NZ614852B2 - Amorphous (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid - Google Patents
Amorphous (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid Download PDFInfo
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- NZ614852B2 NZ614852B2 NZ614852A NZ61485212A NZ614852B2 NZ 614852 B2 NZ614852 B2 NZ 614852B2 NZ 614852 A NZ614852 A NZ 614852A NZ 61485212 A NZ61485212 A NZ 61485212A NZ 614852 B2 NZ614852 B2 NZ 614852B2
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- FATGTHLOZSXOBC-UHFFFAOYSA-N 2-[5-fluoro-2-methyl-3-(quinolin-2-ylmethyl)indol-1-yl]acetic acid Chemical compound C12=CC(F)=CC=C2N(CC(O)=O)C(C)=C1CC1=CC=C(C=CC=C2)C2=N1 FATGTHLOZSXOBC-UHFFFAOYSA-N 0.000 title abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 164
- -1 (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid ([5-Fluoro-2-methyl-3-(2-quinolinylmethyl)-1H-indol-1-yl]acetic acid) Chemical compound 0.000 claims abstract description 113
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims abstract description 75
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- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 64
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- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 description 1
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- XYKWNRUXCOIMFZ-UHFFFAOYSA-N tepoxalin Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(CCC(=O)N(C)O)=N1 XYKWNRUXCOIMFZ-UHFFFAOYSA-N 0.000 description 1
- VXJOXUWCOXCVFK-UHFFFAOYSA-N tetrachloromethane;toluene Chemical compound ClC(Cl)(Cl)Cl.CC1=CC=CC=C1 VXJOXUWCOXCVFK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 230000029069 type 2 immune response Effects 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
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- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Disclosed is a stable composition comprising amorphous (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid ([5-Fluoro-2-methyl-3-(2-quinolinylmethyl)-1H-indol-1-yl]acetic acid) (OC000459) or a pharmaceutically acceptable salt thereof and a polymer selected from polyvinylpyrrolidone (PVP), a polyvinylpyrrolidone-vinylacetate copolymer (PVP-VA), hydroxypropylmethylcellulose (HPMC) and hypromellose-acetate-succinate (HPMCAS) and mixtures thereof. Also disclosed are methods for the synthesis of this amorphous form and its use in the treatment of conditions such as asthma, COPD, dermatitis, infection and multiple sclerosis. ), a polyvinylpyrrolidone-vinylacetate copolymer (PVP-VA), hydroxypropylmethylcellulose (HPMC) and hypromellose-acetate-succinate (HPMCAS) and mixtures thereof. Also disclosed are methods for the synthesis of this amorphous form and its use in the treatment of conditions such as asthma, COPD, dermatitis, infection and multiple sclerosis.
Description
AMORPHOUS 1 5-FLUORO—2-METHYLgQUINOLIN-Z-YLMETHYL-INDOL-
l-YL g-ACETIC ACID
The present invention relates to a novel stable amorphous form of a compound which
is useful as a pharmaceutical, to methods for preparing this amorphous form,
compositions containing it and its use in the treatment and prevention of allergic
diseases such as asthma, allergic rhinitis and atopic dermatitis and other
inflammatory diseases mediated by prostaglandin D2 (PGDg) or other agonists acting
at the CRTHZ receptor on cells including eosinophils, basophils and Th2
lymphocytes.
PGD; is an eicosanoid, a class of chemical mediator synthesised by cells in response
to local tissue , normal stimuli or al stimuli or via cellular tion
pathways. Eicosanoids bind to specific cell surface ors on a wide variety of
tissues throughout the body and mediate s effects in these s. PGD; is
known to be produced by mast cells, macrophages and Th2 lymphocytes and has
been detected in high concentrations in the airways of asthmatic patients challenged
with antigen (Murray et all, (1986), N. Engl. J Med. 315: 800-804). Instillation of
PGDz into airways can provoke many features of the asthmatic response including
bronchoconstriction (Hardy at all, (1984) N. Engl. J Med. 311: 209-213; Sampson et
at, (1997) Thorax 52: 513-518) and eosinophil accumulation (Emery et all, (1989) J.
Appl. Physiol. 67: 959-962).
The potential of exogenously applied PGDZ to induce atory responses has
been confirmed by the use of transgenic mice overexpressing human PGDg synthase
which exhibit exaggerated eosinophilic lung inflammation and Th2 cytokine
production in response to antigen ani et (1]., (2002) J Immunol. 168: 443-449).
The first receptor specific for PGD; to be discovered was the DP receptor which is
linked to ion of the intracellular levels of cAMP. r, PGDg is thought to
mediate much of its proinflammatory activity through interaction with a G protein-
d receptor termed CRTH2 (chemoattractant receptor-homologous molecule
expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and
basophils (Hirai et (11., (2001) J. Exp. Med. 193: 255-261, and EP0851030 and EPA—
1211513 and Bauer at £11., 170594). It seems clear that the effect of PGD2 on
the activation of Th2 cytes and eosinophils is mediated through CRTH2 since
the selective CRTH2 agonists 13,14 dihydro-lS-keto-PGD; (DK-PGDZ) and 15R-
methyl-PGD; can elicit this response and the effects of PGD2 are blocked by an anti—
CRTH2 antibody (Hirai er (1]., 2001; Monneret et all, (2003) J. Pharmacol. Exp.
filter. 304: 349-355). In contrast, the selective DP t BW245C does not
promote migration of Th2 lymphocytes or eosinophils (Hirai et all, 2001; Gervais er
al, (2001) J. Allergy Clin. Immunol. 108: 982-988). Based on this evidence,
antagonising PGDZ at the CRTH2 receptor is an attractive approach to treat the
inflammatory ent of Th27dependent allergic diseases such as asthma, allergic
is and atopic dermatitis.
EP—A—1170594 ts that the method to which it relates can be used to identify
compounds which are of use in the treatment of allergic asthma, atopic dermatitis,
allergic rhinitis, mune, reperfusion injury and a number of inflammatory
conditions, all of which are mediated by the action of PGD; or other agonists at the
CRTH2 receptor.
Since the publication of EP—A—1170594, there have been a great many publications
relating to compounds having CRTH2 antagonist activity. For example, in our
r applications WO-A-2005/044260, W02006/095183, WO2008/012511 and
WO2009/090414, we describe compounds which are antagonists of PGD; at the
CRTH2 receptor. These compounds are indole-l-acetic acid derivatives substituted
at the 3—position with a CHg-aryl group which may be substituted with one or more
further substituents. The compounds described in these documents are potent
antagonists in vitro of PGD2 at the CRTH2 receptor.
The present invention relates, in particular, to (5-Fluoromethyl-3 -quinolin—2-
ylmethyl-indol-l-yl)-acetic acid, which is one of the nds described in WO-A-
2005/044260. This compound has proved to be a particularly useful CRTH2
antagonist and has been demonstrated to be effective both in vitro and in vivo.
Experiments in which this compound was trialled in man against allergic rhinitis are
bed in our earlier applications and WO 2009/063215.
Furthermore, the compound has been tested and found to be effective both in animal
models of asthma and in a clinical trial with human asthma patients (Neil Barnes, Ian
Pavord, Alexander Chuchalin, John Bell, Michael Hunter, Mark Payton, Lisa Pearce
Collins, Roy Pettipher, Jan Steiner, Michael Perkins; “A randomised, double—blind,
placebo-controlled study of the CRTH2 antagonist OC000459 on moderate persistent
asthma”; European atory Journal, 34, supplement 53, September 2009, 564-
5658).
However, S-Fluoro-Z—methyl-B-quinolin—2-ylmethy1-indol—1—yl)—acetic acid
(Compound 1) is only sparingly soluble in most pharmaceutically able
solvents. The only ts in which Compound 1 is readily soluble are aqueous
alkaline solvents such as sodium hydroxide solution because, under these conditions,
Compound 1 is converted into its salt form.
Because ofthe difficulties in formulating nds which are not readily soluble in
conventional solvents, the present inventors set out to develop a form of the
compound which has higher solubility.
One possible solution to the problem of solubility was to p an amorphous form
of nd 1. However, although amorphous forms are sometimes more soluble
than crystalline forms, they are y associated with their own problems. One
such m is that amorphous forms are very often unstable and revert to a
crystalline form after short periods. An unstable amorphous form such as this is
therefore not suitable for ceutical use, Where it is essential to have a stable
al form of the compound.
Surprisingly, however, the inventors were able to develop an amorphous form of
Compound 1 which is stable and does not revert to the crystalline form following
prolonged storage.
It is an object of the present invention to provide a stable composition, a process for
preparing a stable ition, a use of a stable composition, a pharmaceutical or
veterinary composition and/or a kit that overcomes or ameliorates one or more
disadvantages of the prior art or at least to provide the public with a useful choice.
ore, in a first aspect of the invention, there is provided a stable amorphous
form of (5-Fluoromethylquinolinylmethyl-indolyl)-acetic acid
(Compound 1) or a pharmaceutically or veterinarily acceptable salt thereof.
The preparation of this stable amorphous form was by no means straightforward and
a number of methods were attempted before it was obtained. Spray drying of
Compound 1, which might have been ed to lead to an amorphous form did not
do so and the inventors therefore investigated combinations of Compound 1 with
various lipidic excipients and rs. Again, this was not straightforward and
conventional methods such as the preparation of hot melt dispersions in lipidic
excipients or in rs did not result in the production of an amorphous product.
A stable amorphous form of Compound 1 was eventually achieved by forming a
mixture of the nd with a r selected from polyvinylpyrrolidone (PVP),
a polyvinylpyrrolidone-vinylacetate copolymer (PVP-VA),
hydroxypropylmethylcellulose (HPMC) and hypromellose-acetate-succinate
(HPMCAS). It is known to prepare amorphous forms of a compound as a mixture
with a r but in this case, it proved ely difficult to find a polymer which
provided an amorphous form of Compound 1 which had the necessary stability.
Indeed, these were the only polymers tested with which a stable amorphous form
could be obtained.
Therefore, the invention further provides a stable composition sing
amorphous (5-Fluoromethylquinolinylmethyl-indolyl)-acetic acid
(Compound 1) or a pharmaceutically or veterinarily acceptable salt thereof and a
polymer selected from polyvinylpyrrolidone (PVP), a polyvinylpyrrolidone-
vinylacetate mer (PVP-VA), hydroxypropylmethylcellulose (HPMC),
WO 19841
hypromellose-acetate—succinate S) and mixtures thereof.
This composition, in addition to the surprising stability of the amorphous nd
1 was also found to have solubility properties which were greatly superior to what
might have been expected. The ition of Compound 1 was highly soluble in
simulated gastric fluid and this was indeed surprising since the compound is acidic
and crystalline forms have been found to be insoluble in aqueous acids, though they
have relatively high solubility at alkaline pH.
In the context of the present invention, the term “amorphous (5-Fluoromethyl
quinolin—2~ylmethyl—indol~l—yl)—acetic acid” relates to oro—2-methyl—3—
inylmethyl-indolyl)-acetic acid in which less than about 10%, and
preferably less than about 5% of the compound is present in a crystalline form. The
presence of crystalline material can be detected by X-ray powder diffraction
(XRPD).
The term “stable” s to a compound which after e for up to 2 weeks, more
suitably up to 4 weeks, still more suitably up to 12 weeks, or at least 12 weeks and
especially up to 6 months, particularly at least 6 months at 25°C and 60% relative
humidity, 40°C and 75% relative humidity or at 50°C and t humidity, when
protected from moisture is:
at least 95% chemically identical to the starting sample and
retains an amorphous form.
Suitably, a stable compound Will be at least 96% and more suitably at least 97%
chemically identical to the starting sample and which retains an amorphous form
after storage for up to 12 weeks, more suitably at least 12 weeks, protected from
moisture at 25°C and 60% relative humidity, 40°C and 75% relative humidity or at
50°C and ambient humidity.
In particular, a stable compound may be at least 95%, at least 96%, at least 97% or
even at least 98% chemically identical to the starting sample and which retains an
amorphous form after storage for up to 6 months, especially at least 6 , at
°C and 60% relative humidity or at 40°C and 75% relative humidity when
protected from moisture.
In some cases, the stable compound may be at least 99% chemically identical to the
starting sample and which retains an amorphous form after storage for up to 6
, ally at least 6 months, at 25°C and 60% relative humidity when
ted from moisture.
Chemical identity to the starting material may be determined using high performance
liquid chromatography (HPLC).
Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of
general formulae (1) and (II) include basic addition salts such as sodium, potassium,
calcium, aluminium, zinc, magnesium and other metal salts as well as choline,
diethanolamine, ethanolamine, ethyl diamine, megulmine and other well known
basic addition salts as summarised in uhn er al, (2007) J. Med. Chem. 50:
6665-6672 and/or known to those skilled in the art.
The sodium and potassium salts are particularly le for use in the present
invention, more especially the sodium salt.
In some circumstances, more stable compositions are obtained using Compound 1 as
the free acid rather than in the form of a salt.
Suitably, the weight ratio of polymer to Compound 1 or salt thereof is at least 1.5 :1,
for example from 1.5:1 to 15:1, though more usually, it is from 1.5:1 to 12:1. Most
ly, the weight ratio of polymer to Compound 1 or salt thereof is from about
1.5:1 to 9:1.
Although PVP, PVP-VA, HPMC, HPMCAS and mixtures of these polymers may all
be used to form the itions of the present invention, PVP, HPMC, PVP—VA
and mixtures thereof are particularly suitable. Still more suitable compositions may
be formed using PVP and PVP-VA, and the most stable amorphous compositions are
formed using PVP.
When PVP-VA is used in the composition of the present invention, a particularly
suitable form is a copolymer of l-Vinyl-Z-pyrrolidone and Vinyl acetate in a ratio of
6:4 by mass. A le r is sold under the trade mark Kollidon VA 64.
Any nylpyrrolidone (PVP) is suitable for use in the composition of the
invention, for example PVP K12, PVP K17, PVP K25 or PVP K30. A particularly
Suitable material is PVP K30, although suitable compositions have also been
successfully prepared using other PVP materials such as PVP K12.
The compositions of the invention are typically solid dispersions of Compound 1 or a
pharmaceutically or veterinarily acceptable salt thereof in polymer and can be
formed by conventional methods such as mixing followed by solvent evaporation or,
more usually, by spray drying.
A solid sion according to the invention may be prepared by a process
comprising:
ia. ving the polymer in a first solvent at a concentration of from 50—
110g/L;
iia. adding solid crystalline Compound 1 or a pharmaceutically or veterinarily
acceptable salt f to the solution to form a suspension, wherein the weight ratio
of polymer to nd 1 or salt thereof is at least 1.5:1, typically from about 1.5:1
to 15 : 1;
iiia. adding a second solvent, wherein the second solvent is chosen such that it is
le to solubilise Compound 1 or the salt f and wherein the volume ratio of
second solvent to first solvent is from 0.1:1 to 0.5:];
iva. stirring the mixture at about 5 to 60°C until a solution is obtained;
va. removing t until the volume of solvent remaining is from about 20—
50% of the total volume of t originally added; and either
via. evaporating the solution to dryness; or
viia adding a third t, wherein the third solvent is chosen such that it is
suitable to solubilise Compound 1 or the salt thereof and wherein the amount of the
third solvent is such that the total Solids concentration in the solution (i.e.
concentration of polymer + Compound 1) is from 5 to 15%; and
viiia. spray drying the solution obtained in (viia) to obtain a solid dispersion of
nd 1 or the salt thereof in polymer according to the invention.
