U.S. patent application number 13/857693 was filed with the patent office on 2014-03-06 for solid forms of pemetrexed.
This patent application is currently assigned to DR. REDDY'S LABORATORIES, INC.. The applicant listed for this patent is DR. REDDY'S LABORATORIES, INC., DR. REDDY'S LABORATORIES LTD.. Invention is credited to Surya Narayana Devarakonda, Vamsi Krishna Mudapaka, Venu Nalivela, Sekhar Munaswamy Nariyam, Raghavendracharyulu Venkata Palle, Vijay Bhailalbhai Patel, Raghupati Rama Subrahmanyam Vinjamuri, Sesha Reddy Yarraguntla.
Application Number | 20140066463 13/857693 |
Document ID | / |
Family ID | 39580036 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066463 |
Kind Code |
A1 |
Palle; Raghavendracharyulu Venkata
; et al. |
March 6, 2014 |
SOLID FORMS OF PEMETREXED
Abstract
There is provided polymorphs and amorphous form of pemetrexed or
its pharmaceutical acceptable salts and process for making
thereof.
Inventors: |
Palle; Raghavendracharyulu
Venkata; (Hyderabad, IN) ; Nariyam; Sekhar
Munaswamy; (Hyderabad, IN) ; Patel; Vijay
Bhailalbhai; (Hyderabad, IN) ; Vinjamuri; Raghupati
Rama Subrahmanyam; (Hyderabad, IN) ; Devarakonda;
Surya Narayana; (Hyderabad, IN) ; Yarraguntla; Sesha
Reddy; (Hyderabad, IN) ; Mudapaka; Vamsi Krishna;
(Khammam, IN) ; Nalivela; Venu; (Warangal,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DR. REDDY'S LABORATORIES, INC.
DR. REDDY'S LABORATORIES LTD. |
Bridgewater
Hyderabad |
NJ |
US
IN |
|
|
Assignee: |
DR. REDDY'S LABORATORIES,
INC.
Bridgewater
NJ
DR. REDDY'S LABORATORIES LTD.
Hyderabad
|
Family ID: |
39580036 |
Appl. No.: |
13/857693 |
Filed: |
April 5, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12593966 |
Sep 30, 2009 |
8507508 |
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PCT/US2008/059244 |
Apr 3, 2008 |
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13857693 |
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60979245 |
Oct 11, 2007 |
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Current U.S.
Class: |
514/265.1 ;
544/280 |
Current CPC
Class: |
C07D 487/04 20130101;
C23C 16/401 20130101; C08J 2483/00 20130101; C08J 7/0427 20200101;
A61P 35/00 20180101; C23C 16/0272 20130101; C08J 2333/06
20130101 |
Class at
Publication: |
514/265.1 ;
544/280 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 3, 2007 |
IN |
704/CHE/2007 |
Claims
1.-44. (canceled)
45. A compound, which is an amorphous form of disodium salt of
pemetrexed.
46. The compound of claim 45, wherein said amorphous form of
disodium salt of pemetrexed has water content of less than about
15% w/w.
47. The compound of claim 45, wherein said amorphous form of
disodium salt of pemetrexed has water content between about 5% and
about 10% w/w.
48. A composition comprising a compound of claim 45 as a solid,
wherein at least 50% by weight of said solid disodium salt of
pemetrexed is an amorphous form of disodium salt of pemetrexed.
49. The composition of claim 48, which is in the form of a powder
suitable as active ingredient for pharmaceutical products.
50. The composition of claim 48, wherein at least 95% by weight of
said solid disodium salt of pemetrexed is in the amorphous
form.
51. The composition of claim 50, wherein at least 2% by weight of
said solid disodium salt of pemetrexed is in the crystalline
form.
52. The composition of claim 48, wherein at least 5% w/w of said
solid disodium salt of pemetrexed is a crystalline form of disodium
salt of pemetrexed.
53. The composition of claim 52, wherein said crystalline disodium
salt of pemetrexed has an X-ray diffraction pattern, expressed in
terms of 2 theta angles and obtained with a diffractometer equipped
with a copper K .alpha.-radiation source, wherein said X-ray powder
diffraction pattern includes five or more peaks selected from the
group consisting of peaks with 2 theta angles of 4.0.+-.0.2,
17.3.+-.0.2, 18.0.+-.0.2, 19.5.+-.0.2, 20.4.+-.0.2, 21.0.+-.0.2,
29.0.+-.0.2 and 43.3.+-.0.2 degrees.
54. The composition of claim 53, which has X-ray powder diffraction
pattern substantially in accordance with FIG. 8.
55. A compound, which is a crystalline form of disodium salt of
pemetrexed having an X-ray diffraction pattern, expressed in terms
of 2.theta. angles and obtained with a diffractometer equipped with
a copper K .alpha.-radiation source, wherein said X-ray powder
diffraction pattern includes five or more peaks selected from the
group consisting of peaks with 2 theta angles of 4.0.+-.0.2,
17.3.+-.0.2, 18.0.+-.0.2, 19.5.+-.0.2, 20.4.+-.0.2, 21.0.+-.0.2,
29.0.+-.0.2 and 43.3, .+-.0.2.
56. A solid dispersion of disodium salt of pemetrexed which
comprises i) a compound of claim 45; and ii) a pharmaceutically
acceptable carrier, wherein the solid dispersion has a solubility
in water ranging from about 50 mg/ml to about 150 mg/ml.
57. The solid dispersion of claim 56, wherein the amorphous content
is equal to or greater than about 95 wt %.
58. The solid dispersion of claim 56, which is substantially free
from crystalline forms of disodium pemetrexed.
59. The solid dispersion of claim 56, wherein said pharmaceutically
acceptable carrier is polyvinylpyrrolidone.
60. The solid dispersion of claim 56, wherein said pharmaceutically
acceptable carrier is hydroxypropylmethyl cellulose (HPMC).
61. The solid dispersion of claim 56, which comprises from about
10% to about 90% of disodium salt of pemetrexed; and from about 90%
to about 10% of the carrier.
62. The solid dispersion of claim 56, which has solubility in water
ranging from about 50 mg/ml to about 150 mg/ml.
63. A process for preparing the compound of claim 45 comprising: i)
providing a solution of pemetrexed disodium in a solvent; and ii)
removing the solvent.
64. The process of claim 63, further comprising drying the solid
isolated after solvent removal.
65. The process of claim 63, wherein said solvent is an organic
solvent.
66. The process of claim 63, wherein said solvent is water.
67. The process of claim 63, wherein said solvent is removed by
spray drying.
68. The process of claim 66, wherein said removing step is carried
out by using spray drier at an inlet temperature of about
100.degree. C. or less.
69. The process of claim 63, wherein said solvent is isopropyl
alcohol, methanol, acetone, ethyl methyl ketone, methyl isobutyl
ketone, water or mixtures thereof.
70. The process of claim 63, wherein the providing step comprises
dissolving disodium pemetrexed and a pharmaceutically acceptable
carrier in the solvent.
71. The process of claim 70, wherein said pharmaceutically
acceptable carrier is polyvinylpyrrolidone.
72. The process of claim 70, wherein said pharmaceutically
acceptable carrier is hydroxypropylmethyl cellulose (HPMC).
73. A process for making a solid containing a mixture of amorphous
and crystalline forms of disodium salt of pemetrexed, said process
comprising: i) providing a solution of disodium salt of pemetrexed
in water; ii) adding an organic hydrocarbon solvent which is
capable of forming an azeotropic mixture with water; and iii)
carrying out an azeotropic distillation until a solid is
obtained.
