NZ630486B2 - Process for the humanization of animal skim milk and products obtained thereby - Google Patents
Process for the humanization of animal skim milk and products obtained thereby Download PDFInfo
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- NZ630486B2 NZ630486B2 NZ630486A NZ63048612A NZ630486B2 NZ 630486 B2 NZ630486 B2 NZ 630486B2 NZ 630486 A NZ630486 A NZ 630486A NZ 63048612 A NZ63048612 A NZ 63048612A NZ 630486 B2 NZ630486 B2 NZ 630486B2
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- 238000002329 infrared spectrum Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000002572 peristaltic Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000001376 precipitating Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Abstract
The disclosure relates to a process for the treatment of animal skim milk and for the production of an infant formula base product from animal skim milk, which process is highly efficient and cost effective, as only membrane filtration techniques, such as microfiltration and ultrafiltration, are required. By carefully controlling the process parameters, a product is obtained in which most of the major components are within the desired range for an infant formula base product. The invention also relates to products obtainable by the process according to the invention. uired. By carefully controlling the process parameters, a product is obtained in which most of the major components are within the desired range for an infant formula base product. The invention also relates to products obtainable by the process according to the invention.
Description
SOLID FORMS OF A PHARMACEUTICALLY ACTIVE SUBSTANCE
[0001] The present invention relates to various forms and formulations of compounds, for
example, compounds that have use in pharmaceutical applications.
[0002] The compound Propanesulfonic acid {3-[5-(4-chloro-phenyl)-1 H-pyrrolo[2,3-
b]pyridinecarbonyl]-2,4-difluoro-phenyl}-amide (compound 1) is represented by formula 1:
ci
H
00
(1)
[0003] The compound of formula I has been described in WO 2007002433 and WO
2007002325. The crystalline forms 1 and 2 (also I and II), the amorphous form, as well as
the tosylate and mesylate salt of compound I are disclosed in International Application No.
PCTIUS1 0/29489.
[0004] Active pharmaceutical ingredients (API’s) may be prepared in a variety of different
forms, such as for example salts, solvates, hydrates, co-crystals. API’s may also be in their
amorphous state or one or several crystalline forms (polymorphs). Depending on the form,
the physicochemical properties of an API may change, leading to e.g. different solubility,
thermodynamic stability, density or melting point of different forms. Such physicochemical
properties therefore may have significant influence of the efficacy or bioavailability of a
known API
Summary of the Invention
[0005] The present invention provides solid forms of the compound of formula 1 selected
from the group consisting of:
(10410525_1):GGG
2
a) a substantially amorphous form of compound I , selected from form XVII, XVIII,
XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI or combinations thereof, wherein
compound 1 is molecularly dispersed;
b) a solvate of form III, IV, V, VI, VII, IX, X, XI, X1 1, XI 11, XIV, or XV;
c) a polymorph of form VIII or XVI; and
d) the sulfuric acid-, hydrobromic acid- or hydrochloric acid salt of compound I.
[0006] In one particular embodiment, said solid form is selected from a solvate of form Ill, IV,
V, VI, VII, IX, X, XI, XI 1, XI 11, XIV or XV.
[0007] In another particularly preferred embodiment, said solid form is selected from a
polymorph of form VIII or XVI.
[0008] In yet another preferred embodiment, said solid form is selected from the sulfuric
acid-, hydrobromic acid- or hydrochloric acid salt of compound 1.
[0009] In still another preferred embodiment, said solid form is a substantially amorphous
form of compound 1, selected from form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or
XXVI or combinations thereof, wherein compound I is molecularly dispersed.
[0009a] In another embodiment the invention provides a solid form of a compound of
formula 1,
H
N s
00
(1),
wherein said solid form is
a) a polymorph of:
form VIII characterized in that it comprises signals in its X-ray powder diffraction
pattern at positions 5.0, 11.3, 11.6, 12.0, 13.8, 16.2, 16.7, 19.0, 20.1, 20.8, 22.5
and 27.1 degrees 2Theta (– 0.2 degrees 2Theta) or
form XVI characterized by its Raman spectrum as presented in Figure 15.
(104 10525 1):GGG
2a
[0009b] In another embodiment the invention provides a solid form of a compound of
formula 1,
CI
H
N
o "0
(1),
wherein said solid form is a solvate of:
form Ill characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 9.5, 10.0, 13.0, 16.7, 18.7, 20.1, 21.0 and 25.6 degrees 2Theta (–
0.2 degrees 2Theta),
form IV characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 5.5, 7.4, 11.0, 13.4, 14.8, 16.0, 16.7, 17.1, 17.9, 19.1, 19.5, 20.1,
.5, 20.9, 21.2, 22.2, 23.0, 23.6, 24.2, 24.5 and 25.1 degrees 2lheta (– 0.2 degrees
2Theta),
form V characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 12.7, 13.1, 14.3, 16.3, 19.0, 20.1, 22.4, 25.1, 27.1 and 28.9 degrees
2Theta (– 0.2 degrees 2Theta),
form VI characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 7.8, 10.3, 11.4, 11.8, 15.1, 15.6, 16.1, 16.6, 18.6, 18.9, 19.2, 20.4,
21.0, 21.6, 22.8, 24.6, 25.1, 25.8, 26.1, 27.4 and 28.8 degrees 2lheta (– 0.2 degrees
2Theta),
form VII characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 7.6, 9.4, 9.9, 13.1, 15.9, 16.2, 17.0, 18.1, 18.8, 19.9,
.5, 20.7, 21.4, 21.8, 24.3, 24.9 and 25.3 degrees 2Theta (– 0.2 degrees 2Theta),
form IX characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 9.5, 9.9, 13.0, 15.9, 16.4, 17.0, 17.9, 18.7, 19.9, 20.7, 21.7, 24.8 and
.1 degrees 2Theta (– 0.2 degrees 2Theta),
form X characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 7.4, 9.2, 10.8, 13.6, 14.9, 19.0, 20.2, 21.4, 22.4, 23.7, 25.5, 27.0 and
29.8 degrees 2Theta (– 0.2 degrees Meta),
form XI characterized by an X-ray powder diffraction pattern comprising characteristic
peaks at approximately 8.0, 12.1, 12.6, 13.4, 13.9, 14.8, 16.2, 17.6, 18.5, 19.2, 20.1, 21.0,
21.4, 21.7, 23.5, 25.3, 25.5, 26.6, 27.0 and 30.8 degrees 2Theta (– 0.2 degrees 2Theta),
104 105 25_i) :GGG
2b
form XI characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 7.5, 9.9, 12.1, 13.6, 16.2, 16.7, 17.1, 17.5, 18.3, 18.5,
.1, 21.7, 22.4, 23.4, 24.3, 25.6, 26.9 and 31.6 degrees 2Theta (– 0.2 degrees 2Theta),
form XIII characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 5.1, 5.8, 6.9, 15.3, 16.2, 17.4, 18.4, 18.9, 19.5, 20.4,
21.1, 21.5, 22.2, 22.6, 25.2 and 25.7 degrees 2Theta (– 0.2 degrees 2lheta),
form XIV characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 5.2, 10.2, 12.9, 13.9, 17.1, 17.6, 18.7, 19.8, 20.1, 20.5,
21.0, 21.7, 22.8, 24.1, 25.1, 25.5, 27.1 and 27.4 degrees 2Theta (– 0.2 degrees 2Theta),
or
form XV characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 12.6, 13.8, 14.6, 16.2, 16.6, 17.8, 18.3, 20.4, 20.7,
21.4, 22.4, 23.2, 24.2, 24.5, 25.5, 26.9, 27.8 and 28.7 degrees 2Theta (– 0.2 degrees
2Theta).