In (ia) above, the first solvent is selected from suitable organic solvents, for example
ol, dichloromethane or a mixture thereof. A particularly suitable first solvent
for use in (ia) is a 1:1 mixture (by volume) of methanol and dichloromethane. A
more suitable concentration for the solution is from 60-100g/L, typically 70-90g/L.
In (iia) above, the amount of Compound 1 or the salt f is suitably chosen such
that the weight ratio of polymer to Compound 1 or the salt thereof is from 1.5:1 to
12:1, most suitably from about 1.521 to 9:1.
In (iiia) above, DMSO is a particularly suitable second solvent and the volume ratio
of second solvent to first solvent is more usually from 0.221 to 0.4:1 and typically
about 0.3:1.
In (iva), stirring usually takes place for a period of about 20-90 minutes, more
typically about 25-70 minutes and especially about 30-60 minutes. Stirring is
generally carried out at about 5-300C, more usually at room temperature, i.e. about
16-2500
In (va), the solvent is usually removed by evaporation, which may be achieved by
direct heating in which the temperature is typically increased from room ature
to a ature of about 100 to 120°C. Alternatively, the solvent can be partially
removed by heating the solution in a water bath at 100°C. Heating of the solution
may be continued until a suitable amount of t has been removed and this is
generally when the volume of t remaining is from about 20-50% of the total
volume of solvent added (i.e. the total volume of the first and second ts),
ly 25-45% of the total volume of solvent added and especially about 30-40% of
the total volume of solvent added. The time taken to achieve this may vary
depending upon the starting volume of solvent.
After (va), a solid dispersion may be obtained by simply removing the remainder of
the solvent by evaporating the solution to dryness. It is, however, preferable to
obtain the solid dispersion by spray drying as set out in (viia) and (viiia). In (viia)
suitable third solvents include DMSO, acetone and mixtures f, especially
DMSO or a mixture of DMSO and e is in a ratio of 1:1 to 1:3 DMSO to
acetone, more usually about 1:2 DMSO to acetone, e.g about 1.8:1 to 1:1. The total
solids tration of the final solution is more usually 7—12% and typically 8-10%
w/v.
In an alternative process, a solid dispersion according to the invention may be
prepared by a process comprising:
ib. preparing a solution of Compound 1 and a polymer in a suitable solvent,
wherein:
the weight ratio of polymer to Compound 1 or salt thereof is at least 1.5:1,
typically from about 1.5:1 to 15:1; and
the ratio of Compound 1: solvent is from about 1:35 to 1:65 w/v; and
iib. spray drying the solution obtained in (i) to obtain a solid dispersion of
Compound 1 or the salt thereof in polymer according to the invention.
Typically, the solvent used in step (ib) is a mixture of DMSO and acetone, with the
ratio ofDMSO to acetone being from about 25:75 to 45:55, more usually from about
:70 and 40:60 and typically about 35:65.
Thus, the ratio of Compound 1: DMSO will vary from about 1:125 to 1:225 W/V,
y about 1:15 to 1:20 and typically about 1:175 W/V; and
the ratio of Compound 1: acetone will vary from about 1:375 to 1:275 w/v, y
about 1:35 to 1:30 and typically about 1:325 w/v.
When the solvent is a e ofDMSO and e, the solution of step (ib) may be
ed by adding the polymer and Compound 1 or a pharmaceutically or
veterinarily able salt thereof to the appropriate amount of DMSO and
subsequently adding acetone.
In general, the DMSO solution will be heated, usually to a temperature of about 90-
1100C, usually about 100°C before adding the acetone. The acetone may be added
under reflux and the solution d to cool to about 50-700C, more usually 55-
60°C. This temperature is typically maintained during the spray drying step (iib).
The spray drying of steps (Viiia) and (iib) is carried out under standard conditions
using nitrogen as the atomisation gas and air as the drying gas. Typically, when
conducted on a laboratory scale as illustrated in the examples below, the nitrogen
flow rate is about 465-480L/h, for example about 473L/h and the air flow is 90—100%
(corresponding to about 35-40m3/h0ur. A suitable nozzle size is 1-2mm and the feed
rate used may be about 3-15mL/minute. The inlet temperature may range from about
140 to 23 0°C and the outlet temperature from about 75 to 130°C. A person skilled in
the art of spray drying would have no difficulty in ing appropriate conditions
for larger batches.
In a further aspect of the invention there is provided stable amorphous Compound 1
or a pharmaceutically or veterinarily acceptable salt thereof or a composition as
defined above comprising amorphous Compound 1 or a ceutically or
veterinarily acceptable salt thereof for use in medicine, ularly in the treatment
or prevention of asthma, asthma exacerbations, chronic obstructive pulmonary
disease, ic rhinitis, conjunctivitis, nasal , atopic dermatitis, contact
hypersensitivity (including contact dermatitis), eosiniphilic cough, eosinophilic
bronchitis, eosinophilic gastroenteritis, eosinophilic oesophagitis, food allergies,
inflammatory bowel disease, ulcerative colitis, Crohn’s disease, mastocytosis,
urticaria, hypereosinophilic syndrome, hyper IgE syndrome, fibrotic diseases,
Churg-Strauss syndrome and multiple sclerosis.
In another aspect of the ion, there is provided a use of a stable composition as
defined above, in the manufacture of a medicine.
The compound is also of use in the ent of infection.
The term a” includes all types of asthma, for e allergic , non
allergic asthma, eosinophilic asthma, steroid resistant asthma, Th2 dependent asthma,
non-Th2 dependent asthma and aspirin induced asthma. In one embodiment, the
asthma is allergic asthma and in another embodiment the asthma is eosinophilic
asthma.
a exacerbations” es exacerbations induced by viral infections,
especially infection with respiratory ial virus (RSV) or rhinovirus.
Allergic rhinitis includes both perennial allergic rhinitis and seasonal allergic rhinitis.
“Conjunctivitis” includes, in particular, allergic conjunctivitis, vernal
keratoconjunctivitis and atopic keratoconjunctivitis.
“Infection” includes bacterial, viral or fungal infection. The infection may occur in
WO 19841
patients who are atopic or are at risk of becoming atopic and may be, for example a
rhinovirus, influenza or RSV infection, especially in asthmatic patients.
Alternatively, the infection may be a bacterial ion for example a
Staphylococcus aureus infection, particularly in patients ing from atopic
dermatitis .
The term ic diseases” includes, in particular, fibrotic diseases
caused/exacerbated by Th2 immune responses, for example idiopathic pulmonary
fibrosis, scleroderma and hypertrophic scars.
The amorphous form of Compound 1 or the composition of the invention may also
be of use in the treatment of other ediated diseases. Diseases which may be
mediated by PGD2 include autoimmune diseases such as systemic lupus
matus, psoriasis, acne, allograft rejection, rheumatoid arthritis, psoriatic
arthritis and osteoarthritis.
The invention further provides a method for the treatment or prevention of a disease
or condition selected from those listed above, the method comprising administering
to a patient in need of such treatment an effective amount of stable amorphous
Compound 1 or a pharmaceutically or veterinarily acceptable salt thereof or a
composition as defined above comprising amorphous Compound 1.
There is also provided the use of stable amorphous nd 1 or a
pharmaceutically or veterinarily acceptable salt thereof or a composition as defined
above in the preparation of an agent for the treatment or prevention of a disease or
condition ed from those listed above.
Stable amorphous Compound 1 or the composition defined above comprising
ous compound 1 must be formulated in an appropriate manner depending
upon the diseases or conditions it is required to treat.
The patient will be a mammal, for example a human.
Therefore, in a r aspect of the invention there is provided a pharmaceutical or
veterinary composition comprising a composition comprising amorphous Compound
1 or a pharmaceutically or narily acceptable salt f or a composition as
defined above together with a pharmaceutically acceptable ent. Other active
materials may also be present, as may be considered appropriate or advisable for the
disease or condition being treated or prevented.
The excipient, or, if more than one be present, each of the excipients, must be
acceptable in the sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient.
The formulations include thOSe suitable for oral (including viscous oral
formulations), rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal,
oral viscous and sublingual), vagina] or parenteral (including subcutaneous,
intramuscular, intravenous and intradermal) administration and may be prepared by
any methods well known in the art ofpharmacy.
The route of administration will depend upon the condition to be treated but
preferred compositions are formulated for oral, nasal, bronchial or topical
administration.
The composition may be prepared by ng into association the amorphous
Compound 1 or salt thereof with the excipient. In general, the ations are
prepared by uniformly and intimately bringing into association the active agent with
liquid carriers or finely divided solid carriers or both, and then if necessary shaping
the product. The invention s to methods for preparing a pharmaceutical
composition comprising bringing the ition defined above comprising
ous Compound 1 in conjunction or association with a pharmaceutically or
narily acceptable carrier or vehicle.
Formulations for oral administration in the present invention may be presented as:
discrete units such as capsules, sachets or tablets each containing a predetermined
amount of the amorphous Compound 1 or salt thereof; as a powder or granules; as a
on or a suspension of amorphous Compound 1 in an aqueous liquid or a non-
aqueous liquid; or as an oil-in—water liquid emulsion or a water in oil liquid
emulsion; or as a bolus etc.
For compositions for oral stration (e.g. tablets, capsules, formulations
comprising a mucoadherent etc), the term “acceptable carrier” includes vehicles such
as common excipients e.g. binding agents, for example syrup, acacia, gelatin,
sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose,
ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose,
sucrOSe and ; fillers and carriers, for example corn starch, gelatin, lactose,
sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium
de and alginic acid; wetting agents/surfactants such as poloxarners,
polysorbates, sodium docusate and sodium lauryl sulfate; disintegrants such as starch
or sodium starch glycolate; and lubricants such as magnesium te, sodium
stearate and other metallic stearates, ol stearate, c acid, silicone fluid, talc
waxes, oils and colloidal silica. Sweetening agents and flavouring agents such as
peppermint, oil of Wintergreen, cherry flavouring and the like can also be used. It
may be desirable to add a colouring agent to make the dosage form readily
fiable. Tablets may also be coated by methods well known in the art.
A tablet may be made by compression or moulding, optionally with one or more
accessory ingredients. Compressed s may be prepared by compressing in a
suitable machine the amorphous Compound 1 in a free flowing form such as a
powder or es, optionally mixed with a binder, lubricant, inert diluent,
preservative, surface-active or dispersing agent. Moulded tablets may be made by
moulding in a suitable e a mixture of the powdered compound moistened with
an inert liquid diluent. The tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of the active agent.
WO 19841
Some formulations may comprise a mucoadherent, for example a
mucopolysaccharide such as sodium hyaluronate. Such compositions may be
formulated as, for example, liquids, liquid syrups, soft gels, liquid gels, flowable gels
or aqueous suspensions and may, in on to the active agent and the
mucoadherent, also contain one or more additional excipients as set out above.
Liquid formulations will usually also contain a liquid carrier, which may be a solvent
or suspending agent, for example water or saline solution and may also contain a
substance to increase their viscosity, for example sodium carboxymethylcellulose,
sorbitol or dextran.
Other formulations suitable for oral administration include lozenges sing the
active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles
comprising the amorphous Compound 1 in an inert base such as gelatin and glycerin,
or sucrose and acacia; and mouthwashes comprising the active agent in a suitable
liquid carrier.
For l application to the skin, the ition may be made up into a cream,
ointment, jelly, solution or suspension etc. Cream or ointment formulations that may
be used for the drug are conventional formulations well known in the art, for
example, as bed in standard text books of pharmaceutics such as the British
Pharmacopoeia.
The composition defined above may be used for the treatment of the respiratory tract
by nasal, bronchial or buccal administration of, for e, aerosols or sprays
which can disperse the pharmacological active ingredient in the fo1m of a powder or
in the form of drops of a solution or suSpension. Pharmaceutical compositions with
powder—dispersing properties (e.g., dry powder inhalers) usually n, in addition
to the active ingredient, a suitable carrier such lactose and, if desired, adjuncts, such
as surfactants and/or diluents and/or flow aids and/or lubricants. ceutical
compositions with powder-dispersing properties (e.g., metered dose inhalers) usually
contain, in addition to the active ingredient, a liquid propellant with a boiling point
below room temperature and, if desired, adjuncts, such as liquid or solid non—ionic or
anionic surfactants and/or diluents. ceutical compositions in which the
pharmacological active ingredient is in on (e.g., either solution for nebulisation
or metered dose inhalers) contain, in addition to this, a suitable propellant, and
furthermore, if necessary, an additional solvent and/or a stabiliser. Instead of the
propellant, ssed air can also be used, it being le for this to be produced
as required by means of a suitable compression and expansion .
Parenteral formulations will generally be sterile.
lly, the dose of Compound 1 will be about 1 to 400 mg per day, more usually
to 400 mg per day. The dOSe will be chosen so as to in the concentration of
drug in the plasma at a level effective to inhibit PGD2 at the CRTH2 receptor. The
precise amount of Compound 1 which is therapeutically effective, and the route by
which such compound is best administered, is readily determined by one of ordinary
skill in the art by comparing the blood level of the agent to the concentration required
to have a therapeutic effect.
The pharmaceutical composition is most suitably formulated as a once-a—day
administration, although more frequent dosing may be used in some cases, for
example twice, three times or four times daily . On the other hand, it may
mes be possible to dose less frequently than once daily, for example once
every two days. In some circumstances a dosage regimen may be used in which the
composition is administered for a first period and then, during a second period,
administration ceases or, alternatively, the composition administered at a lower dose.
Such a dosage regimen is described in .
The composition as defined above may be used in combination with one or more
active agents which are useful in the treatment of the diseases and conditions listed
above, although these active agents are not necessarily inhibitors of PGD2 at the
CRTH2 receptor.
Therefore, the pharmaceutical composition described above may additionally contain
one or more of these active agents.
There is also provided the use of the ition as defined above in the preparation
of an agent for the treatment of diseases and conditions mediated by CRTH2 receptor
agonists, ally PGDZ, wherein the agent also comprises an additional active
agent useful for the treatment of the same diseases and conditions.