74. The process of claim 73, wherein said organic hydrocarbon
solvent is toluene or xylene.
75. The process of claim 73, wherein said organic hydrocarbon
solvent is toluene.
76. A compound, which is Form A of pemetrexed diacid having X-ray
powder diffraction pattern (XRPD) with peaks at about 5.8, 12.4,
18.3, 18.6, 19.6, 20.4, 24.5, 24.9, 25.8, 28.9, 29.2, 29.6, and
32.8, .+-.0.2 degrees 20.
77. The compound of claim 76 having X-ray powder diffraction
pattern substantially in accordance with FIG. 12.
78. A process for preparing a crystalline form A of pemetrexed
diacid, comprising the steps of: a) providing a solution of
pemetrexed diacid in ethanol; b) cooling the mass to cause
precipitation of a solid; and c) isolating the precipitated solid,
which is the crystalline form A of pemetrexed diacid.
79. The process of claim 78, which further comprises drying the
solid.
80. The process of claim 78, wherein said providing a solution step
comprises i) reacting dimethyl
N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L--
glutamic acid PTSA salt with aqueous sodium hydroxide solution; and
ii) treating the reaction mass with an external acid until pH
reaches about 3.
81. The process of claim 80, wherein said external acid is
hydrochloric acid.
82. A compound which is Form B of pemetrexed diacid having X-ray
powder diffraction pattern (XRPD) with peaks at about 5.7, 12.1,
12.3, 17.7, 18.4, 20.2, 22.2, 22.5, 22.7, 24.7, 25.6, 25.8, 26.6,
28.2, 30.3, 31.3, and 31.8, .+-.0.2 degrees 20.
83. The compound of claim 82 having X-ray powder diffraction
pattern substantially in accordance with FIG. 16.
84. A process for making a crystalline form B of pemetrexed diacid
comprising: a) providing a solution of pemetrexed diacid in
isopropyl alcohol; b) cooling the mass to cause precipitation of a
solid; and c) isolating the precipitated solid, which is the
crystalline form B of pemetrexed diacid.
85. The process of claim 84, further comprising drying the
solid.
86. The process of claim 84, wherein said providing step comprises
i) reacting Dimethyl
N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L--
glutamic acid PTSA salt with aqueous sodium hydroxide solution; and
ii) treating the reaction mass with an external acid until pH
reaches about 3.
87. The process of claim 86, wherein said external acid is
hydrochloric acid.
Description
TECHNICAL FIELD
[0001] The present patent application relates to solid forms of
pemetrexed and its salts and processes for preparing it. The
application also relates to amorphous pemetrexed disodium salt and
a process for preparation thereof.
BACKGROUND
[0002] Pemetrexed disodium is chemically described as L-Glutamic
acid,
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-
benzoyl]-disodium salt heptahydrate, represented by the chemical
structure of Formula (I).
##STR00001##
[0003] Pemetrexed is an anti-folate anti-neoplastic agent that
exerts its action by disrupting folate-dependent metabolic
processes essential for cell replication. It is believed to work by
inhibiting three enzymes that are required in purine and pyrimidine
biosynthesis--thymidylate synthase (TS), dihydrofolate reductase
(DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).
Pemetrexed is available in the market under the brand name
ALIMTA.RTM..
[0004] Taylor et al., in U.S. Pat. No. 5,344,932 describe
pemetrexed, its related compounds and pharmaceutically acceptable
cation.
[0005] Chelius et al., in WO 01/14379 A2 disclose pemetrexed
disodium crystalline hydrate Form I and process for preparation
thereof.
[0006] Chelius et al., in WO 01/62760 disclose pemetrexed disodium
heptahydrate crystalline Form II and process for the preparation
thereof.
[0007] Journal of Organic Process Research & Development,
Volume 3, 1999, page 184 describes a process for the preparation of
pemetrexed diacid.
[0008] Busolli et al., in WO2008021411 disclose process for
preparation of pharmaceutically acceptable salt of pemetrexed
diacid.
[0009] Busolli et al., in WO2008021405A1 disclose seven crystalline
forms of pemetrexed diacid designated as Form A, B, C, D, E, F,
& G and processes for preparation thereof.
[0010] There remains a continuing need for new solid forms of
pemetrexed disodium and diacid that are sufficiently stable, and
the processes of preparation amenable to scale up to production
quantities.
SUMMARY
[0011] In one aspect, there is provided a compound, which is an
amorphous form of disodium salt of pemetrexed. Various embodiments
and variants are provided.
[0012] In another aspect, there is provided a composition that
includes disodium salt of pemetrexed as a solid, wherein at least
50% by weight of the solid disodium salt of pemetrexed is an
amorphous form of disodium salt of pemetrexed. Various embodiments
and variants are provided.
[0013] In another aspect, there is provided a compound, which is a
crystalline form of disodium salt of pemetrexed having an X-ray
diffraction pattern, expressed in terms of 2 theta angles and
obtained with a diffractometer equipped with a copper K
.alpha.-radiation source, wherein said X-ray powder diffraction
pattern includes five or more peaks selected from the group
consisting of peaks with 2 theta angles of 4.0.+-.0.2, 17.3.+-.0.2,
18.0.+-.0.2, 19.5.+-.0.2, 20.4.+-.0.2, 21.0.+-.0.2, 29.0.+-.0.2 and
43.3.+-.0.2.
[0014] In yet another aspect, there is provided a solid dispersion
of disodium salt of pemetrexed which includes i) disodium salt of
pemetrexed in an amorphous form; and ii) a pharmaceutically
acceptable carrier.
[0015] In yet another aspect, there is provided a process for
preparing amorphous pemetrexed disodium, including: [0016] i)
providing a solution of pemetrexed disodium in a solvent; and
[0017] ii) removing the solvent.
[0018] In yet another aspect, there is provided a process for
making a solid, which is a mixture of amorphous and crystalline
forms of disodium salt of pemetrexed, the process including: [0019]
i) providing a solution of disodium salt of pemetrexed in water;
[0020] ii) adding an organic hydrocarbon solvent which is capable
of forming an azeotropic mixture with water; and [0021] iii)
carrying out an azeotropic distillation until a solid is
obtained.
[0022] In yet another aspect, there is provided a compound, which
is Form A of pemetrexed diacid having X-ray powder diffraction
pattern (XRPD) with peaks at about 5.8, 12.4, 18.3, 18.6, 19.6,
20.4, 24.5, 24.9, 25.8, 28.9, 29.2, 29.6, and 32.8, .+-.0.2 degrees
20.
[0023] In yet another aspect, there is provided a process for
preparing a crystalline form A of pemetrexed diacid, comprising the
steps of: [0024] a) providing a solution of pemetrexed diacid in
ethanol; [0025] b) cooling the mass to cause precipitation of a
solid; and [0026] c) isolating the precipitated solid, which is the
crystalline form A of pemetrexed diacid.
[0027] In yet another aspect, there is provided a compound which is
Form B of pemetrexed diacid having X-ray powder diffraction pattern
(XRPD) with peaks at about 5.7, 12.1, 12.3, 17.7, 18.4, 20.2, 22.2,
22.5, 22.7, 24.7, 25.6, 25.8, 26.6, 28.2, 30.3, 31.3, and 31.8,
.+-.0.2 degrees 20.