[0009c] In another embodiment the invention provides a solid form of a compound of
formula 1,
H
N
0"
(1),
wherein said solid form is selected from the group consisting of:
a sulfuric acid salt characterized by an X-ray powder diffraction pattern comprising
characteristic peaks at approximately 4.7, 6.7, 10.6, 13.3, 14.5, 15.7, 16.4, 18.3, 18.6, 18.9,
19.5, 20.1, 20.9, 21.2, 23.2, 23.7, 24.0, 26.9 and 30.0 degrees 2Theta (– 0.2 degrees
2Theta),
a hydrobromic acid salt characterized by an X-ray powder diffraction pattern
comprising characteristic peas at approximately 5.7, 6.8, 11.4, 13.6, 18.1, 19.8, 20.2, 21.4,
21.8, 24.6, 26.1, 27.3 and 29.2 degrees 2Theta (– 0.2 degrees 2Theta), and
a hydrochloric acid salt characterized by an X-ray powder diffraction pattern
comprising characteristic peaks at approximately 6.6, 7.8, 11.2, 12.6, 14.1, 14.7, 16.3, 17.8,
19.3, 19.6, 20.7, 21.5, 22.7, 24.1, 25.4 and 25.8 degrees 2Theta (– 0.2 degrees 2Theta).
(10410525_1):GGG
2c
[0009d] In another embodiment the invention provides a solid form of a compound of
formula 1,
C :I
N
H
00
N
H (1),
designated "pattern 6" characterized in that it comprises signals in its X-ray powder
diffraction curve at positions 7.0, 8.4, 8.9, 13.0, 13.8, 17.7, 18.8, 20.7, 25.8 and 29.7
degrees 2Theta (– 0.2 degrees 2Theta).
[0010] In another embodiment, the invention provides a method for treating a disease or
condition in a mammal in need thereof. The method includes administering to the mammal
an effective amount of a composition comprising a solid form compound as described
herein. In certain embodiments, the diseases or conditions are mediated by b-Raf mutants
having V600E, V600M, V600R, V600K or V600G mutations. In other embodiments, the
diseases or conditions include, but are not limited to melanoma, thyroid cancer and
colorectal cancer.
[00010a] In another embodiment the invention provides a pharmaceutical composition
comprising at least one of the solid forms according to the invention, together with a
pharmaceutically acceptable additive, carrier or excipient.
[00010b] In another embodiment the invention provides the solid forms, methods of making
them, compositions containing them and uses as described herein before.
[000IOc] In another embodiment the invention provides use of a solid form according to the
invention for the manufacture of a medicament for the treatment of melanoma, thyroid
cancer or colon cancer.
[0011] The solid forms disclosed herein may be further processed into any type of solid
pharmaceutical preparations or dosage forms, which are known to the person of skill in the
art. Particularly preferred are oral dosage forms such as tablets, capsules, pills, powders,
suspensions, pasts and the like. Detailed descriptions of suitable excipients as well as
methods for making such pharmaceutical preparations can for example be found in:
Raymond C. Rowe et al, Handbook of Pharmaceutical Excipients, 6th edition, 2009,
Pharmaceutical Press (PubI); ISBN-10: 0853697922.
(104105 25_1):GGG
[0012] Consequently, so obtained pharmaceutical preparations form further embodiments
provided herein.
Brief Description of the Figures
[0013] Figure 1 shows XRPD patterns of the amorphous form of compound 1 as obtainable
by the method disclosed in Example 1.
[0014] Figure 2 shows the XRPD patterns of form III of compound 1 as obtained by the
method disclosed in Example 3.
[0015] Figure 3 shows the XRPD patterns of form IV of compound 1 as obtained by the
method disclosed in Example 4.
[0016] Figure 4 shows the XRPD patterns of form V of compound 1 as obtained by the
method disclosed in Example 5.
[0017] Figure 5 shows the XRPD patterns of form VI of compound 1 as obtained by the
method disclosed in Example 6.
[0018] Figure 6 shows the XRPD patterns of form VII of compound 1 as obtained by the
method disclosed in Example 7.
[0019] Figure 7 shows the XRPD patterns of form VIII of compound 1 as obtained by the
method disclosed in Example 8.
[0020] Figure 8 shows the XRPD patterns of form IX of compound 1 as obtained by the
method disclosed in Example 9.
[0021] Figure 9 shows the XRPD patterns of form X of compound 1 as obtained by the
method disclosed in Example 10.
[0022] Figure 10 shows the XRPD patterns of form XI of compound 1 as obtained by the
method disclosed in Example 11.
[0023] Figure 11 shows the XRPD patterns of form XII of compound 1 as obtained by the
method disclosed in Example 12.
[0024] Figure 12 shows the XRPD patterns of form XIII of compound 1 as obtained by the
method disclosed in Example 13.
[0025] Figure 13 shows the XRPD patterns of form XIV of compound 1 as obtained by the
method disclosed in Example 14.
[0026] Figure 14 shows the XRPD patterns of form XV of compound 1 as obtained by the
method disclosed in Example 15.
[0027] Figure 15 shows the Raman spectrum of form XVI of compound 1 as obtained by the
method disclosed in Example 16.
[0028] Figure 16 shows the XRPD patterns of pattern 6 of compound 1 as obtained by the
method disclosed in Example 17.
[0029] Figure 17 shows the XRPD patterns of sulfuric acid salt of compound 1 as obtained
by the method disclosed in Example 18.
[0030] Figure 18 shows the XRPD patterns of hydrobromic acid salt of compound 1 as
obtained by the method disclosed in Example 19.
[0031] Figure 19 shows the XRPD patterns of hydrochloric acid salt of compound 1 as
obtained by the method disclosed in Example 20.
[0032] Figure 20 shows the XRPD patterns of form XVII of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0033] Figure 21 shows the XRPD patterns of form XVIII of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0034] Figure 22 shows the XRPD patterns of form XIX of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0035] Figure 23 shows the XRPD patterns of form XX of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0036] Figure 24 shows the XRPD patterns of form XXI of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0037] Figure 25 shows the XRPD patterns of form XXII of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0038] Figure 26 shows the XRPD patterns of form XXIII of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0039] Figure 27 shows the XRPD patterns of form XXIV of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0040] Figure 28 shows the XRPD patterns of form XXV of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
[0041] Figure 29 shows the XRPD patterns of form XXVI of compound 1 as obtained by the
method disclosed in Examples 21 and 22.
Detailed Description of the Invention
Definitions
[0042] The term “compound 1” as used herein means Propanesulfonic acid {3-[5-(4-
chloro-phenyl)-1H-pyrrolo[2,3-b]pyridinecarbonyl]-2,4-difluoro-phenyl}-amide, which is
sometimes also designated as PLX-4032.
[0043] As used herein, the general term “amorphous forms” denotes a material that lacks
long range order and as such does not show sharp X-ray peaks. The X-Ray Powder
Diffraction (XRPD) pattern of an amorphous material is characterized by one or more
amorphous halos. More specifically, the term “amorphous form” as used herein refers to the
amorphous form of Propanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-
b]pyridinecarbonyl]-2,4-difluoro-phenyl}-amide (compound 1) as such, provided said
amorphous form does not form a one phase system, such as for example a solid dispersion or
microprecipitated bulk powder (MBP) together with any type of supporting material such as
polymers or the like.
[0044] The term “amorphous halo” means a broad diffraction maximum in the X-ray powder
diffraction pattern of an amorphous substance, i.e. the amorphous form of compound 1. The
FWHM (full width at half maximum) of an amorphous halo is usually bigger than two
degrees in 2-theta.
[0045] The “Form II” of compound 1 as referred to herein means the thermodynamically
stable form of Propanesulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine
carbonyl]-2,4-difluoro-phenyl}-amide.