These additional active agents may be other CRTH2 receptor antagonists or may
have a completely different mode of action. They include existing ies for
allergic and other inflammatory diseases including:
Suplatast tosylate and similar compounds;
[32 adrenoreceptor agonists such as metaproterenol, isoproterenol, naline,
albuterol, amol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline,
bitolterol mesylate and pirbuterol or methylxanthines such as theophylline,
oxitriphylline and aminophylline, mast cell stabilisers such as sodium cromoglycate
or muscarinic receptor antagonists such as tiotropium, aclidinium and ipratropium;
antihistamines, for example histamine H1 receptor nists such as loratadine,
cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine,
oloPatadine and chlorpheniramine 0r H4 receptor antagonists;
on and a2 adrenoreceptor agonists such as propylhexedrine phenylephrine,
phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline
hydrochloride, ydrozoline hydrochloride, xylometazoline hydrochloride and
ethylnorepinephiine hydrochloride;
modulators of chemokine receptor function, for example CCRI, CCRZ, CCR2A,
CCRZB, CCR3, CCR4, CCRS, CCR6, CCR7, CCRS, CCR9, CCRIO and CCR11
(for the C-C family) or CXCR], CXCRZ, CXCR3, CXCR4 and CXCR5 (for the C—
X-C family) and CX3CR1 for the C-X3-C family;
Leukotriene antagonists such as montelukast, pranlukast and zafirlukast
leukotriene biosynthesis inhibitors such as xygenase tors or S-
lipoxygenase activating protein (FLAP) inhibitors such as on, ABT-761,
fenleuton, tepoxalin, Abbott—79175, ubstituted)-thiophene~2—
alkylsolfonamides, 2,6-di-tert—butylphenol hydrazones, methoxytetrahydropyrans
such as ZD2138, SB-210661, pyridinyl—substituted—2-cyanonaphthalene compounds
such as L—739010, 2-cyanoquinoline compounds such as L-746,530, indole and
quinoline compounds such as , MIC—886 and BAY x 1005;
Phosphodiesterase inhibitors, including PDE4 inhibitors such as roflumilast;
anti-IgE antibody therapies such as omalizumab;
anti—infectives such as c acid (particularly for the treatment of atopic
itis);
anti—fungals such as clotrimazole (particularly for the treatment of atopic dermatitis);
immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of
inflammatory skin e or alternatively FK-506, rapamycin, cyclosporine,
azathioprine or methotrexate;
Immunotherapy agents including en inununotherapy such as Grazax;
corticosteroids such as prednisone, prednisolone, flunisolide, ciclesonide,
triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone
propionate mometasone furoate and fluticasone furoate;
drugs which promote Th1 cytokine se such as interferons, TNF or GM-CSF.
CRTH2 antagonists may als0 be combined with therapies that are in development for
inflammatory indications ing:
other antagonists of PGD2 acting at other receptors such as DP antagonists;
drugs that modulate cytokine production such as inhibitors of TNFoc converting
enzyme (TACE) anti-TNF monoclonal dies, TNF receptor immunoglobulin
molecules, inhibitors of other TNF isoforms, non-selective COX-1/COX-2 inhibitors
such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen,
ofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid,
indomethacin, sulindac and e, pyrazolones such as phenylbutazone, salicylates
such as aspirin; COX-2 inhibitors such as meloxicam, xib, rofecoxib,
valdecoxib and etoricoxib, low dose methotrexate, lefunomide, ciclesonide,
hydroxychloroquine, d—penicillamine, auranofin or parenteral or oral gold;
drugs that modulate the activity of Th2 cytokines including IL—4, IL-5, IL—9, IL-13
and their receptors, for example ng monoclonal antibodies (e.g. mepolizumab)
and soluble ors;
PPAR-gagonists such as rosiglitazone, piaglitazone; or with
anti-RSV antibodies such as Synagis (palivizumab) and agents that may be used to
treat rhinovirus infection in the future e.g. interferon-alpha, interferon-beta or other
interferons.
Combinations of stable amorphous Compound 1 or of the composition as defined
above with leukotriene antagonists such as montelukast, pranlukast and zafirlukast
are particularly suitable, especially combinations with montelukast.
Other particularly suitable combinations of stable amorphous Compound 1 or of the
composition as defined above are those with histamine H1 receptor antagonists such
as loratadine, zine, desloratadine, levocetirizine, fexofenadine, astemizole,
azelastine, olopatadine and chlorpheniramine.
In yet a further aspect of the ion, there is provided a product comprising stable
amorphous Compound 1 or the composition as defined above and one or more of the
agents listed above as a ed preparation for simultaneous, separate or
sequential use in the treatment of a disease or condition mediated by the action of
PGD2 at the CRTH2 receptor.
In r aspect of the ion, there is provided a use of a stable ition as
defined above and one or more agents as listed above in the manufacture of a
combined preparation for the ent of a disease or ion mediated by PGD2
at the CRTH2 receptor, wherein the combined preparation is formulated for
simultaneous, separate or sequential administration.
In yet another aspect of the invention, there is provided a kit for the treatment of a
disease or condition mediated by the action of PGD2 at the CRTH2 receptor
comprising a first container comprising the composition as defined above and a
second container comprising one or more of the active agents listed above.
The invention will now be described in greater detail with reference to the examples
and to the figures in which:
FIGURE 1 shows XRPD patterns of Compound 1 as-received, after g through
a 60 mesh sieve and blended with microcrystalline cellulose (MCC) (1, 5 and 20%
Compound 1).
FIGURE 2 shows XRPD patterns of Compound 1 in lots 001 to 007 and 012.
FIGURE 3 shows XRPD patterns of Compound 1 in lots 014 to 017 and 019.
FIGURE 4 shows XRPD patterns of Compound 1 in solid dispersion/spray drying
lots 020 to 023.
FIGURE 5 shows XRPD patterns of Compound 1 in solid dispersion/spray drying
lots 027 to 030.
FIGURE 6 shows XRPD ns of nd 1 in solid dispersion/spray drying
lots 031 to 033.
FIGURE 7 shows XRPD patterns of initial and stability s of 30% drug load
HPMC spray-dry intermediates.
FIGURE 8 shows XRPD patterns of initial and ity samples of 30% drug load
PVP spray-dry intermediates.
FIGURE 9 shows XRPD data for PVP SDI lots 031 and 033 after 2, 4 and 12
Weeks.
FIGURE 10 shows XRPD data for PVP SDI lot 031 after 6 months.
FIGURE II is a solubility plot of crystalline Compound 1, Lot 031 and Lot 033 in
USP simulated gastric fluid at pH 1.2; results expressed on the primary Y axis as a
percentage of material in solution with respect to the standard at 0.1209 mg/ml, and
on the secondary Y axis as absolute amount of material dissolved in mg/ml. In
Figure 11:
—l— represents Lot 031
—A— represents Lot 033
4— represents crystalline Compound 1
FIGURE 12 is a solubility plot of crystalline Compound 1, Lot 031 and Lot 033 in
USP simulated intestinal fluid at pH 6.8; results expressed on the primary Y axis as a
percentage of material in solution with respect to the standard at 0.1209 mg/ml, and
on the ary Y axis as absolute amount of material dissolved in mg/ml. In
Figure 12:
—l— ents Lot 031
—A— represents Lot 033
—0— represents lline Compound 1
FIGURE 13 shows XRPD diffractograms for Lots C007, C008 and C010 at T=0 in
the stability trial.
FIGURE 14 shows XRPD diffractograms for Lot C008 at T=0 (black trace) after 1
month at 25°C/60%RH (red trace) and after 1 month at 40°C/75%RH (green trace).
FIGURE 15 shows XRPD diffractograms for Lot C010 at T=0 (black trace) after 1
month at 25°C/60%RH (red trace) and after 1 month at 40°C/75%RH (green trace).
FIGURE 16 shows XRPD diffractograms for Lots C008 and C010 after 3 months
stability storage
FIGURE 17 shows XRPD diffractograms for Lot C008 after 6 months stability
storage
In the Examples, the following abbreviations are used:
API Active pharmaceutical ingredient
DCM dichloromethane
DMSO MN—dimethylsrdfoxide
HPMC hydroxypropylmethylcellulose
HPBCD 2—hydroxypropyl—[3—cyclodextrin
HPMCAS Hypromellose-Acetate-Succinate
MCC rystalline cellulose
MeOH methanol
NaOH sodium hydroxide
ND Not ined
N/De Not detected
NL/h normal liter / hour
NT Not tested
PVP polyvinylpyrrolidone
RH Relative humidity
RRT ve retention time
RT Room temperature
SDI Spray—dry Intermediates (i.e. spray dried compositions which
can be used to prepare pharmaceutical formulations).
SGF Simulated gastric fluid (US Pharmacopeia)
SIF Simulated intestinal fluid (US Pharmacopeia)
Kollidon® VA 64 is a nylpyrrolidone/vinyl acetate copolymer supplied by
BASF.
In the Examples, the following methods were used.
X-Ray ction
The crystal structure of the compound was studied by X-Ray Powder Diffraction
(XRPD) using a Siemens D-5000 X—ray diffractometer with Co Ka radiation
(14.7890 A) at a scanning speed of 002° 20 s"1 With a l 5 step time over a range of
2—40° 20. Diffractograrns in Figure 16 were done using a Phillips X’PERT with Cu
(1K radiation (A. = 1.54056A) at a scan speed of 002" s'1 20 over a range of 5-46° 20.
HPLC Methods
a ~ AnalyncalMethodi592
. 11; 3 Dnssoluton Methd '-
Waters Symmetry Shield RP8,150x3.9 mm, 5pm
40 °C
°C
Detector ngth 229 11111
Mobile Phase A (MPA) TEAPT : Acetonitrile (80:20 by vol)
Mobile Phase B (MPB) TEAP7L : Acetonitrile (20:80 by vol)
Isocratic 80% MPA / 20%
Time MPA MPB
.0 100
45.0 33
50.0 12
51.0
55.0 0
56.0 100
60.0 100
Flow Rate
Retention Time ~ 20 s ~ 4 minutes
Sample Diluent 3 (IOmM) in Acetonitrile : water (70:30 by vol)
* Used for solubilization studies (Figures 11 and 12)
‘i‘ 0.1% (V/v) orthophosphoric acid adjusted to pH 6.5 with triethylamine
Example 1 — Preparation of (S-FInoromethylquinolinylmethyl-indol—lyl
)-acetic acid (Compound 1)
Compound 1 was prepared according to a method similar to that set out in WO-A-
92579. The method for synthesis can be summarised in Scheme 1 and Step 2
may be carried out according to the process described in UK Patent Application No.
11215511, filed 15 December 2011.
2012/052504
Scheme 1
Step 1
'n BrACOZEt
———-'
12 K2003. CHacN, A
Step 2 \
H / \O
F N/
\ o N/
quinolin-Z-yl aldehyde
) #4——— C \ N
EtOQC TFA, EtasiH, CHZCIZ )
EtOZC
(5-Huoro-2—methyl-indoly|)
acetic acid ethyl ester (5-fluoro—2—methylquinolinyl methyl-
‘l-yl) acetic acid ethyl ester
Step 3
/ \
N’ 1. LiOH, THF, H20
0 \ ’
2. HCIm
EtOZC
Reagent (5-Fluoromethy1-indol—l—yl)—acetic (5-Fluorornethyl-3 -quinolin
and acid ethyl ester (736 mg; 1 ylmethyl~indol—1—yl)—acetic acid ethyl
ions equivalent) ester (444 mg; 1 equivalent)
Quinolin-Z-yl-aldehyde (502 mg; 1 Lithium hydroxide (199.5 mg; 4
equivalent) equivalents)
Triethylsilane (2.5 ml; 5 equivalents) Tetrahydrofuran : water (100 ml; 1:1)
Trifluoroacetic acid (0.7 ml; 2.9 1 hour at room temperature
equivalents) 95% yield ofproduct after
Dichloromethane (50 m1) concentration
0°C then allowed to warm to room
temperature over 2 hours and stirred
overnight
729 mg ofproduct (62% yield) of
.roduct after togra hy
Example 2 — Solubility Screening
Before carrying out spray drying experiments, a solvent screening was performed to
determine potential solvent that will allow sufficient concentration of Compound 1 in
spray drying solution. Approximately 50 mg of Compound 1 was added to 100 mL
of each ted solvent until visual observation of solution tion. ons
were kept in closed container for 12 h at room temperature under continuous stirring.
The results are shown in Table l.
“'K l!"l“‘llHWH‘HIU‘Hll
, I, ilii’l‘ttil'
Chloroform
Dichloromethane (DCM)
Carbon tetrachloride
Toluene
Tween 80 (1% WV)
Span 80 (1% v/V)
Sodium dodecyl sulfate (2% w/v)
Hexadecyltrimethylammonium (0.05 % w/v)
Tris(hydroxymethyl) thane (1% w/v)
DMSO/DCM (75/25 V/V)
DMSO/DCM (50/50 V/V)
DMSO/HZO (75/25 V/V)
DMSO/ H20 (50/50 v/v) < 0.5
thanol (75/25 v/v) 0.5 1 1.0
DMSO/Ethanol (50/50 v/v) 0.5 — 1 0
Sodium hydroxide 0.5 N > 90 (at 45°C)
The results of the solubility screening show that Compound 1 is particularly soluble
in sodium hydroxide. However, this high solubility is believed to occur because in
sodium hydroxide, Compound 1 is converted to its sodium salt. The solution
containing 90 g/L of Compound 1 was cooled down to room temperature which
resulted in the formation of a solid precipitate. This precipitate was filtered and
washed 5 times with cold water (1 -2°C). The solid was dried for 36 h at 45°C under
vacuum (-15 mm Hg) and the dry cake was ground with a mortar/pestle and sieved
through a 50 mesh . The material was identified as the sodium salt of
Compound 1.
Apart from sodium hydroxide, the solvent in which Compound 1 is most soluble is
DMSO and this is also a suitable solvent for Compound 1. Thus, according to
solvent ing results (Table 1), DMSO and sodium hydroxide were selected as
solvent for the spray drying of Compound 1.
Comparative Example 3 — Spray Drying of Compound 1
Comparative Example 3A 7 Spray drying of Compound 1 in DMSO {Lot 001 g:
1 g of Compound 1 was dissolved in 200 mL of DMSO. The solution was spray-
dried using a Mini Spray Dryer model B—290 (Buchi, Zurich, Switzerland) with the
following operating parameters: 1.5 mm nozzle; 3.8:t0.1 mL/min spray rate;
220i4°C inlet temperature; 120i3°C outlet temperature; 550i20 NL/h atomization
flow, and 90% air flow (~35 m3/h). Under these conditions, 311 mg of spray-dried
material was collected (yield = 31%).
Comparative Example 3B 7 Spray drying of Compound 1 in sodium hydroxide (Lot
002 g:
1.74 g of Compound 1 was dissolved in 100 mL of 0.05N NaOH (17.4 g/L) (molar
ratio Compound 1: NaOH, 1:1) by heating the solution at 45°C. The solution was
cool down to room temperature and the solution was spray dried using the Buchi B-
290 with the following operating parameters: 1.5 mm nozzle; 3.3i0.1 mL/min spray
rate; C inlet temperature; 71i1°C outlet temperature; 350i20 NL/h
atomization flow, and 95% air flow (~37 m3/h). Under these conditions, 1.066 g of
spray dried material was ted (yield = 61%).
ative e 3C — Spray drying of Compound 1 in DMSO {Lot 017 g:
0.25 g of Compound 1 was dissolved in 500 mL of DMSO. The solution was spray-
dried using a Mini Spray Dryer model B-290 (Buchi, Zurich, Switzerland) using
compressed air as the drying gas and with the ing operating parameters: 1.5 mm
; 0.1 mL/min spray rate (feed rate); 210:1:7OC inlet temperature; 119i3°C
outlet temperature; 473 NL/h atomization flow, and 90% air flow (~35 m3/h). Under
these conditions, 86.5 mg of spray dried material was collected (yield = 35%).
Comparative Example 4 - Hot-melt dispersions in hydrophilic polymers
ative Example 4A [Lot 0031:
Compound 1 (0.4 g)/ Kollidon VA 64 (BASF, lot: 43962047G0) (1.6 g) solid
dispersion was prepared by physical e. The mixture was melted using an open
aluminum pan (30 mL). The mixture was kept at a temperature of 60—70°C for 30
minutes. After solidification at RT, the resulting material was ground using
mortar/pestle and passed through a 40 mesh screen to form granules.