[0028] In yet another aspect, there is provided a process for
making a crystalline form B of pemetrexed diacid comprising: [0029]
a) providing a solution of pemetrexed diacid in isopropyl alcohol;
[0030] b) cooling the mass to cause precipitation of a solid; and
[0031] c) isolating the precipitated solid, which is the
crystalline form B of pemetrexed diacid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 shows an illustrative example of X-ray powder
diffraction pattern of an amorphous form of disodium salt of
pemetrexed prepared according to Example 1.
[0033] FIG. 2 shows an illustrative example of thermogravimetric
analysis curve of amorphous pemetrexed disodium prepared according
to Example 1.
[0034] FIG. 3 shows an illustrative example of X-ray powder
diffraction pattern of amorphous solid dispersion of pemetrexed
disodium with Povidone K-30 prepared according to Example 5.
[0035] FIG. 4 shows an illustrative example of X-ray powder
diffraction pattern of amorphous solid dispersion of pemetrexed
disodium with HPMC prepared according to Example 6.
[0036] FIG. 5 shows an illustrative example of X-ray powder
diffraction pattern of pemetrexed disodium prepared according to
Example 7.
[0037] FIG. 6 shows an illustrative example of thermogravimetric
analysis curve of pemetrexed disodium prepared according to Example
7.
[0038] FIG. 7 shows an illustrative example of infrared absorption
spectrum of pemetrexed disodium prepared according to Example
7.
[0039] FIG. 8 shows an illustrative example of X-ray powder
diffraction pattern of solid disodium salt of pemetrexed prepared
according to Example 8.
[0040] FIG. 9 shows an illustrative example of thermogravimetric
analysis curve of solid disodium salt of pemetrexed prepared
according to Example 8.
[0041] FIG. 10 shows an illustrative example of infrared absorption
spectrum solid disodium salt of pemetrexed prepared according to
Example 8.
[0042] FIG. 11 shows an illustrative example of differential
scanning calorimetry thermogram of solid disodium salt of
pemetrexed prepared according to Example 8.
[0043] FIG. 12 shows an illustrative example of X-ray powder
diffraction pattern of crystalline Form A of pemetrexed prepared
according to Example 9.
[0044] FIG. 13 shows an illustrative example of thermogravimetric
analysis curve of crystalline Form A of pemetrexed prepared
according to Example 9.
[0045] FIG. 14 shows an illustrative example of infrared absorption
spectrum of crystalline Form A of pemetrexed prepared according to
Example 9.
[0046] FIG. 15 shows an illustrative example of differential
scanning calorimetry curve of crystalline Form A of pemetrexed
prepared according to Example 9.
[0047] FIG. 16 shows an illustrative example of X-ray powder
diffraction pattern of crystalline Form B of pemetrexed prepared
according to Example 10.
[0048] FIG. 17 shows an illustrative example of thermogravimetric
analysis curve of crystalline Form B of pemetrexed prepared
according to Example 10.
[0049] FIG. 18 shows an illustrative example of infrared absorption
spectrum of crystalline Form B of pemetrexed prepared according to
Example 10.
[0050] FIG. 19 shows an illustrative example of differential
scanning calorimetry thermogram of crystalline Form B of pemetrexed
prepared according to Example 10.
DETAILED DESCRIPTION
[0051] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods and materials are described.
[0052] Unless stated to the contrary, any use of the words such as
"including," "containing," "comprising," "having" and the like,
means "including without limitation" and shall not be construed to
limit any general statement that it follows to the specific or
similar items or matters immediately following it. Embodiments of
the invention are not mutually exclusive, but may be implemented in
various combinations. The described embodiments of the invention
and the disclosed examples are given for the purpose of
illustration rather than limitation of the invention as set forth
the appended claims.
[0053] For purposes of the present invention, the following terms
are defined below.
[0054] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical product that is generally non-toxic and
is not biologically undesirable and includes that which is
acceptable for veterinary use and/or human pharmaceutical use.
[0055] The term "compound" is used to refer to a molecular entity
of defined chemical structure.
[0056] The term "composition" includes, but is not limited to, a
powder, a suspension, an emulsion and/or mixtures thereof. The term
composition is intended to encompass a product containing the
specified ingredients in the specified amounts, as well as any
product, which results, directly or indirectly, from combination of
the specified ingredients in the specified amounts. A "composition"
may contain a single compound or a mixture of compounds. As used
with respect to an active pharmaceutical ingredient, the term
"composition" may define a mixture of different solid forms of the
same compound.
[0057] The term "pharmaceutical composition" is intended to
encompass a product that includes the active ingredient(s),
pharmaceutically acceptable excipients that make up the carrier, as
well as any product which results, directly or indirectly, from
combination, complexation or aggregation of any two or more of the
ingredients, or from dissociation of one or more of the
ingredients, or from other types of reactions or interactions of
one or more of the ingredients. Accordingly, the pharmaceutical
compositions described herein encompass any composition made by
admixing the active ingredient, additional active ingredient(s),
and pharmaceutically acceptable excipients.
[0058] The term "excipient" means a component of a pharmaceutical
product that is not the active ingredient, such as filler, diluent,
carrier, and so on. The excipients that are useful in preparing a
pharmaceutical composition are preferably generally safe, non-toxic
and neither biologically nor otherwise undesirable, and are
acceptable for veterinary use as well as human pharmaceutical use.
A "pharmaceutically acceptable excipient" as used in the
specification and claims includes both one and more than one such
excipient.
[0059] When referring to a chemical reaction or a process, the
terms "treating", "contacting" and "reacting" are used
interchangeably herein and refer to adding or mixing two or more
reagents under appropriate conditions to produce the indicated
and/or the desired product. It should be appreciated that the
reaction, which produces the indicated and/or the desired product,
may not necessarily result directly from the combination of two
reagents, which were initially added, i.e., there may be one or
more intermediates which are produced in the mixture which
ultimately leads to the formation of the indicated and/or the
desired product. Also, the term "isolating" is used to indicate
separation of the compound being isolated regardless of the purity
of the isolated compound from any unwanted substance which presents
with the compound as a mixture. Thus, degree of the purity of the
isolated or separated compound does not affect the status of
"isolating".
[0060] The term "water content" is used herein to refer to the
amount of water present in the solid, in % terms with respect to
the weight of the solid, as measured by traditional techniques for
determination of water in solids, such as the Karl Fisher test.
[0061] The term "solid dispersion" denotes a homogeneous solid
containing at least two components of different chemical identity,
which components are intimately mixed with one another at a
molecular level. For example, such solid dispersion is obtained
when two components are present as solute in a liquid solution in a
solvent, and obtained as a residue upon solvent evaporation.
[0062] The term "solvent" defines any liquid medium in which
component(s) is/are dissolved, including an individual solvent or a
mixture of solvents.
[0063] A single compound may give rise to a variety of solids
having distinct physical properties. Different solid forms of the
same drug may exhibit different properties, including
characteristics that have functional implications with respect to
their use as active ingredients of pharmaceutical products. For
example, polymorphs of the same drug may have substantial
differences in such pharmaceutically important properties as
dissolution rates and bioavailability. Likewise, different
polymorphs may have different processing properties, such as
hydroscopicity, flowability, and the like, which could affect their
suitability as active pharmaceuticals for commercial
production.