[0046] The term “molecularly dispersed”, as used herein, refers to the random distribution of
compound 1 within a polymer. More particularly, a compound (for example, compound 1)
may be dispersed within a matrix formed by the polymer in its solid state such that the
compound 1 and the matrix form a one phase system (solid dispersion) and compound 1 is
immobilized in its amorphous form. An example of such solid dispersion is a microprecipitated bulk powder (MBP). Whether a compound is molecularly dispersed in a polymer
may be evidenced in a variety of ways, e.g., by the resulting solid molecular complex having
a single glass transition temperature.
[0047] The term “flash cooling” as used herein means cooling with liquid nitrogen.
[0048] The term “approximately“ in connection with the XRPD patterns as disclosed herein
means that there is an uncertainty in the measurements of the degrees 2Theta of ± 0.2 degrees
(expressed in degrees 2Theta).
[0049] The term “polymorph” as used herein means one of the different crystal structures in
which a compound can crystallize. Polymorphs are best characterized by their space group
and unit-cell parameters. This term is reserved for materials with the same elemental analysis.
[0050] The term “solvate” as used herein means a crystal form that contains either
stoichiometric or nonstoichiometric amounts of solvent.
[0051] The term “substantially amorphous” material embraces material which has no more
than about 10% crystallinity; and “amorphous” material embraces material which has no
more than about 2% crystallinity. In some embodiments, the “amorphous” material means
material having no more than 1%, 0.5% or 0.1 % crystallinity.
[0052] “Ambient temperature” means any temperature in the range of 18 to 28 °C, preferably
to 24 °C.
[0053] The term “composition” refers to a pharmaceutical preparation suitable for
administration to an intended animal subject for therapeutic purposes that contains at least
one pharmaceutically active compound, including any solid form thereof. The composition
may include at least one additional pharmaceutically acceptable component to provide an
improved formulation of the compound, such as a suitable carrier, additive or excipient.
[0054] The term “pharmaceutically acceptable” indicates that the indicated material does not
have properties that would cause a reasonably prudent medical practitioner to avoid
administration of the material to a patient, taking into consideration the disease or conditions
to be treated and the respective route of administration. For example, it is commonly
required that such a material be essentially sterile, e.g., for injectibles.
[0055] The term “therapeutically effective” or "effective amount" indicates that the materials
or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms
of a disease or medical condition, and/or to prolong the survival of the subject being treated.
In certain embodiments, a "therapeutically-effective amount" of Compound I refers to such
dosages and/or administration for such periods of time necessary to inhibit human b-Raf
containing the V600E mutation. In some embodiments, the human b-Raf includes V600A,
V600M, V600R, V600K or V600G mutations. Moreover, a therapeutically effective amount
may be one in which the overall therapeutically-beneficial effects outweigh the toxic or
undesirable side effects. A therapeutically-effective amount of Compound I may vary
according to disease state, age and weight of the subject being treated. Thus, dosage
regimens are typically adjusted to the individual requirements in each particular case and are
within the skill in the art. In certain embodiments, an appropriate daily dose for
administration of Compound 1 to an adult human may be from about 100 mg to about 3200
mg; or from about 250 mg to about 2000 mg, although the upper limit may be exceeded when
indicated. A daily dosage of Compound 1 can be administered as a single dose, in divided
doses, or, for parenteral administration, it may be given as subcutaneous injection.
[0056] In the spray dry dispersion process, Compound 1 and a polymer may be dissolved in a
common solvent having a low boiling point, e.g., ethanol, methanol, acetone, etc. By means
of spray drying or lyophilization, the solvent is evaporated by flash evaporation at the
temperature close to boiling point or under a high vacuum (low vapor pressure), leaving the
Compound 1 precipitated in a matrix formed by the polymer. In certain embodiments
Compound 1 is in a mesylate or tosylate salt form, and thus preferably has improved
solubility.
[0057] The term “methacrylic acid copolymers” as used herein in the spray dry dispersion
process includes, but are not limited to, methacrylic acid copolymers, methacrylic acid -
methacrylate copolymers, methacrylic acid - ethyl acrylate copolymers, ammonio
methacrylate copolymers, aminoalkyl methacrylate copolymers and the like. In certain
embodiments, a “methacrylic acid copolymer” may be EUDRAGIT® L 100 and
EUDRAGIT® L 12,5 (also referred to as, or conforms with: “Methacrylic Acid Copolymer,
Type A;” “Methacrylic Acid - Methyl Methacrylate Copolymer (1:1);” “Methacrylic Acid
Copolymer L;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® S 100 and EUDRAGIT® S
12,5 (also referred to as, or conforms with: “Methacrylic Acid Copolymer, Type B;”
“Methacrylic Acid - Methyl Methacrylate Copolymer (1:2);” “Methacrylic Acid Copolymer
S;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® L 100-55 (also referred to as, or
conforms with: “Methacrylic Acid Copolymer, Type C;” “Methacrylic Acid - Ethyl Acrylate
Copolymer (1:1) Type A;” “Dried Methacrylic Acid Copolymer LD;” or “DMF 2584”);
EUDRAGIT® L 30 D-55 (also referred to as, or conforms with: "Methacrylic Acid
Copolymer Dispersion;" "Methacrylic Acid - Ethyl Acrylate Copolymer (1:1) Dispersion
Per Cent;” “Methacrylic Acid Copolymer LD;” JPE DMF 2584; PR-MF 8216);
EUDRAGIT® FS 30 D (also referred to as DMF 13941 or DMF 2006-176); EUDRAGIT® RL
100 (also referred to as, or conforms with: “Ammonio Methacrylate Copolymer, Type A;”
“Ammonio Methacrylate Copolymer (Type A);” “Aminoalkyl Methacrylate Copolymer RS;”
“DMF 1242” or “PR-MF 6918”); EUDRAGIT® RL PO (also referred to as, or conforms with:
“Ammonio Methacrylate Copolymer, Type A;” "Ammonio Methacrylate Copolymer (Type
A);" "Aminoalkyl Methacrylate Copolymer RS;" “DMF 1242”); EUDRAGIT® RL 12,5 (also
referred to as, or conforms with “Ammonio Methacrylate Copolymer, Type A;” “Ammonio
Methacrylate Copolymer (Type A);” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® L 100-
55 (also referred to as, or conforms with: “Methacrylic Acid Copolymer, Type C;”
“Methacrylic Acid - Ethyl Acrylate Copolymer (1:1) Type A;” “Dried Methacrylic Acid
Copolymer LD;” “DMF 2584”); EUDRAGIT® L 30 D-55 (also referred to as, or conforms
with: "Methacrylic Acid Copolymer Dispersion" NF “Methacrylic Acid - Ethyl Acrylate
Copolymer (1:1) Dispersion 30 Per Cent;” "Methacrylic Acid Copolymer LD;” “DMF 2584”
or “PR-MF 8216”); EUDRAGIT® FS 30 D (also referred to as, or conforms with: “DMF
13941” or “DMF 2006-176”); EUDRAGIT® RL 100 (also referred to as, or conforms with:
“Ammonio Methacrylate Copolymer, Type A;” “Ammonio Methacrylate Copolymer (Type
A);” “Aminoalkyl Methacrylate Copolymer RS;” “DMF 1242;” or “PR-MF 6918”);
EUDRAGIT® RL PO (also referred to as, or conforms with: "Ammonio Methacrylate
Copolymer, Type A;” “Ammonio Methacrylate Copolymer (Type A);” “Aminoalkyl
Methacrylate Copolymer RS;” or “DMF 1242”); EUDRAGIT® RL 12,5 (also referred to as,
or conforms with: polymer conforms to “Ammonio Methacrylate Copolymer, Type A;”