Comparative Example 4B {Lot 006):
Compound 1 (0.2 g)/ Kollidon VA 64 (BASF, lot: 47G0) (1.8 g) solid
dispersion was prepared by physical mixture. The mixture was melted using an open
aluminum pan (30 mL). The mixture was kept at a temperature of 60-70°C for 30
minutes. The mixture was cooled down to room temperature. The resulting material
was ground using mortar/pestle and passed through a 40 mesh screen to form
granules.
Comparative Example 4C {Lot 007 1:
Compound 1 (0.4 g)/ Hypromellose acetate succinate S) (Biddle Sawyer
Corp, lot: 6093192) solid dispersion was prepared by physical mixture. The mixture
was melted using an open aluminum pan (30 mL). The mixture was kept at a
ature of 50-60°C for 30 minutes. The mixture was cooled down to room
temperature. The resulting material was crushed using mortar/pestle and passed
through a 40 mesh screen to form granules.
Comparative Example 5 — Solid Dispersions of Compound 1 in Gelucire
ative Example 5A [Lot 004):
Compound 1 (0.4 g) was dispersed in the melted Gelucire 44/14 (Gattefossé, lot:
115489) (1.6 g). The e was kept under stirring for 30 minutes at a ature
of 60°C using a water-bath.
Comparative Example 5B [Lot 0051: Compound 1 (0.1 g) was dispersed in the
melted Gelucire 44/14 (Gattefossé, lot: 115489) (1.4 g) containing Polyethylene
Glycol 400 (PEG 400) (A&C, lot: TL0801AAJC/78022/02M02CA) (0.5 g). The
mixture was kept under stirring for 30 minutes at a temperature of 60°C using a
water—bath.
Comparative Example 5C (Lot 008): Compound 1 (0.2 g) was dispersed in the
melted Gelucire 44/14 fossé, lot: 115489) (1.7 g) containing Sodium Lauryl
Sulphate (SLS) (BioShop, lot 7M6316) (0.1 g). The mixture was kept under stirring
for 30 minutes at a temperature of 60°C using a water-bath.
Comparative Example 5D [Lot 009 1:
Compound 1 (0.2 g) was dispersed in the melted re 44/14 (Gattefossé, 1ot:
) (1.7 g) containing Poloxamer 407 (BASF, lot: WO40222) (0.1 g). The
mixture was kept under stirring for 30 minutes at a temperature of 60°C using a
water-bath.
Comparative Example 5E {Lot 010):
Compound 1 (0.05 g) was dispersed in the melted Gelucire 44/14 (Gattefosse', lot:
) (1.4 g) containing Polyethylene Glycol 400 (PEG 400) (A&C, lot:
TL080lAAJC/78022/02M02CA) (0.55 g). The mixture was kept under stirring for
minutes at a temperature of 60°C using a water-bath.
Comparative Example 5F {Lot 011):
nd 1 (0.05 g) was dispersed in the melted Gelucire 44/14 (Gattefossé, lot:
) (0.99 g) containing Polyethylene Glycol 200 (PEG 200) (A&C, lot:
20700603) (0.94 g) and 0.02 g of SLS (BioShop, lot ). The mixture was kept
under stirring for 30 minutes at a temperature of 60°C using a water-bath.
Comparative Example 5G_(Lgt 0012):
Compound 1 (0.2 g) was dispersed in the melted Gelucire 50/13 (Gattefossé, lot:
104818) (3.8 g). The mixture was kept under stirring for 30 minutes at a temperature
of 60°C using a bath.
Comparative Example 5H [Lot 013 1:
Compound 1 (0.18 g) was dispersed in the melted Gelueire 50/13 (Gattefossé, lot:
104818) (1.66 g) containing Poloxamer 407 (BASF, lot: WO40222) (0.16 g). The
mixture was kept under stirring for 30 s at a temperature of 60°C using a
water-bath.
Comparative Example 51 [Lot 0241:
nd 1 (2.0 g) was diSpersed in the melted Gelucire 44/14 (Gattefossé, lot:
115489) (8.0 g). The mixture was kept under stirring for 30 minutes at a temperature
of 60—80°C. Hot melt formulation was encapsulated in size "1" white opaque hard
gelatin capsules (Capsugel, lot: 91) for an equivalent of 100 mg of Compound
1/capsule.
Comparative Example 5J [Lot 0251:
Compound 1 (2.0 g) was dispersed in the melted Gelueire 44/14 (Gattefossé, lot:
115489) (7.88 g) containing SLS (BioShop, lot 7M6316) (0.12 g). The mixture was
kept under ng for 30 minutes at a temperature of C. Hot melt ation
was encapsulated in size "1" white opaque hard gelatin capsules gel, lot:
70292091) for an equivalent of 100 mg of Compound l/capsule.
Comparative Example 5K {Lot 0261:
Compound 1 (2.0 g) was dispersed in the melted Gelucire 44/14 (Gattefossé, lot:
115489) (7.88 g) containing Poloxamer 407 (BASF, lot: W040222) (0.12 g). The
mixture was kept under stirring for 30 minutes at a temperature of 60-80°C. Hot
melt formulation was encapsulated in size ”1" white opaque hard gelatin capsules
(Capsugel, lot: 70292091) for an equivalent of 100 mg of Compound l/capsule.
Comparative Example 5L {Lot 027 1:
Compound 1 (2.0 g) was dispersed in the melted Gelucire 44/14 (Gattefossé, lot:
115489) (5.0 g) ning PEG 400 (A&C, lot: TLOSOIAAJC/78022/02M02CA)
(3.0 g). The mixture was kept under stirring for 30 s at a temperature of 60-
80°C. Hot melt formulation was encapsulated in size "1" white Opaque hard gelatin
capsules (Capsugel, lot: 70292091) for an equivalent of 100 mg of Compound
1/capsule.
Comparative Example 5M (Lot 034 1:
Compound 1 (6.07 g) was sed in the melted Gelucire 44/14 (Gattefossé, lot:
115489) (14.70 g) containing PEG 400 (A&C, lot: TL0801AAJC/78022/02M02CA)
(8.94 g) and SLS (BioShop, lot 9E11662) (0.30 g). The mixture was kept under
stirring for 30 minutes at a temperature of 60-8000 Hot melt formulation was
encapsulated in size "1" white opaque hard gelatin capsules (Capsugel, lot:
70292091) for an equivalent of 100 mg of Compound ule.
Example 6 — Solid Dispersions of Compound 1
During the preparation of all batches, nd 1 was first sieved with a 60 mesh
) sieve.
Example 6A — Solid dispersion in HPMC by physical mixture (Lot 014)
The Compound 1/HPMC solid dispersion was prepared by physical mixture and
solvent evaporation. 0.9 g of HPMC E5 (low viscosity grade) (Dow, lot:
2407 (014-1 and 014-2) and UF16012412 )) was dissolved in 10 mL
of methanol (MeOH)/dichloron1ethane (DCM) (50/50 v/v) under stirring at room
temperature (RT). 0.1 g of Compound 1 was added to the polymeric solution. After
API addition, 3 mL of dimethyl sulfoxide (DMSO) were added and the suspension
was stirred for 30 minutes (014-1 and 014-2) and 1 hour (014-3) at RT. The mixture
was ed in transparent glass bottle and stirred with a magnetic stir. The solvent
was ated as follows:
0 lot 014-1: by direct heating;
0 lot 014—2: using a water-bath at 100°C with an air jet for a period of time of 7
hours and under stirring;
- lot 014-3A: using a water—bath at 100°C during approximately 1.5 hours under
stirring and 64 hours in a vacuum system (a small desiccators containing
anhydrous calcium sulfate) placed into the oven at 50°C;
0 lot 014—3B: using a water-bath at 100°C during approximately 1.5 hours under
stirring and 64 hours in the fume hood at RT;
0 lot 014-3C: using a water-bath at 100°C during approximately 1.5 hours under
stirring and 64 hours in the fume hood at RT. After, 5 mL of MeOH were added
and the sample was dried under air jet until total solvent evaporation.
Example 6B-1 — Solid dispersion in HPMC by spray—drying [Lot 015—1 1:
The on was prepared as lot 014. 9.0 g ofHPMC E5 (low viscosity grade) (Dow,
lot: UF16012412) were dissolved in 100 mL of MeOH/DCM (50/50 v/v) under
stirring (38 minutes) at RT. Later, 30 mL of DMSO and 1.0 g of Compound 1 were
added to the polymeric on. The sion was stirred for 1 hour at RT. The
mixture was prepared in transparent glass bottle and stirred with a magnetic bar.
Partial ation of the solvent was achieved by direct heating at a temperature of
70-90°C until a clear solution was obtained (volume 50 mL). This solution was
viscous at temperatures of 70-90°C and formed a arent gel at RT. Before the
spray-drying process while maintaining the solution at the same temperature, 22 mL
of MeOH/DCM (SO/50 v/v) were added for total solids t in the spray drying
solution of ~14% w/v. The addition of solvent was necessary in order to reduce the
viscosity and to facilitate the spray—drying process. This on was spray-dried
using the Buchi B-290 with the following operating parameters: 1.5 mm nozzle; ~7.5
mL/min Spray rate; 194i2°C inlet temperature; 0C outlet temperature; 473
NL/h atomization flow, and 95% air flow (~37 m3/h).
Example 6B-2 — Solid dispersion in HPMC by spray-drying (Lot 015-2 1:
The solution was prepared as lot 015. 9.0 g ofHPMC E5 (low viscosity grade) (Dow,
lot: UF16012412) were dissolved in 100 mL of MeOH/DCM (50/50 v/v) under
stirring at RT. Later, 30 mL of DMSO and 1.0 g of Compound 1 were added to the
polymeric solution. The suspension was stirred for 1 hour at RT. The mixture was
prepared in transparent glass bottle and stirred with a magnetic bar. Partial
evaporation of the solvent was achieved using a water~bath at 100°C until a clear
solution was obtained (volume 60 mL). The solution was viscous at temperatures of
"IO-90°C and formed a transparent gel at RT. 1 hour later, the formed gel was heated
using a water—bath at 100°C and 115 mL of MeOH/DCM (50/50 V/v) were added for
total solids content in the spray drying solution of ~5.7% w/v. The addition of
solvent formed an opaque suspension. This sion was erred to an amber
glass bottle and kept between 4-8°C until spray-drying step. The suspension was
spray—dried using the Buchi B-290 with the ing operating parameters: 1.5 mm
nozzle; ~39 mL/min spray rate; C inlet temperature; 96i3°C outlet
ature; 473 NL/h atomization flow, and 95% air flow (~37 m3/h). The stirring
was maintained during the spray-drying to avoid precipitation.
Example 6B-3 — Solid dispersion in HPMC by spray-drying (Lot 015-31:
The solution was prepared as lot 015. 9.0 g ofHPMC E5 (low viscosity grade) (Dow,
lot: UF16012412) were dissolved in 100 n1L of MeOH/DCM (50/50 v/v) under
stirring at RT. Later. 30 mL of DMSO and 1.0 g of Compound 1 were added to the
ric solution. The suspension was stirred for 1 hour at RT. The mixture was
prepared in transparent glass bottle and stirred with a magnetic bar. Partial
evaporation of the solvent was achieved using a water-bath at 100°C until a clear
solution was obtained e ~50 mL). The transparent solution was viscous at
temperatures of 70-90°C. 50 mL ofDMSO were added for total solids content in the
spray drying solution of 10% w/v. The solution was maintained under
stirring/heating and was dried using the Buchi B—290 with the ing
operating parameters: 1.5 mm nozzle; ~4 mL/min spray rate; 212i2°C inlet
temperature; 106i5°C outlet temperature; 473 NL/h atomization flow, and 95% air
flow (~37 1113/11).
2012/052504
Com arative Exam le 6C — Solid dis ersion in HP CD b h sical mixture Lot
The Compound 1/HPBCD solid dispersion was prepared by physical mixture and
solvent evaporation. 0.9 g of HPBCD (Cavasol® W7 HP Pharma, ISP lot: 73Lot
024) were dissolved in 10 mL of MeOH/DCM (50/50 v/v) under stirring at RT. 0.1
g of Compound 1 was added to the solution. After API addition, 3 mL of DMSO
were added and the suspension was stirred for 30 minutes at RT. The mixture was
prepared in transparent glass bottles and stirred with magnetic bar. The solvent was
evaporated as lot 014-3C but with the addition of 10 mL of MeOH, 24 h of drying
were needed.
Example 6D — Solid dispersion in PVPK30 by physical mixture {Lot 0181:
The Compound 1/PVPK30 solid dispersion was prepared by al mixture and
solvent evaporation. 0.9 g of PVPK30 (ISP, lot: 05700181648) were dissolved in 10
mL of methanol/dichloromethane (50/50 v/v) under stirring at RT. 0.1 g of
Compound 1 was added to the solution. After API addition, 3 mL of DMSO were
added and the suspension was stirred for 1 h at RT. The mixture was prepared in
transparent glass s and stirred with magnetic bar. After partial evaporation of
the solvents using a water-bath at 100°C, Compound 1 was completely ved
(final volume ~5 mL). The solvent was evaporated as lot .
Exam 1e 6E — Solid dis ersion in PVPK30 b s ra - in Lot 019 :
The Compound 1/PVPK30 solid sion was prepared by physical mixture and
t evaporation. 9.0 g of PVPK30 (ISP, lot: 05700181648) were dissolved in
100 mL of MeOH/DCM (50/50 v/v) under ng at RT. 1.0 g of Compound 1 was
added to the solution. After API addition, 30 mL of DMSO were added and the
suspension was stirred for 1 h at RT. The solution was prepared in transparent glass
bottles and stirred with magnetic bar. Partial evaporation of the solvent was
achieved using a water—bath at 100°C. A transparent non viscous solution was
obtained after n (final volume ~50 mL). The solution was cool down to room
temperature and transferred to an amber glass bottle which was kept between 4—8°C
until spray—drying step. Before the spray-drying step, 50 mL of DMSO were added
for total solids content in the spray drying solution of 10%. The solution was
maintained under stirring/heating and was spray-dried using the Buchi B-290 with
the following operating parameters: 1.5 mm ; ~4 mL/min spray rate; 214::10C
inlet temperature; 114i5°C outlet temperature; 473 NL/h atomization flow, and 90%
air flow (~35 m3/h).
Example 6F-1 — Solid dispersion in HPMC by Spray-drying [Lot 0201 1:
6.0 g of HPMC E5 (Dow, lot: 2412) were dissolved in 100 mL of
MeOH/DCM (50/50 v/v) under stirring at RT. Later, 30 mL of DMSO and 4.0 g of
Compound 1 were added to the polymeric solution. The sion was stirred for 1
h at RT. The mixture was prepared in transparent glass bottle and stirred with a
magnetic bar. Partial evaporation of the solvent was achieved using by direct heating
until a clear on was ed (volume 50 mL). The transparent solution was
slightly viscous. 50 mL of DMSO were added for total solids content in the spray
drying solution of 10%. The solution was maintained under stirring/heating and was
spray-dried using the Buchi B-290 with the following operating parameters: 1.5 mm
nozzle; ~5 mL/min spray rate; 200::20C inlet temperature; 110i3°C outlet
temperature; 473 NL/h atomization flow, and 95% air flow (~37 m3/h).