[0064] All TGA curves obtained from the present invention were
carried out in a TGAQ500V620.6 Build 31 instrument with a ramp
10.degree. C./minute up to 380.degree. C. The infrared (IR)
spectra, wherever provided, have been recorded on a Perkin Elmer
System Spectrum 1 model spectrophotometer or Thermo Nexus 470
spectrometer, between 450 cm.sup.-1 and 4000 cm.sup.-1, with a
resolution of 4 cm.sup.-1 in a potassium bromide pellet, the test
compound being at the concentration of 1% by weight. Differential
scanning calorimetric analysis was carried out in a DSC Q200 V23 9
Build 78 model or DSC Q200 V23 10 Build 79 model from TA
Instruments with a ramp of 10.degree. C./minute to 300.degree.
C.
[0065] All XRPD data reported herein were obtained using a Bruker
or PANalytical AXS D8 Advance Powder X-ray Diffractometer at Cu
K.alpha. radiation, having the wavelength 1.5418 .ANG.. Since some
margin of error is possible in the assignment of 2 theta angles and
d-spacings, the preferred method of comparing X-ray powder
diffraction patterns in order to identify a particular crystalline
form is to overlay the X-ray powder diffraction pattern of the
unknown form over the X-ray powder diffraction pattern of a known
form. For all analytical data discussed in this application, it
should be kept in mind that specific values depend on many factors,
e.g., specific instrument, sample preparation and individual
operator.
[0066] The present patent application provides amorphous form of
pemetrexed disodium. In a broad aspect, any amorphous form of
disodium salt of pemetrexed is contemplated, whether present in a
substantially pure amorphous state or as part of a mixture.
Particularly contemplated is a solid of disodium salt of pemetrexed
that includes a large amorphous fraction, preferably more than 95%
by weight, and a small crystalline fraction, preferably, more than
2% by weight. Non-solvated form of amorphous pemetrexed disodium,
as well as solvated and hydrated forms are contemplated.
[0067] FIG. 1 provides an example of XRPD pattern for amorphous
solid of pemetrexed disodium. The amorphous pemetrexed disodium has
a characteristic thermogravimetric curve (TGA) corresponding to a
weight loss of about 8.268% w/w, as shown in FIG. 2. The process
for making an amorphous form of pemetrexed is separately
contemplated and set forth herein below in more detail.
[0068] In one embodiment, amorphous form of disodium salt of
pemetrexed is present as component of a solid dispersion that
includes i) disodium salt of pemetrexed in an amorphous form; and
ii) a pharmaceutically-acceptable carrier. Preferably, the solid
dispersion includes from about 10% to about 90% of disodium salt of
pemetrexed; and from about 10% to about 90% of the carrier.
[0069] The solid dispersion may be prepared, for example, by
dissolving a disodium salt of pemetrexed and the carrier in a
solvent and removing the solvent. The preferred solvent are is
water. The process of making the solid dispersion is separately
contemplated and set forth below in more detail.
[0070] The preferred carriers include cellulose derivatives and
polyvinylpyrollidone. In one variant, the carrier is a cellulose
derivative. The cellulose derivative is expected to have certain
properties that make it useful as a carrier. Preferably, the
cellulose derivative suitable as a carrier in the solid dispersion
has sufficient solubility to dissolve in the liquid volatile
solvent at levels sufficient to ensure the desired ratio of the
components in the final dispersion and manufacturing suitability.
Solubility in methanol may be used as a useful way to measure the
desired solubility for the cellulose derivative of choice. It is
preferred the suitable cellulose derivative possesses solubility in
methanol equal to or greater than 0.01 g/ml, preferably, equal to
or greater than 0.1 g/ml. In one variant, the cellulose derivative
is hydroxypropylmethyl cellulose (HPMC). The XRPD of amorphous
solid dispersion of pemetrexed disodium with Povidone-K-30 is
illustrated in FIG. 3. The XRPD of amorphous solid dispersion of
pemetrexed disodium with HPMC is illustrated in FIG. 4.
[0071] It is preferred that the solid dispersion has certain
defined solubility characteristics to make it more suitable for use
in pharmaceutical formulations. Preferably, the solid dispersion
has solubility in water ranging from about 50 mg/ml to about 150
mg/ml. In one particular variant, which is separately contemplated,
there is provided a solid dispersion that includes amorphous
disodium salt of pemetrexed and HPMC in the ratio of 50:50 by
weight which has solubility in water of about 83 mg/ml. In another
particular variant, which is separately contemplated, there is
provided a solid dispersion that includes amorphous disodium salt
of pemetrexed and PVP in the ratio of 50:50 by weight which has
solubility in water of about 137 mg/ml.
[0072] Separately contemplated is a process for making amorphous
form of sodium salt of pemetrexed, in the form of a free solid or
as a solid dispersion with at least one pharmaceutically acceptable
carrier, which process includes: [0073] i) providing a solution of
pemetrexed disodium, alone or in combination with pharmaceutically
acceptable carrier, in a solvent; and [0074] ii) removing the
solvent.
[0075] Step i) involves providing a solution of pemetrexed
disodium. Providing a solution of pemetrexed disodium includes
dissolving pemetrexed disodium either alone or optionally in
combination with pharmaceutically acceptable carrier in a solvent
or a mixture of solvents, or such a solution may be obtained
directly from a reaction in which pemetrexed disodium is formed.
Any polymorphic form may be used in the preparation of solution
such as crystalline or semicrystalline forms, including solvates
and hydrates.
[0076] The solvent may be water, dimethylsulfoxide (DMSO);
dimethylformamide (DMF); alcohols such as isopropyl alcohol (IPA)
and methanol; ketones such as acetone, ethyl methyl ketone, and
methyl isobutyl ketone; and mixtures thereof. The preferred
solvents are water or aqueous alcoholic solutions. The dissolution
temperature may range from about 20.degree. C. to about 100.degree.
C. or reflux temperature of the solvent. Preferably, dissolution is
carried out at a room temperature.
[0077] The quantity of solvent used for dissolution depends on the
solvent and the dissolution temperature opted for the process. The
concentration of pemetrexed disodium in the solution may generally
range from about 0.1 to about 10 g/ml in the solvent.
[0078] When the solution of pemetrexed disodium is prepared along
with a pharmaceutically acceptable carrier, the order of charging
the different materials is not critical for the product obtained. A
specific order may be preferred with respect to the equipment
actually used and will be easily determined by a person skilled in
the art. In any case, the pemetrexed disodium must be completely
soluble in the solvent and should provide a clear solution. The
presence of undissolved crystals could lead to the formation of a
material, which is not completely amorphous. Pemetrexed disodium
and the pharmaceutically acceptable carrier used can be dissolved
either in the same solvent or they may be dissolved in different
solvents and then combined to form a mixture.
[0079] If desired, the solution may be filtered to remove the
undissolved particles. The undissolved particles may be removed
suitably by filtration, centrifugation, decantation, and other
techniques. The solution may be filtered by passing through paper,
glass fiber, or other membrane material, or a clarifying agent such
as celite. Depending upon the equipment used and the concentration
and temperature of the solution, the filtration apparatus may need
to be preheated to avoid premature crystallization.
[0080] Pharmaceutically acceptable carriers that may be used for
the preparation of amorphous solid dispersion of pemetrexed
disodium include, but are not limited to, pharmaceutical
hydrophilic carriers such as polyvinylpyrrolidone (homopolymers or
copolymers of N-vinylpyrrolidone; povidone), gums, cellulose
derivatives (including hydroxypropyl methylcellulose (HPMC),
hydroxypropyl cellulose, manitol and others), cyclodextrins,
gelatins, hypromellose phthalate, sugars, polyhydric alcohols,
polyethylene glycol, polyethylene oxides, polyoxyethylene
derivatives, polyvinyl alcohol, propylene glycol derivatives and
the like. The use of mixtures of more than one of the
pharmaceutical carriers to provide desired release profiles or for
the enhancement of stability is within the scope of this invention.