“Ammonio Methacrylate Copolymer (Type A);” “DMF 1242” or “PR-MF 6918”);
EUDRAGIT® RL 30 D (also referred to as, or conforms with: “Ammonio Methacrylate
Copolymer Dispersion, Type A;” “Ammonio Methacrylate Copolymer (Type A);” or “DMF
1242”); EUDRAGIT® RS 100 (also referred to as, or conforms with: "Ammonio
Methacrylate Copolymer, Type B;” NF “Ammonio Methacrylate Copolymer (Type B);”
“Aminoalkyl Methacrylate Copolymer RS;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT®
RS PO (also referred to as, or conforms with: “Ammonio Methacrylate Copolymer, Type B;”
“Ammonio Methacrylate Copolymer (Type B);” “Aminoalkyl Methacrylate Copolymer RS;”
or “DMF 1242”); EUDRAGIT® RS 12,5 (also referred to as, or conforms with: “Ammonio
Methacrylate Copolymer, Type B;” NF polymer conforms to “Ammonio Methacrylate
Copolymer (Type B);” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® RS 30 D (also
referred to as, or conforms with: “Ammonio Methacrylate Copolymer Dispersion, Type B;”
NF polymer conforms to "Ammonio Methacrylate Copolymer (Type B);" or “DMF 1242”);
EUDRAGIT® E 100 (also referred to as, or conforms with: “Amino Methacrylate
Copolymer;” NF “Basic Butylated Methacrylate Copolymer;” “Aminoalkyl Methacrylate
Copolymer E;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® E PO (also referred to as, or
conforms with: “Basic Butylated Methacrylate Copolymer;” “Aminoalkyl Methacrylate
Copolymer E;” “Amino Methacrylate Copolymer;” “DMF 1242”); EUDRAGIT® E 12,5
(also referred to as, or conforms with: “Amino Methacrylate Copolymer;” “Basic Butylated
Methacrylate Copolymer;” “DMF 1242” or “PR-MF 6918”); EUDRAGIT® NE 30 D (also
referred to as, or conforms with: “Ethyl Acrylate and Methyl Methacrylate Copolymer
Dispersion;” “Polyacrylate Dispersion 30 Per Cent;” (“Poly(ethylacrylat-methylmethacrylat)-
Dispersion 30 %”); “Ethyl Acrylate Methyl Methacrylate Copolymer Dispersion;” “DMF
2822” or “PR-MF 6918”); EUDRAGIT® NE 40 D (also referred to as, or conforms with:
DMF 2822); EUDRAGIT® NM 30 D (also referred to as “Polyacrylate Dispersion 30 Per
Cent;” “(Poly(ethylacrylat-methylmethacrylat)-Dispersion 30 %);” or “DMF 2822”;
PLASTOID® B (also referred to as, or conforms with: “DMF 12102”), or the like.
[0058] The term “API” as used herein means active pharmaceutical ingredient.
[0059] The term “DSC” as used herein means Differential Scanning Calorimetry.
[0060] The term “DVS” as used herein means Dynamic Vapor Sorption.
[0061] The term “IR” as used herein means Infra Red spectroscopy.
[0062] The term “Raman” as used herein means Raman spectroscopy.
[0063] The term “XRPD” as used herein means X-Ray Powder Diffraction.
[0064] The term “TGA” as used herein means ThermoGravimetric Analysis.
Characterization Methods
[0065] DSC curves were recorded using a Mettler-Toledo™ differential scanning
calorimeter DSC820, DSC821 or DSC 1 with a FRS05 sensor. System suitability tests were
performed with Indium as reference substance and calibrations were carried out using Indium,
Benzoic acid, Biphenyl and Zinc as reference substances.
[0066] For the measurements, approximately 2 - 6 mg of sample were placed in aluminum
pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement,
the lids were automatically pierced resulting in approx. 1.5 mm pin holes. The samples were
then heated under a flow of nitrogen of about 100 mL/min using heating rates of usually 10
K/min.
[0067] TGA analysis was performed on a Mettler-Toledo™ thermogravimetric analyzer
(TGA850 or TGA851). System suitability tests were performed with Hydranal as reference
substance and calibrations using Aluminum and Indium as reference substances.
[0068] For the thermogravimetric analyses, approx. 5 10 mg of sample were placed in
aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to
measurement, the lids were automatically pierced resulting in approx. 1.5 mm pin holes. The
samples were then heated under a flow of nitrogen of about 50 mL/min using a heating rate
of 5 K/min.
[0069] DVS isotherms were collected on a DVS-1 (SMS Surface Measurements Systems)
moisture balance system. The sorption/desorption isotherms were measured stepwise in a
range of 0% RH to 90% RH at 25 °C. A weight change of <0.002 mg/min was chosen as
criterion to switch to the next level of relative humidity (with a maximum equilibration time
of six hours, if the weight criterion was not met). The data were corrected for the initial
moisture content of the samples; that is, the weight after drying the sample at 0% relative
humidity was taken as the zero point.
[0070] IR spectra were recorded as film of a Nujol suspension of approximately 5 mg of
sample and few Nujol between two sodium chloride plates, with an FTIR spectrometer in
transmittance. The Spectrometer is a Nicolet™ 20SXB or equivalent (resolution 2 cm-1, 32
or more coadded scans, MCT detector).
[0071] Raman spectra were recorded in the range of 150-1800 cm-1 at excitation of 785 nm
with an ARAMIS (HoribaJobinYvon) Raman microscope equipped with a Peltier cooled
CCD detector, and a 1200 l/mm grating.
[0072] X-ray powder diffraction patterns were recorded at ambient conditions in
transmission geometry with a STOE STADIP diffractometer (Cu K radiation, primary
monochromator, position sensitive detector, angular range 3° to 42° 2Theta, approximately 60
minutes total measurement time). Approximately 25 mg of sample were prepared and
analyzed without further processing (e.g. grinding or sieving) of the substance. Alternatively,
X-ray diffraction patterns were measured on a Scintag X1 powder X-ray diffractometer
equipped with a sealed copper K1 radiation source. The samples were scanned from 2 to
36 2 at a rate of 1 per minute with incident beam slit widths of 2 and 4 mm and diffracted
beam slit widths of 0.3 and 0.2 mm.
[0073] The amorphous form of compound I according to the present invention is
preferentially substantially pure, meaning the amorphous form includes less than about 15%,
preferably less than about 10%, preferably less than about 5%, preferably less than about 1%,
even more preferably less than 0.1% by weight of impurities, including other polymorph
forms of compound 1. In some embodiments, at least about 30-99% by weight of the total of
compound 1 in the composition is present as the amorphous form. In further embodiments, at
least about 70%, at least about 80%, at least about 90%, at least about 99% or at least about
99.9% by weight of the total of compound 1 in the composition is present as the amorphous
form. Also provided by the invention are compositions consisting essentially of compound 1
wherein at least about 97-99% by weight of the compound 1 is present in the composition as
an amorphous form, a polymorph form, a solvate form as described herein or combinations
thereof.
[0074] The polymorph, solvate or amorphous form of compound I according to the present
invention can also be present in mixtures. In some embodiments, amorphous form XVII can
be present in mixtures with one or more other amorphous forms selected from XVIII, XIX,
XX, XXI, XXII, XXIII, XXIV, XXV or XXVI. Solvate form III can be present in mixtures
with one or more solvate forms selected from IV, V, VI, VII, IX, X, XI, XII, XIII, XIV or
XV. Polymorph form VIII can be present in a mixture with polymorph form XVI.
[0075] Suitable solvents for preparation of spray dry dispersion amorphous forms of
compound 1 include, but are not limited to acetone, water, alcohols, mixtures thereof, and the
like. The alcohols include, but are not limited to, ethanol, methanol, isopropanol and
mixtures thereof.