Exam 1e 6F-2— Solid dis ersion in HPMCb s ra -dr in Lot 020-2 :
6.0 g of HPMC E5 (Dow, lot: UF16012412) were dissolved in 100 mL of
MeOH/DCM (50/50 v/v) under ng at RT. Later, 30 mL of DMSO and 4.0 g of
Compound 1 were added to the polymeric solution. The suspension was stirred for l
h at RT. The mixture was prepared in transparent glass bottle protected from light
and stirred with a magnetic bar. Partial ation of the Solvent was achieved
using a bath at 100°C. When a volume of 50 mL was reached, the solution was
directly heated under continuous stirring until a clear solution was obtained (5-7
minutes). The transparent on was slightly viscous. 50 mL of DMSO were
added for total solids content in the spray drying solution of 10%. The on was
directly spray-dried using the Buchi B—290 with the following operating parameters:
1.5 mm nozzle; 2.5 mL/min spray rate; 200i2°C inlet temperature; 106:1:30C outlet
temperature; 473 NL/h atomization flow, and 90% air flow (~35 m3/h).
Exam le 6G-1 — Solid dis ersion in PVPK30 b s ra -d 'n Lot 021-1 :
6.0 g of PVPK30 (ISP, lot: 05700181648) were dissolved in 100 mL of MeOH/DCM
(50/50 v/v) under stirring at RT. Later, 30 mL of DMSO and 4.0 g of Compound 1
were added to the polymeric solution. The suspension was d for 1 h at RT. The
mixture was prepared in transparent glass bottle and stirred with a magnetic bar.
Partial evaporation of the t was achieved using by direct heating until a clear
solution was obtained (volume 50 mL). The transparent solution was scous.
50 mL of DMSO were added for total solids content in the spray drying solution of
%. This solution was directly introduced into the spray-drier and spray—dried using
the following operating parameters: 1.5 mm nozzle; ~4 mL/min spray rate; 200i2°C
inlet temperature; 94i1°C outlet temperature; 473 NL/h atomization flow; and 90%
air flow (~35 1113/11).
Exam le 6G—2 — Solid dis ersion in PVPK30 b s ra - in Lot 021—2 :
6.0 g of PVPK30 (ISP, lot: 05700181648) were dissolved in 100 mL of MeOH/DCM
(50/50 v/v) under stirring at RT. Later; 30 ml. of DMSO and 4.0 g of nd 1
were added to the polymeric solution. The suspension was d for 1 h at RT. The
mixture was prepared in transparent glass bottle protected from light and stirred with
a magnetic bar. Partial evaporation of the solvent was achieved using a water-bath at
100°C. When a volume of 50 mL was reached, the solution was directly heated under
continuous stirring until a clear solution was obtained (5-7 s). The transparent
on was non-viscous. 50 mL of DMSO were added for total solids content in
the spray drying solution of 10%. No precipitation was observed after approximately
24 h at RT. This solution was directly introduced into the spray-drier and spray-
dried using the following operating parameters: 1.5 mm ; ~3 mL/min spray
rate; 200i2°C inlet ature; 105i5°C outlet temperature; 473 NL/h atomization
flow, and 90% air flow (~35 1).
Example 6H — Solid dispersion in HPMC by spray-drying (Lot 0221:
7.0 g of HPMC E5 (Dow, lot: UF16012412) were dissolved in 100 mL of
MeOH/DCM (50/50 v/v) under stirring at RT. Later, 30 mL of DMSO and 3.0 g of
Compound 1 were added to the polymeric solution. The sion was stirred for 1
h at RT. The mixture was prepared in arent glass bottle protected from light
and stirred with a ic bar. Partial evaporation of the solvent was achieved
using a water-bath at 100°C. When a volume of 50 mL was reached, the on
was directly heated under continuous stirring until a clear solution was ed (5-7
minutes). The transparent solution was slightly viscous. 50 mL of DMSO were
added for total solids content in the spray drying solution of 10%. After
imately 24 h at RT a slight precipitation was observed. When this solution
was placed in the water-batch for a few s, the precipitate disappeared and no
precipitation was observed again. The solution was directly introduced into the
spray-drier and spray-dried using the following operating parameters: 1.5 mm
nozzle; ~3 mL/min spray rate; 202i2°C inlet temperature; 102i2°C outlet
temperature; 473 NL/h atomization flow, and 90% air flow (~35 m3/h).
Example 61 — Solid dispersion in PVPK30 by spray—drying {Lot 023 l:
7.0 g ofPVPK30 (ISP, lot: 05700181648) were dissolved in 100 mL ofMeOH/DCM
(50/50 v/v) under stirring at RT. Later, 30 mL of DMSO and 3.0 g of Compound 1
were added to the polymeric solution. The suspension was stirred for 1 h at RT. The
e was prepared in transparent glass bottle protected from light and stirred with
a magnetic bar. Partial evaporation of the solvent was ed using a water—bath at
100°C. When a volume of 50 mL was reached, the solution was directly heated under
continuous stirring until a clear solution was obtained (5-7 minutes). The transparent
solution was non~viscous. 50 mL of DMSO were added for total solids content in
the spray drying solution of 10%. The solution was introduced into the drier
and spray-dried using the following operating parameters: 1.5 mm nozzle; ~3
mL/min spray rate; 202i20C inlet temperature; 96i8°C outlet temperature; 473 NL/h
atomization flow, and 90% air flow (~35 m3/h).
Example 6] - Solid dispersion in HPMC by spray-drying {Lot 028 1:
17.5 g of HPMC E5 (Dow, lot: UF16012412) were dissolved in 250 mL of
MeOH/DCM (50/50 v/v) under stirring at RT. Later, 75 mL of DMSO and 7.5 g of
Compound 1 were added to the ric solution. The suspension was stirred for
minutes at RT. The mixture was prepared in transparent glass bottle and stirred
with a ic bar. Partial evaporation of the t was achieved by direct
heating from 25 °C (To) to 109°C (Tf (100 min)) until approximately 120 mL of a clear
solution was ed (after 100 minutes of heating). After that the heating was
stopped and 130 mL of DMSO were added for total solids content in the spray drying
solution of 10%. This solution was directly introduced into the spray-drier and
spray-dried using the following operating parameters: 1.5 mm nozzle; 4.0 mL/min
spray rate; 210i1°C inlet temperature; 112i7°C outlet ature; 473 NL/h
atomization flow, and 90% air flow (~35 m3/h). The product from the tion
vessel (Figure 1) was identified L028A and the product recovered from the cylinder
(spray dry chamber) as L028B.
Exam 1e 6K— Solid dis ersion in PVPK30 b s ra - in Lot 029 :
17.5 g of PVPK30 (ISP, lot: 05700181648) were dissolved in 250 mL of
MeOH/DCM (50/50 V/v) under stirring at RT. Later, 75 mL of DMSO and 7.5 g of
Compound 1 were added to the polymeric solution. The suspension was stirred for
minutes at RT. The mixture was prepared in transparent glass bottle and stirred
with a magnetic bar. Partial evaporation of the t was achieved by direct
heating from 25 0C (To) to 110°C (Tf (65 min)) until imately 120 mL of a clear
solution was obtained (after 66 minutes of heating). After that the heating was
stopped and 130 mL ofDMSO were added for total solids content in the spray drying
solution of 10%. This solution was ly introduced into the spray—drier and
spray-dried using the following operating parameters: 1.5 mm nozzle; 3.5 mL/min
spray rate; 220i1°C inlet temperature; 128i2°C outlet temperature; 473 NL/h
atomization flow, and 95-100% air flow (~38 mg/h). The t from the collection
vessel (Figure 1) was identified L029A and the product recovered from the cylinder
(spray dry r) as L029B.
Example 6L — Solid dispersion in HPMCAS by spray-drying [Lot 030 )2
7.0 g of Hypromellose—Acetate-Succinate LG grade (HPMCAS) (Shin-Etsu
Chemical, lot: 8113240) were dissolved in 100 mL of MeOH/DCM (50/50 v/v)
under stirring at RT. Later, 30 mL of DMSO and 3.0 g of Compound 1 were added
to the polymeric solution. The suspension was stirred for 30 minutes at RT. The
mixture was ed in transparent glass bottle and stirred with a magnetic bar.
Partial evaporation of the solvent was achieved by direct heating from 25 °C (To) to
119°C (Tf (69 mm) until approximately 50 mL of a clear solution was obtained (after
69 minutes of heating). After that the heating was d and 50 mL of DMSO
were added for total solids content in the spray drying solution of 10%. This solution
was directly introduced into the spray-drier and spray-dried using the following
operating parameters: 1.5 mm nozzle; 2.5 mL/min spray rate; 219i2°C inlet
temperature; 120i3°C outlet temperature; 473 NL/h atomization flow, and 95-100%
air flow (~38 m3/h). The product from the collection vessel (Figure 1) was identified
L030A and the t recovered from the cylinder (spray dry chamber) as L030B.
Example 6M — Solid dispersion in PVPK30 by spray-drying [Lot 031 1:
10.4 g of PVPK30 (ISP, lot: 81648) were ved in 130 mL of
MeOH/DCM (50/50 v/v) under stirring at RT. Later, 39 mL of DMSO and 2.6 g of
Compound 1 were added to the polymeric solution. The suspension was stirred for
minutes at RT. The mixture was prepared in transparent glass bottle and stirred
with a magnetic bar. Partial evaporation of the solvent was achieved by direct
g from 23°C (To) to 113°C (Tf(90 mm) until approximately 65 mL of a clear
on was obtained (after 90 minutes of heating). After that the heating was
stopped and 30 mL of DMSO and 60 mL of e were added for total solids
content in the spray drying solution of 8.4%. This solution was directly introduced
into the spray-drier and spray-dried using the following operating parameters: 1.5
mrn nozzle; 4.1 mL/min spray rate; 148i5°C inlet temperature; 83::30C outlet
ature; 473 NL/h atomization flow, and 95% air flow (~37 m3/h).
Example 6N — Solid dispersion in HPMCES by spray—drying [Lot 0321:
.4 g of HPMC E5 (Dow, lot: UF16012412) were dissolved in 130 mL of
MeOH/DCM (50/50 v/v) under stirring at RT. Later, 39 mL of DMSO and 2.6 g of
Compound 1 were added to the polymeric on. The suspension was stirred for
minutes at RT. The mixture was ed in transparent glass bottle and stirred
with a magnetic bar. Partial evaporation of the solvent was achieved by direct
heating from 25°C to 130°C until approximately 65 mL of a clear solution was
obtained (after 80 minutes of heating). After that the heating was stopped and 30 mL
of DMSO and 60 mL of Acetone were added for total solids content in the spray
drying solution of 8.4%. This solution was directly introduced into the spray-drier
and spray-dried using the following operating parameters: 1.5 mm nozzle; 4.2
mL/min spray rate; 160i10C inlet temperature; 92i10C outlet temperature; 473 NL/h
atomization flow, and 95% air flow (~37 1113/11).
Example 60 — Solid dispersion in PVPK30 by spray-drying {Lot 033 l:
19.95 g of PVPK30 (ISP, lot: 05700181648) were dissolved in 250 mL of
MeOH/DCM (50/50 v/v) under ng at RT. 5.06 g of Compound 1 were added to
the polymeric solution. The suspension was stirred for 60 minutes at RT. 75 mL of
DMSO were added under continuous stirring. The mixture was prepared in
transparent glass bottle and stirred with a magnetic bar. Partial evaporation of the
solvent was achieved by direct heating from 23 °C to 103°C until approximately 110
mL of a clear solution was ed (after 92 minutes of heating). After that, the
heating was stopped and 25 mL of DMSO and 90 ml. of Acetone were added for
total solids t in the spray drying solution of 11%. This on was directly
introduced into the drier and spray-dried using the following operating
parameters: 1.5 mm nozzle; 4.6 mL/min spray rate; 159i4°C inlet ature;
97i2°C outlet temperature; 473 NL/h atomization flow, and 95% air flow (~37
m3/h).
Example 7 — Crystal Structure Evaluation
The ivity of the XRPD method was evaluated in a spiking experiment in which
1, 5 and 20% of nd 1 was mixed with microcrystalline cellulose (MCC)
(Avicel PH101, FMC, lot: P105815404) and the results are shown in Figure 1.
The XRPD diffractogram of 1, 5 and 20% nd 1:MCC es were
compared to those of pure Compound 1 and mixtures of MCC and Compound 1. The
X—ray diffraction of major crystalline peaks of Compound 1, situated at
imately 13.6 and 17.7°20, can be observed in the X—ray diffraction pattern of
the mixture containing 5% of crystalline Compound 1 which confirms that the XRPD
limit of detection of crystalline Compound 1 is approximately 5% (Figure 1).
The XRPD patterns of Compound 1 before and after the sieving step was identical
(Figure 1), indicating that sieving with a 60 mesh did not affect the crystal structure
of this material.
The formulations tested by XRPD are summarized in Table 2. Except for sample
014-2, all the samples were analyzed ately after preparation.
.. .. 3 . .1011“ll1'||l“llllllllull”. lllil “Ill 1 illhll'l‘liiéilll865187011111“
001, 017(Co p. Ex. 3A, 3C) OC000459 s-is 100
002 (Comp. Ex. 3B) OC000459 sodium salt 100
003 (Comp. Ex. 4A) OC000459:Kollidon VA 64 20:80
004 (Comp. Ex. 5A) 59:Ge1ucire 44/14 20:80
005 (Comp. Ex. 5B) OC000459:Gelucire 44/14:PEG 400 5:70:25
006 (Comp. Ex. 4B) OC000459:Kollidon VA 64 10:90
007 (Comp. Ex. 4C) OC000459:HPMCAS 20:80
012 (Comp. Ex. 5G) OC000459:Gelucire 50/13 5:95
014, 015 (Examples 6A, 6B) OC000459:HPMC 10:90
016 (Comp. Ex. 6C) OC000459: HPBCD 10:90
019 (Example 6E) OC000459zPVPK30 10:90
020 (Example 6F) OC000459:HPMC 40:60
021 (Example 6G) OC000459zPVPK30 40:60
022, 028 (Examples 6H, 6]) OC000459:HPMC 30:70
l 023, 029 les 61, 6K) OC000459:PVPK30 30:70
027 (Comp. Ex. 5L) OC000459:Gelucire 44/14:PEG 400 I 20:50:30
030 (Example 6L) OC000459:HPMCAS 30:70
031, 033 (Examples 6M, 60) OC000459:PVPK30 I 20:80
032 (Example 6N) OC000459:HPMC 20:80
Figures 1 to 5 show the distinct XRP diffractogram for the as-received and
formulated samples of Compound 1.
As shown in Figure 2, the lline structure of Compound I ed stable after
spray—drying (lot 001) and dispersion in Gelucire 44/14 (lot 004) and Gelucire 50/13
(lot 012). However, an apparent increase of amorphous content was observed
following the dispersion in PVP-VA (lots 003 and 006). Interestingly, a conversion
into the amorphous form was observed for the spray-dried material dissolved using
sodium ide (lot 002).
XRPD data ed for lot 014 (Figure 3) also suggest that a solid sion of
% API / 90% HPMC after dissolution in DCM-MeOH—DMSO as solvent system
resulted in drug amorphization. It was noted that DMSO solvent evaporation was a
problem in the solid dispersion in HPMC (lot 014) and in PVPK30 (lot 018). Only
sample 014-3C showed an appropriate drying of the material. Dispersion of 10%
API in HPBCD (lot 016) only led to partial amorphization of nd 1. In lot
018, DMSO could not be tely removed with the technique used and,
consequently, this lot was not tested by XRPD.