Also, all viscosity grades, molecular weights, commercially
available products, their copolymers, mixtures are all within the
scope of this invention without limitation.
[0081] These lists of solvents and pharmaceutically acceptable
carriers are merely representative of those that can be used, and
the lists are not intended to be exhaustive.
[0082] Step ii) involves removing the solvent. Removal of the
solvent may be carried out suitably using techniques such as
evaporation, atmospheric distillation, or distillation under
vacuum. Suitable techniques which may be used for solvent removal
include spray drying, distillation using a rotational evaporator
device such as a Buchi Rotavapor, agitated thin film drying
("ATFD"), and the like. These techniques are applicable to both
aqueous and organic solutions of pemetrexed disodium and mixtures
of pemetrexed disodium with a pharmaceutically acceptable carrier.
However, solutions using the more volatile organic solvents
generally provide easier processing.
[0083] Preferably, removal of the solvent is done by spray drying
of a solution of pemetrexed disodium or its mixture with the
pharmaceutically acceptable carrier.
[0084] The amorphous pemetrexed disodium or amorphous solid
dispersion of pemetrexed disodium with pharmaceutically acceptable
carrier obtained by spray drying process may be suitably utilized
for the preparation of pharmaceutical compositions.
[0085] Spray drying and ATFD are more suitable for industrial scale
production with a batch size of about 100 g or about 1 kg, or
greater. Other techniques such as Buchi Rota-vapor drying and dry
distillation under vacuum may be suitable for laboratory-scale
processes such as for quantities less than about 100 g.
[0086] Evaporation of the solvent may be conducted under a vacuum,
such as below about 100 mm Hg to below about 600 mm Hg, at
temperatures such as about -30.degree. C. to about 100.degree. C.
Any temperature and vacuum conditions can be used as long as there
is no increase in the impurity levels and any major variations in
the product characteristics.
[0087] The amorphous material obtained from step ii) may be
collected from the equipment using techniques such as by scraping,
or by shaking the container, or using techniques specific to the
particular apparatus.
[0088] The product may be dried, if desired.
[0089] Drying may be carried out under reduced pressure until the
residual solvent content reduces to an amount that is within the
limits given by the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for
Human Use ("ICH") guidelines. The guideline solvent level depends
on the type of solvent but is not more than about 5000 ppm, or
preferably about 4000 ppm, or more preferably about 3000 ppm.
[0090] The drying can be carried out at reduced pressures, such as
below about 650 mmHg or below about 50 mmHg, at temperatures such
as about 35.degree. C. to about 70.degree. C. The drying can be
carried out for any desired time period that achieves the desired
result, such as times about 1 to 20 hours, or longer. Drying may
also be carried out for shorter or longer periods of time depending
on the product specifications.
[0091] Drying can be suitably carried out in equipment such as a
tray dryer, vacuum oven, air oven, or using a fluidized bed drier,
spin flash dryer, and flash dryer.
[0092] It is generally preferred that a rapid drying is often
utilized to provide the desired amorphous form free from residual
organic solvent.
[0093] The amorphous material obtained as pemetrexed disodium or
its hydrate or its solid dispersion may have water content of about
15% w/w or less. In some extended exposure conditions, it may
acquire moisture up to about 21%, however, the amorphous form
remain retained significantly. In a preferred embodiment, the water
content may range of about 5% to about 10% w/w.
[0094] Separately contemplated is a composition containing solid
disodium salt of pemetrexed, of which at least 50%, by total weight
of the solid disodium salt of pemetrexed in the composition, is in
the amorphous form. In the more preferred form of this composition,
the solid disodium salt of pemetrexed is suitable for use as active
ingredient in formulating pharmaceutical products. The remainder of
the solid disodium salt of pemetrexed in the composition, i.e., 50%
or less of the total weight of disodium salt of pemetrexed, may be
crystalline forms. An example of crystalline form is the
crystalline form of disodium salt of pemetrexed described herein
below. Other examples of crystalline forms of disodium salt of
pemetrexed are described, for example, in US 2008/0045711, which is
incorporated herein by reference for the purpose stated and in its
entirety. In an embodiment, the composition may include at least
90% of the amorphous form of disodium salt of pemetrexed with
respect to total weight of the solid disodium salt of pemetrexed in
the composition. In another embodiment, the composition may include
at least 95% of the amorphous form of disodium salt of pemetrexed
with respect to the total weight of the solid disodium salt of
pemetrexed in the composition. In a particular variant of this
embodiment, the composition includes more than 2% of a crystalline
form of disodium salt of pemetrexed. In yet another embodiment, the
composition is substantially free of any forms of disodium salt of
pemetrexed other than its amorphous form.
[0095] The composition containing a mixture of amorphous and
crystalline forms may be prepared for example by direct mixing of
amorphous and crystalline portions. Also, with respect to specific
variant described below, the composition may be prepared as
described below.
[0096] X-ray diffraction provides a convenient and practical means
for quantitative determination of the relative amounts of
crystalline and/or amorphous forms in a solid mixture. X-ray
diffraction is adaptable to quantitative applications because the
intensities of the diffraction peaks of a given compound in a
mixture are proportional to the fraction of the corresponding
powder in the mixture. The percent composition of crystalline
disodium salt of pemetrexed in an unknown composition can be
determined. Preferably, the measurements are made on solid powder
disodium salt of pemetrexed. The X-ray powder diffraction patterns
of an unknown composition may be compared to known quantitative
standards containing pure crystalline forms of disodium salt of
pemetrexed to identify the percent ratio of a particular
crystalline form. If amorphous form is the major fraction of the
composition, the amount may be further compared to the total weight
of the solid subject to analysis. This is done by comparing the
relative intensities of the peaks from the diffraction pattern of
the unknown solid powder composition with a calibration curve
derived from the X-ray diffraction patterns of pure known samples.
The curve can be calibrated based on the X-ray powder diffraction
pattern for the strongest peak from a pure sample of crystalline
forms of disodium salt of pemetrexed. The calibration curve may be
created in a manner known to those of skill in the art. For
example, five or more artificial mixtures of crystalline forms of
disodium salt of pemetrexed, at different amounts, may be prepared.
In a non-limiting example, such mixtures may contain, 2%, 5%, 7%,
8%, and 10% of disodium salt of pemetrexed for each crystalline
form. Then, X-ray diffraction patterns are obtained for each
artificial mixture using standard X-ray diffraction techniques.
Slight variations in peak positions, if any, may be accounted for
by adjusting the location of the peak to be measured. The
intensities of the selected characteristic peak(s) for each of the
artificial mixtures are then plotted against the known weight
percentages of the crystalline form. The resulting plot is a
calibration curve that allows determination of the amount of the
crystalline forms of disodium salt of pemetrexed in an unknown
sample. For the unknown mixture of crystalline and amorphous forms
of disodium salt of pemetrexed, the intensities of the selected
characteristic peak(s) in the mixture, relative to an intensity of
this peak in a calibration mixture, may be used to determine the
percentage of the given crystalline form in the composition, with
the remainder determined to be the amorphous material. The overall
crystallinity may be determined as follows:
[0097] % Crystallinity=(C/A+C-B).times.100, where C is area under
crystalline peaks, A is area under amorphous halo, and B is
background noise due to air scattering, fluorescence, etc.