[0076] The solid forms of compound 1 as disclosed herein can be used in a wide variety of
preparations for administration of drugs, and in particular for oral dosage forms. Exemplary
dosage forms include powders or granules that can be taken orally either dry or reconstituted
by addition of water to form a paste, slurry, suspension or solution; tablets, capsules, or pills.
Various additives can be mixed, ground or granulated with the solid dispersion as described
herein to form a material suitable for the above dosage forms. Potentially beneficial additives
may fall generally into the following classes: other matrix materials or diluents, surface active
agents, drug complexing agents or solubilizers, fillers, disintegrants, binders and lubricants.
With respect to the solvates and polymorphs as disclosed herein, pH modifiers (e.g., acids,
bases, or buffers) may also be added. Examples of other matrix materials, fillers, or diluents
include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
Examples of surface active agents include sodium lauryl sulfate and polysorbate 80.
Examples of drug complexing agents or solubilizers include the polyethylene glycols,
caffeine, xanthene, gentisic acid and cylodextrins. Examples of disintegrants include sodium
starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, and
croscarmellose sodium. Examples of binders include methyl cellulose, microcrystalline
cellulose, starch, and gums such as guar gum, and tragacanth. Examples of lubricants include
magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as
citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid,
and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium
oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and
the like, and buffers generally comprising mixtures of acids and the salts of said acids. At
least one function of inclusion of such pH modifiers is to control the dissolution rate of the
drug, matrix polymer, or both, thereby controlling the local drug concentration during
dissolution.
[0077] In addition to the above additives or excipients, use of any conventional materials and
procedures for formulation and preparation of oral dosage forms using the compositions
disclosed herein known by those skilled in the art are potentially useful. For example, the
skilled artisans may formulate the compositions in an appropriate manner, and in accordance
with accepted practices, such as those described in Remington's Pharmaceutical Sciences
(Gennaro, Ed., Mack Publishing Co., Pa. 1990).
[0078] Consequently, a further embodiment includes a pharmaceutical preparation containing
the solid dispersion as obtained by a method as described herein.
[0079] In certain embodiments, the present invention provides a method for preparing a
substantially amorphous form of compound (1), the amorphous form is selected from form
XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI or combinations thereof.
The method includes preparing a spray dry dispersion solution of compound (1) and drying
the dispersion solution of compound (1) under conditions sufficient to obtain the amorphous
form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV or XXVI or combinations
thereof. In one embodiment, the spray dry dispersion solution is dried under vacuum. In one
embodiment, a spray dry dispersion solution is prepared by dispersing a solution of
compound (1) into a polymer solution under conditions sufficient to obtain the spray dry
dispersion solution. Any solvents or a mixture of solvents that are suitable to dissolve
compound (1) can be used. Exemplary solvents for dissolving compound (1) include , but are
not limited to, tetrahydrofuran (THF), acetone, acetonitrile, benzene, ethanol, toluene, ether,
ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or a mixture of any
two or more thereof. In certain instances, an acid, such as hydrochloric acid, sulfuric acid or
nitric acid is added into an organic solvent system in a ratio sufficient to assist the dissolution
of compound (1). The polymer solution can be prepared by dissolving a polymer in an
organic solvent or a mixture of solvents with a suitable ratio. In certain instances, the
polymer is dissolved in a solvent or a mixture of solvents at a temperature ranging from 20 -
100 °C, 30-50 °C or 40-100 °C. Any polymers as described herein can be used for the
preparation of the polymer solution. Exemplary solvents for preparing the polymer solution
include, but are not limited to THF, acetone, acetonitrile, benzene, ethanol, toluene, ether,
ethyl acetate, DMF, DMSO, H2O or a mixture threof.
[0080] In certain embodiments, the invention provides a method for treating a disease or
condition in a mammal in need thereof, said method comprising administering to said
mammal an effective amount of a composition comprising at least one solid form of
compound I selected from the group consisting of:
a) a substantially amorphous form of compound 1, selected from form XVII,
XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI or combinations
thereof, wherein compound 1 is molecularly dispersed;
b) a solvate of form III, IV, V, VI, VII, IX, X, XI, XII, XIII, XIV, or XV;
c) a polymorph of form VIII or XVI; and
d) the sulfuric acid-, hydrobromic acid- or hydrochloric acid salt of compound 1.
[0081] In certain embodiments, the disease or condition for which the above-described
method is employed is melanoma, thyroid cancer or colon cancer.
[0082] In certain embodiments, the invention provides a method for treating a disease or
condition in a mammal in need thereof, said method comprising administering to said
mammal an effective amount of a composition comprising at least one solid form of
compound I as described herein.
[0083] In certain embodiments, the disease or condition for which the above-described
method is employed is melanoma, thyroid cancer or colon cancer.
Examples
Example 1 (Reference Example)
Preparation of amorphous form of propanesulfonic acid {3-[5-(4-chlorophenyl)-1Hpyrrolo [2,3-b] pyridinecarbonyl-2,4-difluoro-phenyl]-amide} (compound 1)
[0084] Amorphous material can be generally obtained by flash cooling of a melt and spray
drying. Other processes such as for example lyophilization may also be used.
a) Preparation of amorphous material by spray drying
[0085] 5.0 g of compound 1 were dissolved in 150 g of tetrahydrofuran (THF) at ambient
temperature. The solution was filtered via a 5 µm filter. The clear solution was spray dried
using a Buechi spray-dryer (model B290) using the following parameters:
Air flow inlet [m3/h] 40
Air inlet temperature [°C] 100
Solvent flow [%] 20
Spray drying flow [%] 100
Condensator [°C] -10
Yield: 2.8 g (56 %) amorphous compound 1.
b) Preparation of amorphous material by flash cooling of a melt
[0086] 2 g of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b] pyridine
carbonyl-2,4-difluoro-phenyl]-amide} were heated to 300 °C in a stainless steel pan on a
heating plate. Additionally, the material was heated using a heat gun. After obtaining a
complete melt the pan was submerged into liquid nitrogen. After 10 min. the pan was
removed and put into a desiccator for 48 h. For better handling, the glassy material was
crushed using a mortar.
c) Characterization of the amorphous form
[0087] The amorphous form can be characterized by the lack of sharp X-ray diffraction peaks
in its XRPD pattern, as well as a glass transition temperature as obtainable via DSC
measurement in the range of about 100 °C to 110 °C. The exact glass transition temperature
is largely dependent on the water/solvent content. Figure 1 shows XRPD patterns of the
amorphous form of compound 1 as obtainable by the method disclosed in this example.
Example 2
(Reference Example)
Preparation of Form I of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0088] Polymorphic form I can generally be obtained by drying of the hemi-acetone solvate
(Form IX) at >70 °C.
Example 3
Preparation of form III of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
a) Preparation of form III by equilibration in acetonitrile
[0089] 221.3 mg of amorphous material were digested in 500 L of acetonitrile at ambient
temperature for 2 days. The material was then isolated by filtration and dried at 22 °C/5 mbar
for 48 h.
b) Characterization of form III
[0090] Form III can be characterized by XRPD patterns obtained with Cu K radiation
having characteristic peaks expressed in degrees 2Theta at approximately 9.5, 10.0, 13.0,
16.7, 18.7, 20.1, 21.0, 25.6. The XRPD (X-Ray Powder Diffraction) pattern of a typical lot of
form III of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b] pyridine
carbonyl-2,4-difluoro-phenyl]-amide} is shown in Figure 2.