The results ed for lots 015 and 019 (Figure 3) confirmed the arnorphization of
nd 1 after solid dispersion/spray drying of this API (10%) in HPMC and in
PVPK30 using DCM-MeOH—DMSO as solvent system. Solution from lots 015 and
019 became transparent with the final volume 50 mL where 1 g of API and 9 g of
polymer were completely dissolved (20% w/v of solids). These solutions were
viscous. In order to make a solution that was suitable for spray-drying, it was
necessary to add more solvent to reduce the viscosity. In lot 015—1, 22 mL of
MeOH/DCM (50/50 v/v) were added. When the solvent was added the tiny
suspended particles were observed. This could be due to the HPMC. In lot 015-2,
the addition of 115 mL of MeOH/DCM (SO/50 v/v) resulted in a stable suspension
(5.7% w/v of solids). This sion was sprayed at RT under stirring. The
solution from lot 015-3 resulted in a transparent slightly viscous liquid when 50 ml.
of DMSO were added. ons from lot 015-1 (14% w/v of solids) and 015-3
(10% w/v of solids) were kept under heating during the spray—drying. The solution
from lot 019 resulted in a transparent non—viscous solution when 50 mL of DMSO
were added (10% w/v of solids). This on could be sprayed at RT and without
ion.
Under non-optimized ions, the spray-drying yield of lots 015-2, 015-3 and 019
were 49, 59 and 65%, respectively. The percent yield refers to the percentage of the
amounts recovered in the collection vessel from the amount of the solids dissolved.
The preparation of the solution Will be optimized in r studies to better define
the operation parameters.
For the samples ning 40 % of Compound 1 dispersed with HPMC and
PVPK30 (lots 020 and 021 respectively), around 5 % or less of the drug remains in
the crystalline form the rest being in the amorphous state (Figure 4). 30% of
Compound 1 co-precipitated with PVP by spray-drying leads complete conversion
into amorphous form (lot 023). However, using HPMC as polymer a very small
quantity of the drug (probably less than 5%) remained crystalline (lot 022).
50-54% of spray-dried material from lots 020 to 023 was recovered in the collector.
For lot 021—2 21 yield of 72% was obtained. For these lots the powders were not
sticky and showed an acceptable flowability. The PVP co—precipitates presented a
finer particle size.
In agreement with us XRPD s, Compound 1 dispersed in Gelucire (lot
027) remained in the crystalline form (Figure 5) even in the presence of PEG400.
For samples prepared by solid dispersion/spray drying with HPMC (lot 028) and
with PVPK30 (lot 029) at a 30% drug load, the results were similar to those observed
for lots 022 and 023 (Figure 5). However, the intensity of the characteristic
crystalline peaks at 20 ~13.5, ~17.5 and ~27.5 decreases slightly for lot 028B
compared with lot 028A. The major differences between 028A and 028B were the
time of tion to drying air (~210°C) and the particle size, both were greater in
lot 028B than 028A (product from the collection vessel). sing the stress and
difference in l size can produce disorder in the corresponding crystal structure.
The different crystal arrangements may lead to an infinite number of le local
amorphous structures.
The yield for lot 028 was 68% (46% of the amounts was recovered in the collection
vessel), for lot 029 was 75% (61% in the collection vessel) and for lot 030 32% (11%
in the collection vessel). Under these operating conditions the yield for lot 028 and
029 was improved but only 32% of the spray-dried material was recovered from lot
030. This was due to the sticking nature of HPMCAS under used conditions (DMSO
as solvent and temperatures of 219i20C).
For PVP (lots 031 and 033) and HPMC (lot 032) SDI (API 20%), a mixture of
DMSO/acetone was used as solvent for the spray drying process. Therefore, the inlet
temperature could be reduced from 220°C to 150-160°C. These samples were also
tested by XRPD measurement. Diffractograms can be found in Figure 6. The results
show that the lots containing 20% of API and prepared with a mixture of
DMSO/Acetone were converted to the amorphous form. For these lots (031, 032 and
033), the spray drying yield was 65, 47 and 49%, respectively. During the spray-
drying process of lots 032 and 033 an important amount of material accumulated in
the dry chamber. This can probably be ascribed to problems during ation.
, the gas atomizing flow rate to the feed rate ratio ces the yield and the
particle size. A lower ratio leads to g of the drying chamber by the sprayed
droplets resulting in a lower yield. Also, when the atomizing flow rate is low, the
drop exiting the nozzle tends to be greater so the resulting dried le will be
larger. In addition, the concentration of solids in the spray drying solution affects the
particle size. Low solid concentration decreases the amount of solid in each droplet
exiting the nozzle. Therefore, When the solvent in the droplet evaporates, a smaller
particle remains. For lot 031 the total solids content in the Spray drying solution was
around 8% and 11% for lot 033.
To summarise, the lots having amorphous character were found to be lots 002
rative Example 3B), 014 (Example 6A), 015 (Example 6B), 019-023
(Example 6E, Example 6F, Example 6G, Example 6H, Example 61) and 028-033
le 6.1, Example 6K, Example 6L, Example 6M, Example 6N, Example 60).
It is also probable that lot 018 le 6D) was an amorphous product but there
were difficulties in removing the solvent.
The product of Comparative Example 3B was the sodium salt of nd 1 rather
than the free acid.
Therefore, amorphous nd 1 was present in solid dispersions of the
compound in:
HPMC:
Lot Ratio Compound 1:Polymer
014 10:90
:90
40:60
:70
:70
:80
23 30:70
31 20:80
33 l 20:80 (approx)
HPMCAS (lot 30).
Lot Ratio Comn ound 1:Pol mer
:70
Example 8 — Analytical Testing Results
In order to determine whether the spray drying led to osition of Compound 1,
analytical testing was d out on the solutions before spray drying and the spray
dried powder. In each case, the t of Compound 1 in the sample was measured,
as was the content of ation products.
Analysis was carried out by HPLC using the analytical method set out above.
ical testing results for the spray dried compositions of lots 020 and 021
(Examples 6F and 6G) are presented in Table 3, those for lots 022 and 023
(Examples 6H and 61) in Table 4 and those for Lots 031 to 033 (Examples 6L, 6M,
6N and 60) in Table 5.
In the tables, the “solution” is the solution before spray drying and the content of
Compound 1 was measured by HPLC and is presented in the table as a percentage of
the calculated content of Compound 1.
The content of Compound 1 in the spray dried powder was also ed. In order
to do this, the powder was taken up in a 30:70 mixture of phosphate buffer (pH 8.0)
and acetonitrile and the solution analysed by HPLC to determine the amount of
Compound 1 present.
In the tables, the “related substances” are degradation products of Compound 1 and
“largest” refers to the largest HPLC peak.
2012/052504
Table 3 — Analytical Results for Lots 020 and 021
1‘ if
mlfllfil illlfi --.|.....u.
40 4 40
dom s.IO.u .1m b
ma f9..W fme an" l H
pm.mhS .l m6 Pm;MWadeYrCI!lflla0k CWPm mmmnee pP03W3d.eYremWfle S
mflO1 ah.lb.lacosfeflOdesm3.?
90 8 972. 925.
Tm1 .. l 25 T0ml .. l .4 TOm M4 T04La1 0 6 00
Lm0g2652.t La0 051.622 t L3«10g1 St.
/I\ .T 0 8 l 1.m r|\ T6121.. 2 xi)
Table 4 — Analytical Results for Lots 022 and 023
||||||l ........
i! ii. 5:-
......
3 0 3 0 3 3 0
Cbm S0 u.n0 C
ww a fe fnmm H eH W1mm61 k
PmMeS n t D...P0lawEdY8 infl eS p alo mfnnmmnm PM;aWd.eYul.6/:“fl03W%S
1man0 n b
99 84 .4 9 1 8
nml .. 7. 0.0 T0.T.fl .. 3 . 7 T0 asfefiWI0&2”; 63 T.0t.n|.a .. 0 2 00
0.41 0.68 0.17 0.10
(RRT 0.81) (RRT 0.81) (RRT 0.31) (RRT 0.80)
. Pale-Yellow Pale—Yellow ellow
' f“ powder/flakes powder/flakes powder/flakes
. 57%
E Total: 0. 71 Total : 0.52
. Largest: Largest:
0.15 1.07 0.15
' (RRT 0.81) (RRT 0.81) (RRT 0.81)
MeOH:75 MeOHz3
DCM: N/De DCM: N/De Not tested
DMSO: 65320 DMSO: 46881
Acetone: 10 Acetone: 9
From Tables 3 to 5, it appears that HPMC SDI at 40 (Table 3), 30 (Table 4), or 20%
API (Table 5) generally has a lower assay and higher total related substances when
compared to PVP SDI at comparable drug load.
Example 9 — Stability Under Controlled Storage Conditions
Samples from lots 022 le 6H; HPMC SDI 30% Compound 1) and 023
(Example 61; PVP SDI 30% Compound 1) were incubated under different stability
conditions: long term (25°C/60% RH), aCcelerated 75% RH) and at
50°C/Ambient stability conditions for verification of amorphous state ity. The
bulk powder was packaged in open and closed 50 cc HDPE bottles. The short—term
stability study was conducted according to the ity protocol described in Table 6.
The samples were evaluated by XRPD for amorphous state and by HPLC for
assay/degradation products at time zero and at subsequent time points.
Table 6 — Stability Protocol, Spray Dried Compound 1, Lots 022 and 023
Packa-_in_ material Humidit (%)
40 Amb
(<10%)
Lot 022 (Example 6H; HPMC SDI Open cap 50cc HDPE
% Command 1)
Lot 023 (Example 61; PVP SDI
% Compound 1)
Lot 022 (Example 6H; HPMC SDI Closed cap
% Compound 1) I-[DPE bottle
Lot 023 le 61; PVP SDI
% Compound 1)
XRPD patterns of initial and stability samples of 30% drug load HPMC and PVP
SDI are shown in Figures 7 and 8 respectively. The s stability s
showed characteristic peaks of crystalline OC000459 under all conditions tested for
the HPMC SDI which indicated partial recrystallization of the amorphous form
during storage (Figure 7). However, XRPD patterns of initial and 2-weeks closed
cap ity samples of PVP SDI showed no Sign of tallization in stability
samples (Figure 8). For both, HPMC and PVP SDI samples exposed to heat and/or
moisture (open cap condition), conversion into crystalline form was ObServed.
XRPD data for PVP SDI (lot 023) 5 weeks-stability samples are shown in Figure 8.
There was no change in XRPD pattern for the sample stored at 25°C/60%RH (closed
cap) during 5 weeks. This confirms the stability of the amorphous form under these
conditions. XRPD data for 50°C sample showed similar diffractogram compared to
the 2—weeks stability sample with minor increase in peak intensity. This increase
was lower than that ed for 40°C/75%RH—closed cap sample suggesting that
re content contributes to tallization of amorphous form.
Assay/Related substances of initial and stability samples of 30% drug load HPMC
and PVP SDI (lots 022 and 023) are tabulated in Tables 7 and 8, respectively.
Table 7 — Compound 1 HPMC SDI, Lot 022, ity Samples analytical
g Results
Pale-Yellow powder/flakes
Pale—Yellow Pale—Yellow Pale~Yellow Pale-Yellow Pale-Yellow
T:k2
powder;I powder/ powder:I powder! powder/
flakes flakes flakes flakes flakes
Total Impurities: 3.07 Largest: 0.68 (RRT 0.81)
Total: 4.19 Total: 4.35 Total: 5.92 Total: 4.27 Total: 5.78
Largest: Largest: Largest: Largest: Largest:
1.22 1.17 1.98 1.12 1.76
(RRT 1.73) (RRT 1.78) (RRT 1.78) (RRT 1.78) (RRT 1.78)
As observed previously, HPMC SDI appears to have a lower assay and higher total
related substances values when compared to PVP SDI. Assay of 2-week HPMC
samples stored at 25°C/60% RH. and 40°C/75% RH. (open cap) were similar to
initial sample (T=O). For closed-cap samples the assay values were lower. Related
substances increased for all samples. Assays of PVP SDI samples were quite stable
after 2 weeks storage in closed container. Related nces increased for all
samples.
The 4-Week timepoint was not analyzed for the HMPC SDI (lot 022). Assay values
of 4—weeks ity testing of PVP SDI stored at 0% RH. and 50°C/510%RH
in closed HPDE bottle were comparable to T=0 but lower for the sample stored at
40°C/75% R.H. The related substances did not increase at any condition when
compared With the values at the 2 week time point.
Table 8 — Compound 1 PVP SDI, Lot 023, ity Samples analytical Testing
Results
T:2 Pale—Yellow Pale—Yellow Pale—Yellow Pale~Yellow Pale-Yellow
powder/flakes powder/flakes powder/flakes powder/flakes powderiflakes
Pale-Yellow Pale-Yellow
Not Tested
powder/flakes /flakes
91.8
89.3
Not Tested Not Tested
Total Impurities. 0.28% Largest: 0.10% (RRT 0.81)
Total: 1.07 Total: 1.00 Total: 1.30 Total: 0.96 Total: 1.51
Largest: Largest: Largest: Largest: Largest:
0.31 0.29 0.44 0.25 0.52
(RRT 1.78) (RRT 1.78) (RRT 1.78) (RRT 1.78) (RRT 1.78)
Total: 0.81 Total: 0.97 Total: 0.90
Largest: 0.21 Not Tested Largest: 0.24 Not Tested Largest: 0.28
RRT 0.81) (RRT 0.81) (RRT 0.81)
Also, samples from lot 031 (Example 6M; PVP SDI 20% Compound 1) were
ted under long term (25°C/60% RH) and accelerated (40°C/75% RH) ICH
stability conditions. Samples from lots 033 (Example 60; PVP SDI 20% Compound
1) were incubated at 4°C and 50°C. The bulk powder was packaged in double PE
bags with a desiccant in sealed aluminium bag into the HDPE bottle. The short—term
ity study was conducted according to the ity protocol described in Table 9.
Table 9 ~— Stability Protocol, Spray Dried Compound 1, Lots 031 and 033
Packanin material Humidity (%)
Lot 031 (Example 6M; PVP Double PE bags with
SDI 20% Compound 1) a desiccant in a
sealed aluminium bag
SDI 20% Compound 1) into HDPE bottle
SDI 20% Comound l)
Lot 033 (Example 60; PVP
SDI 20% Compound 1)
As shown inFigure 9, stability of the amorphous form of Compound 1 (20% with
PVP) after 2, 4 and 12 weeks at 25°C/60%RH, 40°C/75% RH and at 50°C was
verified by XRPD and no changes were observed in their ous character. The
chemical stability was also verified. The assay for both lot 031 and lot 033 and
d substances for lot 031 remained r to T=0 for up to 12 weeks. The
amount of related substances increasing slightly for lot 033 but decreasing for lot
031. Water content in the stability samples was increased by approximately 2—3%.
After 6 months, only lot 031 was tested. When stored for 6 months at 25°C/60% RH
and 40°C/75%RH lot 31 remained stable as judged by amorphous content, assay
and ty content, although there was a very small increase in total impurities at
the rated condition (0.71% to 0.97% area). Assay values were not
significantly changed from initial and there was no change in the X-ray amorphous
content e 10). The results show that the amorphous Compound 1 stabilized
with PVP is able to withstand rated storage conditions for at least 6 months
when protected against moisture ingress.