[0098] In a particular variant, the present patent application
provides a composition containing a major amount of amorphous form
of disodium salt of pemetrexed and minor amount of crystalline form
of disodium salt of pemetrexed. Preferably, the composition
contains more than 50% of amorphous form of disodium salt of
pemetrexed and at least 5% of crystalline form of disodium salt of
pemetrexed. For this variant, it is particularly contemplated that
the crystalline form of disodium salt of pemetrexed is the
polymorph with X-ray powder diffraction pattern having peaks as set
forth in Table 1:
TABLE-US-00001 TABLE 1 Degree 2- Theta d-spacing [.ANG.] Intensity
[%] 4.0 21.9 25.9 4.4 19.8 18.5 7.8 11.2 4.3 9.3 9.4 6.6 12.6 6.9
3.2 17.2 5.1 21.7 18.0 4.9 100 19.4 4.5 21.0 20.3 4.3 33.5 21.0 4.2
66.1 24.2 3.6 2.3 25.9 3.4 17.2 27.5 3.2 14.2 29.0 3.0 16.0 36.2
2.4 4.7 43.2 2.0 41.4
FIG. 8 shows an example of the XRD for the composition as described
above. A composition containing a mixture of amorphous and
crystalline forms of disodium salt of pemetrexed substantially in
accordance with FIG. 8 is separately contemplated.
[0099] While the invention is not limited to any specific theory,
it is believed that the crystalline form of disodium Form III has
characteristic peaks at diffraction angles (2 theta) at 4.0, 17.3,
18.0, 19.5, 20.4, 21.0, 29.0 and 43.3, .+-.0.2 degrees. Each peak
is shown with measurement permissible error of .+-.0.2 degrees.
This crystalline form of disodium salt of pemetrexed, hereby
designated as Form III, is separately contemplated. The process for
making the mixture of amorphous and crystalline forms of
pemetrexed, in particular for making the specific variant described
herein is described in greater detail below.
[0100] Also provided is a process for making the composition, which
is a mixture of amorphous and crystalline forms of disodium salt of
pemetrexed, the process including: [0101] i) providing a solution
of disodium salt of pemetrexed in water; [0102] ii) adding an
organic hydrocarbon solvent which is capable of forming an
azeotropic mixture with water; and [0103] iii) carrying out an
azeotropic distillation until a solid is obtained.
[0104] The first step involves providing a solution of pemetrexed
disodium in water. This may be accomplished by dissolving
pemetrexed disodium in water or a mixture of water with the
solvent, or such a solution may be obtained directly from a
reaction in which pemetrexed disodium is formed. Any polymorphic
form may be used in the preparation of solution such as crystalline
or semi-crystalline forms, including solvates and hydrates. The
dissolution temperature may range from about 20.degree. C. to about
100.degree. C. or reflux temperature of the solvent. Preferably
dissolution is carried out at a room temperature.
[0105] The quantity of solvent used for dissolution depends on the
solvent and the dissolution temperature opted for the process. The
concentration of pemetrexed disodium in the solution may generally
range from about 0.1 to about 10 g/ml in the solvent.
[0106] The water may be then removed by azeotropic distillation
with the organic hydrocarbon solvent. Suitable organic hydrocarbon
solvent for the preparation of the composition containing the
mixture of solid forms may be selected from toluene, xylenes or the
like, preferably toluene.
[0107] Suitable temperature for the preparation of Form III depends
on the ratio of water and organic hydrocarbon solvent of the
pemetrexed disodium solution. For instance, when the solvent is a
mixture of water and toluene in 12.2:87.8 v/v ratio, the
temperature is about 100-105.degree. C.
[0108] If desired, the solid may be dried to afford the desired
solid. Drying can be carried out under reduced pressure until the
residual solvent content reduces to an amount that is within the
limits given by the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for
Human Use ("ICH") guidelines. The guideline solvent level depends
on the type of solvent but is not more than about 5000 ppm, or
preferably about 4000 ppm, or more preferably about 3000 ppm.
[0109] The drying can be carried out at reduced pressures, such as
below about 650 mmHg or below about 50 mmHg, at temperatures such
as about 35.degree. C. to about 70.degree. C. The drying can be
carried out for any desired time period that achieves the desired
result, such as times about 1 to 20 hours, or longer. Drying may
also be carried out for shorter or longer periods of time depending
on the product specifications.
[0110] Drying can be carried out in equipment such as a tray dryer,
vacuum oven, air oven, or using a fluidized bed drier, spin flash
dryer, and flash dryer.
[0111] It is generally preferred that a rapid drying is often
utilized to provide the desired crystalline form free from residual
organic solvent.
[0112] The solid pemetrexed disodium that includes crystalline Form
III obtained as described herein may have amorphous content more
than about 50 wt %. In one variant, the pemetrexed disodium that
includes crystalline Form III may include about 50 wt % to about 60
wt % of amorphous material.
[0113] Pemetrexed disodium containing a mixture of amorphous solid
and crystalline Form III has a characteristic thermogravimetric
curve (TGA) corresponding to a weight loss of about 22% w/w, as
shown in FIG. 9. Pemetrexed disodium containing a mixture of
amorphous solid and crystalline Form III has an infrared absorption
spectrum in potassium bromide comprising peaks at about 3340, 2930,
2355, 1596, 1403, 1089, and 596, .+-.5 cm.sup.-1. Infrared
absorption spectrum of Pemetrexed disodium containing a mixture of
amorphous solid and crystalline Form III recorded with potassium
bromide is substantially in accordance with the spectrum of FIG.
10. Pemetrexed disodium containing a mixture of amorphous solid and
crystalline Form III is further characterized by its DSC
thermogram, which is substantially in accordance with FIG. 11.
Pemetrexed disodium semi-crystalline Form III is further
characterized by its DSC curve having endothermic peaks at about
86, 244, and 271.degree. C., and an exothermic peak at about
278.degree. C.
[0114] Also provided is crystalline Form A of pemetrexed diacid,
which has XRPD pattern with characteristic peaks at approximately:
5.8, 12.4, 18.3, 18.6, 19.6, 20.4, 24.5, 24.9, 25.8, 28.9, 29.2,
29.6, and 32.8, .+-.0.2 degrees 20. The pemetrexed diacid having
XRPD pattern substantially in accordance with FIG. 12 in separately
contemplated. Pemetrexed diacid crystalline Form A has a
characteristic thermogravimetric (TGA) curve corresponding to a
weight loss of about 26% w/w, as shown in FIG. 13. Pemetrexed
diacid crystalline Form A is characterized by an infrared
absorption spectrum in potassium bromide comprising peaks at about
3286, 3228, 2940, 1685, 1543.9, 1399, 1348, 1300, 1226, and 663,
.+-.5 cm.sup.-1. Pemetrexed diacid crystalline Form A having
infrared absorption spectrum in potassium bromide substantially in
accordance with the spectrum of FIG. 14 is separately contemplated.
Pemetrexed diacid crystalline Form A is further characterized by
its DSC thermogram, which is shown in FIG. 15, having endothermic
peaks at about 71, and 163.degree. C.
[0115] The process for the preparation of pemetrexed diacid
crystalline Form A includes reacting Dimethyl
N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L--
glutamic acid PTSA salt with aqueous sodium hydroxide solution,
followed by neutralization with an acid up to a pH about 3 in the
presence of ethanol. Acid utilized for neutralization may be
selected from hydrochloric acid, hydrobromic acid, sulfuric acid,
acetic acid, p-toluene sulfuric acid, and the like. Suitable
temperature for conducting the reaction may range from about
20.degree. C. to about 80.degree. C.