Example 4
Preparation of form IV of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0091] Form IV is a THF 0.75-solvate and can be generally obtained by processes
comprising compound 1 and THF as solvent.
a) Preparation of form IV by evaporative crystallization from THF
[0092] 254.3 mg of compound 1 (form II) were dissolved in 6 mL of THF at 65 °C. After 12
h the clear solution was cooled to 5 °C. The crystals were isolated by filtration and dried at
ambient conditions.
b) Characterization of form IV
[0093] Form IV can be characterized by its XRPD patterns obtained with Cu K radiation
having characteristic peaks expressed in degrees 2Theta at approximately: 5.5, 7.4, 11.0, 13.4,
14.8, 16.0, 16.7, 17.1, 17.9, 19.1, 19.5, 20.1, 20.5, 20.9, 21.2, 22.2, 23.0, 23.6, 24.2, 24.5,
.1. Figure 3 shows the XRPD pattern of a typical lot of form IV of compound 1.
Example 5
Preparation of form V of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0094] Form V is a dioxane mono-solvate and can be obtained by processes comprising
compound 1 and dioxane as solvent.
a) Preparation of form V by equilibration in dioxane
[0095] 110.3 mg of amorphous material of compound 1 were suspended in 500 L of
dioxane. The wet material was digested at ambient temperature for 2 days. The material was
then isolated by filtration and dried at 22 °C/5 mbar for 48 h.
b) Characterization of form V
[0096] Form V can be characterized by its XRPD pattern obtained with Cu K radiation
having characteristic peaks expressed in degrees 2Theta at approximately: 12.7, 13.1, 14.3,
16.3, 19.0, 20.1, 22.4, 25.1, 27.1, 28.9. Figure 4 shows the XRPD pattern of a typical lot of
form V of compound 1.
Example 6
Preparation of form VI of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0097] Form VI is a DMF mono-solvate and can be obtained by procedures comprising
compound 1 and DMF as solvent.
a) Preparation of form VI by equilibration in DMF
[0098] 120.3 mg of amorphous material were slurried in 500 L of DMF at ambient
temperature for 2 days. The brownish material was isolated by filtration and dried at 30 °C / 5
mbar 48 h.
b) Characterization of form VI
[0099] Form VI can be characterized by its XRPD pattern obtained with Cu Kradiation
having characteristic peaks expressed in degrees 2Theta at approximately: 7.8, 10.3, 11.4,
11.8, 15.1, 15.6, 16.1, 16.6, 18.6, 18.9, 19.2, 20.4, 21.0, 21.6, 22.8, 24.6, 25.1, 25.8, 26.1,
27.4, 28.8. Figure 5 shows the XRPD pattern of a typical lot of form VI of compound 1.
Example 7
Preparation of form VII of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[00100] Form VII is a THF hemi-solvate and can be obtained by processes comprising
compound 1 and THF as solvent.
a) Preparation of form VII by equilibration in THF
[00101] 196.3 mg of amorphous material were digested in 500 L of THF for 3 days at
ambient temperature. The brownish material was then isolated by filtration and dried at 22 °
C/5 mbar for 24 h.
b) Characterization of form VII
[00102] Form VII can be characterized by its XRPD pattern obtained with Cu K
radiation having characteristic peaks expressed in degrees 2Theta at approximately: 7.6, 9.4,
9.9, 13.1, 15.9, 16.2, 17.0, 18.1, 18.8, 19.9, 20.5, 20.7, 21.4, 21.8, 24.3, 24.9, 25.3. Figure 6
shows the XRPD pattern of a typical lot of form VII of compound 1.
Example 8
Preparation of form VIII of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-
b] pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
a) Preparation of form VIII by incubation of amorphous material
[00103] 210 mg of amorphous material of compound 1 were tempered at 130 °C for 24
h using a ball tube furnace. Then the brownish material was cooled to ambient temperature.
b) Characterization of form VIII
[0100] Form VIII can be characterized by its XRPD pattern obtained with Cu K radiation
having characteristic peaks expressed in degrees 2Theta at approximately: 5.0, 11.3, 11.6,
12.0, 13.8, 16.2, 16.7, 19.0, 20.1, 20.8, 22.5, 27.1. Figure 7 shows the XRPD pattern of a
typical lot of form VIII of compound 1.
Example 9
Preparation of form IX of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0101] Form IX is an acetone hemi-solvate and can be obtained by processes comprising
compound 1 and acetone as solvent.
a) Preparation of form IX by equilibration in acetone
[0102] 180.5 mg of amorphous material of compound 1were digested in 500 L of acetone
for 3 days at ambient temperature. Then the brownish material was isolated by filtration and
dried at ambient temperature for 24 h.
b) Characterization of form IX
[0103] Form IX can be characterized by its XRPD pattern obtained with Cu Kradiation
having characteristic peaks expressed in degrees 2Theta at approximately: 9.5, 9.9, 13.0, 15.9,
16.4, 17.0, 17.9, 18.7, 19.9, 20.7, 21.7, 24.8, 25.1. Figure 8 shows the XRPD pattern of a
typical lot of form IX of compound 1.
Example 10
Preparation of Form X of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0104] Form X is a pyridine mono-solvate and can be generally obtained by processes
comprising compound 1 and pyridine as solvent.
a) Preparation of form X by equilibration in pyridine
[0105] 150.0 mg of compound 1 (Form II) were digested in 200 L of pyridine at ambient
temperature for 10 days. Then the brownish material was isolated by filtration and dried at
22 °C at 5 mbar for 48 h.
b)Characterization of form X
[0106] Form X can be characterized by its XRPD pattern obtained with Cu K radiation
having characteristic peaks expressed in degrees 2Theta at approximately: 7.4, 9.2, 10.8, 13.6,
14.9, 19.0, 20.2, 21.4, 22.4, 23.7, 25.5, 27.0, 29. Figure 9 shows the XRPD pattern of a
typical lot of form X of compound 1.
Example 11
Preparation of form XI of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0107] Form XI is a 2-methylpyridine mono-solvate and can be generally obtained by
processes comprising compound 1 and 2-methylpyridine as solvent.
a) Preparation of form XI by evaporative crystallization from 2-
methylpyridine
[0108] 150.0 mg of compound 1 (e.g. in its amorphous form or form II) were dissolved in 4
mL of 2-methylpyridine. The solution was allowed to evaporate passively at ambient
temperature. After 10 d the material was further dried at 22 °C/5 mbar for 48 h.
b) Characterization of form XI
[0109] Form XI can be characterized by its XRPD pattern obtained with Cu K radiation
having characteristic peaks expressed in degrees 2Theta at approximately 8.0, 12.1, 12.6,
13.4, 13.9, 14.8, 16.2, 17.6, 18.5, 19.2, 20.1, 21.0, 21.4, 21.7, 23.5, 25.3, 25.5, 26.6, 27.0,
.8. Figure 10 shows the XRPD pattern of a typical lot of form XI of compound 1.
Example 12
Preparation of form XII of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0110] Form XII is a diisopropylamine mono-solvate and can generally be obtained by
processes comprising compound 1 and diisopropylamine as solvent.
a) Preparation of form XII by evaporative crystallization from 2-
methylpyridine
[0111] 243.0 mg of compound 1 (form II) were slurried in 500 L of diisopropylamine at 60
°C for 9 days. Then, the brownish material was isolated by filtration and dried at 22 °C/5 mbar
for 48 h.
b) Characterization of form XII
[0112] Form XII can be characterized by an X-ray powder diffraction pattern obtained with
Cu K radiation having characteristic peaks expressed in degrees 2Theta at approximately:
7.5, 9.9, 12.1, 13.6, 16.2, 16.7, 17.1, 17.5, 18.3, 18.5, 20.1, 21.7, 22.4, 23.4, 24.3, 25.6, 26.9,
31.6. Figure 11 shows the XRPD pattern of a typical lot of form XII of compound 1.
Example 13
Preparation of form XIII of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-
b] pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0113] Form XIII is a morpholine mono-solvate and can generally be obtained by processes
comprising compound 1 and morpholine as solvent.
a) Preparation of from XIII by incubation with morpholine vapor
[0114] 250.3 mg of amorphous material were incubated with morpholine vapor for 44 d at
ambient temperature.
b) Characterization of form XIII
[0115] From XIII can be characterized by an X-ray powder diffraction pattern obtained with
Cu K radiation having characteristic peaks expressed in degrees 2Theta at approximately
.1, 5.8, 6.9, 15.3, 16.2, 17.4, 18.4, 18.9, 19.5, 20.4, 21.1, 21.5, 22.2, 22.6, 25.2, 25.7. Figure
12 shows the XRPD pattern of a typical lot of form XIII of compound 1.