2012/052504
Table 10: Compound 1/ PVP Lots 031 and 033 Stability Testing Results
Pale-Yellow powder/flakes Pale—Yellow powder/flakes
Pale—Yellow flakes
T=0.5 mth Not Tested Pale-Yellow powder/flakes
and clumps
Yen... cumsp Pale-Yellow /flakes
Pale-Yellow flakes and
Yellow clumps Pale-Yellow powder/flakes
elum-s
Pale-Yellow flakes and
11:6 mth Yellow clumps Not tested
clumps
T= 97.8 98.0
T=0.5 mth Not Tested 97.3 98.0
T=1 mth Not Tested 97.6 98.3
”m98.4-
Not tested
Not tested
Total : 0.52%
Total : 0.71%
T:0 Single largest impurity: 0.15%
Single t impurity: 0.15% @ RRT 0.80
r RRT 0.80
Total : 0.65%
Single largest Total : 0.65%
T=0.5 mth Not Tested ty Single largest impurity
0.14% @ RRT 0.17% @ RRT 0.80
0.80
Total : 0.72%
Single largest Total : 0.71%
T=1 mth Not Tested impurity Single largest impurity
0.14% @ RRT 0.18% @ RRT 0.80
0.80
Total : 0.57%
Total : 0.47% Single largest Total : 0.63%
T:3 mth Single largest impurity impurity Single largest impurity
0.12%@RRT 0.80 0.16%@RRT 0.21%@RRT 0.80
0.80
Total : 0.97%
Total : 0.79% Single largest
T:6 mth Single largest impurity impurity Not tested
0.14% @ RRT 0.80 0.20% @ RRT
0.80
Example 10 — Solubility in Aqueous solutions
Crystalline and amorphous Compound l/polymer ation solubility was
determined in different aqueous media (Tables 8A and 8B).
As shown in Table 11A, the highest concentrations were observed for non-spray-
dried Compound 1 sodium salt. As mentioned earlier the high
3 solubility of the
Compound 1 sodium salt most probably resulted from the sion of the
Compound 1 to its d form. In on to crystalline Compound 1 (as received
sample), formulations containing amorphous form (Tables 11A and 11B) were more
soluble than crystalline form under all studied conditions. Highest concentrations
were observed in sodium buffer pH 8.0 with 2% SDS.
Table 11A: Compound 1 Solubility (mg/mL) Testing ResuItS
0.0036 0.0091 0.1712 Not tested
2.605 0.0050 0.0066 Not tested
2.487 0.0006 0.0947 Not tested
8.554 0.0002 0.0658 Not tested
1.744 1.782 0.1838 0.2140
.571 2.740 0.2508 Not tested
Not tested 30 1 7 0.0518 0.0529
Not tested >26 >22 0.0120 Not tested
Not tested T >21 >14 0.0097 Not tested
Not tested 1 4.114 3.597 > 0.4 Not tested
Not tested 1 0.1275 0.1623 0.1492 Not tested
Not tested 1 3.216 0.2260 0.0877 Not teste.0
Not tested Not tested Not tested Not tested 0.6987
4‘ Standard ted
Purity: 98.6 %
Table 11B: nd 1 Solubility (mg/mL) Testing Results
:HW‘WIii!" ‘l‘w “"iiii'i ’ 10w-1 '
I . 0’1 lili E
1 ” a?
. iii” ‘Iflii‘Wil'wflfl'
,7 fl" . L‘II
‘ JIM
1: .' .
' ‘ 'ii.‘igifilmtmtinléfiat/gifi‘j “(r";|l!§£‘[tfilii'
.. millillhiziiiiilt iiliéurlfl
. . 0.0008 0.0045 0.0009
0.0347 0.0421 0.0796 0.0404 0.0172
Not tested 0.0138 0.0104 0.0322 0.0230
0.2227 0.1107 I 0.1625 0.1348 0.2298
0.8359 0.4859 0.5751 0.9587
The data in Table 12 show that water solubility increases ically for Compound
1 sodium salt in relation to Compound 1 as-received. Overall, Compound 1
amorphous forms also showed an increase in water solubility compared to the
crystalline form. Given the limited number of experiments med, the PVP SDI
(10:90 drug to polymer ratio) lot 019 showed the r increase in water solubility.
At drug load of 20% or more, HPMC appeared to improve the lity better when
compared to PVP. Also, it appeared that a higher proportion of polymer generally
improved the solubility of Compound 1.
The formulation containing Gelucire 44/14 (50%)/PEG400 (30%) (lot 027) did not
improve solubility of Compound 1 in water (Table 12) which is consistent with the
fact that the API remained crystalline.
Table 12: Water Solubility Increases for Compound 1
‘ H—I N/A '
_Compound1 _100' 6 NA
Compound 1 Sodium
.37 2561667
sod1um salt salt
Lot 002 (Comp. Digglga 16.87 2811667
e 3B)
salt
Lot 019
(Example 6E)
Lot 015-]
HPMC
(Example 6B)
Lot 032
HPMC
(Example 6N)
Lot 031
(Exam... 6M)
Lot 022
HPMC
(Example 6H)
Lot 023
(Example 61)
Lot 020—1
HPMC
(Example an -
Lot 021-1
(Exmplem
Lot 020-2
HPMC 0.0074 1233
(Example 6F-2)
Lot 021-2
0'00” 133
le 6G—2)
Lot 027 (Comp.
0.0006 100
Example 5K)
Example 11 - Solubility in Simulated Gastric and Intestinal Fluids
The solubilization profile was obtained of various compositions in USP Simulated
Gastric Fluid (SGF) and USP Simulated Intestinal Fluid (SIF) with pH 1.2 and 6.8,
respectively. Although r are exact reproductions of physiological media, it was
decided to evaluate the solubility with the media maintained at 37°C, with gentle
g, and sampling at various time points up to 60 minutes. The concentration of
the solution was based on the hypothesis that the test should simulate a dissolution
test for a 100 mg dose th tablet or capsule in 900 ml of dissolution media.
The solubility was tested for the crystalline compound 1 with a purity of 98.9%, and
for the amorphous compositions of Examples 6M and 60 (Lots 031 and 03 3).
The following procedure was followed:
0 A shaking water bath was filled and water ature left to equilibrate to
37°C for 24 hours.
0 USP simulated gastric fluid was prepared as described in the UPS 31,
Solutions: Test solutions.
- USP ted intestinal fluid was prepared as described in the UPS 31,
Solutions: Test solutions.
0 The equivalent of 12.5 mg of nd 1 was weighed and transferred into
a 125 mL Erlenmeyer flask, with 100 mL of medium. This is equivalent to 1 X
100 mg dose strength tablet in 900 mL of dissolution medium.
0 The flasks were mounted to the submerged shaker.
o The shaker was set to a linear motion equivalent to l ional movement
per second.
0 Using a probe with a 45 um filter, samples were taken after 5, 10, 15, 30 and
60 min and injected in the HPLC
The amount of dissolved material was determined with respect to a standard and is
reported as the percentage of material dissolved with respect to the standard as well
as in absolute mg/ml. The tical concentrations of the standard and the samples
are presented in Table 13.
Table 13: Theoretical Standard and Sample Concentrations
. 1|“!‘lllliifillllllltii‘11!'Hl'i'ialarm, it“..- 111! .. til”gl“‘:fl%glllflli I we.H
., arrillIllitllllllHMll‘H'El11mg“ 111s ‘
. wasil 1‘i ii“1 151.
Mobile Phase 0.12093
Crystalline Compound 1 0.12009
Lot 031 (Exam nle 6M) SGF 0.11762
SGF 0.12866
SIP 0.12207
SIP 0.11684
The solubility profiles of the samples are ted in Figures 10 and 11 representing
SGF and SIP respectively. As expected the API shows very poor lity under
these pH conditions. This has been demonstrated previously. However, the
amorphous spray dried material shows significantly better solubility, with both lots
achieving close to 90% dissolution in SGF. It is odd, however, that Lot 031
le 6M) showed only 50% dissolution on SIF. This is unexpected for l
reasons: 1) both Lots 031 and 033 are very similar in nature, using the same polymer
and solvent during the manufacturing s, and 2) solubility would have been
expected to be higher at the higher pH level.
Visually, the solutions were not clear, and still contained material in suspension. In
the case of the pure API, it is assumed that this is the API itself in suspension. 1n the
case of the SDI, the material in sion is mostly polymer. This makes it
extremely difficult to Visually determine if the entire active has been solubilized or
not. However, the filtrate ed into the HPLC was limpid, although it may be
possible that a small amount of the SDI material may have passed the 45 micron
filter. No further on of the sample was performed prior to injection.
As a result, it is quite possible that the low lity results for Lot 031 in SIF could
be a manipulation error. It is also interesting to note that complete solubility seems
to be achieved very quickly. The profiles show a small drop in solubility after 60
minutes, which may suggest some precipitation.
WO 19841
Example 12 — Further ous Compositions
In an attempt to investigate the use of other polymers and to adjust the reaction
protocol to minimise the amount of solvent used, further experiments were
conducted and Lots C005 to C010 were prepared by spray-drying from solutions
produced by the method set out below.
Solutions of Compound 1 were prepared using appropriately sized three neck flasks
equipped with a reflux , addition funnel and thermometer. DMSO was added
in to the flask and kept under continuous ic stirring. Polymer and Compound
1 were subsequently added into the flask. Using a dry sand bath, the solution was
slowly heated to about 100°C and kept at this temperature until a clear yellow
solution was obtained. While still heating the solution, e was slowly added
into the flask. The solution under reflux was cooled down between 55-60°C and
maintained at this temperature during the spray drying process. The solution was
spray dried using a Mini Spray Dryer model 13-290 (Buchi) equipped with 1.5 mm
nozzle and the operating parameters presented below. After the spray drying the
solution, the heater was stopped but the air flow was maintained until a final outlet
temperature of 30-40°C (about 15 min) was reached. The collected Compound 1
spray dried intermediates were immediately stored in hermetically closed amber
glass bottle. Note that for lots C009 and C010, the filtration unit of the spray dryer
was modified to avoid decreased of the air flow rate (inducing a lower outlet
temperature) associated with the accumulation of powder on the filter. The cyclone
and product tion vessel assembly was also isolated with glass wool.
Lot C005
ed from 10g Compound 1 and 40g PVP K30= spray dried from a mixture of
325ml acetone and 175m] DMSO.
Compound 1:PVP K30 = 20:80.
Spray dryer operational parameters:
Inlet temperature 220 :: 2°C
Outlet Temperature 122 j: 2°C
Atomization flow (NL/h) 473 (approx.)
Air flow (m3/h) 38 x)
Feed rate n) 12.5
Lot C006
Prepared from 5g Compound 1 and 20g PVP K30, spray dried from a mixture of
162.5ml acetone and 87.5ml DMSO.
Compound 1:PVP K30 = 20:80.
Spray dryer operational parameters:
Inlet temperature 220 :: 2°C
Outlet Temperature 122 :: 2°C
Atomization flow (NL/h) 414 (approx.)
Air flow (m3/h) 38 (approx)
Feed rate (ml/min) 10
Lot C007
Prepared from 5 g Compound 1 and 20g Kollidon® VA64 spray dried from a mixture
of 162.5ml acetone and 87.51111 DMSO.
Compound 1:PVP-VA = 20:80
Spray dryer operational parameters:
Inlet temperature 220 :l: 1°C
Outlet Temperature 121 j: 1°C
Atomization flow (NL/h) 414 (approx.)
Air flow (m3/h) 38 (approx)
Feed rate n) 9.6
Let C008
Prepared from 10g Compound 1 and 15g PVP K30, spray dried from a mixture of
325ml acetone and 1751111 DMSO.
Compound 1: PVP K30 = 40:60.
Spray dryer operational parameters:
Inlet ature 220 i 1°C
Outlet Temperature 124 d: 3°C
ation flow (NL/h) 414 (approx)
Air flow (HP/h) 38 (approx)
Feed rate (ml/min) 8.9
Lot C009
Prepared from 22g Compound 1 and 33g PVP K30, spray dried from a mixture of
715ml acetone and 385ml DMSO.
Compound 1: PVP K30 = 40:60.
Spray dryer operational parameters:
Inlet temperature 221 i 1°C
Outlet Temperature 128 :l: 2°C
Atomization flow (NL/h) 473 x)
Air flow (HF/h) 38 (approx)
Feed rate (ml/min) 9.7
Lot C010
Prepared from 20g Compound 1 and 30g Kollidon® VA64 spray dried from a
mixture of 650ml acetone and 350ml DMSO.
Compound l:PVP-VA = 40:60.
Spray dryer operational parameters:
Inlet temperature 219 i 2°C
Outlet Temperature 130 i 4°C
Atomization flow (NL/h) 414 (approx)
Air flow (m3/h) 38 (approx)
Feed rate (ml/min) 9.3
XRPD s showed that in all of these compositions, Compound 1 was present in
an amorphous form.
e 13 — Stability Study
To evaluate the stability of the compositions of Example 12, three Spray dried
formulations were selected:
- Lot C007 459/Kollidon VA64 20/80 w/w);
- Lot C008 (OC000459/PVP K30 40/60 w/w);
- Lot C010 (0C000459/ Kollidon VA64 40/60 w/w).
All lots were vacuum dried at 50°C, ~20 mmHg for 72 h prior to the initiation of the
stability study. For lot C007, samples were only incubated at 5°C and 40°C/75% RH
due to the small quantity of material available. For lots C008 and C010 samples
were incubated at 5°C/ambient, 0%, 40°C/75% and SODC/ambient RH. All
samples were stored in double polyethylene (PE) bags with a desiccant sachet
between the two bags, sealed inside an aluminium bag put into 250 cc HDPE bottles.
The bottles were capped with polypropylene caps followed by induction sealing and
were placed into controlled environment chambers.
Figure 13 presents XRPD of the three lots at T:0. At T=1 month, only the XRPD of
lots C008 and C010 were carried out and their results are displayed in Figures 14 and
, respectively. After 1 month, no significant changes of diffractograms were
observed compared to T=0 at both accelerated and long-term stability conditions.
However, XRPD data revealed that after 3 months at 40°C/75% R.H. lot C010
showed definitive signs of re—crystallization when compared to lot C008 e 16).
It appears that, under these ions, on VA64 (lot C010) is less suitable as a
izer when ed to PVP K30 (lot C008) for amorphous Compound 1.
Samples at other storage conditions did not appear to re-crystallize and remained
amorphous.
Table 14 ys the analytical data of stability results for all lots at T=0 as well
as data for lots C008 and C010 at 1 and 3 months, and data for lot C008 at 6 months
under various storage conditions. Assay values remained constant for both lots C008
and C010 at all conditions through the 3-month time point. At 6 months, the assay
s (not ted for water content or al solvent, Table 14) were in the
range 90.0% — 96.3%. At T21-month, an increase of 2—2.5% in water content was
observed for lots C008 and 0010 compared to results at T=0. It was hypothesized
that these observations may have been an analytical artefact due to the sample not
having been analyzed promptly. However, following prompt analysis the 3-month
time point samples also showed an increase when compared to T=0 (056.5%). This
phenomenon was also observed in the stability study de5cribed in Example 9 with
lots 031 and 033, which revealed that despite similar precautions to prevent
moisture-ingress the SDI is a very hygroscopic material. The copic nature of
the SDI was also noticeable at T=6—months, where an se of 7.7% in water
content was observed for lot C008 at 40°C/75%RH compared to results at T:0.