[0116] Also provided is crystalline Form B of pemetrexed diacid
having XRPD pattern characteristic peaks approximately at: 5.7,
12.1, 12.3, 17.7, 18.4, 20.2, 22.2, 22.5, 22.7, 24.7, 25.6, 25.8,
26.6, 28.2, 30.3, 31.3, and 31.8, .+-.0.2 degrees 2.theta..
Crystalline Form B of pemetrexed diacid having XRPD pattern
substantially in accordance with FIG. 16 is separately
contemplated. Pemetrexed diacid crystalline Form B of the present
invention has a characteristic thermogravimetric (TGA) curve
corresponding to a weight loss of about 5% w/w, and is shown in
FIG. 17. Pemetrexed diacid crystalline Form B may be further
characterized by an infrared absorption spectrum in potassium
bromide having characteristic absorption peaks at about 3424, 3310,
3190, 2941, 2354, 1694, 1524, 1374, 1087, 945, 776, and 662, .+-.5
cm.sup.-1. Pemetrexed diacid crystalline Form B with infrared
spectra substantially in accordance with FIG. 18 is separately
contemplated. Pemetrexed diacid crystalline Form B is further
characterized by its DSC thermogram, which is shown in FIG. 19,
having endothermic peaks at about 114, 134, 195, and 249.degree.
C.
[0117] The process for preparing pemetrexed diacid crystalline Form
B includes reacting
4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]ben-
zoic acid methyl ester with aqueous sodium hydroxide solution, and
subsequently neutralized with an acid up to a pH about 3 in the
presence of a Isopropyl alcohol followed by drying by conventional
method as described in the specification earlier. Acid utilized for
neutralization may be selected from hydrochloric acid, hydrobromic
acid, sulfuric acid, acetic acid, p-toluene sulfuric acid, and the
like. Suitable temperature for conducting the reaction may range
from about 20.degree. C. to about 80.degree. C. The dried product
can optionally be milled to get a desired particle size. Milling or
micronization can be performed prior to drying, or after the
completion of drying of the product. The milling operation reduces
the size of particles and increases surface area of particles by
colliding particles with each other at high velocities. Milling can
be done suitably using jet milling equipment like an air jet mill,
or using other conventional milling equipment.
[0118] In yet another embodiment, there is provided a
pharmaceutical composition comprising the amorphous pemetrexed
disodium or amorphous solid dispersion of pemetrexed disodium with
at least one pharmaceutically acceptable carrier or polymorphs of
pemetrexed diacid or its pharmaceutically acceptable salts produced
by the processes of the present invention with at least one
pharmaceutically acceptable excipient.
[0119] Amorphous pemetrexed disodium or amorphous solid dispersion
of pemetrexed disodium with at least one pharmaceutically
acceptable carrier or Polymorphs of pemetrexed or its
pharmaceutically acceptable salts obtained by processes of the
present invention can be formulated as solid compositions for oral
administration in the form of capsules, tablets, pills, powders or
granules. In these compositions, the active product according to
the invention is mixed with one or more pharmaceutically acceptable
excipients. The drug substance can be formulated as liquid
compositions for oral administration including for example
solutions, suspensions, syrups, elixirs and emulsions, containing
inert diluents solvents or vehicles such as water, sorbitol,
glycerine, propylene glycol or liquid paraffin, may be used.
[0120] The compositions for parenteral administration can be
suspensions, emulsions or aqueous or non-aqueous, sterile
solutions. As a solvent or vehicle, propylene glycol, polyethylene
glycol, vegetable oils, especially olive oil, and injectable
organic esters, e.g. ethyl oleate, may be employed. These
compositions can contain adjuvants, especially wetting, emulsifying
and dispersing agents. The sterilization may be carried out in
several ways, e.g. using a bacteriological filter, by incorporating
sterilizing agents in the composition, by irradiation or by
heating. They may be prepared in the form of sterile compositions,
which can be dissolved at the time of use in sterile water or any
other sterile injectable medium.
[0121] Pharmaceutically acceptable excipients that are of use in
the present invention include but are not limited to diluents such
as starch, pregelatinized starch, lactose, powdered cellulose,
microcrystalline cellulose, dicalcium phosphate, tricalcium
phosphate, mannitol, sorbitol, sugar and the like; binders such as
acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
pregelatinized starch and the like; disintegrants such as starch,
sodium starch glycolate, pregelatinized starch, crospovidone,
croscarmellose sodium, colloidal silicon dioxide and the like;
lubricants such as stearic acid, magnesium stearate, zinc stearate
and the like; glidants such as colloidal silicon dioxide and the
like; solubility or wetting enhancers such as anionic or cationic
or neutral surfactants, complex forming agents such as various
grades of cyclodextrins, resins; release rate controlling agents
such as hydroxypropyl cellulose, hydroxymethyl cellulose,
hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose,
various grades of methyl methacrylates, waxes and the like. Other
pharmaceutically acceptable excipients that are of use include but
not limited to film formers, plasticizers, colorants, flavoring
agents, sweeteners, viscosity enhancers, preservatives,
antioxidants and the like.
[0122] Having described the invention with reference to certain
specific aspects and embodiments, other embodiments will become
apparent to one skilled in the art from consideration of the
specification. The invention is further defined by reference to the
following examples describing in greater detail certain specific
aspects and embodiments, the examples not being intended to limit
the scope of the invention in any manner. It will be apparent to
those skilled in the art that many modifications, both to materials
and methods, may be practiced without departing from the scope of
the invention.
EXAMPLES
Example 1
Preparation of Amorphous Pemetrexed Disodium Using Spray Drier
(Using Water and Methanol in the Ratio of 7.4:92.6)
[0123] Pemetrexed disodium (5 g) was dissolved in the solvent
mixture of methanol (240 ml) and demenaralized water (19 ml) at a
temperature of 25 to 35.degree. C. and then filtered the solution,
followed by washing with methanol (10 ml). Total amount of solution
was evaporated completely until dryness using spray dryer
parameters: [0124] Inlet Temperature: 75.degree. C. [0125] Pump:
20% [0126] Aspirator: 50% [0127] N.sub.2 pressure: 5 Kg/cm.sup.2 to
get the dried title compound.
[0128] Yield: 1.7 g.
[0129] TGA: 8.268% weight loss.
[0130] The obtained sample kept in a sealed polythene bag at a
temperature of 20.degree. C. to 25.degree. C. for a period of 58
days to check the physical stability. The material was found to
retain its amorphous nature after 58 days of holding at ambient
room temperature, as indicated by retention of the original XRPD
pattern.
Water content: 11.51% by Karl Fisher method. XRPD and physical
observation after 58 days--Amorphous
Example 2
Preparation of Amorphous Pemetrexed Disodium (Using Water and
Methanol in the Ratio of 6.9:93.1)
[0131] Pemetrexed disodium (3 g) was dissolved in methanol (100 ml)
followed by demenaralized water (10 ml) was charged. Methanol (20
ml) and demenaralized water (1 ml) were charged to the obtained
suspension and then the suspension was heated to a temperature of
55.degree. C. Methanol (20 ml) was added to the suspension. The
solution was filtered and washed with methanol (10 ml). The
obtained total filtrate was evaporated completely using spray drier
using spray dryer parameters: [0132] Inlet temperature: 100.degree.
