtain crystalline form A
of Tigecycline hydrochloride.
TABLE-US-00008 TABLE A HCL TIGE- ACETO- [MOL HPLC- CYCLINE NITRILE
EQUIV- YIELD PURITY [MG] [ML] ALENTS] FORM [%] [AREA %] a 500 12
1.0 A 100 99.50 b 1000 24 1.1 A 101 99.46
Example 2
Preparation of Crystalline Form A of Tigecycline Hydrochloride
[0100] A suspension of Tigecycline was prepared by mixing a solid
Tigecycline sample and acetonitrile in amounts as shown in Table B.
The mixture was than stirred for about 1 hour at room temperature
before concentrated hydrochloric acid was added in amounts
corresponding to Table B. After stirring for about 4 hours the
solid was filtered off and dried at room temperature under vacuum
to obtain crystalline form A of Tigecycline hydrochloride.
TABLE-US-00009 TABLE B HCL TIGE- ACETO- [MOL HPLC- CYCLINE NITRILE
EQUIV- YIELD PURITY [MG] [ML] ALENTS] FORM [%] [AREA %] a 2500 60
1.0 A 94 99.48 b 1000 24 1.1 A 88 99.55 c 1000 24 1.2 A 101 99.47 d
3000 72 1.3 A 102 98.91 e 1000 24 1.4 A 100 99.31 f 500 12 1.5 A 94
98.65
Example 3
Preparation of Crystalline Form A of Tigecycline Hydrochloride
[0101] A solution of Tigecycline was prepared by mixing 500 mg of a
solid Tigecycline sample with 10 ml acetone. Within about 5 minutes
a precipitate appeared and the suspension was further stirred for
1.75 h. 143 .mu.l (1.0 mol equivalent) 5N hydrochloric acid were
added to the suspension and stirring was continued for 5 hours.
Finally the solid was filtered off, washed with acetone and dried
at room temperature under vacuum to obtain 440 mg (97% yield) of
crystalline form A of Tigecycline hydrochloride (98.73% purity by
HPLC).
Example 4
Preparation of Crystalline Form A of Tigecycline Hydrochloride
[0102] 50.0 mg Tigecycline (Tygacil.RTM. 50 mg, Wyeth, powder for
infusion) were dissolved in 1 ml acetone and the solution was
stirred at room temperature. After about one minute an orange
precipitate appeared (form VI). Afterwards 8.4 mg (1 eq)
concentrated hydrochloric acid were added and the suspension was
stirred at room temperature. The colour of the suspension changed
after about 5 minutes from orange to yellow and the suspension was
stirred for 2.5 hours at room temperature. The solid was filtered
off, washed with acetone and dried under vacuum at room temperature
to obtain 51.8 mg (98% yield) of crystalline form A of Tigecycline
hydrochloride.
Example 5
Preparation of Crystalline Form A of Tigecycline Hydrochloride
[0103] 50.0 mg Tigecycline (Tygacil.RTM. 50 mg, Wyeth.RTM., powder
for infusion) were dissolved in 500 .mu.l ethylmethylketone and the
solution was stirred at room temperature. After about one minute an
orange precipitate appeared (essentially pure form III). Afterwards
8.4 mg (1 eq) concentrated hydrochloric acid were added and the
suspension was stirred for approximately 3 hours. The solid was
filtered off, washed with ethylmethylketone and dried under vacuum
at room temperature to obtain 43.7 mg (82% yield) of crystalline
form A of Tigecycline hydrochloride.
Example 6
Preparation of Crystalline Form B of Tigecycline Hydrochloride
[0104] A suspension of Tigecycline was prepared by mixing a solid
Tigecycline sample and methylenehloride in amounts as shown in
Table C. The mixture was than stirred at room temperature and 5N
hydrochloric acid was added in amounts corresponding to Table C.
After stirring for about 92 hours the solid was filtered off and
dried at room temperature under vacuum to obtain crystalline form B
of Tigecycline hydrochloride.
TABLE-US-00010 TABLE C HCL TIGE- ACETO- [MOL HPLC- CYCLINE NITRILE
EQUIV- YIELD PURITY [MG] [ML] ALENTS] FORM [%] [AREA %] a 500 6 1.0
B 61 97.59 b 500 6 1.1 B 68 97.01 c 500 6 1.3 B 33 97.03 d 500 6
1.4 B 36 97.80
Example 7
Water solubility testing
[0105] A UV-vis Lambda 35 spectrophotometer (Perkin-Elmer) was used
(.lamda.=347 nm, 1.0 cm quartz cells). Perkin Elmer.RTM. UV Win
Lab-5.1 software was used.
[0106] A saturated solution of Tigecycline respectively Tigecycline
hydrochloride in distilled water was prepared and the suspension
was stirred at room temperature for 30 minutes with a stirring
speed of 1000 U/min. The suspension was filtrated through a 0.45
.mu.m filter. Finally the resulting solution was diluted 10000-fold
and measured against water at a wavelength of 347 nm.
* * * * *