Example 14
Preparation of form XIV of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-
b] pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0116] Form XIV is a DMSO mono-solvate and can be generally obtained by processes
comprising compound 1 and DMSO as solvent.
a) Preparation of form XIV by evaporative crystallization from DMSO
[0117] 1.2 g compound 1 (form II) were dissolved in 5 mL of DMSO at ambient temperature.
The clear solution was concentrated in a vacuum tray dryer at 40 °C / 20 mbar for 2 days. The
crystals were isolated by filtration and dried at ambient conditions for 4 days.
b) Characterization of form XIV
[0118] Form XIV can be characterized by an X-ray powder diffraction pattern obtained with
Cu Kradiation having characteristic peaks expressed in degrees 2Theta at approximately
.2, 10.2, 12.9, 13.9, 17.1, 17.6, 18.7, 19.8, 20.1, 20.5, 21.0, 21.7, 22.8, 24.1, 25.1, 25.5, 27.1,
27.4. Figure 13 shows the XRPD pattern of a typical lot of form XIV of compound 1.
Example 15
Preparation of form XV of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b]
pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0119] Form XV is a DMSO mono-solvate and can generally be obtained by processes
comprising compound 1 in DMSO as solvent.
a) Preparation of form XV by incubation with DMSO vapor
[0120] Drops of a solution of 100 mg compound 1 in 500 L of DMSO were placed on a
glass slide. After evaporation of the solvent small crystals were observed. In 3 out of 9 drops
form XV was observed. The other crystallization trials yielded form XIV.
b) Characterization of form XV
[0121] Form XV can be characterized by an X-ray powder diffraction pattern obtained with
Cu K radiation having characteristic peaks expressed in degrees 2Theta at approximately
12.6, 13.8, 14.6, 16.2, 16.6, 17.8, 18.3, 20.4, 20.7, 21.4, 22.4, 23.2, 24.2, 24.5, 25.5, 26.9,
27.8, 28.7. Figure 14 shows the XRPD pattern of form XV of compound 1.
Example 16
Preparation of form XVI of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-
b] pyridinecarbonyl-2,4-difluoro-phenyl]-amide}
[0122] Polymorphic form XVI can be obtained by heating amorphous melt films on glass
slides. Form XVI could not be crystallized pure, but with form VIII.
a) Preparation of form XVI
[0123] Small amounts of compound 1(form II) were heated between a microscopic glass
slide and cover glass to about 280 °C. The melt was then cooled to low temperatures by
transferring the slide directly onto a cold metal block (e.g. cooled to –18 or –196 °C). The
transfer should be as quick as possible. The obtained amorphous melt film is then placed on a
heating stage on a microscope and observed under cross-polarized light. Upon heating with
heating rates between 1 and 10 °C/min crystallization can be observed in the range from 140 -
150 °C. During this process, form VIII and form XVI crystallize side by side.
b) Characterization of form XVI
[0124] Form XVI can be characterized by a Raman spectrum as shown in Figure 15.
Example 17
Preparation of “Pattern 6”
[0125] Small amount of the amorphous material was prepared in 1 mm diameter glass
capillary and heated to 150°C in a hot stage attached to a STOE Stadi P diffractometer.
Subsequently the sample was analyzed at 150°C.
b) Characterization of Pattern 6
[0126] Pattern 6 can be characterized by an X-ray powder diffraction pattern obtained with
Cu K radiation having characteristic peaks expressed in degrees 2Theta at approximately
7.0, 8.4, 8.9, 13.0, 13.8, 17.7, 18.8, 20.7, 25.8, 29.7. Figure 16 shows the XRPD pattern of
Pattern 6 of compound 1.
Example 18
Preparation of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b] pyridine
carbonyl-2,4-difluoro-phenyl]-amide} sulfuric acid salt
[0127] The sulfuric acid salt can be obtained by processes, comprising compound 1 and
sulfuric acid.
a) Preparation of the sulfuric acid salt in tetrahydrofuran
[0128] 6.15 g of compound 1 are slurried in 168.7 g of tetrahydrofuran. The suspension is
heated to 55 °C. A clear solution is obtained. At 30 °C a solution of 1.4 g sulfuric acid in 5 g
2-propanol is added. At 40 °C and 20 mbar 80 mL of the solvent are removed by distillation.
Subsequently 22.3 g tert.-butylmethylether are added. The solution is stirred for 12 hours at
°C and starts to crystallize. The solid is isolated by filtration and rinsed by 17.8 g of
tetrahydrofurane.
[0129] The product is dried at 40 °C / 2 mbar for 12 h. Yield: 4.2 g (57.5%).
b) Characterization of the sulfuric acid salt
[0130] The sulfuric acid salt can be characterized by an X-ray powder diffraction pattern
obtained with Cu K radiation having characteristic peaks expressed in degrees 2Theta at
approximately 4.7, 6.7, 10.6, 13.3, 14.5, 15.7, 16.4, 18.3, 18.6, 18.9, 19.5, 20.1, 20.9, 21.2,
23.2, 23.7, 24.0, 26.9, 30.0. Figure 17 shows the XRPD pattern of a typical lot of sulfuric
acid salt of compound 1. The sulfuric acid salt of compound 1 can be further characterized by
a melting point with onset temperature (DSC) of about 221 °C to 228 °C.
Example 19
Preparation of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b] pyridine
carbonyl-2,4-difluoro-phenyl]-amide} hydrobromic acid salt (bromide salt)
[0131] The hydrobromic acid salt can be obtained by processes comprising compound 1 and
hydrogen bromide.
a) Preparation of the hydrobromic acid salt in tetrahydrofuran
[0132] 6.15 g of compound 1 are slurried in 168.7 g of tetrahydrofuran. The suspension is
heated to 55 °C. A clear solution is obtained. At 30 °C a solution of 3.4 g hydrobromic acid
solution (33% HBr in acetic acid) is added and a white solid is precipitating. The suspension
is stirred for 2 hours at 20 °C. The solid is isolated by filtration and rinsed by 17.8 g of
tetrahydrofuran.
[0133] The product is dried at 40 °C / 2 mbar for 12 h. Yield: 4.6 g (61.7%).
b) Characterization of the bromide salt
[0134] The bromide salt can be characterized by an X-ray powder diffraction pattern
obtained with Cu K radiation having characteristic peaks expressed in degrees 2Theta at
approximately 5.7, 6.8, 11.4, 13.6, 18.1, 19.8, 20.2, 21.4, 21.8, 24.6, 26.1, 27.3, 29.2. Figure
18 shows a XRPD pattern of a typical lot of bromide salt of compound 1.This salt can be
further characterized by a melting point with onset temperature (DSC) in the range of about
240 °C to 246 °C. Melting occurs under decomposition and can vary substantially.
Example 20
Preparation of propanesulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo [2,3-b] pyridine
carbonyl-2,4-difluoro-phenyl]-amide} hydrochloric acid salt
[0135] The hydrochloric acid salt can be obtained by processes comprising compound 1 and
hydrogen chloride.
a) Preparation of the hydrochloric acid salt in tetrahydrofuran
[0136] 10.0 g of compound 1 are slurried in 176 g of tetrahydrofuran. The suspension is
stirred at 20 °C. 4.8 g of a hydrochloric acid solution (4 M in dioxane) is added within 30
minutes. A white solid is precipitated. The suspension is stirred for additional 3 hour at 40 °C
and subsequently cooled down to 20 °C. The solid is isolated by filtration and rinsed by 17.8
g of tetrahydrofuran.