C. [0133] Pump: 20% [0134] Aspirator: 70% [0135] N.sub.2 pressure:
5 Kg/cm.sup.2 to get the title compound.
[0136] Yield: 0.7 g
[0137] TGA: 9.81% weight loss.
Example 3
Preparation of Amorphous Pemetrexed Disodium by Reducing the
Methanol Quantity (Using Water and Methanol in the Ratio of
50:50)
[0138] Pemetrexed disodium (5 g) was dissolved in demenaralized
water (35 ml). Methanol (35 ml) was added to the solution and then
filtered. The obtained filtrate was subjected to spray drying drier
using spray dryer parameters: [0139] Inlet temperature: 100.degree.
C. [0140] Pump: 10% (3 ml/minute) [0141] Aspirator: 70% [0142]
N.sub.2 pressure: 5 Kg/cm.sup.2 followed by vacuum drying at a
temperature of 45.degree. C. to get the title amorphous
material.
[0143] Yield: 1.8 g
[0144] Water content: 6.09% by KF method
[0145] The obtained sample kept in a sealed polythene bag at a
temperature of 20 to 25.degree. C. for a period of 7 days to check
the physical stability. The material was found to retain its
amorphous form after 7 days of holding, as indicated by retention
of the original XRPD pattern.
Example 4
Preparation of Amorphous Pemetrexed Disodium (Using Water and
Methanol in the Ratio 37.2:68.8)
[0146] Pemetrexed disodium (20 g) was dissolved in demenaralized
water (140 ml). Methanol (280 ml) was added to the obtained
solution at a temperature of 25 to 35.degree. C. and filtered the
solution followed by washing with methanol (30 ml). The obtained
total filtrate was subjected to evaporation until dryness using
spray drier to obtain title compound.
[0147] Yield: 11.14 g
[0148] Water content: 6.49% by KF method
[0149] The obtained sample kept in a sealed polythene bag at a
temperature of 20 to 25.degree. C. for a period of 3 days to check
the physical stability. The material was found to retain its
polymorphic form after 3 days of holding, as indicated by retention
of the original XRPD pattern.
[0150] The sample was kept in a petri dish and stored at room
temperature for a period of 24 hours to check the physical
stability. The material was found to retain its polymorphic form
after 24 hours of holding, as indicated by maintenance of the
original XRPD pattern.
Example 5
Preparation of Amorphous Solid Dispersion of Pemetrexed Disodium
with Povidone K-30
[0151] Pemetrexed disodium (2.5 g), Povidone (Grade K-30; 2.5 g)
and demineralized water (35 ml) were charged into a flask and
stirred the whole mixture for 5 minutes. Methanol (70 ml) was added
to the obtained suspension at a temperature of 30.degree. C. and
stirred for 15 minutes. The suspension was filtered and washed with
methanol (10 ml). The obtained total filtrate was subjected to
spray drying at a temperature of 100.degree. C. for a period of 1
hour using Spray dryer parameters: [0152] Inlet temperature:
100.degree. C. [0153] N.sub.2 pressure: 5 kg/cm.sup.2 [0154]
Aspirator: 70% [0155] Pump: 20% to get titled amorphous solid
dispersion of Pemetrexed Disodium with Povidone K-30
[0156] Yield: 2 g
[0157] Water content: 7.51 wt % by KF.
Example 06
Preparation of Amorphous Solid Dispersion of Pemetrexed Disodium
with HPMC
[0158] HPMC (2.5 g) was suspended into demineralized water (17.5
ml). Pemetrexed disodium (2.5 g), demineralized water (17.5 ml),
methanol (60 ml) were added to the obtained suspension at a
temperature of 28.degree. C. and stirred the whole solution for a
period of 25 minutes. The obtained solution was filtered and washed
with methanol (10 ml). The resultant filtrate was evaporated using
spray drier at a temperature of 100.degree. C. for a period of 30
minutes using Spray drier parameters: [0159] Inlet: 100.degree. C.
[0160] N.sub.2: 5 kg/cm.sup.2 [0161] Aspirator: 70% [0162] Pump:
20% to get the titled dispersion of Pemetrexed Disodium with
HPMC.
[0163] Water content: 7.67 wt % by KF.
Example 7
Preparation of Pemetrexed Disodium (Using Freeze Drying
Process)
[0164] Pemetrexed disodium (1.0 g) was dissolved in water (7.5 ml)
and the solution was taken into a freeze dryer at about 24.degree.
C. The resultant solution was subjected to freeze drying at
-15.degree. C. for about 15 hours, leaving a solid after completion
of the freeze-drying. The solid was collected to afford 880 mg of
the title compound.
[0165] TGA weight loss: 20.88%
Example 8
Preparation of Mixture of Amorphous and Crystalline Form III of
Pemetrexed Disodium by Azeotrophic Distillation
[0166] Pemetrexed disodium (1.0 g) was dissolved in water (7 ml)
and the resultant solution was charged into a Buchi Rotavapor.
Toluene (50 ml) was charged followed by azeotropic distillation of
water at about 103.degree. C. The distillation step was repeated 8
times to afford 800 mg of the title compound.
[0167] TGA weight loss: 21.94%
[0168] % Crystallinity=22.1 wt %
Example 9
Preparation of Pemetrexed Crystalline Form A
[0169] Sodium hydroxide (6.91 g) was dissolved in water (172.8) and
then the solution was charged into a round bottom flask under a
nitrogen atmosphere. Dimethyl
N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L--
glutamic acid PTSA salt (25 g) was charged into the flask. The
reaction mixture was stirred for 1 hour and then diluted with
ethanol (172.8 ml. The reaction mixture was subjected to pH
adjustment to 3.05 with 1N HCl (20 ml) at 27.degree. C. The
reaction mixture was heated to 70.degree. C. and stirred for 10
minutes, then was allowed to cool to 27.degree. C. and stirred for
15 minutes. The reaction suspension was filtered and the solid
washed with a mixture (150 ml) of water and ethanol (1:1 by
volume). The wet solid was suction dried for 30 minutes and dried
at 45.degree. C. under vacuum of 650 mm Hg to afford 14.5 g of
title compound.
[0170] TGA weight loss: 25.8%
Example 10
Preparation of Pemetrexed Crystalline Form B
[0171] Sodium hydroxide (13.8 g) was dissolved in water (345 ml)
and then the solution was charged into a round bottom flask under a
nitrogen atmosphere. Dimethyl
N-[4-(2-{4-hydroxy-6-aminopyrrolo-[2,3-d]pyrimidin-3-yl}ethyl)benzoyl]-L--
glutamic acid PTSA salt (50 g) was charged into the flask. The
reaction mixture was stirred for 1 hour and then diluted with
isopropyl alcohol (345 ml), and then pH adjusted to 3.01 with 1N
HCl (25.8 ml). The reaction mixture was heated to 65.degree. C. and
stirred for 30 minutes, then was allowed to cool to 27.degree. C.
and stirred for 30 minutes. The reaction suspension was filtered
and the solid washed with a mixture (160 ml) of water and isopropyl
alcohol (1:1 by volume). The wet solid was suction dried for 30
minutes and dried at 45.degree. C. under vacuum of 650 mm Hg to
afford 31 g of the title compound.
[0172] TGA weight loss: 5.1%.
[0173] Most of the foregoing alternative embodiments are not
mutually exclusive, but may be implemented in various combinations.
As these and other variations and combinations of the features
discussed above can be utilized without departing from the
invention as defined by the claims, the foregoing description of
the embodiments should be taken by way of illustration rather than
by way of limitation of the invention as defined by the appended
claims.
* * * * *