Table 14: Stability Results of OC000459 SDI Lots C007, C008 and C010
Sample Lot C007 Lot C008 ’Lot C010
Drug Load (% WM) 20% 40% 40%
Stability Condition 5°C/ 40°C 5°C/ 25°C / 40°C / 5°C/ 25°C 1’ 40°C /
Arnb 1' Amb RH 60% RH 75% RH Amb RH 60% RH 75% RH
RH 75%
Appearance T=0 Pale yellow Pale yellow powder Pale yellow powder
visual 1 powder
T31 NT Pale yellow powder Pale yellow powder
T=3 NT Pale yellow powder Pale yellow powder
T=6 NT Pale yellow powder NT
Assay (% of 101 3% 100.6% * 98.7% *
nominal
content) NT 109.6% 100.5% ND 98.5% ** 99.6%
*1: an: **
T=3 NT ND 102.3% 101.0% ND 99.1% 98.7%
mth * a: a 4: a a a a a a a *
T:6 NT NT
2.4%
Content ("/0
Lot C007 Lot C008 Lot C010
wlw) Karl-
Fischer 4.9% NT 3.2% 3.4%
6.2% NT 2.1% 4.7%
10I6%
Related Total 0.17% Total 0.19% Total 0.39%
Substances ' Largest t impurity 0.12% @ Largest impurity 0.15% @ RRT
(%area) impurity RRTO.83 0.83
0.13% @
RRT 0.82
Total Total Total Total Total Total
0.32% 0.14% 0.14% 0.53% 0.45% 0.47%
Largest Largest Largest Largest Largest t
impurity impurity impurity impurity ty impurity
0.13% @ 0.07% @ 0.07% @ 0.17% @ 0.16% @ 0.17% @
RRT RRT RRT RRT RRT RRT
0.83 0.83 0.83 0.83 0.83 0.83
Total Total Total Total Total Total
0.087% 0.34% 0.37% 0.90% 0.99% 1.04%
Largest Largest Largest Largest Largest Largest
impurity impurity impurity ty impurity impurity
0.13% @ 0.07% @ 0.09% @ 0.15% @ 0.17% @ 0.20% @
RRT RRT RRT RRT RRT RRT
2.08 1.74 0.83 0.83 0.83 0.83
Total 0.44% Total 0.52% Total 0.60% NT
Largest Largest Largest
impurity 0.12% impurity 0.14% impurity 0.19%
@RRT 0.83 @RRT 0.83 @RRT 0.83
Residual Acetone: ND Acetone: ND Acetone: ND
Solvents DMSO: DMSO: 33088 DMSO: 28600
(ppm) 17723
DMSO: DMSO: DMSO:
26136 23739 7948
TT=0 corresponds to the Lot C007, C008 C010 Vacuum Dried at 50°C, -20 mmHg
for 72 h;
* Corrected using the T=0 results for residual solvent and water content
** Corrected using the T=0 results for residual solvent and T=1 month results for
Water content
*** ted using the T=3 month results for residual solvent and T=3 month
results for water content as per the ing equation :
%Assay X 100 = % Label Claim Compd 1 ‘dried basis”
100 ~ % Moisture ~ ual Solvent
****Assay could not be ted for water content and residual solvent because the
latter was not determined.
The single largest impurity ed at RT 0.83 for all lots did not show any
rthy changes under the tested stability conditions after 3 months (lot C010) or
6 months (lot C008). There was an apparent increase in Total Impurity content after
3 months when compared to T:0 for both lots C008 and 010 at all conditions tested.
An increase was also observed for Lot C008 at T=6 months at all ions,
although the magnitude of the increase at 5°C was smaller. However, for lot C008
there was no significant se in any individual impurity at either 25°C/60% RH
or 40°C/75% RH. For lot C010 at 3 months there was evidence of an increase in two
impurities at RT 1.74 and 2.01 when compared to the previous time points. The
level for these two impurities at 3 months was essentially the same across all three
storage conditions. It is therefore concluded that degradation of the sample had not
occurred since the level for the two impurities showed no evidence of increase with
storage temperature. In addition, this increase in Total Impurity content did not
appear to be linked to any decrease in Assay. For both lots the Total Impurity content
remained below the ve specification value of 2%.
The Examples demonstrate that an amorphous form of Compound 1 could be
obtained by spray drying with HPMC PVP , PVP-VA; or HPMCAS.
The ous forms obtained by spray drying with PVP and HPMC had y
improved solubility in aqueous solvents compared with the crystalline form. Higher
solubility was ed for formulations with higher concentrations of polymer. The
formulation containing 10% Compound 1 and 90% PVP (Example 6E) had higher
solubility in aqueous solvents than the lent formulation ning HPMC
(Example 6B) but for higher concentrations of Compound 1, formulations containing
HPMC generally had slightly greater solubility in aqueous solvents than formulations
containing PVP.
Thus, both the form with PVP and that with HPMC had increased solubility in
aqueous media.
Finally, the ous dispersion of Compound 1 in PVP proved to have
significantly greater solubility in simulated gastric fluid and intestinal fluid than
might have been expected.
The amorphous forms have been demonstrated to be stable over periods of up to 6
months, depending on the storage conditions and, indeed, may prove to be stable
over longer periods than this.
The greatest stability is ed with compositions comprising Compound 1 and
PVP, especially PVP K30.
Unless the context clearly requires ise, throughout the description and the
claims, the words “comprise”, “comprising”, and the like, are to be construed in an
inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the
sense of ding, but not limited to”.
The reference to any prior art in the specification is not, and should not be taken as,
an acknowledgement or any form of suggestion that the prior art forms part of the
common general knowledge in New Zealand.
Claims (30)
1. A stable ition comprising amorphous (5-Fluoromethylquinolin- 2-ylmethyl-indolyl)-acetic acid (Compound 1) or a pharmaceutically or veterinarily acceptable salt thereof and a polymer selected from polyvinylpyrrolidone (PVP), a polyvinylpyrrolidone-vinylacetate copolymer (PVP-VA), hydroxypropylmethylcellulose (HPMC) and hypromellose-acetate-succinate (HPMCAS) and es thereof.
2. A stable composition as claimed in claim 1, wherein the weight ratio of polymer to Compound 1 or salt thereof is from 1.5:1 to 15:1.
3. A stable composition as claimed in claim 1 or claim 2, wherein the weight ratio of polymer to Compound 1 or salt thereof is from 1.5:1 to 9:1.
4. A stable composition as d in any one of claims 1 to 3, wherein the polymer is PVP, HMPC, PVP-VA or mixtures thereof.
5. A stable composition as claimed in claim 4, wherein the polymer is PVP-VA.
6. A stable composition as claimed in claim 5, wherein the PVP-VA is a copolymer of 1-vinylpyrrolidone and vinyl e in a ratio of 6:4 by mass.
7. A stable composition as claimed in claim 4, wherein the polymer is PVP.
8. A stable composition as claimed in claim 7, wherein the PVP is PVP K30.
9. A stable composition as claimed in any one of claims 1 to 8, which is a solid sion of Compound 1 or salt thereof in the polymer.
10. A process for preparing a stable composition as d in claim 9, the process comprising: ia. dissolving the polymer in a first solvent at a concentration of from 50- 110g/L; iia. adding solid crystalline Compound 1 or a pharmaceutically or narily acceptable salt thereof to the solution to form a suspension, n the weight ratio of polymer to Compound 1 is from about 1.5:1 to 15:1; iiia. adding a second solvent, wherein the second solvent is chosen such that it is suitable to lise Compound 1 or the salt thereof and wherein the volume ratio of second t to first solvent is from 0.1:1 to 0.5:1; iva. ng the mixture at about 5 to 60oC until a solution is obtained; va. removing solvent until the volume of solvent remaining is from about 20- 50% of the total volume of solvent originally added; and either via. evaporating the on to dryness; or viia. adding a third solvent, wherein the third solvent is chosen such that it is suitable to solubilise Compound 1 or the salt thereof and wherein the amount of the third solvent is such that the total solids concentration in the solution (i.e. concentration of polymer + Compound 1) is from 5 to 15%; and viiia. spray drying the solution obtained in (viia) to obtain a solid dispersion of Compound 1 or the salt thereof in r.
11. A process as claimed in claim 10 wherein, in (ia), the first solvent is selected from methanol, dichloromethane or a mixture thereof.
12. A process as claimed in claim 11, wherein the solvent is a 1:1 mixture (by volume) of methanol and dichloromethane.
13. A process as claimed in any one of claims 10 to 12 wherein, in (iia), the amount of Compound 1 or salt thereof is chosen such that the weight ratio of polymer to Compound 1 or salt thereof is from about 1.5:1 to 9:1.
14. A process as claimed in any one of claims 10 to 13 wherein, in (iiia), the second t is DMSO.
15. A process as claimed in claim 14 wherein the volume ratio of second solvent to first solvent is about 0.3:1.
16. A process as claimed in any one of claims 10 to 15 wherein, in (va), the solvent is d until the volume of solvent remaining is from about 20-50% of the total volume of solvent added (i.e. the total volume of the first and second ts).
17. A process for preparing a stable composition as d in claim 9, the process comprising: ib. ing a solution of Compound 1 and a polymer in a suitable solvent, wherein: the weight ratio of polymer to Compound 1 or salt thereof is at least 1.5:1, typically from about 1.5:1 to 15:1; and the ratio of Compound 1: solvent is from about 1:35 to 1:65 w/v; and iib. spray drying the solution obtained in (i) to obtain a solid sion.
18. A process as claimed in claim 17, wherein the solvent used in step (ib) is a mixture of DMSO and acetone, with the ratio of DMSO to acetone being from about 25:75 to 45:55 v/v.
19. A process as claimed in claim 18, wherein the ratio of DMSO to acetone 35:65 v/v.
20. A stable composition as claimed in any one of claims 1 to 9 for use in medicine.
21. Use of a stable composition as claimed in any one of claims 1 to 9 in the manufacture of a medicine.
22. A stable composition as claimed in any one of claims 1 to 9 for use in the treatment or prevention of asthma, asthma exacerbations, chronic ctive pulmonary disease, allergic rhinitis conjunctivitis, nasal polyps, atopic dermatitis, t hypersensitivity (including contact dermatitis), eosiniphilic cough, eosinophilic bronchitis, eosinophilic gastroenteritis, eosinophilic oesophagitis, food allergies, matory bowel e, ulcerative s, Crohn’s disease, mastocytosis, urticaria, hypereosinophilic syndrome, hyper IgE syndrome, infection, fibrotic diseases, Churg-Strauss syndrome or multiple sclerosis.
23. The use of a stable composition as d in any one of claims 1 to 9 in the preparation of an agent for the treatment or prevention of asthma, asthma exacerbations, chronic obstructive pulmonary disease, allergic rhinitis ctivitis, nasal polyps, atopic dermatitis, contact hypersensitivity (including contact dermatitis), eosiniphilic cough, eosinophilic bronchitis, philic gastroenteritis, eosinophilic oesophagitis, food allergies, inflammatory bowel e, ulcerative colitis, Crohn’s disease, mastocytosis, urticaria, hypereosinophilic syndrome, hyper IgE me, infection, fibrotic diseases, Churg-Strauss syndrome and multiple sclerosis.
24. A pharmaceutical or veterinary composition comprising a stable composition as d in any one of claims 1 to 9 together with a pharmaceutically acceptable excipient or carrier.
25. A pharmaceutical or veterinary composition as claimed in claim 24, further comprising one or more additional active agents selected from: Suplatast tosylate and similar compounds; b2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol or methylxanthines such as theophylline, oxitriphylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as tiotropium, aclidinium and opium; antihistamines, for example histamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, olopatadine and chlorpheniramine or H4 receptor antagonists; α1 and α2 adrenoreceptor agonists such as propylhexedrine phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, azoline hydrochloride, tetrahydrozoline hydrochloride, tazoline hydrochloride and ethylnorepinephrine hydrochloride; modulators of chemokine receptor function, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C ) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the CX-C family) and CX3CR1 for the C-X3-C family; Leukotriene antagonists such as montelukast, kast and zafirlukast leukotriene biosynthesis tors such as xygenase inhibitors or 5- lipoxygenase activating protein (FLAP) inhibitors such as zileuton, 1, fenleuton, lin, Abbott-79175, N-(5-substituted)-thiophene alkylsolfonamides, 2,6-di-tert-butylphenol hydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661, pyridinyl-substitutedcyanonaphthalene compounds such as L-739010, 2-cyanoquinoline compounds such as L-746,530, indole and quinoline compounds such as MK-591, MK-886 and BAY x 1005; Phosphodiesterase inhibitors, including PDE4 tors such as roflumilast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as mazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin e or alternatively FK-506, rapamycin, cyclosporine, azathioprine or rexate; Immunotherapy agents including allergen immunotherapy such as Grazax; corticosteroids such as prednisone, prednisolone, flunisolide, onide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate; drugs which promote Th1 cytokine response such as interferons, TNF or GM-CSF; therapies that are in development for inflammatory indications including: other antagonists of PGD2 acting at other receptors such as DP antagonists; drugs that modulate cytokine production such as inhibitors of TNFα converting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-2 inhibitors such as piroxicam, enac, nic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin; COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, oxib and etoricoxib, low dose rexate, lefunomide, onide, hydroxychloroquine, d-penicillamine, auranofin or eral or oral gold; drugs that modulate the activity of Th2 cytokines including IL-4, IL-5, IL-9, IL-13 and their receptors, for e blocking monoclonal antibodies (e.g. mepolizumab) and soluble receptors; PPAR-γ agonists such as rosiglitazone, piaglitazone; or with SV antibodies such as Synagis (palivizumab) and agents that may be used to treat rhinovirus infection in the future e.g. interferon-alpha, interferon-beta or other interferons.
26. A pharmaceutical or veterinary ition as claimed in claim 25, wherein the additional active agent is a leukotriene antagonist such as montelukast, pranlukast and zafirlukast or a histamine H1 receptor antagonist such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, olopatadine and heniramine.
27. A stable composition as claimed in any one of claims 1 to 9 and one or more of the agents listed in claim 25 as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 receptor.
28. Use of a stable composition as claimed in any one of claims 1 to 9 and one or more of the agents listed in claim 25 in the manufacture of a combined preparation for the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 receptor, wherein the combined preparation is formulated for simultaneous, separate or sequential stration.
29. A kit for the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 receptor sing a first container sing a stable composition as d in any one of claims 1 to 9 and a second container comprising one or more of the active agents listed in claim 25.
30. A stable composition as claimed in claims 1, 20, 22 or 27 substantially as hereinbefore bed with particular reference to any one or more of the Examples and/or
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1103837.9 | 2011-03-07 | ||
GBGB1103837.9A GB201103837D0 (en) | 2011-03-07 | 2011-03-07 | Amorphous (5-Fluoro-2-Methyl-3-Quinolin-2-Ylmethyl-Indol-1-Yl)-acetic acid |
PCT/EP2012/052504 WO2012119841A1 (en) | 2011-03-07 | 2012-02-14 | Amorphous (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid |
Publications (2)
Publication Number | Publication Date |
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NZ614852A NZ614852A (en) | 2015-04-24 |
NZ614852B2 true NZ614852B2 (en) | 2015-07-28 |
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