[0137] The product is dried at 40 °C / 2 mbar for 12 h. Yield: 8.9 g (83.7%)
b) Characterization of the chloride salt
[0138] The chloride salt can be characterized by an X-ray powder diffraction pattern obtained
with Cu Kradiation having characteristic peaks expressed in degrees 2Theta at
approximately 6.6, 7.8, 11.2, 12.6, 14.1, 14.7, 16.3, 17.8, 19.3, 19.6, 20.7, 21.5, 22.7, 24.1,
.4, 25.8. Figure 19 shows the XRPD pattern of a typical lot of hydrochloric acid salt of
compound 1.
Example 21
Spray dry dispersion solution preparation
[0139] Compound (1) was dispersed in acetone or a mix of THF/acetone, an excess of 1 mol
equivalent of 2M hydrochloric acid was dispensed into the vessel and stirred until dissolved.
Isopropanol was dispensed into the vessel and allowed to stir. Excess hydrochloric acid was
sufficient in maintaining solution stability for spray drying.
[0140] Polymer solutions of hydroxypropyl methyl cellulose acetate succinate (HPMCAS),
copolymers of methacrylic acid and ethylacrylate (L100-55) or copolymer of
vinylpyrrolidone-vinyl acetate (PVPVA) were prepared respectively by dissolving polymers
into ethanol, adding an appropriate amount of acetone to the dissolved polymer solution,
dispensing compound (1) into the polymer solution, and heating the solution to
approximately 45 °C until all components were fully dissolved. The solutions were cooled
back to room temperature prior to spray drying.
Example 22
Spray dry dispersion solution preparation and manufacturing
[0141] Each formula was spray dried using a target inlet temperature of 100-105 °C, an outlet
temperature of 55 °C, and an atomizing gas pressure of 0.5 bar. The feed material was
atomized using a 0.5 mm two-fluid Schlick nozzle for all runs. Collection of the product is at
the cyclone. A variable speed peristaltic pump, Master Flex, equipped with #14 Tygon
Chemical tubing, was used to deliver the feed material.
[0142] Spray dried dispersions were vacuum oven dried overnight for 65 hours at 37 °C
under a reduced pressure between -25 to -30 in Hg (Stage 1). These samples were further
vacuum oven dried for an additional 65 hours at 45 °C under a reduced pressure between -25
to -30 in Hg (Stage 2). Spray dried dispersions were vacuum oven dried for 65 hours at 45 °C
under a reduced pressure between -25 to -30 in Hg. Residual solvent are below 5000 PPM.
[0143] Spray dry dispersion solutions for amorphous forms XVII, XVIII, XIX, XX, XXI,
XXII, XXIII, XXIV, XXV or XXVI were prepared according to the procedure set forth in
Example 21. Spray dry dispersion formulas of amorphous forms XVII, XVIII, XIX, XX,
XXI, XXII, XXIII, XXIV, XXV or XXVI were prepared according to the procedure set forth
in Example 22.
[0144] Table 1 illustrates the spray dry dispersion of formulations of amorphous forms XVII,
XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV and XXVI.
Table 1
Compound No. Polymer Formulation Solvent
XVII HPMCAS Compound (1)-30%
HPMCAS – 70%
THF: Acetone –
%:80%
XVIII Compound (1)-30%
HPMCAS – 70%
THF: Acetone –
%:80%
XIX Compound (1)-30%
HPMCAS – 70%
THF: Acetone –
%:80%
XX Compound (1)-30%
HPMCAS – 70%
HCl salt
Acetone 100%
XXI Compound (1)-50%
HPMCAS – 50%
HCl salt
Acetone 100%
XXII Compound (1)-33%
HPMCAS – 67%
HCl Salt
Acetone: IPA:
water – 95%:3.8%:
1.2%
XXIII Compound (1)-40%
HPMCAS – 60%
HCl Salt
Acetone: IPA:
water – 95%:3.8%:
1.2%
XXIV L100-55 Compound (1)-50%
L100-55 – 50%
HCl salt
THF: Acetone –
%:80%
XXV PVPVA Compound (1)-33.3%
PVPVA – 33.3%
PVPK30 – 33.3%
Acetone: Ethanol –
%:80%
XXVI PVPVA Compound (1)-33%
PVPVA – 67%
Acetone: Ethanol –
%:80%
Example 23
Characterization of the compounds
a) Characterization of solid form XVII
[0145] Solid form XVII was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak
with minor sharp peaks expressed in degrees 2Theta. The locations of the minor sharp peaks
are shown in the table below. Figure 20 shows a XRPD pattern of a typical lot of a
substantially amorphous solid state form XVII.
b) Characterization of solid form XVIII
[0146] Solid form XVIII was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern exhibits two broad halo peaks
expressed in degrees 2Theta as shown in Figure 21.
c) Characterization of solid form XIX
[0147] Solid form XIX was characterized by X-ray powder diffraction analysis obtained with
Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak with
minor sharp peaks expressed in degrees 2Theta. Figure 22 shows a XRPD pattern of a
typical lot of a substantially amorphous solid state form XIX.
d) Characterization of solid form XX
[0148] Solid form XX was characterized by X-ray powder diffraction analysis obtained with
Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak with
minor sharp peaks expressed in degrees 2Theta. Figure 23 shows a XRPD pattern of a
typical lot of a substantially amorphous solid state form XX.
e) Characterization of solid form XXI
[0149] Solid form XXI was characterized by X-ray powder diffraction analysis obtained with
Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak with
minor sharp peaks expressed in degrees 2Theta. Figure 24 shows a XRPD pattern of a
typical lot of a substantially amorphous solid state form XXI.
f) Characterization of solid form XXII
[0150] Solid form XXII was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak
expressed in degrees 2Theta. Figure 25 shows a XRPD pattern of a typical lot of a
substantially amorphous solid state form XXII.
g) Characterization of solid form XXIII
[0151] Solid form XXIII was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak
expressed in degrees 2Theta. Figure 26 shows a XRPD pattern of a typical lot of a
substantially amorphous solid state form XXIII.
h) Characterization of solid form XXIV
[0152] Solid form XXIV was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak
with minor sharp peaks expressed in degrees 2Theta. Figure 27 shows a XRPD pattern of a
typical lot of a substantially amorphous solid state form XXIV.
i) Characterization of solid form XXV
[0153] Solid form XXV was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak
expressed in degrees 2Theta. Figure 28 shows a XRPD pattern of a typical lot of a
substantially amorphous solid state form XXV.
j) Characterization of solid form XXVI
[0154] Solid form XXVI was characterized by X-ray powder diffraction analysis obtained
with Cu K radiation. The X-ray powder diffraction pattern consists of a broad halo peak
expressed in degrees 2Theta. Figure 29 shows a XRPD pattern of a typical lot of a
substantially amorphous solid state form XXVI..
Claims (1)
1. A solid form of a compound of formula 1, CI H N (1), wherein said solid form is a) a polymorph of: form VIII characterized in that it comprises signals in its X-ray powder diffraction pattern at positions 5.0, 11.3, 11.6, 12.0, 13.8, 16.2, 16.7, 19.0, 20.1, 20.8, 22.5 and 27.1 degrees Meta (– 0.2 degrees Metal or form XVI characterized by its Raman spectrum as presented in
Applications Claiming Priority (1)
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PCT/NL2012/050148 WO2013137714A1 (en) | 2012-03-12 | 2012-03-12 | Process for the humanization of animal skim milk and products obtained thereby |
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NZ630486B2 true NZ630486B2 (en) | 2017-01-05 |
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